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 THE DIABETES
IN PREGNANCY
DILEMMA
LEADING CHANGE WITH
PROVEN SOLUTIONS
SECOND EDITION

Edited by

Oded Langer

2015
PEOPLE’S MEDICAL PUBLISHING HOUSE—USA
SHELTON, CONNECTICUT

CH00.indd 1 22/01/15 10:04 PM

 People’s Medical Publishing House-USA
2 Enterprise Drive, Suite 509
Shelton, CT 06484
Tel: 203-402-0646
Fax: 203-402-0854
E-mail: [email protected]
© 2015 PMPH-USA, LTD
All rights reserved. Without limiting the rights under copyright reserved above, no part of this publication may be reproduced, stored in or introduced
into a retrieval system, or transmitted, in any form or by any means (electronic, mechanical, photocopying, recording, or otherwise), without the prior
written permission of the publisher.
14 15 16 17/PMPH/9 8 7 6 5 4 3 2 1
ISBN-13 978-1-60795-182-7
ISBN-10 1-60795-182-7
eISBN-13 978-1-60795-278-7
Printed in China by People’s Medical Publishing House.
Editor: Linda H. Mehta; Copyeditor/Typesetter: diacriTech; Cover designer: Allison Dibble
Library of Congress Cataloging-in-Publication Data
The diabetes in pregnancy dilemma / edited by Oded Langer. — Second edition.
p. ; cm.
Includes bibliographical references and index.
ISBN 978-1-60795-182-7 (alk. paper) — ISBN 1-60795-182-7 (alk. paper) — ISBN 978-1-60795-278-7 (ebook)
I. Langer, Oded, editor.
[DNLM: 1. Pregnancy in Diabetics—therapy. 2. Diabetes Complications. 3. Diabetes Mellitus. WQ 248]
RG580.D5
618.3’646—dc23
2014044251

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Notice: The authors and publisher have made every effort to ensure that the patient care recommended herein, including choice of drugs and drug
dosages, is in accord with the accepted standard and practice at the time of publication. However, since research and regulation constantly change
clinical standards, the reader is urged to check the product information sheet included in the package of each drug, which includes recommended
doses, warnings, and contraindications. This is particularly important with new or infrequently used drugs. Any treatment regimen, particularly one
involving medication, involves inherent risk that must be weighed on a case-by-case basis against the benefits anticipated. The reader is cautioned
that the purpose of this book is to inform and enlighten; the information contained herein is not intended as, and should not be employed as, a sub-
stitute for individual diagnosis and treatment.

CH00.indd 2 22/01/15 10:04 PM

 DEDICATION
This second edition of this textbook is dedicated to my family, with special recognition of my wife, Nieli. She has
always believed that each partner must be allowed to grow; thanks for being there to inspire, encourage, and support me
in pursuit of my goals. I am lucky to have been able to share them with you.

AND

To all my teachers and colleagues who have encouraged me to accept the challenges. I thank you. It is my firm belief
that when you are through changing, learning, and accepting challenges, you are really through.

CH00.indd 3 22/01/15 10:04 PM

CH00.indd 4 22/01/15 10:04 PM
 CONTENTS

PREFACE vii CHAPTER 10 Life Span Outcomes for the Child of the
Diabetic Mother
Ron Charach and Eyal Sheiner 109
INTRODUCTION The Lay of the Land
Oded Langer ix
PART II General Clinical Management of the Pregnant
CONTRIBUTORS xv Diabetic
CHAPTER 11 Glucose Monitoring in Pregnancy
SECTION I THE SCIENTIFIC RATIONALE FOR Compromised by Diabetes
GLOBAL ISSUES AFFECTING DIABETES IN Liran Hiersch and Yariv Yogev 121
PREGNANCY CHAPTER 12 Innovations in the Application of Advanced
CHAPTER 1 The Professional Responsibility Model of Glucose Sensing Technologies to Clinical Decision Making:
Obstetric Ethics: Clinical Application to the Management CGM in Practice
of Diabetes in Pregnancy Roger Mazze, Oded Langer, and Matthew Murphy 131
Frank A. Chervenak and Laurence B. McCullough 3
CHAPTER 13 Patient Compliance: The Elusive Variable
CHAPTER 2 Evidence-Based Medical Practice: in Diabetes Management
Its Use and Misuse Nieli Langer 141
Oded Langer and Nieli Langer 9
CHAPTER 14 The Association Between Glucose
CHAPTER 3 Pharmacologic Considerations Affecting Thresholds and Perinatal Complications
Hypoglycemic Therapy During Pregnancy Oded Langer 149
Maisa N. Feghali, Menachem Miodovnik, and
Jason G. Umans 17 CHAPTER 15 Medical Nutrition Therapy
Roger Mazze, Matthew Murphy, and Oded Langer 163
CHAPTER 4 Pharmacotherapy for Diabetes in Pregnancy:
Critical Review of Fetal Safety CHAPTER 16 The Use of Insulin in Diabetes in
Gideon Koren and Denice S. Feig 29 Pregnancy: From the Old to the New
Oded Langer 175
CHAPTER 5 Diabetes and Related Metabolic States and
the Placenta CHAPTER 17 Exercise: The Logical Intervention
Carolyn M. Salafia, Jennifer Straughen, for Diabetes in Pregnancy
and Dawn P. Misra 41 Raul Artal and Tracy Tomlinson 189

CHAPTER 6 Metabolic and Hormonal Changes in Normal CHAPTER 18 The Genetic Architecture of Diabetes
and Diabetic Pregnancy in Pregnancy
Amir Aviram and Yariv Yogev 53 Stephanie A. Stein, Ravi Kant, Rana Malek,
and Alan R. Shuldiner 197
CHAPTER 7 Fetal Macrosomia: Etiological Factors
Oded Langer 63 CHAPTER 19 Fetal Testing in Pregnancies
Complicated by Diabetes Mellitus: Why, How, and
CHAPTER 8 Fetal Growth Restriction
for Whom?
Dana Block-Abraham and Ahmet Alexander Baschat 75
Oded Langer 205

CHAPTER 20 Hypertensive Disorders in Pregnancy

SECTION II THE SCIENTIFIC RATIONALE FOR THE
Complicated by Diabetes
MANAGEMENT OF DIABETES IN PREGNANCY Hind N. Moussa and Baha M. Sibai 219
PART I Outcome Measurements of Diabetes in
Pregnancy PART III Pregnancy Complicated by Gestational
CHAPTER 9 The Infant of the Diabetic Mother: Short-Term Diabetes Mellitus
Implications and Management CHAPTER 21 Pathogenesis of Gestational
Francis B. Mimouni, Galit Mamouni Sheffer, Diabetes Mellitus
and Dror Mandel 99 Thaddeus Waters and Patrick Catalano 233

CH00.indd 5 22/01/15 10:04 PM

 vi Contents

CHAPTER 22 Gestational Diabetes: The Consequences CHAPTER 31 Type 2 Diabetes in Pregnancy: A Growing
of Not Treating Concern
Oded Langer 243 Oded Langer 363
CHAPTER 23 Obesity in Pregnancy: A Sign of the Times? CHAPTER 32 Diabetic Ketoacidosis in Pregnancy
Oded Langer 257 Eran Ashwal and Yariv Yogev 379
CHAPTER 24 The Metabolic Syndrome and Long-Term CHAPTER 33 Confronting Hypoglycemia in the
Implications for the Mother Pregnant Diabetic
Elizabeth O. Beale and Jorge H. Mestman 279 Barak M. Rosenn 387
CHAPTER 25 Screening for Gestational Diabetes CHAPTER 34 Diabetic Retinopathy
Oded Langer 291 Maisa N. Feghali, Menachem Miodovnik, and
Jason G. Umans 401
CHAPTER 26 Gestational Diabetes: A Diagnostic
Dilemma? A Difference, to be a Difference, CHAPTER 35 Diabetic Nephropathy in Pregnancy
Must Make a Difference Jason G. Umans, Maisa N. Feghali, and
Oded Langer 299 Menachem Miodovnik 409
CHAPTER 27 Oral Antidiabetic Agents in Pregnancy: CHAPTER 36 Fetal Lung Maturation in Pregnancies
Their Time Has Come Complicated by Maternal Diabetes
Oded Langer 311 Gladys A. Ramos and Thomas R. Moore 421
CHAPTER 28 The Role of Polycystic Ovary Syndrome: CHAPTER 37 Timing and Mode of Delivery
Management of Type 2 and Gestational Diabetes Mellitus Oded Langer 425
Raoul Orvieto  335
CHAPTER 38 Management of Labor: Augmentation,
Induction, and Glucose Control
PART IV Pregnancy Complicated by Pre-existing Elly Xenakis and Oded Langer 439
Diabetes
CHAPTER 29 Preconception Care in Diabetes:
Shortcomings and Challenges INDEX 445
Thomas R. Moore 343
CHAPTER 30 Epidemiology and Prenatal Diagnosis of
Congenital Malformations in Diabetic Embryopathy
Zhiyong Zhao and E. Albert Reece 349

CH00.indd 6 22/01/15 10:04 PM

 PREFACE
The rationale for the publication of a second edition of the text strong foundation in research synthesis founded on evidence-based
was prompted by new advances in the field, the proliferation of medicine so that pregnancy has a s­ uccessful outcome. The book,
more questions than answers in the areas of diagnosis and man- too, draws attention to the need for a multidisciplinary approach
agement, and the growth of outcomes research occurring against that will maximize whole-­person care of the pregnant diabetic
a backdrop of healthcare reform, managed care, cost contain- woman. As a result, the text not only provides a major source of
ment, and quality improvement. Diabetes continues to be one of up-to-date information, but also is a teaching tool for clinicians,
the most common medical complications in pregnancy, affecting investigators, diabetic educators, medical students, residents,
women worldwide and even more prevalent in specific geographic and fellows; managed care teams (nurses, dietitians, and social
regions and ethnic populations. Diabetes mellitus complicates workers); and medicine, family practice, endocrine, and obstet-
pregnancy results, causing considerable maternal–fetal morbid- rics-gynecology (maternal–fetal specialists) faculty; and private
ity and mortality, adding substantial burdens on families and the practitioners in the management of diabetes in pregnancy.
healthcare system. In light of the fact that only 80% of women To the extent that the book advances student, faculty, and
with gestational diabetes and 40–60% with preexisting diabetes practitioners’ capacity to understand, conceptualize, and apply the
achieve favorable glycemic control during pregnancy, our book, information relevant to the needs of the pregnant diabetic and her
The Diabetes in Pregnancy Dilemma: Leading Change with fetus, I believe that we may continue to contribute to the quality
Proven Solutions (Second Edition) specifically addresses the of life and care of these persons. This textbook would not have
broad range of diagnostic and management issues presented by been possible if not for the major contributions made by universal
the diabetic mother and her fetus. The book incorporates state-of- experts in the field. Many of the contributors are pioneers and
the-art topics not usually addressed in books devoted to diabetes: leaders in the field of diabetes in pregnancy. They are my col-
history of the disease; the metabolic syndrome; obesity; threshold leagues, collaborators, and friends. I thank them and salute their
for treatment; oral hypoglycemic agents; type 2 diabetes; fetal efforts.
growth restriction; patient empowerment, compliance, and phar-
macotherapy; fetal safety; and ethical implications of treatment. Oded Langer, MD, PhD
The text provides the basis for practical skill development with a

CH00.indd 7 22/01/15 10:04 PM

CH00.indd 8 22/01/15 10:04 PM
 INTRODUCTION

The Lay of the Land diabetes. They bluntly described “the urine of diabetics was very
large in amount and it was so sweet that it attracted dogs.”4

Oded Langer, MD, PhD KNOWLEDGE OF DIABETES IN THE MIDDLE AGES

Be who you are and say what you feel,
AND THE RENAISSANCE
The practice of medicine in the Middle Ages until approximately
because those who mind don’t matter and those
1450 CE was fundamentally a restatement and acceptance of
who matter don’t mind.
Greek practices. The famous Arabian physician Avicenna (980–
—Dr. Seuss 1027) recorded further observations that maintained and extended
the previous Greek knowledge of the disease. Avicenna observed
History is interim reports issued periodically. The story of diabe- that diabetic patients have an irregular appetite associated with
tes mellitus is a remarkable narrative covering 3500 years of med- thirst, mental exhaustion, and loss of sexual function. In fact, he
ical history that closely parallels the documented human story. described many of the symptoms and complications observed
Studying this disease over time reveals a jarring fact: the inci- today, such as carbuncles and furuncles. In addition, he reported
dence of diabetes has increased dramatically, from an uncommon that diabetes probably affected the liver, causing its enlargement.2
complaint in ancient times to one that may potentially affect the Maimonides was a renowned medieval physician, rabbi, and
lives of more than 300 million people by the year 2025. philosopher. He claimed to have observed more than 20 cases
while Galen, describing the condition as rare, documented having
treated only two cases. Maimonides proposed that the sweet water
THE RECOGNITION OF DIABETES IN ANTIQUITY of the Nile and the prevailing heat that spreads over the kidneys
The earliest descriptions of the symptoms of diabetes are to be caused diabetes.4 No major progress in understanding diabetes
found in the recorded observations of ancient physicians. Ancient was made until the sixteenth century. Physicians began thinking
Egypt was the first civilization known to have an extensive study of possible causes and exploring these ideas. Renaissance physi-
of medicine and to have left behind written records that describe cians, such as Paracelsus, challenged the medical doctrines of the
the nature of ailments, their origins, practices, and procedures. time and attempted to reform medical thinking. They questioned
The first reference to diabetes mellitus is attributed to the Ebers conventional thinking with a renewed spirit of curiosity, objectiv-
Papyrus. A German Egyptologist, Georg Ebers, acquired this ity, and experimentation. This period of reawakening in all dis-
papyrus in 1872, and the document relates to the ancient Egyptian ciplines accomplished two major breakthroughs in the approach
practice of medicine and mentions remedies “to eliminate urine and practice of medicine: it questioned authority and began to
which is too plentiful” (polyuria). The passage, written about reject dogma by reverting back to the Socratic method of attempt-
1550 BCE, provides evidence that its sources were many centu- ing to provide responses with evidence; and it laid the foundation
ries older.1 for an accurate knowledge of human anatomy.
Egyptian medicine has influenced medical practices, includ- Thomas Willis, in 1674, was the first physician to rediscover
ing those of ancient Greece. While the writing of Hippocrates, the and record the sweetness of the urine in diabetes referring to it
father of Greek medicine, describes excessive urinary flow with as “the pissing evil.” He proposed that diabetes was primarily a
wasting of the body, Galen, his disciple, referred to the ailment as disease of the blood and not the kidneys. He made the best qualita-
“diarrhea of the urine” and “the thirsty disease.” Arataeus, Galen’s tive urinalysis studies possible at the time.1 His work and Matthew
contemporary, was the first to use the term “diabetes,” meaning Dobson’s experiments 100 years later conclusively established the
to pass through or to siphon, in connection with these symptoms. diagnosis of diabetes in the presence of sugar in the urine and
Arataeus described the afflicted patients as “never ceasing to blood. Cullen, a prominent British clinician and educator, added
make water and the discharge is an incessant sluice let off; the the descriptive adjective “mellitus” (1769) from the Latin word
thirst is ungovernable.”1 for honey. Cullen wrote to Dobson, “You have done something in
In another part of the ancient world, the Hindu physicians putting it beyond all doubt by your experiments….” Thereafter,
Charaka, Susruta, and Vaghbata described polyuria and glyco- diabetes was no longer considered a rare ailment.1,4
suria. The Hindu medical writings of the sixth century refer to
diabetes as honey urine. They noted the attraction of flies and ants The Experimental Period
to the sweet urine of ailing patients.2 In addition, the affliction Experimental work as early as 1682 by Brunner demonstrated
was described as a “disease of the rich, brought about by glut- that the pancreas was the diseased organ in diabetic individuals.5
tony or over-indulgence in flour and sugar.”3 Ancient Chinese Experiments performed by Claude Bernard revealed that the liver
and Japanese physicians likewise recognized the symptoms of releases a substance that affects blood sugar levels. In 1857, he

CH00.indd 9 22/01/15 10:04 PM

 x Introduction

isolated a starch-like substance, which he called “glycogen,” that symptoms of the disease. John Rollo’s work in 1797, as well as
was the precursor of glucose, “the internal secretion” of the liver. that of Allen in New York in 1919, documented a reduction in
This observation established the role of the liver as a vital organ the symptoms of diabetes with a strict dietary regimen. Before
in diabetes.6 Langerhans, in his doctoral thesis presented in 1769, the discovery of insulin, the work of Drs. Joslin of Boston and
described small islands within the pancreas now known as the islets Laurence of London presaged the revolution in the treatment of
of Langerhans, even though he acknowledged at the time that he diabetes and the potential for a positive pregnancy outcome for
did not know the function of these ductless cells.7 Opie observed diabetic women. With the discovery and use of insulin, a new
changes in the structure of the islet tissue of the pancreas of patients hope arose for diabetic women and their reproductive potential.
dying of diabetes. Minkowski’s (1889) removal of the pancreas With the introduction of insulin, maternal mortality fell dramat-
from a dog unexpectedly resulted in uncontrolled polyuria and the ically but perinatal mortality decreased over time. However, the
progression towards diabetes. The observational work of Opie and introduction of insulin did not ameliorate the problems of macro-
the experiments of Minkowski began to link islet cell disease and somia and the associated traumatic injury to mother and fetus as
diabetes.3,8 It was a major turning point in determining the endo- well as continuing complications such as neonatal hypoglycemia,
crine function of the pancreas; it became clear that the substance congenital malformations, preeclampsia, and infection.13
secreted by the islet cells was inadequate in diabetic patients. During the 1940s, insulin had made pregnancy relatively
As with research in all diseases, many investigators concur- safe for the diabetic mother. However, patients with severe dia-
rently work in different labs worldwide to find breakthroughs. betes who in the pre-insulin era would never have been pregnant
Insulin was almost discovered in 1906 by Zuelzer in Berlin, in were now being treated. During this period, several attempts were
1912 by Scott in Chicago, but was actually extracted by Paulesco made to ameliorate fetal death due to diabetes. It was observed
in Romania in 1920. However, the world recognizes the definitive that there was a significant stillbirth rate beyond 36 weeks of ges-
discovery and isolation of insulin to the Toronto group (1921–22), tation. As a result, diabetic patients were routinely delivered at
the collaborative work of Banting, Best, Collip, and Macleod.9 or before 36 weeks by cesarean section or by induction of labor
if fetal death had not already occurred or if maternal complica-
tions indicated an early delivery. Today, when cesarean section is
PREGNANCY AND DIABETES BEFORE THE being performed for more and more indications, some research-
DISCOVERY OF INSULIN ers during the 1940s cautioned against adding another indication.
Diabetes was an affliction with a dismal prognosis. The dominant Shir wrote, “Cesarean section is still a dangerous operation and
philosophy of the period before 1850 was that a successful preg- diabetes does not render it less so.”14
nancy was virtually impossible when compromised by untreated During this time, several clinics were organized in the United
diabetes. Pregnancy worsened the disease and shortened the lives States and Europe for the care of pregnant women with diabe-
of these women, many of whom died either during or shortly after tes using an interdisciplinary approach featuring the cooperation
the pregnancy. Blott wrote that “true diabetes is inconsistent with of diabetologists, obstetricians, and pediatricians. Pedersen15 in
conception.”3 It was not until 1882 with Duncan’s description of Denmark found that fetal mortality rate was significantly lower in
22 pregnancies that the prevailing philosophy was questioned.10 patients who were followed throughout pregnancy in comparison
The trend, however, of high maternal and fetal mortality during to those who were first diagnosed with the disease at or about the
or soon after pregnancy from uncontrolled diabetes persisted until time of delivery. There was an emerging philosophy that closer
the discovery of insulin. De Lee wrote that abortion and premature surveillance and more frequent patient visits improved fetal out-
labor occurred in at least 33% of pregnancies of diabetic women. come. Thus, long-term management, frequent hospitalizations,
Perinatal mortality was close to 79%; maternal mortality about and early delivery became the norm. At the Joslin Clinic in Boston
30%, usually from diabetic ketoacidosis. In addition, diabetes under the leadership of Priscilla White,16 new clinical recommen-
was described as becoming progressively worse with each preg- dations for the care of pregnant diabetic women consisted of strict
nancy.11 It is necessary to note that unrelated to diabetes, at this glycemic control, long-term hospitalization, and sound obstetrical
point in time, maternal and neonatal mortality was high for many management.
reasons. Poor interventional obstetric care with increased risk of During the 1950s, risk factors for the development of abnor-
puerperal sepsis in addition to social and economic deprivations mal carbohydrate metabolism in pregnancy were defined. In
further compromised pregnancies. The link between congenital addition, screening programs were proposed, and soon thereafter
malformations and maternal diabetes in pregnancy is of more normal values for the interpretation of the glucose tolerance test
recent concern because not only are the historical records on the (OGTT) were suggested.17–18
frequency of congenital malformations incomplete, but also they
were not specifically identified as a result of diabetic pregnancies. Gestational diabetes as a clinical entity
The interrelationship of preeclampsia to diabetes is also difficult Gestational diabetes (GDM), defined as “carbohydrate intoler-
to trace before organized antenatal care.12 ance of varying severity with onset or first recognition during
pregnancy,” is a fairly recent addition to our knowledge about
diabetes in pregnancy. In the first recorded case, Bennewitz
THE ADVENT OF INSULIN FOR PREGNANCIES considered diabetes a symptom of the pregnancy, and since the
COMPROMISED BY DIABETES symptoms and the glycosuria disappeared after two successive
Up until this time, the only effective treatment for diabetes has pregnancies, he had some evidence to support his views.19 Other
been dietary. Restriction of food was known to ameliorate the studies conducted in the United States and Scotland during the

CH00.indd 10 22/01/15 10:04 PM

 Introduction xi

1940s reported that lesser degrees of maternal hyperglycemia complications. Perinatal outcome does not appear to be signif-
were also a risk to pregnancy outcome.20–22 O’Sullivan first used icantly different from other insulin-dependent diabetes when
the term gestational diabetes in 1961. In the United States, the metabolic control is stringently maintained.31 Studies have sug-
emphasis was on establishing criteria for the 100-g oral glucose gested that congenital malformations are caused by derangement
tolerance test in pregnancy as an index of the subsequent risk of in metabolism during organogenesis.32 During the 1980s a major
the mother to develop diabetes; the well-known O’Sullivan crite- effort was mounted to control blood sugar before conception. The
ria were derived from this foundation.23 At about the same time, findings from Fuhrman’s study demonstrated that normalization
Mestman reported increased perinatal mortality associated with of metabolism with tight glycemic control during preconception
abnormal oral glucose tolerance in the obstetric population of Los and the organogenesis period can reduce the incidence of congen-
Angeles County Hospital. Most of the women were either Latino ital malformations.33 However, women become pregnant without
(60%) or African-American; few Caucasians were represented in having achieved established levels of glycemic control despite
this population.24 Gestational diabetes as a clinical entity was slow preconception counseling.
to win converts, partly because of the relatively short phase of Scientific evidence demonstrates that self-management edu-
hyperglycemia during the latter part of pregnancy and its disap- cation with self-monitoring blood glucose is the cornerstone of
pearance after the delivery. It has become increasingly accepted care for all persons with diabetes. In pregnancy, human insulin
as a disease not only for the immediate outcome of pregnancy is recommended since the use of insulin analogues has not been
but also for the long-term effects on child and mother (maternal adequately tested. Data on insulin lispro and insulin aspart are
development in later life of type 2 diabetes).19 limited. Studies have demonstrated an improvement in glycemic
control, an increased patient satisfaction, and a decrease in hypo-
glycemic episodes; but there is scant data on maternal and neona-
MODERN ERA IN THE MANAGEMENT OF tal outcomes.
DIABETES IN PREGNANCY Intensified therapy in the management of GDM and preges-
Strong pressures were exerted by the medical community to tational diabetes is an approach to achieving established levels of
develop methods to increase the rate of insulin release from its glycemic control. It involves memory-based, self-­monitoring blood
injection site so that control of blood sugar concentrations could glucose (SMBG), multiple injections of insulin or its equivalent, con-
be improved. Over the years, pharmaceutical laboratories have trol of diet, and an interdisciplinary practitioner effort. Regardless of
developed increasingly reliable and stable insulin preparations. the treatment modality used, insulin or oral anti-­diabetic drugs, the
Monomeric insulin preparations are now established in the reper- purpose is to achieve the established level of glycemic control that
toire of clinical therapies. Human insulin became widely available diminishes the rate of hypoglycemia and ketosis and maximizes per-
in the 1980s. This led to the availability of mutant insulin (insulin inatal outcome. As suggested by Freinkel,34 “normalizing maternal–
analogues) that was designed primarily to have improved pharma- fetal metabolism throughout every day of pregnancy would result in
cokinetic features for subcutaneous administration. healthy infants, with a potential of achieving normal intellectual and
The modern era in the management of diabetes in pregnancy growth development.”
began in the 1960s with the introduction of reliable chemical and/
or physical measures to assess gestational age, fetal well-being, WHAT HAVE BEEN, AND CONTINUE TO BE, THE
and placental function: ultrasonography made early assessment
of gestational age and accurate fetal growth determination possi- DILEMMAS ASSOCIATED WITH DIABETES IN
ble25; the biophysical profile became routine in the management PREGNANCY?
of high-risk pregnancies26; antepartum fetal heart rate testing was A dilemma refers to a difficult or persistent problem. Major life
introduced; and Gluck et al. proposed the determination of the dilemmas are associated with ill health. “When health is absent,
lecithyin-to-sphingomyelin ratio in the amniotic fluid as a test for wisdom cannot reveal itself, art cannot become manifest, strength
fetal lung maturity.27 With proper use and interpretation of these cannot be exerted, wealth is useless, and reason is powerless.”
tests, two of the four causes of fetal loss were reduced: sudden (Herophilus, an ancient Greek physician).
intrauterine death and neonatal death caused by hyaline mem- Pregnancy is a special time in a woman’s life when she is
brane disease. In addition, physicians were able to avoid unneces- coping with the anxiety of the pregnancy, delivery, and welfare of
sary early delivery. Other advances included fetal blood-sampling the fetus. This waiting period becomes even more anxiety-producing
techniques during labor, glucose monitoring, insulin pumps, and if the pregnancy is complicated with diabetes. Diabetes constitutes
neonatal intensive care units. one of the most common and significant complications of medicine
In 1977, Karlsson and Kjellmer28 reported that there was a in general and pregnancy in particular. Every pregnant woman needs
linear relationship between glycemic control and perinatal mortal- and should expect high-quality, evidence-based medical care. We,
ity. It was the advent of self-monitoring blood glucose that made as women’s health physicians, should be satisfied with providing
possible strict blood sugar control from early pregnancy on and nothing less.
a resulting decline in adverse neonatal events. The results of this Measuring the success of treatment is based on the evalua-
technology and other corroborating evidence led to intensified tion of the outcome in a given complication. The Saint Vincent’s
glucose management to as close to nondiabetic levels as possible; Declaration (October, 1989) targeted the achievement of preg-
perinatal mortality began to decrease.29–30 nancy outcomes in diabetic women to approximate those of
Except for coronary artery disease, pregnancy has not been nondiabetic women within the forthcoming 5-year period. This
shown to be contraindicated in diabetic women with vascular was not only the summary statement of the meeting organized

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 xii Introduction

by WHO and the IDF, but also a challenge to all clinicians and of glycemia) for initiation of pharmacological therapy. Neonatal
researchers interested in diabetes in pregnancy. A difference, in fat contributes approximately 12–14% of total birth weight; it
order to be a difference, must make a difference. Today, almost accounts for about 50% of the variance. However, the amount
25 years later, morbidity and mortality data in both GDM and of fetal fat in the subcutaneous locations used in anthropometric
pre-existing diabetes remain relatively unchanged.35–36 The debate models may account for 40–80% of total fetal fat.40
of the past few decades over whether gestational diabetes is a The evaluation of the fetus of a diabetic mother should
clinical entity37–39 has been resolved, demonstrating that treatment include in the first trimester a transvaginal ultrasound examination
can improve pregnancy outcome. Yet, in both medical forums to rule out gross congenital abnormalities and CRL (crown rump
and academic research, the diabetes in pregnancy community of length) measurements for dating. A complementary abdominal
clinicians and researchers has been too engrossed in fine-tuning ultrasound examination for congenital malformations needs to be
diagnostic criteria and not more vigorously invested in pregnancy performed at approximately 20–23 weeks’ gestation. AC (abdom-
outcome. If we want to change our minds, we have to change our inal circumference), fetal weight estimation, body composition,
exposure. Changing our fixed ideas or positions doesn’t happen and cardiac evaluation (echocardiography) will enhance identifi-
quickly—it is often a slow and tedious process. Integration and cation of the constitutionally large or small infants. During the
relationship-building by people (clinicians and researchers) talk- third trimester, serial sonographic measurements need to be per-
ing to the peers they trust who represent the change in question formed in order to assist in the selection of the treatment modality
is the route to sounder medical practice with fewer turf wars. The and the detection of deviant fetal growth.41
focus for the next decade is to respond to the outcome dilemma For pre-existing diabetes, preconception care is a major
by seeking the means to uphold the Saint Vincent’s Declaration. dilemma if we seek to adequately address the problem of con-
Worldwide collaboration and dissemination of information is still genital malformation. To date, the majority of women attend the
the cornerstone for stimulating ideas and encouraging creative, first prenatal visit after organogenesis. For GDM (gestational dia-
evidence-driven research. This focus may help make the content betes mellitus), the window of opportunity for affecting outcome
of the St. Vincent’s Declaration a reality. is narrow, that is, 8 to 12 weeks. Criteria for the assignment of
“Measurement is the first step that leads to control and treatment modality are lacking; that is, should treatment be based
improvement. If you can’t measure something, you can’t under- on diet alone, diet and exercise, insulin, or oral hypoglycemic
stand it. If you can’t understand it, you can’t control it. If you can’t agents? Furthermore, there is no benchmark for altering therapy
control it, you can’t improve it” (H. James Harrington). What to when the desired glycemic results have not been achieved. We cli-
test and how to test in diabetes management remains another nicians and researchers agree that early diagnosis, adequate treat-
unresolved dilemma, especially with the introduction of new tech- ment, and close follow-up are essential in order to minimize and
nology: that is, self-monitoring blood glucose, continuous blood often eliminate many of the diabetes-related complications. In
glucose insulin pumps, and continuous blood glucose monitoring. our zeal to diagnosis and treat, however, we have not established
Another dilemma in need of resolution is an efficient and effica- universal criteria that enable a fluid, less controversial, less error-
cious means to analyze the data generated by these technologies prone route towards enhanced perinatal and maternal outcome.
in order to enhance diabetes management. Still another significant In light of extended life expectancy and adequate diabetic
dilemma involves the as yet not well defined threshold that needs management for both the pregnant and nonpregnant patient,
to be targeted to initiate and maintain glucose control. we need to address the diabetes epidemic worldwide when the
To date, there are numerous logarithmic formulae for esti- number of known and undiagnosed individuals (approximately
mating fetal weight, but there is a lack of uniformity and accuracy 9% for type 2 in the United States alone) is reaching staggering
in measurement. Virtually all EFW (estimated fetal weight) for- proportions. The double medical offensive of diabetes and obesity,
mulae systematically overestimate birth weight. The imprecision that is, “diabesity,” with their short- and long-term complications
of the formulae to account for fat deposits in fetuses and difficul- contributes an additional dilemma of how to maximize maternal
ties in measuring the abdominal circumference (AC) of fetuses of care before pregnancy. We, as women’s healthcare practitioners,
diabetic mothers may provide another explanation for the inaccu- are responsible for women throughout the life cycle and not solely
racies in EFW. However, most formulae are better at predicting during pregnancy.
macrosomia than are predictions based on gestational age alone. The goal of the second edition of this textbook is to provide a
In infants of women with poorly controlled diabetes, there is char- forum to mitigate the dilemmas caused by diabetes in pregnancy by
acteristic enlargement of the majority of the organs but not of offering evidence-based responses by world-renowned clinicians
the brain. Increased weight of insulin-sensitive tissues including and researchers often working and writing together in pursuit of
liver, pancreas, heart, lungs, and adrenals has been demonstrated this goal. The above-described dilemmas in no way seek to mini-
in the infants of diabetic mothers (e.g., an increase in liver size of mize the significance of basic science research in pathophysiology,
179%). On the basis of this finding, it was suggested that morpho- immunology, and metabolic pathways associated with diabetes in
metry be used to measure fetal liver length. pregnancy. Perhaps mapping of the human genome, which marks
It was found that the increase in liver length was evident as a new era in scientific research in the twentyfirst century, will pro-
early as the 18th week of gestation and became more marked with vide the next chapter to be written in the history of diabetes.
increased duration of pregnancy. Furthermore, individual liver I, and my distinguished group of expert contributors, have
length measures did not always remain constant when they were sought to provide a comprehensive approach to a very important
followed serially throughout pregnancy. This approach may pro- topic. The book will be of interest and of help not only to obste-
vide an early fetal marker in addition to maternal markers (level tricians and gynecologists, but also to endocrinologists, internists,

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 Introduction xiii

and primary care physicians. Every health professional who cares 19. Hadden D. The development of diabetes and its relation to preg-
for women of reproductive age must be concerned with issues of nancy: The long-term and short-term historical viewpoint. In:
gestational and pregestational diabetes. These include fetal mac- Sutherland HW, Stowers JM, Pearson DWM, eds. Carbohydrate
rosomia, congenital malformations, spontaneous abortions, and Metabolism in Pregnancy and the Newborn II. Springer-Verlag:
also complications arising as a result of obesity, hypoglycemia, London, 1989; 1–8.
hypertension, including retinopathy and nephropathy. A compre- 20. Miller H. The effect of the pre-diabetic state on the survival of the
hensive understanding and firm foundation in the knowledge of fetus and the birth weight of the newborn infant. N Engl J Med.
1945; 233:376–8.
the potential disease complications will positively alter the suc-
21. Hurwitz D, Jensen D. Carbohydrate metabolism in normal preg-
cess rate for both mother and infant.
nancy. N Engl J Med. 1946; 234:327–9.
Women with diabetes want to have children and want to
22. Gilbert J, Dunlop D. Diabetic fertility, maternal mortality and fetal
deliver them healthy while addressing the complications of their
loss rate. Br Med J. 1949; i:48–51.
own disease. To the extent that this text advances student, fac- 23. O’Sullivan J, Mahan C. Criteria for the oral glucose tolerance test
ulty, and practitioners’ capacity to understand, conceptualize, and in pregnancy. Diabetes. 1964; 13:278–85.
apply the information relevant to the needs of the pregnant dia- 24. Mestman J, Anderson G, Barton P. Carbohydrate metabolism in
betic and her fetus, I believe that we may contribute to the quality pregnancy. Am J Obstet Gynecol. 1971; 109:41–5.
of life and care of these persons. We the authors hope that the 25. Campbell S. An improved method of fetal cephalometry by ultra-
information and the recommendations offered in this text will sound. J Obstet Gynecol Br Commonw. 1968; 75:568–76.
advance this mission. 26. Ray M, Freeman R, Pine S, et al. Clinical experience with the oxy-
tocin challenge test. Am J Obstet Gynecol. 1972; 114:1–9.
27. Gluck L, Kulovich M, Borer R, et al. Diagnosis of the respiratory
REFERENCES distress syndrome by amniocentesis. Am J Obstet Gynecol. 1971;
1. Barach J. Historical facts in diabetes. Ann Med History. 1928; 109:440–5.
10:387. 28. Karlsson K, Kjellmer I. The outcome of diabetic pregnancies in
2. Frank L. Diabetes in the texts of old Hindu medicine. Am J relation to the mother’s blood sugar level. Am J Obstet Gynecol.
Gastroenterol. 1957; 27:76. 1972; 112:213.
3. Peel J. A historical review of diabetes and pregnancy. Obstet 29. Pedersen J, Molsted-Pedersen L, Andersen B. Assessors of fetal
Gynecol Br Comm. 1972; 79:385–95. perinatal mortality in diabetic pregnancy. Diabetes. 1974; 23: 302.
4. Ballard J. A descriptive outline of the history of medicine from its 30. Walford S, Gale E, Allison S, et al. Self-monitoring of blood glu-
earliest days of 600 BC. Ann Med Hist. 1924; 6:53. cose: Improvement of diabetic control. Lancet. 1978; 1:732–5.
5. Brunner J. Experiments Nova Circa Pancreas. Amsterdam: 31. Coustan D, Berkowitz R, Hobbins J. Tight metabolic control of
H Weststenium, 1683. overt diabetes in pregnancy. Am J Med. 1980; 68:845.
6. Young F. Claude Bernard and the discovery of glycogen: A century 32. Miller E, Hare J, Cloherty J, et al. Elevated maternal hemoglobin
of retrospect. Br Med J. 1957; 22(5033):1431–7. A1c in early pregnancy and major congenital anomalies in infants
7. Langerhans P. Beitrage zue mikroskopischen Anatomie der of diabetic mothers. N Engl J Med. 1981; 304:1331.
Bauchspeicheldruse [doctoral dissertation]. Berlin, Buchduckerei 33. Fuhrman K, Reiher H, Semmler K, et al. The effect of intensi-
von Gustav Lange, 1869. fied conventional insulin therapy before and during pregnancy on
8. Opie E. On the relation of chronic interstitial pancreatitis to the the malformation rate of offspring of diabetic mothers. Exp Clin
islands of Langerhans and to diabetes mellitus. J Exp Med. 1900– Endocrinol. 1984; 83:173.
1901; 5:397. 34. Freinkel N. Banting Lecture 1980: Of pregnancy and progeny.
9. Bliss M. The Discovery of Insulin. Paul Harris Publishing: Diabetes. 1980; 29:1023–35.
Edinburgh, 1983; 20–58. 35. Langer O. Type 2 diabetes in pregnancy: Exposing deceptive
10. Duncan G. Diabetes Mellitus: Principles and Treatment. appearances. J Mat Fetal Neonatal Med. 2008; 21(3):181–9.
Philadelphia: WB Saunders, 1951. 36. Colstrup M, Mathiesen R, Ringholm L. Pregnancy in women with
11. De Lee J. The Principles and Practice of Obstetrics, 3rd edition. type 1 diabetes: Have the goals of St. Vincent’s Declaration con-
Philadelphia: WB Saunders, 1920. cerning fetal and neonatal complications? J Mat Fetal Neonatal
12. Hadden D. History of diabetic pregnancy. In: Textbook of Diabetes Med. 2013 PMID23570252.
and Pregnancy. Hod M, Jovanovic L, De Renzo GC, de Leiva A, 37. Landon M, Spong C, Thorn E, et al. A multicenter randomized trial
Langer O, eds. London: Dunitz, 2003; 1–12. of treatment for mild gestational diabetes. N Engl J Med. 2009;
13. Papaspyros N. The History of Diabetes Mellitus, 2nd edition. 361:1339–48.
Stuttgart: Thieme, 1952. 38. Crowther C, Hiller J, Moses J, et al. Australian carbohydrate intol-
14. Shir M. Diabetes in pregnancy with observations in 28 cases. Am J erance study in pregnant women (ACHOIS) trial group. Effect of
Obstet Gynecol. 1938; 1032–5. treatment of gestational diabetes mellitus on pregnancy outcomes.
15. Pedersen J, Brandstrup E. Fetal mortality in pregnant diabetics. N Engl J Med. 2005;352:2477–86.
Lancet.1956; 27:607–10. 39. Langer O, Yogev Y, Most O, Xenakis EM. Gestational diabetes:
16. White P. Pregnancy complicating diabetes. Am J Med. 1949; the consequences of not treating. Am J Obstet Gynecol. 2005;
609–16. 192:989–97.
17. Moss J, Mulholland H. Diabetes and pregnancy with special refer- 40. Langer O. Ultrasound biometry evolves in the management of dia-
ence to the pre-diabetic state. Ann Intern Med. 1951; 34:678–91. betes in pregnancy. Ultrasound Obstet Gynecol. 2005; 26: 585–595.
18. Wilkerson H, Remain Q. Studies of abnormal metabolism in preg- 41. Nicolaides K. Turning the pyramid of prenatal care. Fetal Diag
nancy. Diabetes. 1957; 6:324–9. Ther. 2011; 29:183–196.

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CH00.indd 14 22/01/15 10:04 PM
 CONTRIBUTORS

Raul Artal, MD, FACOG, FACSM Frank A Chervenak, MD

Professor and Chairman Emeritus Given Foundation Professor and Chairman
Department of Obstetrics, Gynecology and Women’s Health Department of Obstetrics and Gynecology
Saint Louis University Weill Medical College of Cornell University
St. Louis, Missouri Obstetrician and Gynecologist–in-Chief
New York Presbyterian Hospital
Eran Ashwal, MD New York, New York
Helen Schneider Hospital for Women
Rabin Medical Center Maisa N. Feghali, MD
Sackler Faculty of Medicine Maternal–Fetal Medicine and Obstetric Pharmacology
Tel Aviv University Department of Obstetrics, Gynecology and Reproductive
Tel Aviv, Israel Sciences
Magee Women’s Hospital of UPMC
Amir Aviram, MD University of Pittsburgh
Helen Schneider Hospital for Women Pittsburgh, Pennsylvania
Rabin Medical Center
Sackler Faculty of Medicine Denice S. Feig, MD, MSc
Tel Aviv University Associate Professor
Tel Aviv, Israel Department of Medicine
University of Toronto
Ahmet A. Baschat, MD Toronto, Ontario, Canada
Director, Johns Hopkins Center for Fetal Therapy
Professor of Obstetrics Gynecology Liran Hiersch, MD
John Hopkins University School of Medicine Helen Schneider Hospital for Women
Baltimore, Maryland Rabin Medical Center
Sackler Faculty of Medicine
Elizabeth O. Beale, MBBCh Tel Aviv University
Division of Endocrinology and Diabetes Tel Aviv, Israel
Assistant Professor, Department of Medicine
Keck School of Medicine Ravi Kant, MBBS, MD
University of Southern California Endocrinology, Diabetes and Metabolism
Los Angeles, California University of Maryland School of Medicine
Baltimore, Maryland
Dana Block-Abraham, DO
Department of Obstetrics and Gynecology Gideon Koren, MD, FRCPC, FACMT, FACCT
Maternal–Fetal Medicine Director and Senior Scientist
University of Maryland Medical Center The Motherisk Program
Baltimore, Maryland The Hospital for Sick Children
Professor of Pediatrics, Pharmacology, Pharmacy and Medical
Patrick M. Catalano, MD Genetics
Professor of Reproductive Biology The University of Toronto
Case Western Reserve University Professor of Physiology/Pharmacology
Cleveland, Ohio The University of Western Ontario
Toronto, Ontario, Canada
Ron Charach, MD, MHA
Department of Obstetrics and Gynecology Nieli Langer, PhD
Soroka University Medical Center Professor
Faculty of Health Sciences Editor-in-Chief
Ben-Gurion University of the Negev Educational Gerontology
Beer-Sheva, Israel Knoxville, Tennessee

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 xvi Contributors

Oded Langer, MD, PhD Dawn P. Misra, PhD

Immediate Past Babcock Professor Professor
Columbia University College of Physicians and Surgeons Department of Family Medicine and Public Health Sciences
Chairman Department of Obstetrics and Gynecology Wayne State University
St. Luke’s–Roosevelt Hospital Center Detroit, Michigan
New York, New York
Thomas R. Moore, MD
Rana Malek, MD Professor
Assistant Professor Department Reproductive Medicine
Endocrinology, Diabetes & Nutrition Dean for Clinical Affairs
University of Maryland School of Medicine University of California, San Diego Health System
Baltimore, Maryland San Diego, California
Dror Mandel, MD
Hind N. Moussa, MD
Associate Professor of Pediatrics
Maternal–Fetal Medicine
Tel Aviv University
Department of Obstetrics,
Director, Neonatal Intensive Care Unit
Gynecology and Reproductive Sciences
Lis Maternity Hospital
The University of Texas Medical School at Houston
Tel Aviv Sourasky Medical Center
Houston, Texas
Tel Aviv, Israel

Roger S. Mazze, PhD Matthew Murphy, BS

Visiting Professor, Nanjing Medical University Mayo Clinic
Nanjing, Jiangsu Province Division of Endocrinology
China Rochester, Minnesota

Laurence B. McCullough, PhD Raul Orvieto, MD

Professor of Medicine and Medical Ethics Professor of Obstetrics & Gynecology
Tomlin Chair in Medical Ethics and Health Policy Director, Fertility & IVF Unit
Associate Director for Education Center for Medical Ethics and Chaim Sheba Medical Center
Health Policy Tel Hashomer Hospital
Baylor College of Medicine Sackler Faculty of Medicine
Houston, Texas Tel Aviv University
Tel Aviv, Israel
Jorge H. Mestman, MD
Professor of Medicine and Obstetrics & Gynecology Gladys A. Ramos, MD
Director, USC Center for Diabetes and Metabolic Diseases Associate Clinical Professor
Keck School of Medicine Department of Reproductive Medicine
University of Southern California University of California, San Diego Health System
Los Angeles, California San Diego, California
Francis Mimouni, MD
Professor and Director of Neonatology E. Albert Reece, MD, PhD, MBA
The Shaare Zedek Medical Center, Jerusalem Vice President for Medical Affairs, University of Maryland
Professor of Pediatrics, Tel Aviv University John Z. and Akiko K. Bowers Distinguished Professor
Tel Aviv, Israel Dean, University of Maryland School of Medicine
Baltimore, Maryland
Galit Mimonuni, MD
Department of Obstetrics and Gynecology Barak M. Rosenn, MD
Rabin Medical Center Director of Obstetrics and Maternal–Fetal Medicine
Petah-Tikva, Israel Mt. Sinai Roosevelt Hospital
Professor of Obstetrics, Gynecology, and
Menachem Miodovnik, MD Reproductive Science
Medical Officer, Pregnancy and Perinatology Branch Icahn School of Medicine at Mount Sinai
Eunice Kennedy Shriver National Institute of Child Health and New York, New York
Human Development
National Institutes of Health Carolyn M. Salafia, MD, MS
Professor of Obstetrics and Gynecology Laboratory Head, Placental Modulation
Georgetown University School of Medicine Institute for Basic Research in Developmental Disabilities
Washington, DC Staten Island, New York

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 Contributors xvii

Eyal Sheiner, MD, PhD Jason G. Umans, MD, PhD

Professor, Faculty Health Sciences Associate Professor
Ben-Gurion University of the Negev Departments of Medicine and Obstetrics & Gynecology
Director, Maternity D Georgetown University Medical Center
Department of Obstetrics and Gynecology Washington, DC
Deputy Director General
Soroka University Medical Center Thaddeus P. Waters, MD
Vice Dean for Student Affairs Assistant Professor
Beer-Sheva, Israel Department of Obstetrics and Gynecology
Loyola University Medical Center
Alan R. Shuldiner, MD Maywood, Illinois
John A. Whitehurst Professor of Medicine
Associate Dean for Personalized Medicine Elly Xenakis, MD
Director, Program in Personalized and Genomic Medicine Jane and Roland Blumberg Professorship
Head, Division of Endocrinology, Diabetes and Nutrition Deputy Chairman for Clinical Affairs
University of Maryland School of Medicine Interim Division Chief, Maternal–Fetal Medicine
Baltimore, Maryland Department of Obstetrics and Gynecology
University of Texas Health Science Center
Baha M. Sibai, MD San Antonio, Texas
Professor and Director, Maternal–Fetal Medicine Fellowship
Program Yariv Yogev, MD
Department Obstetrics, Gynecology and Reproductive Sciences Professor of Obstetrics and Gynecology
The University of Texas Medical School at Houston Chairman, The Israeli Society for Maternal and Fetal Medicine
Houston, Texas Director, Division Obstetrics and Delivery Ward
Helen Schneider Hospital for Women
Stephanie A. Stein, MD Rabin Medical Center
Assistant Professor, Division of Endocrinology Sackler Faculty of Medicine
University of Maryland School of Medicine Tel Aviv University
Baltimore, Maryland Tel Aviv, Israel

Jennifer K. Straughen, PhD Zhiyong Zhao, MD

Department of Family Medicine and Public Health Sciences Department of Obstetrics and Gynecology
Division of Population Health Sciences University Maryland School of Medicine
Wayne State University School of Medicine Baltimore, Maryland
Detroit, Michigan

Tracy Tomlinson, MD, MPH, FACOG

Associate Professor
Department of Obstetrics, Gynecology and Women’s Health
Saint Louis University School of Medicine
St. Louis, Missouri

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CH00.indd 18 22/01/15 10:04 PM
 SECTION I The Scientific Rationale for Global
­Issues Affecting Diabetes in Pregnancy

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CH01.indd 2 1/13/15 10:26 AM
 The Professional Responsibility
Model of Obstetric Ethics
Clinical Application to the Management of
Diabetes in Pregnancy
1
Frank A. Chervenak, MD
Laurence B. McCullough, PhD

The greatest mistake in the treatment of diseases is that there are physicians for the
body and physicians for the soul, although the two cannot be separated…
—Plato

Key Points
• The professional responsibility model of obstetric ethics is an essential dimension of the obstetrical management of
diabetes in pregnancy.
• Beneficence is the ethical principle that obligates physicians to seek the greater balance of clinical good over clinical harm
in patient care.
• Respect for autonomy is the ethical principle that obligates the physician to empower pregnant patients in the informed
consent process.
• The fetus is a patient when it is presented to the physician, and clinical interventions exist that are reliably expected to
protect and promote the health-related interests of the fetus.
• When the fetus is not a patient, nondirective counseling regarding continuation of pregnancy is appropriate.
• The physician’s position on mode of delivery should be based on a careful consideration of beneficence-based obligations
to the pregnant woman and fetal patient, and autonomy-based obligations to the pregnant woman.
• The patient’s preferences for mode of delivery should be considered but are not decisive in beneficence-based clinical
judgment in the professional responsibility model of obstetric ethics.
• In areas of scientific disagreement, when beneficence-based clinical judgment is uncertain, the patient’s preferences have a
more decisive role to play in determining mode of delivery.
• Professionally responsible clinical judgment about the management of pregnancies complicated by diabetes should be
based on beneficence-based and autonomy-based obligations to the pregnant woman and beneficence-based obligations to
the fetal patient.

INTRODUCTION medical care. To avoid paternalism, the physician could opt for
Physicians caring for a pregnant woman with diabetes will face the alternative, that is, the patient’s judgment being the controlling
and need to responsibly manage the ethical issues that arise when factor in decision making. This approach, however, reduces the
the physician’s judgments about what is in her and/or the fetus’ physician’s role to that of mere technician; worse, this approach
clinical interest differ from the woman’s judgment about these may require the physician to act in ways that contradict reasona-
interests. One way to manage such differences would be to claim ble medical judgment.1
that the physician’s judgment should control decision making. In this chapter, we avoid these two extremes by applying
This strategy has been discredited as it leans toward practitioner the professional responsibility model of obstetric ethics to the
paternalism. Paternalism occurs when the physician’s clinical challenges of decision making by the obstetrician and the preg-
judgments fail to take into account the patient’s values and beliefs nant woman with diabetes about what is in her best interests.2
and interfere with her preferences regarding her own health and We begin by explaining the professional responsibility model of

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 4 The Diabetes in Pregnancy Dilemma

obstetric ethics. We then identify the implications of the profes- Two physician–ethicists, John Gregory (1724–1773) of Aberdeen
sional responsibility model for the role of cesarean delivery in the and Edinburgh in Scotland and Thomas Percival (1740–1804) of
care of pregnant women with diabetes. This chapter emphasizes Warrington and Manchester in England conceived the ethical con-
a preventive ethics approach that appreciates the potential for cept of medicine as a profession in response to the guild mentality
ethical conflict and adopts ethically justified strategies to prevent that had come to dominate Western medicine as a legacy of the
those conflicts from occuring.1,3 Preventive ethics helps to build Hippocratic Oath. The individual and group self-interest was epit-
and sustain a strong physician–patient relationship. omized in the Statuta Moralia of the Royal College of Physicians
in London. These “moral statutes” were designed to promote the
self-interest of physicians in such matters as cultivating good repu-
THE PROFESSIONAL RESPONSIBILITY tations by never criticizing each other in public.6
OF OBSTETRIC ETHICS In eighteenth-century British medicine, there was no
The professional responsibility model of obstetric ethics appeals accepted science of medicine and, therefore, no accepted educa-
to the ethical concept of medicine as a profession. Many obste- tional pathway into medical or surgical practice. Instead, there
tricians believe that medical professionalism has roots in the were almost as many concepts of health and disease and treat-
Hippocratic Oath and other ethical texts in the Hippocratic ments as there were physicians. Physicians competed fiercely for
Corpus. This belief does not withstand close scrutiny, because the small private practice market in the homes of the well-to-do,
the Hippocratic Oath can reasonably be read as a guild oath, the emphasizing self-interest and survival in a fiercely competitive
primary purpose of which was to secure the fealty of young men market. Gregory and Percival also wrote their medical ethics in
who were not the sons of physicians of the Coan School and other response to the crisis of trust of the sick. Dorothy and Roy Porter
groups of physicians who subscribed to the tenets of the Oath. have convincingly documented that, at that time, sick persons
The first section of the Oath stipulates the obligations of these did not trust physicians, surgeons, and apothecaries (forerunners
young men to their masters in the guild. The prescriptions and of modern pharmacists) intellectually to know what they were
proscriptions of the Oath are not explained but can be read as doing or morally to be concerned about the well-being of the sick;
self-interested, for example, avoiding high mortality rates and they were concerned, however, with lining their pockets with the
the ruined reputation that they bring in their wake to physicians money of the sick.8
whose patients die in high numbers from pessaries (major sources Gregory and Percival reformed medicine into the profes-
of infection for women into whose vaginas the pessaries would be sion that it has become over the past two centuries. They did so
placed to induce uterine contractions and abortion of a fetus) or by turning to the best scientific method of their day, Baconian,
from surgery, even from “the stone,” that is, bladder stones that experience-based medicine (a forerunner of what is now known
can be discovered upon palpation. The Oath calls for the protec- as evidence-based medicine or the deliberative practice of medi-
tion of technè, rather than patients, as its primary focus. Technè is cine). They embraced the best moral science of their day, Gregory
wrongly translated as the “art” of medicine, in contrast to the sci- to David Hume’s sympathy-based moral science and philosophy
ence of medicine, because technè names the “science” of ancient (1711–1776) and Percival to Richard Price’s (1723–1791) intui-
Greek medicine. We use the scare quotes to indicate that technè tion-based moral science and philosophy.7
is not science but a fixed, unchanging, and unchangeable body of Drawing on these intellectual resources, Gregory and
knowledge about the four humors and their imbalances and the Percival put forward the ethical concept of medicine as a profes-
clinical skills of diagnosing the course and severity of diseases sion with three components. First, physicians should commit to
and injuries and intervening very modestly to alter that course. becoming and remaining scientifically and clinically competent.
From the perspective of modern, genomic scientific medicine, to Second, physicians should use their scientific and clinical com-
make the Oath and accompanying texts the basis of professional- petence primarily to protect and promote the health-related inter-
ism in medicine is very odd, indeed. ests of patients, keeping individual self-interest systematically
Suppose, for the sake of argument, that the Hippocratic secondary. Third, physicians should commit to sustaining medi-
Corpus does indeed present a concept of medicine as a profession cine as a public trust (the phrase is Percival’s) that exists primar-
rather than an unchanging, self-interested guild that comes down ily for the benefit of patients and society, keeping group or guild
to us intact from ancient Greece in what is usually invoked as self-interest systematically secondary.7 The result of Gregory and
the “Hippocratic Tradition.” Vivian Nutton has shown that there Percival’s pioneering medical ethics was to transform physicians
was no Hippocratic tradition.4 The Oath fell out of favor in the from incompetent, self-interested practitioners into professional
early centuries of the Common Era. In medieval and Renaissance physicians. The sick were transformed into patients. Thus was
universities, graduates in medicine took an oath of loyalty to the introduced into the history of medical ethics the physician–patient
faculty. Nutton shows that the mid-twentieth century witnessed relationship that is professional and not primarily contractual in
a conservative reaching back to the revered founder of Western nature.
medicine to valorize a set of values that did not originate in The professional virtue of integrity is based on the ethical
ancient Greece. Galvão-Sobrinho has shown that this is a common concept of medicine as a profession. Professional integrity com-
use of the historical figure of Hippocrates to give value to views prises two commitments. The first is to intellectual excellence that
that the Hippocratic physicians would not recognize and are even is achieved by making the first commitment in the ethical concept
incompatible with the content of the Hippocratic texts.5 of medicine as a profession. The second is to moral excellence that
The ethical concept of medicine as a profession ­originates much is achieved by making the second and third commitments in the
more recently, during the Scottish and English Enlightenments.6,7 ethical concept of medicine as a profession. Professional integrity

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 CHAPTER 1 / The Professional Responsibility Model of Obstetric Ethics 5

sometimes requires health care professionals to protect patients In the professional responsibility model of obstetric ethics,
from themselves. In this respect, the ethical concept of medicine when the fetus is a patient, directive counseling for fetal benefit
is justifiably paternalistic in nature: It rests on the assumption that is ethically justified. In clinical practice, directive counseling for
scientific and clinical competence creates expertise about health fetal benefit involves one or more of the following: recommending
care that the typical patient does not possess. against termination of pregnancy; recommending against nonag-
The ethical concept of being a patient is a function of the eth- gressive management; or recommending aggressive management.
ical concept of medicine as a profession. A human being becomes Aggressive obstetric management includes interventions such as
a patient when he/she presents to a physician or other health care fetal surveillance, tocolysis, cesarean delivery, or delivery in a
professional for clinical management. It is expected that the phy- tertiary-care center when indicated. Nonaggressive obstetric man-
sician’s deliberative (evidence-based, rigorous, transparent, and agement excludes such interventions. Directive counseling for
accountable) clinical judgment will result in a net clinical benefit fetal benefit, however, must always take into account the presence
for that person. The ethical concept of being a patient is benefi- and severity of fetal anomalies, extreme prematurity, and obliga-
cence-based.1,2 tions to the pregnant woman.1
The professional responsibility model of obstetric ethics It is important to appreciate in obstetric clinical judgment
applies the ethical concept of medicine as a profession to obstet- and practice that the strength of directive counseling for fetal ben-
ric practice.2 During the intrapartum period, the obstetrician has efit varies according to the presence and severity of anomalies.
two patients, the pregnant patient and the fetal patient, when the As a rule, the more severe the fetal anomaly the less directive
pregnant woman presents for care. The obstetrician, therefore, has counseling should be for fetal benefit.1,9–11 In particular, when
beneficence-based obligations to both the pregnant and the fetal there is “(1) a very high probability of a correct diagnosis, and
patients to protect and promote their health-related interests. The (2) either (a) very high probability of death as an outcome of the
obstetrician also has autonomy-based obligations to the pregnant anomaly diagnosed or (b) very high probability of severe irrevers-
woman. These obligations focus on empowering the pregnant ible deficit of cognitive developmental capacity as a result of the
woman with information that she needs to make decisions with anomaly diagnosed,” counseling should be nondirective in rec-
her obstetric health care professional about the management of ommending between aggressive and nonaggressive management
her pregnancy. The obstetrician must in all cases take into account options.9–11 By contrast, when lethal anomalies can be diagnosed
and balance beneficence-based and autonomy-based obligations with certainty, there are no beneficence-based obligations to pro-
to the pregnant patient and beneficence-based obligations to the vide aggressive management.9–11 Such fetuses are appropriately
fetal patient. This ethically complex relationship means that the regarded as dying fetuses, and the counseling should be nondirec-
fetal patient is not a separate patient, that is, beneficence-based tive in recommending between nonaggressive management and
obligations to the fetal patient are a part of, but not the entirety of, termination of pregnancy, but directive in recommending against
the ethical relationship between the obstetric health care profes- aggressive management for the sake of maternal benefit.12
sional and the pregnant patient and fetal patient.1,2 The strength of directive counseling for fetal benefit in
The professional responsibility model of obstetric ethics cases of extreme prematurity of viable fetuses does not vary. In
stands in sharp contrast to what we have elsewhere described as particular, this is the case for what we term just-viable fetuses,1
the maternal-rights-based reductionist model of obstetric ethics.2 In those with a gestational age of 24–26 weeks, for which there are
this model, the pregnant woman’s autonomy is the controlling eth- significant rates of survival but high rates of mortality and mor-
ical consideration throughout pregnancy. She has an absolute right bidity.13 These rates of morbidity and mortality can be increased
to bodily integrity unconstrained by any ethical obligations to the by nonaggressive obstetric management, while aggressive
fetus. The fetus is not a patient in this account but is ethically sep- obstetric management may favorably influence outcome. Thus,
arate from the pregnant woman. This model has important impli- it would appear that there are substantial beneficence-based
cations for the relationship between the pregnant woman and the obligations to just-viable fetuses to provide aggressive obstetric
obstetrician. The relationship is purely contractual because the sole management. This is all the more the case in pregnancies beyond
basis of the relationship is the exercise of the pregnant w ­ oman’s 24 weeks gestational age.13 Therefore, directive counseling for
autonomy. In the professional responsibility model, the pregnant fetal benefit is justified in all cases of extreme prematurity of
woman’s right to bodily integrity is not absolute; it is an ethically viable fetuses, considered by itself. Of course, such directive
significant component of autonomy-based obligations to the preg- counseling is ethically justified only when it is based on doc-
nant woman but not the sole controlling ethical consideration, as it umented efficacy of aggressive obstetric management for each
is in the rights-based reductionist model of obstetric ethics. fetal indication.
The maternal-rights-based reductionist model has a radical Directive counseling for fetal benefit must always occur in
implication that its advocates ignore. In such a model of health the context of balancing beneficence-based obligations to the
care, there are no patients. There are only sick individuals (aegro- fetus against beneficence-based and autonomy-based obligations
trus in the Latin texts that precede Gregory and Percival in the to the pregnant woman1,14 (Table 1-1). Any such balancing must
history of Western medical ethics) or clients who contract with recognize that a pregnant woman is obligated only to take rea-
providers. There are no health care professionals, because rights- sonable risks of medical interventions that are reliably expected
based-­reductionist models embrace an absolute right to bodily to benefit the viable fetus or child later. The unique feature of
integrity of the client, which eliminates professional integrity as obstetric ethics is that whether, in a particular case, the viable
an ethically justified constraint on the client’s autonomy because it fetus ought to be regarded as presented to the physician is, in part,
prevents the physician from intervening in a professional manner. a function of the pregnant woman’s autonomy.

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 6 The Diabetes in Pregnancy Dilemma

TABLE 1-1 Ethical Obligations of the Physician in Obstetric Care

Interests of Pregnant Woman Interests of Fetal Patient

Maternal Autonomy-Based Maternal Beneficence-Based Fetal Beneficence-Based Fetal Beneficence-Based

Obligations of Physician Obligations of Physician Obligations of Pregnant Obligations of Physician
Woman

Obviously, any strategy for directive counseling for fetal ben- Our approach begins by asking, “Is cesarean delivery sub-
efit that takes into account the obligations to the pregnant woman stantively supported and vaginal delivery not supported in benefi-
must be open to the possibility of conflict between the physician’s cence-based clinical judgment?”15 Such cases occur with diabetic
recommendation and a pregnant woman’s autonomous decision to pregnancies, based on the clinical factors such as estimation of
the contrary. Such conflict is best managed preventively through fetal weight and the maternal pelvis, degree of control of diabe-
informed consent as an ongoing dialogue throughout the pregnancy, tes in the pregnancy, and previous obstetric history. These clinical
augmented as necessary by negotiation and respectful persuasion.1,3 factors are discussed in detail elsewhere in this volume. When the
Counseling the pregnant woman regarding the management best available evidence or otherwise reliable clinical judgment
of her pregnancy when the fetus is previable should be nondirec- supports the view that the fetus’s interests are best protected by
tive in terms of continuing the pregnancy or having an abortion if cesarean delivery, and there are no maternal contraindications, the
she refuses to confer the status of being a patient on her fetus. If professional responsibility model supports offering and recom-
she does confer such status in a settled way, at that point benef- mending cesarean delivery.
icence-based obligations to her fetus come into existence and In some clinical circumstances, there is scientific contro-
directive counseling for fetal benefit becomes appropriate for these versy as to whether cesarean delivery is the better alternative.
fetuses. Just as for viable fetuses, such counseling must always Competing well-founded beneficence-based clinical judgments
also take into account the presence and severity of fetal anomalies, regarding how to balance the fetal benefit of preventing harm of
extreme prematurity, and obligations owed to the pregnant woman. cesarean delivery generate these controversies, which are dis-
For pregnancies in which the woman is uncertain about cussed elsewhere in this volume. Whenever there is legitimate
whether to confer such status, the authors propose that the fetus scientific disagreement about the benefits and risks of cesarean
be provisionally regarded as a patient.1 This justifies directive versus vaginal delivery, the professional responsibility model
counseling that the woman not engage in behavior that can harm calls for both options to be offered to the pregnant woman and dis-
a fetus in significant and irreversible ways, for example, poorly cussed with her so that she can meaningfully exercise her auton-
controlled hyperglycemia, until the woman settles on whether to omy in the informed consent process. This approach empowers
confer the status of being a patient on the fetus. This also justifies the woman to emphasize her own perspective in balancing mater-
directive counseling about diagnostic surveillance, for example, nal and fetal benefits and risks. It is appropriate for the obstetri-
ultrasound examination to detect anomalies. When anomalies are cian to assist the woman’s decision making about both options in
detected, counseling about the disposition of the woman’s preg- the form of a recommendation.
nancy should be nondirective, as explained earlier. In clinical circumstances, when cesarean delivery is substan-
Nondirective counseling is appropriate in cases of what we tively supported in beneficence-based clinical judgment but vagi-
term near-viable fetuses,1 that is, those who are 22–23 weeks ges- nal delivery is more substantively supported, vaginal delivery is
tational age for which there are anecdotal reports of survival.13 In the better alternative, but not the only one, for example, a pregnant
the authors’ view, aggressive obstetric and neonatal management woman with diabetes whose sugars have been well controlled during
should be regarded as clinical investigation, that is, a form of med- pregnancy and there is no macrosomia. Although cesarean delivery
ical experimentation—not standard of care. There is no obligation is supported in beneficence-based clinical judgment, trial of labor is
on the part of a pregnant woman to confer the status of being a more substantively supported. Therefore, the professional respon-
patient on a near-viable fetus, because the efficacy of aggressive sibility model supports offering and recommending trial of labor.
obstetric and neonatal management has yet to be proven.13

SUMMARY
WHEN TO OFFER, RECOMMEND, AND PERFORM The professional responsibility model of obstetric ethics is an
CESAREAN DELIVERY essential dimension of obstetric practice, especially the care of
When to offer, recommend, and perform cesarean delivery pre- pregnant women with diabetes. In this chapter, we have described
sents clinical ethical challenges to the obstetrician in the manage- the professional responsibility model of obstetric ethics. We
ment of a pregnancy complicated by diabetes. The professional have deployed this model to address when to offer and recom-
responsibility model of obstetric ethics provides reliable, clini- mend cesarean delivery. We believe that the clinical application
cally applicable guidance for the management of these challenges. of the professional responsibility model of obstetric ethics will
This approach is designed to prevent conflict between the obste- strengthen the obstetrician–patient relationship and, therefore,
trician and the pregnant woman about intrapartum management. enhance the quality of care for pregnant women with diabetes.

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 CHAPTER 1 / The Professional Responsibility Model of Obstetric Ethics 7

REFERENCES 8. Porter R, Porter D. Patients’ Progress. Stanford, CA: Stanford

1. McCullough LB, Chervenak FA. Ethics in Obstetrics and University Press; 1989.
Gynecology. New York, NY: Oxford University Press; 1994. 9. Chervenak FA, McCullough LB, Campbell S. Is third trimester
2. Chervenak FA, Brent RL, McCullough LB. The professional abortion justified? Br J Obstet Gynaecol. 1995;102:434–435.
responsibility model of obstetric ethics: avoiding the perils of 10. Chervenak FA, McCullough LB, Campbell S. Third trimes-
clashing rights. Am J Obstet Gynecol. 2011;205:315.e1–315.e5. ter abortion: is compassion enough? Br J Obstet Gynaecol.
3. Chervenak FA, McCullough LB. Clinical guides to preventing eth- 1999;106:293–296.
ical conflicts between pregnant women and their physicians. Am J 11. Chervenak FA, McCullough LB. An ethically justified approach to
Obstet Gynecol. 1990;162:303–307. offering, recommending, performing, and referring for induced abor-
4. Nutton V. The discourses of European practitioners in the tradi- tion and feticide. Am J Obstet Gynecol. 2009;201:560.e1–560.e6.
tion of the Hippocratic texts. In: Baker RB, McCullough LB, eds. 12. Chervenak FA, McCullough LB. Ethical dimensions of non-­
The Cambridge World History of Medicine Ethics. New York, NY: aggressive fetal management. Semin Fetal Neonatal Med.
Cambridge University Press; 2009:359–362. 2008;13:316–319.
5. Galvão-Sobrinho CR. Hippocratic ideals, medical ethics, and the 13. Chervenak FA, McCullough LB, Levene MI. An ethically justified,
practice of medicine in the early middle ages: the legacy of the clinically comprehensive approach to periviability: gynecologic,
Hippocratic Oath. J Hist Med Allied Sci. 1996;51:438–455. obstetric, perinatal, and neonatal dimensions. J Obstet Gynaecol.
6. McCullough LB. John Gregory and the Invention of Professional 2007;27:3–7.
Medical Ethics and the Profession of Medicine. Dordrecht, 14. Chervenak FA, McCullough LB. Perinatal ethics: a practical
Netherlands: Kluwer Academic Publishers; 1998. method of analysis of obligations to mother and fetus. Obstet
7. McCullough LB. The ethical concept of medicine as a profession: Gynecol. 1985;66:442–446.
its origins in modern medical ethics and implications for phy- 15. Chervenak FA, McCullough LB. An ethically justified algorithm
sicians. In: Kenny N, Shelton W, eds. Lost Virtue: Professional for offering, recommending, and performing cesarean delivery
Character Development in Medical Education. New York, NY: and its application in managed care practice. Obstet Gynecol.
Elsevier; 2006:17–27. 1996;87:302–305.

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CH01.indd 8 1/13/15 10:26 AM
 Evidence-Based Medical Practice
Its Use and Misuse
Oded Langer, MD, PhD
Nieli Langer, PhD
2
Where is the wisdom we have lost in knowledge and where is the knowledge we have
lost in information?
—T.S. Eliot

Key Points
• Evidence-based medical practice (EBMP) may provide:
1. Encouragement for rigorous testing of practice-related claims regarding effectiveness
2. Means for disseminating practice-related research findings
3. Enhanced opportunities for doing more good than harm
• EBMP is a bridge between external clinical evidence and individual clinical practice.
• EBMP has many partners and entangling alliances.

INTRODUCTION up-to-date evidentiary practices and policies, they are not provid-
The goal of education and research in all disciplines is to ing their patients with the best medical alternatives. Moreover,
develop critical thinking skills as a method for improving clin- they cannot honor informed consent obligations to provide best
ical decision making. Critical thinkers explore their own atti- possible care. To access, analyze, and apply research findings in
tudes and values, investigate and analyze competing alterna- health care, practitioners will need to understand why, by whom,
tives, and are motivated to articulate their point of view. The and how research studies are conducted.
emphasis on critical thinking is nothing new and can be traced In light of the above, it is amazing that it took until the 1990s
back to ancient times where Socrates believed in education by when a group of clinicians and epidemiologists at McMaster
interrogating rather than by propounding. Socrates challenged University in Ontario, Canada, officially coined the term
his students to think about their knowledge, beliefs, and behav- “­evidence-based medicine.” We cannot help but smile and believe
iors. It is widely known that Socrates would press his students that Socrates would look favorably on the evolution of EBMP
until they could provide evidence to support their arguments while reminding us that we need additional evidence and the dis-
and would dismiss those beliefs and decisions that could not be semination of critical thinking skills to support its use.
supported with proof.
EBMP is a medical movement based on the application of the
Evidence-based medical practice (EBMP) originated in
scientific method to medical practice, including long-established
health care in the mid-twentieth century as an alternative to
existing medical traditions not yet subjected to adequate scientific
authority-based practice (i.e., basing decisions on so-called
scrutiny. It originated because of gaps among evidentiary, ethical,
experts’ opinions). EBMP offers practitioners and administra-
tors a foundation that is compatible with professional codes of and application concerns. From the beginning, the concept faced
ethics (i.e., for informed consent) and educational accreditation mixed reviews: excitement from researchers and resentment from
policies and standards. Although most people engaged in mean- health care practitioners who deemed it impractical in busy medi-
ingful careers in health care will, in all probability, never conduct cal offices. Our attempts since ancient times have been to increase
empirical research, they will be reading research articles in their medical knowledge and enhance the level of medical care. The
professional journals that describe issues relevant to their prac- 21st century has witnessed the confluence of an accumulation of
tices. EBMP is designed to enhance practitioners’ ability to be knowledge, in addition to the tools to access and deliver the fruits
good consumers of research. If practitioners are not familiar with of this knowledge to all interested health care providers.

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 10 The Diabetes in Pregnancy Dilemma

THE BRIDGE BETWEEN EXTERNAL CLINICAL Studies using birth certificates and health insurance claims
to generate data have become popular. Birth certificates pro-
EVIDENCE AND INDIVIDUAL CLINICAL PRACTICE vide data collected for civil and legal purposes, not for research.
Advantages of Randomized Clinical Trials Administrative databases, that is, billing systems or state mandated
It took until the middle of the 20th century before medical record keeping structures were not created for epidemiological
science was to help facilitate the evolution of the randomized research.4 Misclassification is common; some procedure claims are
clinical trial (RCT) that generates some of the information that not accurately recorded and are obtained by nonmedical personnel;
becomes evidence. In medicine, since the randomized controlled some procedures that are provided are not always billed and, there-
trial, when conducted under the appropriate conditions, is so fore, do not appear on the record. As a result, important reproductive
much more likely to inform us and so much less likely to mis- health-related information, such as type of birth defects and specific
lead us, it has become the gold standard for judging whether a hypertension drug used in treatment, may not be routinely recorded;
treatment does more good than harm.1 As the least biased form of comorbidities such as diabetes are poorly recorded; and the type
medical evidence, the RCT offers many advantages. It provides of diabetes is not specified (gestational diabetes mellitus [GDM],
the strongest evidence of causality and represents the best meth- type 1 and type 2); in addition, level of glycemia, body mass index,
odology to test the effectiveness of an intervention, that is, the and diabetic treatment employed is not available in the database for
extent to which an intervention, procedure, or treatment regimen extraction; the type of medication is not specified providing only
produces a desired effect when deployed in the field in routine a general classification, that is, oral agent. As a result, researchers
circumstances.2 When performed with an adequate sample size, extracting data from these records have automatically speculated that
randomization protects against selection bias and confounding glyburide had been administered to all patients when in fact there are
variables. currently several oral agents routinely used that could have been pre-
scribed.4,5 The veiled threat to junior faculty by their older colleagues
Limitations of RCTs to “publish or perish…” has often sanctioned the expedient method
There is, however, an increasing recognition of the limits of of obtaining data from administrative databases for epidemiologic
randomized controlled trials. Although RCTs can determine the research with the resultant “garbage in, garbage out” data obtained.6
effectiveness of an intervention in an experimental setting, dif- Of the thousands of diabetes in pregnancy studies that have
ferent methods of research may be required to determine whether been published, the Cochrane Register of Clinical Trials has iden-
any harmful effects exist or to examine how patients experience tified only 103 that were described as randomized trials. Of these,
any interventions they receive. In addition, randomized trials are 28 studies were excluded. They failed to report information rele-
expensive, not always feasible, and in some cases inappropriate to vant to pregnancy compromised by diabetes and, in some cases,
perform for ethical reasons. the publications reported on the same randomized trial. In general,
EBMP involves tracking down the best external evidence the majority of proposed interventions can only achieve about
with which to answer clinical questions. To determine the accu- 25%–35% reduction in a selected endpoint (i.e., macrosomia,
­
racy of a diagnostic test, cross-sectional studies of patients clini- shoulder dystocia). Therefore, the number of women who have
cally suspected of harboring the relevant disorder is needed, not to be recruited to prove that an intervention actually achieves its
a randomized trial. When studying prognosis, even after a RCT, intended goal would have to be larger than the number currently
proper follow-up studies of patients assembled at a uniform early reported in the majority of studies on diabetes in pregnancy.
point in the clinical course of their disease is advisable. If no ran-
domized trial has been conducted for an illness or complication, The Effect of Research Methodology on Study
researchers and practitioners seek the next best external evidence
Conclusions
and work from there.3
The selection of the research design, the calculated sample size,
and the level of glycemic control achieved in a given study are all
CATEGORIES OF RESEARCH DESIGNS potential confounders for study conclusions. The larger the sample
A basic understanding of common methods of research design is size and the anticipated magnitude of the intervention, the greater
necessary to interpret the evidence presented in a research study. the power, that is, the percent chance that the study will detect a sig-
The case report describes an unexpected event to test whether it nificant difference when there is an actual difference. However, a
is a chance or regularly recurring phenomenon that needs further study with a small sample size that suggests a statistical difference
investigation. The report would have to address the likelihood runs the risk of an alpha error, that is, the probability of a study
of this phenomenon occurring by chance and if the event was showing a statistically significant difference when no real differ-
predictable from any theoretical or empirical observation. The ence exists. In addition, the rate of a complication or the result of an
uncontrolled case series is a weightier case report since the event intervention lower than expected by the acknowledged prevalence
has occurred on numerous occasions; but, the need to address the such as 50% anomalies with a small sample size raises the issue of
same concerns as above applies. The rationale for conducting a selection bias. On the other hand, when study results do not reveal a
case-controlled study is the potential to compare a selected end- difference in perinatal mortality, birth trauma, or shoulder dystocia,
point in the study group to an external reference in the general it does not mean that an important clinical difference does not exist.
population. However, it is important to evaluate the selection pro- The failure of the study to provide evidence of a difference should
cess to create the matched-control, that is, what biases could have not be confused with evidence of no difference. Therefore, a beta
influenced a person being designated a case or control and how error is the probability of failing to show a statistically significant
representative were the subjects? difference when a true difference exits (false negative).

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 CHAPTER 2 / Evidence-Based Medical Practice 11

Composite outcomes are those in which several individual tremendous influence on his peers, on policy makers, and/or the
outcomes are pooled to produce a single outcome. As the number public. When all methods appear to be equally effective and those
of individual adverse outcomes decline in light of improved treat- who depend on the information are not sure which direction to
ments, the use of composite outcomes can overcome this drop by take, the vacuum is filled by an “expert” who has the oratorical
combining different outcomes and enhancing the efficiency of a and persuasive powers to say what is and what is not effective
clinical trial. Outcome selection should obviously translate into a practice. The information, however, may be based on biased
clinically important long-term outcome. It should be noted, how- opinion and conflict of interest but not necessarily the facts.
ever, that using composite outcomes does not necessarily lead to Consumers of research evidence need to ensure that the creden-
increased evidence of the benefit of a specified intervention. In tials of a seemingly notable scholar from a prestigious institution
addition, each element of the composite outcome needs to be pre- do not overawe them.
sented as a secondary outcome so that practitioners can determine Advocates of EBMP explicitly reject the long-standing
the efficacy of these outcomes in their clinical practices. When assumption that theory, traditional training, anecdotal experi-
there are limited available resources for clinical trials, composite ence or custom, consensus, or common sense alone provides
outcomes is an efficient and appropriate design solution that may sufficient guidance for effective decision making and profes-
also best reflect a real clinical outcome.7 sional practice. Intuition and unsystematic clinical expertise are
It should be noted that even after an adequate sample size has insufficient grounds on which to make clinical decisions. On the
been drawn, or the likelihood of making either an alpha or beta other hand, the “value laden nature of clinical decisions” implies
error are small, information regarding level of glycemic control that we cannot rely on evidence alone… knowing the tools of
throughout pregnancy, timing of diagnosis, and onset of therapy ­evidence-based practice are necessary but not sufficient for deliv-
and methods of measuring levels of glycemic control can be seri- ering the highest quality of patient care.13
ous confounders that alter the results of a study. See Chapters 11 One of the origins of EBMP was the study of variations in
and 12 in the text for appropriate examples and specific studies. practice and related outcomes.14 Variations in practices suggest
In reproductive literature, cohort, case-control and cross-­ questions such as “Are they all equally effective?” “Are some
sectional studies are common since many research questions more effective than others?” “Do some result in more harm than
cannot be addressed with an RCT. These observational studies are good?” Evidence has begun to indicate that there are significant
more prone to bias than a RCT. Goodman8 suggests that, “…in differences among hospitals or doctors in a particular specialty.
identifying reasons for our scientific beliefs, we also want to know What you tend to find is a bell curve: a handful of teams with very
how strong a warrant they provide: how good are the reasons poor outcomes for their patients, a handful with incredibly good
and how good must they be to compel us to revise our beliefs?” results, and a great undistinguished middle. Acknowledging this
Therefore, once academicians and clinicians are convinced of the bell curve is very distressing to practitioners since it contradicts
veracity of evidence, staying abreast of research in the field and/or the promise that they have made to patients who become seri-
one’s medical specialty becomes a moral imperative with its foun- ously ill: that they can count on the medical system to give them
dations in both the Hippocratic Oath and the Oath of Maimonides. their very best chance at life. We used to think that a doctor’s
The contribution that Archie Cochrane made to the evolution of ability depends mainly on science and skill. However, even doc-
scientific methodology in the 1970s was to make the evidence less tors with great knowledge and technical skills can have mediocre
removed or disconnected from those people who should be using results. What the best physicians do have, however, is a capacity
it to take care of sick people. Today, the Cochrane and Campbell to learn, whether from research data or clinical experience, and to
Collaborations provide an evolving source of database tools and do so faster than their average peers. What we are also learning,
ideas to facilitate this enterprise.9 however, is that in addition to the above intellectual skills, the
With the advent of the RCT and the ascendancy of the data- best practitioners often possess or strive to acquire more nebulous
bases for retrieval of information, the research community sought attributes such as aggressiveness, consistency, ingenuity, compas-
a means to develop some strategy for sifting, organizing, collat- sion, sensitive listening skills, and broad perspectives from the
ing, and arranging this knowledge of variable quality or reliability. humanities and social sciences.15
One effort to address the problem was an attempt to rank “levels A key characteristic of EBMP is to break down the division
of evidence” according to different aspects of clinical practice, between research and practice, highlighting the importance of cli-
including therapy, prognosis, diagnosis, and so forth. The Oxford nicians’ ability to critically appraise research reviews and devel-
Center for Evidence-Based Medicine does this by stratifying oping a technology to help them do so. It emphasizes clinician use
levels of evidence based on degrees of methodological power and of their scientific training and their judgment to interpret research
advantage based on the original efforts of the Canadian Task Force and individualize patient care accordingly. EBMP is a guide for
on the Periodic Health Examination (1979).10 The US Preventive thinking about how decisions should be made in light of patients’
Services Task Force11 (1996) has also adopted specific criteria for preferences and clinicians’ recommendations. Proponents of
the evaluation of the quality of evidence. EBMP believe that findings from the most relevant scientific stud-
EBMP involves a shift in paradigms. Historically, practition- ies currently available should figure prominently in the practice
ers have relied primarily on their more experienced colleagues decisions of clinicians. Judicious use of evidence involves balanc-
and supervisors, expert opinions, and their own personal experi- ing an assessment of the individual patient’s unique characteris-
ences for professional guidance—subjective information sources tics, personal preferences, and life circumstances against relevant
that too often provided inaccurate and even harmful practice primary research findings or practice guideline recommendations
guidelines.12 A charismatic spokesperson or “expert” may have for patient care.14

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 12 The Diabetes in Pregnancy Dilemma

Misconceptions about EBMP including the criticisms that to whether findings are similar under different study conditions
(1) it will replace or seek to replace practitioner judgment, (2) it using different population samples or comparable study designs.21
leads to a “cookie cutter” approach to medical practice, and (3) The strength of the evidence offered by a meta-analysis depends
it is too time consuming to be routinely employed in real-life on how well the review is conducted. The systematic review often
practice settings also might discourage widespread adoption of involves the skills of several reviewers working independently to
EBMP.16 EBMP should never evolve into rigid practice because screen thousands of abstracts and studies.
effective interventions require that practitioners integrate their However, the high profile of meta-analysis as a method of
professional understandings of patient care with recommenda- analysis in evidence-based medicine practice has led to several
tions derived from the best external evidence and patients’ pref- misconceptions about its purpose and methods.22 Systematic
erences.16 The practice calls for candid descriptions of limitations reviews of nonrandomized studies are also common, and quali-
of research studies and use of research methods that critically test tative studies can be and often are included in meta-analysis as
questions addressed. It also calls for systematic research reviews are case reports. The systematic review is a method for limiting
rather than reviews authored solely by self-declared “experts.” bias. However, since the choice of which study designs to include
is made by the reviewers, bias may sometimes be introduced.23–25
There is also a common myth that meta-analysis requires the
SYSTEMATIC REVIEWS: META-ANALYSIS adoption of a biomedical model of health. Systematic reviews do
Meta-analysis is a statistical procedure for synthesizing research not have preferred biomedical models and that is why there are
results across studies that address a common topic or issue. The systematic reviews in such diverse disciplines as education, social
term means to analyze “after or beyond” the original analysis. It work, and public policy. Reviews on the Cochrane Database of
is the analysis of analyses, completed on a collection of studies Systematic Reviews commonly include “quality of life” as an
usually to draw general conclusions. A major achievement of outcome variable alongside clinical indicators of the effects of
EBMP has been the development of systematic reviews, methods interventions. The systematic review, in medicine and other dis-
by which researchers identify multiple studies on a topic, separate ciplines, is an efficient and effective technique for testing hypoth-
the best ones, and then critically analyze them to come up with a eses, summarizing results of existing studies and assessing the
summary of the best available evidence. It is more than a quarter reliability and validity of studies.25
of a century since Gene Glass coined the term “meta-analysis” to Many researchers as well as clinical practitioners mistakenly
refer to systematic reviews whose results from different primary believe that meta-analysis always involves statistical synthesis.
studies are statistically combined into an overall estimate.17 A major concern is the potential for combining studies that are
Meta-analysis is qualitatively different from other traditional too diverse in treatment interventions, subject selection, outcome
reviews. The purpose of meta-analysis is to estimate the size of measurements, and research design. When no single study pro-
treatment effects to aid clinical decision making. Another major vides the purported evidence, maybe fusing all inaccurate studies
goal is to generate hypotheses to be tested in new clinical trials. together will finally provide the elusive evidence! Some system-
They are not always bigger, and their main aim is not simply to atic reviews summarize studies by describing the methods and
be comprehensive but to answer a specific question, apply strin- results while others use meta-analysis by converting the data from
gent inclusion criteria to studies reviewed, appraise the quality of each study into common measurement scales and combining the
the studies included, and summarize them objectively. However, a studies statistically. Many reviews do not use meta-analysis since
meta-analysis is only as accurate as the data on which it is based. pooling studies without taking into account variations in study
The reader must examine the inclusion and exclusion criteria quality can bias the conclusions of the review.26
carefully in the studies that are grouped for the meta-analysis. Finally, authors and consumers of systematic reviews need to
For example, a study that evaluated different treatment modali- recognize that these reviews do not necessarily produce definitive
ties in a RCT with only 22 patients would not meet the sample answers to health care issues. They often identify the need for
size or power requirements to be included in a meta-analysis.18 additional primary studies and are the vehicle for demonstrating
In two other double-blind randomized trials, the authors evalu- future directions for new research efforts.25 This methodology is
ated the efficacy of low-dose aspirin to prevent preeclampsia. The useful in identifying “what works” beyond the world of EBMP
first study with 34 women found that a significantly reduced inci- and may also provide a platform for the combined knowledge and
dence of pregnancy induced hypertension and preeclampsia.19 The skills of the major players in health care provision today.
subsequent study recruited 471 GDM participants, 774 chronic
hypertensive women, 688 patients with multifetal gestation, and Clinical Guidelines
606 with preeclampsia during a previous pregnancy. The authors Most guidelines are a fusion of clinical experience, expert opin-
found that low-dose aspirin did not significantly reduce the inci- ion, and research evidence. When the process of creating a prac-
dence of preeclampsia or improve perinatal outcome.20 These tice guideline utilizes valid and current research evidence in sys-
studies demonstrate the effect of sample size on alpha and beta tematic reviews, this has the potential to be translated into clinical
errors in research reporting. decision aids for optimized health outcomes for informed policy
Ranking different types of evidence by their level of scien- decision makers in managed care systems and educated clini-
tific support is guided by three principles: quality, quantity, and cians who in turn educate patients. It has been argued, however,
consistency.21 Quality refers to how the individual studies collec- that practice guidelines are too often based on the consensus of
tively minimized bias; quantity addresses the number of studies, “experts” rather than actual evidence. Practice guidelines and con-
sample size, and magnitude of effect; and, consistency pertains sensus statements have sprung up under the sponsorship of groups

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 CHAPTER 2 / Evidence-Based Medical Practice 13

in which the validity of the disseminated message and credibility but interdependent principles. First, whenever possible, practice
of the distributing agent are not always positively related. When should be grounded on prior findings that demonstrate empirically
the principles of EBMP are applied to the creation of these guide- that certain actions performed with a particular type of patient
lines, the potential limitations inherent in guideline development are likely to produce predictable, beneficial, and effective results.
are mostly overcome.27 Second, every patient over time should be individually evaluated
to determine the extent to which the predicted results have been
Who Are the “Players” in Evidence-Based Medical attained as a direct consequence of the practitioner’s actions.
Practice? Judicious use of evidence involves balancing an assessment of the
Evidenced-based medical practice is as much about the knowledge individual patient’s unique characteristics, personal preferences,
and ethics of educators and researchers as it is about the ethics and life circumstances against relevant primary research findings
of practitioners and policy makers in managed care systems. The or practice guideline recommendations for patient care. EBMP
health care system faces challenges from the many players who draws on the results of systematic, rigorous, critical appraisal of
are individually and/or collectively involved in the formulation of research related to important practice questions such as, Is this
policy or as recipients of those decision-making processes. EBMP assessment measure valid? Does this intervention do more good
involves sharing responsibility among all interested players for than harm? Efforts are made to prepare comprehensive, rigorous
decision making in a context of recognized uncertainty. reviews of all research related to questions of effectiveness, pre-
Patients want more effective communication with their care vention, screening (risk and prognosis), description and assess-
providers so that they can make informed choices. A striking char- ment, harm, and self-development.
acteristic of EBMP is the extent to which patients are involved An ultimate objective of EBMP is the practitioner’s consid-
in many different ways.28,29 There is a contemporary emphasis eration of the veracity of the findings of a given piece of research
to compare the values and preferences of patients with recom- and its applicability to his patient or collective patient population.
mended medical protocols and their likely consequences as well He/she will need to (1) know how to read and critique research
as “personalizing” the evidence to fit a specific patient’s life and articles and (2) assess the degree to which an intervention has
health circumstances. There is also a movement to help patients been empirically tested and found promising. To access, analyze,
develop critical appraisal skills that will facilitate more active par- and apply research findings in diabetic studies, practitioners will
ticipation in their health care. The term “evidence-based patient need to understand why, by whom, and how research studies are
choice” emphasizes the importance of involving patients as auton- conducted. Therefore, medical school and continuing medical
omous participants who themselves carry out the required integra- education will need to teach and reinforce the study of research
tion of information from diverse sources in making decisions that design—the overall framework for collecting data once the prob-
suit their values and needs.30 lem has been formulated. In addition, these institutions will need
Another way in which patients are actively involved in their to teach how to read and interpret the data and what they mean.
own care is recognizing their unique knowledge in relation to The main objective of this educational strategy will be to integrate
application of certain regimens. The experts in deciding whether a individual clinical expertise with critical evaluation of evidence
guideline is applicable to a given patient is the patient and provid- discovered from a systematic literature search to solve a problem.
ers not the researchers and academicians who critically appraise Understanding what kind of study has been performed is
research findings. The differing expertise needed to prepare sys- a prerequisite to thoughtful reading of research. What is now
tematic reviews regarding the evidentiary base of a guideline known is that physicians, under the influence of pharmaceutical
and to identify implementation potential highlights the inappro- advertising and promotions, are much more impressionable than
priateness of researchers telling practitioners and patients what was originally believed.31 Only studies with comparison groups
guidelines to use. In EBMP, patients are involved as informed par- allow investigators to assess possible causal associations, a fact
ticipants regarding the evidentiary status of services. There is an often forgotten or ignored. Large amounts of poor data forestall
attempt to promote candidness and clarity in place of secrecy and any amount of good data. Lots of zeroes may look impressive
obscurity. EBMP requires searching for research findings related in research findings yet they still amount to zero. Unfortunately,
to important practice and policy decisions and sharing what is most physicians lack skills in evaluating studies for bias and rele-
found (including nothing) with patients. vancy. This can result in harmful consequences to patients and is
Medical educators and clinicians want scientific bases for one of the reasons the enthusiastic use of the anti-inflammatory
determining “best practice” approaches in addition to the research drug Vioxx caused harm to so many patients.
and statistical tools to learn how to assess the results of studies Clinicians confront voluminous evidence about the clinical
to enhance patient care. However, they need to adapt a common choices they face every day. To remedy the problem, many med-
sense approach to EBMP. This approach integrates individual ical groups issue clinical practice guidelines: experts in a field
clinical expertise with best available evidence (relevant studies sort through the reams of clinical research on a medical condi-
discovered from a systematic search of the health care literature). tion and pore over drug studies; they then publish summaries
Practicing evidence-based medicine implies not only clinical about what treatments work best so that physicians everywhere
expertise (proficiency and judgment acquired through experi- can offer the most appropriate, up-to-date care to their patients.
ence), but expertise in retrieving, interpreting, and applying the While this sounds straightforward, the process can go awry. The
results of scientific studies, and in communicating the risks and recommendations issued recently by the American Association
benefits of different courses of action to patients. EBMP dictates of Clinical Endocrinologists (AACE) for the treatment of dia-
that professional judgments and behavior be guided by two distinct betes elevated second- or third-line drugs to more prominent

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 14 The Diabetes in Pregnancy Dilemma

positions in the prescribing hierarchy, rivaling once uncontested The system is error-prone. History has shown that great sci-
go-to medications life metformin, an inexpensive generic. They entific discoveries have often been achieved with minimal support
also emphasized the riskiness of established treatments like insu- and despite the active hindrance by the discoverer’s “peers.” When
lin and glyburide, which now carry yellow warning labels in the Dr. Rose Yalow first submitted the manuscript on insulin assay for
AACE summary. Several of the now promoted drugs are expen- peer review, she received a resounding rejection. Needless to say,
sive newcomers that lack the track records of clinical effective- it was this work that would be recognized in the future and would
ness and safety by the older, potentially displaced treatments. be the basis for her receiving a Nobel Prize.
Physicians were perhaps given more treatment choices for their It is also not difficult to understand how conflict of interest
patients, but the AACE recommendations could also have been and jealousy can undermine the peer review process. Researchers
influenced by drug manufacturers who helped finance the new whose work challenges the status quo are a threat to those whose
guidelines. What has evolved is the establishment of guidelines careers are entrenched in the paradigm of the day. New ideas can
for guidelines, that is, guideline recommendations by various jeopardize special interest groups and the funding they receive
organizations are rigorously and fairly depicted (Institute of to pursue traditional approaches. As a result, peer reviewers have
Medicine 2011 report) and not tainted by financial ties to the often hindered or even sabotaged scientific breakthroughs. The
pharmaceutical companies that could win or lose based on their flaws in the process reveal bias founded on intellectual positions,
content. Overall, there is need for better study design, execution, personal convictions, as well as biases related to ethnicity, nation-
reporting, and scientific critical appraisal skills by researchers ality, gender, and status. The results of the evaluation process
and health care decision making as well as the drug manufac- have produced occasionally foolish and frequently incorrect state-
turers responsible for sales and distribution. At the end of the ments, a lack of accountability enhanced by anonymity, as well as
day, medicine, like art, is a creative process, and very much a often personally insulting remarks.
team effort. Opinions will differ between reformers and die-hard defend-
Excellent health care practice should be inspired by love and ers of the current peer review system. However, if the scientific
guided by science; both are essential. If a professional practices community is to enhance its credibility, the peer review process
scientifically without compassion, he/she becomes a robot. On the must embrace a sounder and properly validated basis, that is,
other hand, if a practitioner is compassionate but unscientific, his oversight without imposition. It requires a priori that a potential
failure to adapt EBMP methods in light of the burgeoning data- reviewer recuse him/herself if he has a bias against the authors or
bases of relevant empirical findings might marginalize his medi- minimal knowledge on the subject. The referee’s role is to read
cal practice and relegate his patients to substandard professional a manuscript and “… look neither for something to criticize to
interventions. prove his diligence and capability as a referee nor overlook or
condone omissions or errors to prove his graciousness. He should
Researchers and Peer Review bear in mind that he is rendering a service to the editor, in the
Peer review is the main apparatus that research journals use to manner of an expert witness.”33
assess the quality of the many manuscripts competing for the few The quality and usefulness of a journal rests on the quality of
places available for publication. Journal editors solicit evaluations the research submitted, its reviewers’ evaluations, and the editor’s
of submitted manuscripts from outside experts who remain anon- critical judgment skills. To enhance the objectivity and quality of
ymous to the authors by the process. The results of a review can the process, the scientific community needs to make a concerted
consecrate or doom the progress of a particular course of research. effort to select reviewers who are knowledgeable, provide con-
Often the results of clinical trials influence whether they will actu- structive evaluation, and impede the natural biases inherent in the
ally be published. Most journals want to be the first to publish review system.
positive new results. Negative results may not always be reported Peter Doshi,34 recently of Johns Hopkins University, is on a
and are also less likely to be published in prestigious journals.32 mission to influence and encourage the world’s largest pharma-
The role of journals as gatekeepers for the scientific record ceutical firms to open their records to outsiders in an effort to
dates from the 17th century when the Royal Society’s (Great better understand the benefits and potential dangers of the drugs
Britain) council was instructed to review submissions to its that billions of people take every day. He is trying to gain access to
Philosophical Transactions. Despite over 300 years of use, the data from clinical trials and make them public. The current system
pursuit of excellence in research has not been accompanied by a is one in which the meager details of clinical trials are published
parallel pursuit in the evaluation of that excellence. Envisioned as in professional journals often by authors with financial affiliations
a way to ease reviewers’ inhibitions, the practice of using anon- to the companies whose drugs they are promoting. This is not only
ymous reviewers diminishes accountability. Journal editors and conflict of interest but also free commercial advertisement that
anonymous reviewers base decisions about manuscripts on ques- may also be misleading. The efforts of Dr. Doshi and other activ-
tionable criteria and standards from a largely secretive process. ists have encouraged GlaxoSmithKline Pharmaceuticals to pledge
Medical journals often do not include clear statements about their to share detailed data from all global clinical trials conducted
peer review process, while reviewers are rarely informed of their since 2000. If and when that data are eventually publicized, it
role description as reviewers. In addition, because of the massive would amount to more than 1000 clinical trials involving more
number of manuscripts in need of review, fellows in training and than 90 drugs.
any other convenient reader (knowledgeable or not in the specific Another related issue to drug research arises when major
field) are recruited to adjudicate a manuscript’s quality for poten- drug companies export their scientific development to emerg-
tial publication. ing markets such as China. Since 2006, 13 of the top 20 global

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 CHAPTER 2 / Evidence-Based Medical Practice 15

pharmaceutical firms have set up research and development centers know how to use them. However, at a time when we have more
in China because it is cheaper to do research there. Auditors found effective therapeutic tools than ever before, there are increasing
that researchers did not report the results of animal studies in a impediments to the implementation and delivery of those tools.
drug that was already being tested in humans. Animal studies can While millions have limited access to the essential care that is
identify safety risks and are among the main factors drug com- basic to everyday health and well-being, others lack the capacity to
panies use to decide whether to pursue human trials. In addition, pay for this level of care, even if it were available. We spend vastly
workers at the research centers had not properly monitored clin- more on health care than any other nation in the world, yet analysis
ical trials and paid hospitals and participating doctors and other of our health status places us at the middle to the bottom among
hospital personnel fees based on the number of people enrolled in developed countries. In addition, despite all of the emphasis to
a study. It is to the credit of Glaxo that it audited its own research advance our health care system, the medical community and physi-
facility. However, it also demonstrates what can happen when cians have yet to meaningfully step forward to lead improvements,
a drug company rapidly expands its clinical research programs or to advance medicine based on science rather than tradition
overseas without adequate quality controls.35 and anecdote. If we recognize the shortcomings of “…the worst
Managed care providers have historically played key roles in of times…” through thoughtful, informed, compassionate, and
influencing the behaviors of both practitioners and patients. They responsible leadership and participation, we can advance “…an
believe that EBMP is critical to the success of their plans’ clinical epoch of belief…” And “…a spring of hope…” by capitalizing on
performance but there is concern among many that the applica- the wonderful resources and potential of our health care system.
tion of evidence-based guidelines derived from systematic reviews The successful promotion of EBMP can have a profound
may in some cases increase costs. How plans can incorporate positive collective effect on health care if each of the partners
­evidence-based practice into medical management activities and the (researchers/academicians, health care practitioners, patients,
modification of these strategies is a current focus for managed care pharmaceutical companies, and managed care organizations)
providers. Incentives incorporated into systems that reward more advance the principle that scientifically proven evidence-based
efficient health care delivery, reduce waste, and lower costs could medicine is the standard of quality and appropriateness in health
someday resemble a system that celebrates the attributes of EBMP. care. Anecdotes, personal testimonials, and paid advertisements
Managed care appears to be evolving from its original structure and cannot define the gold standard. In this regard, health consum-
rationale in traditional medical practice approaches to utilization ers and their physicians need the highest level of information for
management to participation in an evidence-based culture. As more making health care decisions, that is, EBMP. “What we can do is
high-quality synthesis of information relevant to an organization maximize quality, minimize bias, manage uncertainty, and pro-
and delivery of care become available, greater familiarity with the vide adequate support for those who have the task of ensuring that
retrieval and evaluation of systematic reviews can help managers as our research moves forward, generating all kinds of evidence
use these sources effectively. If this trend continues, the system can for clinical practice and policy, we do not lose sight of human
adapt creative ways of rewarding practitioners, hospitals, and con- health and suffering.”8
sumer adherence to evidence-based, cost-effective performance.

THE FUTURE OF EVIDENCE-BASED MEDICAL

PRACTICE
It was the best of times; it was the worst of times,

It was the age of wisdom; it was the age of

foolishness,

It was the epoch of belief; it was the epoch of

incredulity,

It was the spring of hope; it was the winter of

despair…
—Charles Dickens

With apologies to Charles Dickens, his words suggest the circum-

stances we currently face in the provision of health care. When REFERENCES
historians of the future look back on the 21st century, we have no 1. Sackett DL, Strauss SE, Richardson WS, et al. Evidence-Based
doubt that they will be impressed by the tremendous progress that Medicine: How to Teach and Practice EBM. 2nd ed. Edinburgh,
has been made in science and medicine. A majority of our pop- Scotland, UK: Churchill Livingstone; 2000.
ulation has immediate access to effective health care services of 2. Last JM. A Dictionary of Epidemiology. 3rd ed. New York, NY:
all types provided by knowledgeable health care practitioners who Oxford University Press; 1995.

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 16 The Diabetes in Pregnancy Dilemma

3. Bennett RJ, Sackett DL, Haynes RB, et al. A controlled trial of 20. Caritas S, Sibai B, Hauth J, et al. Low-dose aspirin to prevent
teaching critical appraisal of the clinical literature to medical stu- preeclampsia in women at high risk. NIH/MFMU. N Engl J Med.
dents. JAMA. 1987;257:2451–2454. 1998;338(11):756–757.
4. Grimes DA. Epidemiologic research using administrative databases: 21. Lohr KN. Rating the strength of scientific evidence: relevance for qual-
garbage in, garbage out. Obstet Gynecol. 2010;116(5):1018–1019. ity improvement programs. Int J Qual Health Care. 2004;16:9–18.
5. Northam S, Knapp TR. The reliability and validity of birth certifi- 22. Petticrew M. Systematic reviews from astronomy to zoology:
cates. J Obstet Gynecol Neonatal Nurs. 2006;35:3–12. myths and misconceptions. BMJ. 2001;322:98–101.
6. Ault MR. Combating the garbage-in, gospel-out syndrome. Radiat 23. NHS Center for Reviews and Dissemination. Undertaking
Protect Manag. 2004;20:26–30. Systematic Reviews of Research on Effectiveness: CRD report.
7. Ross S. Composite outcomes in randomized clinical trials: argu- No. 4. York, UK: University of York; 1996.
ments for and against. Am J Obstet Gynecol. 2007;196:119. 24. Popay J, Rogers A, Williams G. Rationale and standards for the sys-
8. Goodman KW. Ethics and Evidence-Based Medicine. Cambridge, tematic review of qualitative literature in health services research.
UK: Cambridge University Press; 2003. Qual Health Res. 1998;8:341–351.
9. Cochrane Collaboration. http://www.cochrane.org. 25. Petticrew M, Song F, Wilson P, et al. Quality-assessed reviews of
10. The periodic health examination. Canadian Task Force health care interventions and the database of abstracts of reviews
on the Periodic Health Examination. Can Med Assoc J. of effectiveness (DARE). Int J Technol Assess Health Care.
1979;121:1193–1254. 1999;15:671–678.
11. U.S. Preventive Services Task Force. Guide to Clinical Preventive 26. Sutton A, Abrams K, Jones D, et al. Systematic reviews of trials and
Services. 2nd ed. Baltimore, MA: Williams and Wilkins; 1996:862. other studies. Health Tech Assess. 1998;2:1–276.
12. Chalmers I. Scientific inquiry and authoritarianism in perinatal care 27. Cook DJ, Greengold NL, Ellrodt AG, et al. The relation between
and education. Birth. 1983;10(3):151–166. systematic reviews and practice guidelines. Ann Int Med.
13. Guyatt G, Rennie D. Users’ Guide to the Medical Literature: A 1997;127(3):210–216.
Manual for Evidence-Based Clinical Practice. The Evidence- 28. Broclain D, Hill S, Oliver S, et al, eds. Cochrane Consumers &
Based Medicine Working Group JAMA & Archives. Chicago, IL: Communication Group. The Cochrane Library. Issue 3. Oxford,
American Medical Association Press; 2002. UK: Update Software; 2002.
14. Gray JAM. The origin of evidence-based practice. In: Edwards A, 29. Entwistle V, O’Donnell M. Evidence-based health care: what
Elwyn G, eds. Evidence-Informed Client Choice. New York, NY: roles for patients? In: Edwards A, Elwyn G, eds. Evidence-Based
Oxford University Press; 2001:19–33. Patient Choice: Inevitable or Impossible? New York, NY: Oxford
15. Gawande A. The bell curve. The New Yorker. December 6, 2004. University Press; 2001.
16. Sackett DL, Richardson WS, Rosenberg W, et al. Evidence-Based 30. Edwards A, Elwyn G, eds. Evidence-Based Patient Choice:
Medicine: How to Practice and Teach EBM. New York, NY: Inevitable or Impossible? New York, NY: Oxford University Press;
Churchill Livingstone; 1997. 2001.
17. Glass G. Primary, secondary, and meta-analysis of research. Educ 31. Wazana A. Physicians and the pharmaceutical industry: is a gift
Res. 1976;10:3–8. ever just a gift? JAMA. 2000;283:373–380.
18. Anjalakshi C, Balajo MS, Seshiah V. A prospective study comparing 32. Simes RJ. Publication bias: the case for an international registry of
insulin and glibenclamide in gestational diabetes mellitus in Asian clinical trials. J Clin Oncol. 1986;4:1529–1541.
Indian women. Diabetes Res Clin Pract. 2007;76(3):474–475. 33. Forscher BK. Rules for referees. Science. 1965;(150):319–321.
19. Schiff E, Peleg E, Goldenberg M, et al. The use of aspirin 34. Breaking the seal on drug research. New York Times. June 30, 2013.
to prevent pregnancy-induced hypertension. N Engl J Med. 35. Thomas K. Drug research in China falls under a cloud. New York
1989;321(6):351–356. Times. July 23, 2013.

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 Pharmacologic Considerations
Affecting Hypoglycemic Therapy
During Pregnancy
3
Maisa N. Feghali, MD
Menachem Miodovnik, MD
Jason G. Umans, MD, PhD

All things are poison, and nothing is without poison; only the dose
permits something not to be poisonous.
—Paracelsus

Key Points
• Drug therapeutics can be significantly altered due to gestational changes in drug metabolism, disposition,
pharmacokinetics, and pharmacodynamics.
• Placental drug transfer is difficult to assess and is influenced by the variable expression and activity of drug transporters.
• Oral hypoglycemic agents are subject to increased clearance during pregnancy, which calls for more aggressive dose
titration and may limit their ability to achieve glycemic goals.
• Insulin analogs are widely used in diabetic pregnancies in the absence of specific pharmacokinetic data.

INTRODUCTION Physiologic Changes Affecting Drug Pharmacokinetics in

Maternal physiology during pregnancy has evolved to favor devel- Pregnancy
opment and growth of the placenta and fetus.1 These adaptations Physiological adaptations to pregnancy, starting in the first trimes-
may affect preexisting disease or result in pregnancy-specific ter and gradually evolving through delivery and the puerperium,
disorders. Similarly, physiologic changes may alter the phar- alter the absorption, distribution, and clearance of most drugs
macokinetics (PKs) or pharmacodynamics that determine drug (Table 3-1).
dosing and effect. It follows that detailed pharmacologic infor-
mation is required to adjust treatment strategies during pregnancy. Absorption
Understanding both glucose metabolism and the gestation-specific Gastrointestinal transit time is prolonged due to delayed gastric
pharmacology of hypoglycemic agents are necessary to individu- emptying along with both small and large bowel hypomotility
alize therapy so as to achieve tight glycemic control and improve during the second and third trimester, normalizing postpartum.3
outcomes. Unfortunately, most drug studies have excluded preg- Decreased gastrointestinal motility might lead to higher oral bio-
nant women, based on often-mistaken concerns regarding fetal availability of slowly absorbed drugs and delayed peak plasma
risk. This “head in the sand” strategy does not, however, minimize concentrations of rapidly absorbed drugs. Meanwhile, increased
either the use or risk of medications during pregnancy. Rather, over cardiac output and intestinal blood flow may allow for increased
two thirds of women receive prescription drugs while pregnant drug absorption overall. Gastric acid production is also decreased
with treatment and dosing strategies based on data from healthy during pregnancy, whereas mucus secretion is increased, leading
male volunteers, and little adjustment for the complex physiology to an increase in gastric pH. Taken together, however, available
of pregnancy and its unique disease states.2 This chapter reviews data suggest that gastrointestinal changes have a minimal effect
altered pharmacology during pregnancy that impacts therapeutics, on the bioavailability and therapeutic effect of most oral drugs,
specifically highlighting applications to hypoglycemic drugs. especially with repeated dosing.

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 18 The Diabetes in Pregnancy Dilemma

TABLE 3-1 Pregnancy-Induced Changes Affecting Drug Therapeutics

System Parameter Nonpregnant Pregnant

Cardiovascular135 Cardiac output (L/min) 4.5 7.0

Plasma volume (L) 2.6 3.5
Extracellular fluid (L) 10–11 13–15
Total body water (L) 31.8 38.6
Liver32
Portal vein blood flow (L/min) 1.25 1.92
Hepatic artery blood flow (L/min) 0.57 1.06
Renal 30
Glomerular filtration rate (mL/min) 97 144

Distribution Elimination
Cardiovascular changes during pregnancy include an increase in Renal drug elimination of most drugs or their metabolites depends on
cardiac output starting in early pregnancy, plateauing by 16 weeks glomerular filtration and then on secretion or reabsorption by specific
of gestation ~7 L/min and remaining elevated until delivery.4 transporters expressed in renal tubular epithelial cells. Glomerular
Pregnancy is also marked by an ~42% increase in plasma volume, filtration rate (GFR) and effective renal plasma flow (RPF) both
to over 3.5 L at term, with parallel increases in total body water increase early in pregnancy, due to balanced afferent and efferent arte-
and in all body fluid compartments (see below).4 Increased preload riolar vasodilation which is mediated by a signaling cascade includ-
(due to increased blood volume and venous return), decreased ing relaxin and nitric oxide.10. By mid-gestation, GFR increases by
afterload (due to decreased systemic vascular resistance), and 40%–65%, and RPF by 50%–85%. Because the increment in RPF
an increase in maternal heart rate account for the rise in cardiac typically exceeds that in GFR, the filtration fraction (GFR/RPF) is
output. These changes, themselves, lead to increased organ spe- reduced during pregnancy.11 Creatinine production is unchanged in
cific blood flow and can facilitate drug absorption, distribution pregnancy but its clearance is increased due to increased filtration
and clearance. Increased local blood flow and vasodilation are and secretion; resulting in lower levels of serum creatinine. Despite a
thought to facilitate drug absorption following intramuscular or uniform increase in GFR during ­pregnancy, differences in renal tubu-
subcutaneous drug delivery, although specific drug data, whether lar transport (secretion or reabsorption) can result in differing effects
for insulin or other parenterally administered drugs, are lacking. on renally cleared drugs. For example, lithium clearance, which is
Maternal body fat expands by ~4 kg, increasing the volume almost exclusively via the kidneys, doubles during the third trimester
of distribution for lipophilic drugs. However, little information is compared to pre-pregnancy.12 Conversely, atenolol clearance, also
available to assess contributions by adipose tissue to altered drug predominantly renal, is only increased by 12% during pregnancy.13
disposition during pregnancy. Meanwhile, expanded extracellular Similarly, the clearance of digoxin (80% renal) is only increased by
volume and total body water likewise increase volume of distri- 21% during the third trimester when compared to postpartum.14 Such
bution for hydrophilic drugs, leading to lower concentrations and variations in drug clearances limit generalization about the effect of
increased clearances in the absence of offsetting adaptations. In pregnancy on renally eliminated drugs and point to important but
many cases, plasma protein binding of drugs decreases during understudied gestational changes in tubular transporters.
pregnancy due to reduced concentrations of both albumin and Drug transporters are widely expressed in all organs
alpha 1-acid glycoprotein.5–7 Decreased protein binding leads to (Table 3-2). For example, intestinal luminal transporters can
higher concentrations of unbound drug, favoring distribution out affect drug absorption from the GI tract, those in hepatic sinusoids
of the vascular space into tissues and, for some drugs, to sites ­determine drug uptake into hepatocytes where they may undergo
of hepatic metabolism. These changes can be clinically important biotransformation, transporters in biliary canaliculi govern secre-
in therapeutic monitoring of plasma drug concentrations, which tion into bile and t­ransporters on both the apical and basolateral
usually do not specifically measure the concentration of free surfaces of renal epithelial cells govern tubular secretion and reab-
(unbound) drug. For example, phenytoin and tacrolimus efficacy sorption. Together, their distribution, substrate specificity, and
and toxicity are related to unbound drug concentration in plasma. activities are important determinants governing drug absorption,
During pregnancy, both drugs exhibit an increased unbound frac- excretion and, in many cases, the extent of drug entry into target
tion due to lower albumin concentrations; a lower red blood cell organs. Knowledge of drug transporter expression and function
count amplifies this effect for tacrolimus.8,9 A clinical dose titra- is necessary for a complete understanding of drug distribution
tion strategy based on achieving whole blood concentrations in and effect. In addition, several placental drug transporters have
the therapeutic range can lead to increased free drug concentra- been identified, with potential effects on fetal drug exposure,
tions and possible toxicity. In pregnancy, a more rigorous, albeit including the family of multi-drug resistance associated protein
cumbersome, strategy would be to monitor free drug concentra- (MRP). Phosphoglycoprotein (P-gp) and breast cancer resistance
tions and adjust drug dosing to maintain the unbound fraction protein (BCRP) are the most studied so far. P-gp is expressed on
within its therapeutic range. the apical microvillous surface of syncytiotrophoblasts whereas

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 CHAPTER 3 / Pharmacologic Considerations Affecting Hypoglycemic Therapy During Pregnancy 19

TABLE 3-2 Major Drug Transporters, Their Locations, and Common Substrates

Transporter Organs/Cells Selected Substrates Selected Inhibitors

P-gp Intestinal enterocytes, kidney Glyburide, digoxin, loperamide, Verapamil, cyclosporine

proximal tubule, hepatocytes, brain ritonavir
endothelial cells, placenta
BCRP Intestinal enterocytes, hepatocytes, Glyburide, statins, porphyrins, Oestrone, 17 β-estradiol
kidney proximal tubule, brain methotrexate
endothelial cells, placenta, mammary
glands
MRP2 Hepatocytes, kidney proximal tubule, Glutathione and glucuronide Cyclosporine, efavirenz
enterocytes(luminal) conjugates, methotrexate
MRP3 Hepatocytes, kidney proximal tubule, Glyburide, Oestradiol 17 Delavirdine, efavirenz
enterocytes (basolateral) β-glucuronide, methotrexate,
glucuronate conjugates
MRP4 kidney proximal tubule, choroid Furosemide, adefovir, tenofovir, Celecoxib, diclofenac
plexus, hepatocytes, platelets methotrexate
MDR3 Hepatocytes Digoxin Verapamil, cyclosporine
OAT1 Kidney proximal tubule, placenta Acyclovir, zidovudine, lamivudine, Probenecid, novobiocin
adefovir, cidofovir
OAT3 Kidney proximal tubule, choroid NSAIDs, cefaclor, ceftizoxime, Probenecid, novobiocin
plexus, blood-brain barrier furosemide
OCT1 Hepatocytes, endothelial cells Metformin, N-methylpyridinium, Quinine, quinidine, disopyramide
pindolol, procainamide, ranitidine,
amantadine
OCT2 Kidney proximal tubules, peripheral Metformin, N-methylpyridinium Cimetidine, cetirizine, quinidine
neurons
OATP2B1 Hepatocytes, endothelial cells Glyburide, statins, fexofenadine Rifampicin, cyclosporine
MATE1 Kidney proximal tubule, liver, skeletal Metformin, N-methylpyridinium Cimetidine, quinidine, procainamide
muscle
MATE2-K Kidney proximal tubule Metformin, N-methylpyridinium Cimetidine, quinidine, pramipexole
PEPT1 Intestinal enterocytes, kidney Cephalexin, cefadroxil, valacyclovir, Glycyl-proline
proximal tubule enalapril, captopril
PEPT2 kidney proximal tubule, choroid Cephalexin, valacyclovir, enalapril, Zofenopril, fosinopril
plexus, lung captopril

Source: Adapted from International Transporter Consortium, et al.145

BCRP is mostly identified on the basolateral membrane and fetal expression. P-gp and BCRP expression were each lower in p­ lacentas
blood vessels.15–18 Efflux transporters on the apical membrane may from women with preeclampsia compared to term ­placentas from
protect the fetus by extruding harmful xenobiotics. Drug trans- uncomplicated pregnancies.29 It is unknown whether transporter
porters may have wide substrate specificity (Table 3-2). P-gp sub- expression and activity are altered further in diabetic pregnancy.
strates include endogenous cortisol, aldosterone, and bilirubin as Hepatic blood flow increases up to 160% during pregnancy,
well as drugs such as antibiotics, antiretrovirals, and steroids.19,20 due to increases in cardiac output and in portal venous return.30–32
Substrates of BCRP include glyburide, antibiotics, antiretrovirals, The effect of increased hepatic flow on drug disposition varies
calcium channel blockers, estrogen and prophyrins.19,21,22 These with the ability of the liver to transport drugs from the circulation
transporters have a number of overlapping substrates for which into hepatocytes. The extraction ratio (ER) refers to the proportion
they have differing affinities.23,24 of a drug taken up from the hepatic arterial circulation into hepat-
A limited number of studies have examined the gestational ocytes, making it available for subsequent elimination. For high
changes of placental drug transporters. Most studies suggest that ER drugs (e.g., morphine and propranolol), overall hepatic elim-
P-gp protein and its associated gene expression are elevated early ination is limited only by hepatic perfusion. By contrast, hepatic
in pregnancy and decrease near term.25,26 Investigations of BCRP clearance of low ER drugs (e.g., diazepam, fluoxetine, or caffeine)
expression have yielded conflicting results with advancing ges- is limited by intrinsic enzyme activity within hepatocytes and
tation.27,28 Pathophysiologic states may also alter transporter would be changed little by increased hepatic perfusion.

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 20 The Diabetes in Pregnancy Dilemma

Beyond hepatic uptake, the major changes in hepatic drug gestational age and maternal health status.45,46 Interestingly, most
clearance appear due to specific changes in the activity of drug placental CYP enzymes exhibit decreased expression and activity
metabolizing enzymes during pregnancy. Hepatic drug metabo- with advancing gestation47 so that studies in the term placenta may
lism includes phase I (oxidation, reduction, or hydrolysis) reactions overestimate fetal exposure to maternally administered drugs ear-
which introduce more polar or reactive moieties into drug molecules, lier in pregnancy. While information on placental CYP activity is
followed in many cases by phase II (conjugation) reactions to glu- limited, new evidence suggests an active role in the metabolism of
curonic acid, sulfate, or other moieties which favor excretion into drugs, for example glyburide. Overall, the placenta appears to play
urine or bile. Oxidative phase I reactions, are predominantly carried a minor role in determining maternal disposition of glyburide, but
out by the cytochrome P450 (CYP) family of enzymes that differ may play a significant role in controlling fetal exposure to the drug
in their genetics and substrate specificity. The activities of CYP3A4 and its metabolites, (see below).48
(50%–100%), CYP2A6 (54%), CYP2D6 (50%), and CYP2C9 Drug permeation across the endothelial-syncytial membrane
(20%) are all increased during pregnancy.33–37. Changes in CYP3A4 of the placenta can be influenced by numerous factors. Most drugs
activity increase the metabolism of drugs such as methadone, nifed- crossing the human placenta diffuse passively. As such, their transfer
ipine, indinavir, and glyburide (see below). By contrast, CYP1A2 is determined by placental blood flow, drug concentration gradient,
and CYP2C19 appear to undergo a gradual decrease in activity with maternal and fetal pH, physiochemical properties of the compound
advancing gestation,38–40 albeit with uncertain effects on drug therapy. (including charge and molecular weight) and the extent of protein
The activity of phase II enzymes, including Uridine 5’-Diphosphate binding.49,50 By comparison, facilitated diffusion, phagocytosis, and
Glucuronosyltransferases (UGTs), is also altered during pregnancy, pinocytosis are less significant routes of placental drug transfer.47
with a 200% increase in UGT1A4 activity during the first and second However several drug transporters have also been identified in the pla-
trimesters, and 300% increase during the third trimester.41 This centa. Their location on the syncytiotrophoblast dictates a preferen-
change leads to lower concentrations of UGT1A4 substrates such tial direction of transport.51 As such, apically located transporters are
as the anticonvulsant lamotrigine,42 leading directly to poorer seizure mostly involved in the efflux of substrates away from the fetal circula-
control with advancing gestation in the absence of appropriate dose tion whereas basally located transporters may facilitate drug transport
titration.42 The effects of pregnancy on enzyme activity can also vary into the fetal circulation. Interestingly, some transporters are located
with maternal genotype. A recent study on the PK of nifedipine, used at both the apical and the basal membrane of the trophoblasts, and
for tocolysis, noted differences in drug clearance due to genetic var- others exhibit bidirectional flow. P-glycoprotein (P-gp), MRP1 and
iability in a specific allele of the CYP3A5 gene.43 Table 3-3 sum- the BCRP are highly expressed in placental tissue.52 Located apically,
marizes the most relevant hepatic drug metabolism enzymes, their they appear to have a major role in the efflux of compounds from the
substrates and the effects of pregnancy on enzyme activity. fetal to the maternal circulation.53–55 Interestingly, most transporters
have numerous substrates and more than one transporter may transfer
a single compound. For example, glyburide efflux is mediated pri-
Determinants of Placental Transfer, Fetal, and marily by MRP1 (43%) and BCRP (25%), while metformin transport
Neonatal Drug Exposure is predominantly due to P-gp (58%) and BCRP (25%).56 When com-
Placental Transporters and Placental Drug Metabolism binations therapies are used, they may lead to possible interaction and
Maternal and fetal circulations are separated by a layer of tissues competition for efflux at the level of placental transporters.
composed of fetal endothelial cells and trophoblasts, the latter
including villus stroma, cytotrophoblasts and syncytiotrophoblasts.
With advancing gestation, the cytotrophoblast becomes discontinu- STUDY STRATEGIES FOR PLACENTAL
ous and the thickness of the syncytiotrophoblast layer decreases.44 DRUG TRANSFER
Perhaps surprisingly, several phase I and phase II drug metabolizing In light of the ethical concerns and potential for fetal risk, differ-
enzymes have been isolated from the placenta. The specific enzymes’ ent models have been developed to assess placental drug trans-
quantity and activity vary as a function of placental development, fer. The choriocarcinoma-derived BeWo cell line57 displays the

TABLE 3-3 Pregnancy-Induced Enzyme-Specific changes

Enzyme Pregnancy-Induced Change Potential Substrates in Obstetrics

CYP3A434,35,136,137 Increased Glyburide, nifedipine, methadone, indinavir

CYP2D6 136,138
Increased Metoprolol, dextromethorphan, paroxetine, duloxetine, fluoxetine, citalopram
CYP2C933,139 Increased Glyburide, NSAIDs, phenytoin, fluoxetine
CYP2C19 33,139
Decreased Glyburide, citalopram, diazepam, omeprazole, pantoprazole, propranolol
CYP1A238,39,136,140 Decreased Theophylline, clozapine, olanzapine, ondansetron, cyclobenzaprine
UGT1A4141–143 Increased Lamotrigine
UGT1A1 41
Increased Acetaminophen
NAT239,40,144 Decreased Caffeine

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 CHAPTER 3 / Pharmacologic Considerations Affecting Hypoglycemic Therapy During Pregnancy 21

morphological and biochemical characteristics of trophoblasts many over insulin in cases with mild hyperglycemia because of
and is widely used to study trophoblast differentiation, placen- quicker patient learning, lower risk for hypoglycemia and higher
tal metabolism, and substrate distribution across the trophoblast compliance.
membrane. BeWo cells can form a confluent polarized mon-
olayer in culture.58 Experimentally, the monolayer is integrated Glyburide
into a membrane separating two chambers. Both chambers can be Glyburide, a second-generation oral sulfonylurea, acts by
sampled for analysis allowing for assessment of transfer across enhancing the secretion of insulin from pancreatic β-cells.
the monolayer. While drug transporters have been identified in Extrapancreatic effects may include improved tissue glucose utili-
BeWo cells, their pattern differs from that in human placenta zation and reversal of early diabetic microangiopathy.66 Clinically,
syncytiotrophoblasts.59,60 it has been the preferred oral drug for the treatment of gestational
Animal models provide the advantage over cell culture sys- diabetes mellitus (GDM). Glyburide increases insulin secretion in
tems of a complete physiological system where placental transfer direct proportion to plasma glucose levels from 60 to 180 mg/dL,
can be assessed. However, large interspecies differences in pla- with lesser effect when glucose is less that 60 mg/dL,67 though
centation and pregnancy duration may impact the generalizability hypoglycemia remains a significant risk in the setting of overdose.
of any findings to humans.15 For these reasons, mechanisms of When given as a single agent, peak plasma glyburide concentra-
placental drug transport, metabolism, and fetal toxicity are most tions are achieved within four hours and absorption is unaffected
often assessed in models of human origin. Various experimen- by food. It is highly protein-bound (98%) and is extensively
tal approaches are available to assess placental drug transport in metabolized via multiple CYP enzymes then glucuronidated,
human ranging from umbilical cord sampling to explant tropho- facilitating subsequent renal and biliary excretion. Its elimina-
blastic tissue preparations and placental cotelydons. The methods, tion half-life is approximately 10 hours in nonpregnant adults and
reviewed below, demonstrate different aspects of placental drug shorter in pregnancy due to increased clearance. A recent PK68
transport. study of glyburide in 40 women with GDM receiving glyburide
Fetal blood sampling and estimation of placental transfer can monotherapy described 50% lower dose-adjusted plasma drug
be achieved by collection of umbilical cord and maternal blood at concentrations in pregnancy.69 The differences in glyburide PK
the time of delivery, providing a measure of fetal/maternal con- between pregnant and nonpregnant women were best explained
centration ratios which can be included in PK models along with by increased hepatic metabolism, given that unbound glyburide
results from repeated maternal sampling. This method is limited apparent oral clearance and formation clearance of its metabo-
to a single sample at delivery collected at a variable duration from lite were each increased in pregnant subjects. Increased glyburide
the last maternal dose. It also does not allow the assessment of clearance likely results from the induction of CYP2C9, CYP3A,
placental metabolism, or of drug distribution in fetal tissues. and/or CYP2C19, given that these are the enzymes involved in
Perfusion of a single human placental cotelydon is an ex glyburide metabolism in vitro70,71 and have been shown previously
vivo model that is used to investigate the rate and mechanism of to be induced in pregnancy.33,36,72
placental drug transfer.61 The placental perfusion model has been While insulin secretion following a mixed meal was normal-
used widely to evaluate placental transfer, metabolism, and the ized in the glyburide PK-PD study, this was inadequate to com-
presence of overall active transport. It overcomes the ethical con- pensate fully for insulin resistance69 in some women. It remains
cerns for fetal risks in the setting of drug exposure and allows for unclear, therefore, whether higher than usual glyburide doses,
human-specific conclusions. However, the model is sensitive to titrated to achieve the same concentrations as in nonpregnant dia-
the gestational age when delivery occurred and perhaps on mater- betic patients, would increase insulin secretion enough to achieve
nal disease. As such, the model provides no insight regarding pla- euglycemia. Indeed, there is a paucity of data, even in nonpreg-
cental transfer in the first trimester. Additionally, interindividual nant patients, as to whether glyburide has a “ceiling” effect or
variation may occur and there is no standard for the number of regarding the shape of its dose-response curve, with some studies
placentas that have to be perfused to validate each experimental suggesting little incremental benefit following increased doses.73,74
model. Even with these uncertainties, it is clear that glyburide dosing
Human trophoblast tissue preparations may also be used to should probably be more aggressive during pregnancy and should
study transport from the maternal circulation into the syncyti- not be restricted to the doses used in nonpregnant type 2 diabetic
otrophoblast as well as placental metabolism across gestation.62 patients. Further, given its short half-life in pregnancy, while it is
This model requires careful consideration of the potential contri- unclear whether glyburide should be dosed more frequently, it is
bution of mesenchymal and endothelial cells to the metabolic pro- obvious that (steady state) therapeutic responses can be assessed
cess.47 Membrane vesicles can be isolated from the apical or basal within two days following each increase in dose, allowing clini-
membrane of trophoblast allowing the study of transport mech- cians to achieve control (or change therapy) more rapidly than in
anisms.63,64 This model allows for characterization of individual usual current practice.
transporters, but does not reflect the in vivo setting. The availability of more sensitive drug assays has revealed
transplacental passage of glyburide, with fetal concentrations
Oral Hypoglycemic Clinical Pharmacology During in fetal cord plasma approximately 70% of those in maternal
Pregnancy plasma,69 albeit with most levels being quite low in the single
Oral agents are first line therapy for type 2 diabetes in nonpreg- samples obtained at the time of delivery. In accord with limited
nant patients.65 They are indicated during pregnancy when diet drug exposures late in pregnancy, there is no evidence of either
and exercise fail to achieve treatment goals and are favored by teratogenicity or fetal toxicity. Significantly, neonatal body

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 22 The Diabetes in Pregnancy Dilemma

composition, cord insulin levels, and rates of hypoglycemia did would result in improved glycemic control. Further, prolonged
not differ in offspring of diabetic gravidas treated with either gly- use reveals the slow accumulation of metformin in both liver and
buride or insulin.75 Multiple placental efflux transporters, predom- in red blood cells, making it difficult to determine the relevance, if
inantly MRP1 with lesser contributions by BCRP and P-gp, serve any, of lower drug levels in plasma.88 An additional consequence
to limit fetal exposure to maternally administered glyburide.56,76 In of this slow accumulation into its hepatic site of action is to limit
addition, the placenta contributes to glyburide metabolism, though the rapidity and confidence with which metformin dose can be
to a much lesser extent than the maternal liver. Placental CYPs titrated to quickly achieve glycemic control, since its effects will
have been shown to form all six known glyburide metabolites, lag far behind changes in its plasma concentration. Finally, there
two of which (M1 and M2b) possess hypoglycemic activity.77 are no data regarding the ER preparation in pregnancy, where
However, in the placenta, glyburide is predominantly transformed changes in GI motility might be expected to minimize any bene-
to M5 through the action of placental microsomal CYP19.48,77 The fits of this preparation.
formation of M5 in close proximity to the fetus could have clinical As might be expected for a small, hydrophilic molecule with
implications for fetal metabolite exposure. However, the pharma- low protein binding, metformin crosses the placenta, albeit with low
cologic and glycemic activities of M5 are yet to been determined. and variable fetal drug levels (maternal transfer rate 1­ 0%–16%).84
Following delivery, while data are limited, glyburide is However, metformin does not increase the risk of neonatal hypo-
undetectable in breast milk, so that calculated maximum infant glycemia if maternal glycemic control is achieved.84 In addition,
exposure would be less than 1.5% of the weight-adjusted maternal there have been no apparent long-term risks of using the drug in
dose.78 Blood glucose levels were normal in all three infants who early gestation. A study assessing 126 infants at age 18 months
were solely breast-fed in that study.78 born to 109 mothers who conceived and continued metformin
during pregnancy found similar size and motor-social development
Metformin in infants exposed to metformin compared to the non-exposed
A biguanide, metformin is considered to be an insulin sensitizer group.89 More recently, the Metformin in Gestational diabetes: The
that acts mainly to reduce hepatic glucose production by sup- Offspring Follow-Up study (MiG TOFU) compared outcomes fol-
pressing gluconeogenesis.79,80 It also enhances peripheral glucose lowing maternal treatment with metformin or insulin on the growth
uptake. Since it does not increase insulin secretion, the risk of and body composition of their offspring.90 Children exposed to
hypoglycemia is trivial. Oral bioavailability is approximately metformin had larger measures of subcutaneous fat, but overall
50%, dose-related, and decreased when metformin is adminis- similar total body fat percentage and mass compared to children
tered with meals. Peak metformin plasma concentrations in non- whose mothers received insulin.90 While maternal outcomes were
pregnant patients are achieved within three hours of oral adminis- similar with metformin and insulin in the original study, these find-
tration for immediate release (IR) tablets and within seven hours ings suggest the need for additional offspring follow-up to deter-
for the extended release (ER) formulation.81 The ER formulation mine the long-term consequences of maternal treatment.
expands to form a gelatinous mass; diffusion through this gel Three studies assessed transfer of metformin into breast milk;
effects sustained absorption and allows once daily dosing with they all suggested that metformin is excreted into breast milk at very
fewer gastrointestinal complaints than the IR formulation.81 low levels.91–93 The mean estimated infant dose as a percentage of
In nonpregnant patients, the protein binding of metformin the mother’s weight-adjusted dose was 0.18%–0.65%.91–93 In one
in plasma is negligible, and the drug does not undergo significant study, blood glucose concentration measured four hours after feed-
metabolism.82 It is excreted unchanged by the kidneys via glomeru- ing was within normal limits in all infants.93 Another study found no
lar filtration and tubular secretion, the latter mediated by basolateral differences in weight, height, or motor-social development at 3 and
organic cation transporters (OCT) and luminal (apical) multidrug 6 months of age between 61 nursing and 50 formula-fed infants
and toxin extrusion (MATE) transporters.83 Metformin’s elimina- who had all been born to mothers treated with metformin through-
tion half-life in nonpregnant adults is approximately five to eight out pregnancy for treatment of polycystic ovary syndrome.94
hours. Not surprisingly, its renal clearance is increased by approx-
imately 50% and 30% in mid and late pregnancy, respectively.84 Insulin and Insulin Analog Clinical Pharmacology During
Maximum drug concentrations were also significantly lower during Pregnancy
pregnancy compared to postpartum.84 Pregnancy-induced changes Exogenous insulin therapy attempts to mimic the profile of ­insulin
in renal clearance can be attributed to increased glomerular filtra- in response to diet and metabolic demands in order to maintain
tion or tubular secretion. In the pregnancy PK study, metformin euglycemia. In the absence of infusion pump therapy, treatment
oral clearance correlated better with net tubular secretion clearance usually depends on the use of separate insulin analogs to mimic
than with creatinine clearance.84 This is likely related to the high the basal secretion by the pancreas and the rapid β-cell response
secretory clearance of metformin by OCT, primarily OCT2.85,86 to meals. In healthy non-obese adults, endogenous insulin is
Enhanced net tubular secretion has been previously reported for secreted at a basal rate of 0.5–1 units per hour, resulting in plasma
digoxin33 and amoxicillin87 during pregnancy, but these mecha- concentrations of 5–15 μU/mL in the fasting state.95 Within
nisms remain understudied in pregnancy. Interestingly, cimetidine 30–60 ­minutes of a meal, insulin levels increase rapidly to a peak
is also both a substrate and inhibitor of OCT2, suggesting the pos- of 60–80 μU/mL, then return to baseline approximately two-four
sibility of drug-drug interactions with metformin in pregnancy. hours later. The first phase of insulin secretion begins within two
Despite its widespread use, metformin’s c­ oncentration-effect minutes of nutrient ingestion and lasts for 10–15 minutes. The
relationship has not been determined, making it unclear whether second phase of prandial insulin secretion follows and is sustained
dose increases to account for increased clearance during pregnancy until normoglycemia is restored.

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 CHAPTER 3 / Pharmacologic Considerations Affecting Hypoglycemic Therapy During Pregnancy 23

This section will review the different insulin formulations, modifications in the end of the insulin β-chain, which serve to
their pharmacologic properties and discuss placental transfer. destabilize insulin hexamers.101,102 Following injection, rapid dis-
Efficacy and safety of different insulin preparations are beyond sociation to monomers and dimers allows more rapid absorption
the scope of this chapter and are addressed elsewhere. compared to human insulin.101–104 PK studies performed in adults
with type 1 diabetes reveal that peak plasma concentrations of
Long-Acting Insulin Analogs rapid-acting analogs are approximately double that of human
In patients receiving insulin injections, the role normally played insulin and that the time needed to achieve peak concentrations
by sustained pulsatile pancreatic secretion is replaced (imper- is less than half that for human insulin.101,103,105 As expected, once
fectly) by prolonged release of insulin from the depot site. past the peak, rapid-acting analog concentration falls more rapidly
Neutral Protamine Hagedorn (NPH) insulin is a suspension compared to human insulin, reaching less that 20% of peak levels
of protamine and insulin in which low concentrations of zinc 4 hours after administration.101,103,105 Overall, the total availability
allow the protamine component to form crystals with insulin. of all three rapid-acting analogs are comparable to that of human
The breakdown of protamine and/or dissipation of zinc following insulin, because the absorption and subsequent elimination of
subcutaneous injection destabilize insulin hexamers and results human insulin takes place over a longer period of time.101,103,105
in the slow release of dimers and monomers into the circulation. These findings lead to a longer total subcutaneous and whole-
Monomeric and dimeric insulin are each biologically active. The body residence time of human insulin compared to rapid-acting
slow release of NPH from its subcutaneous depot and the dissoci- analogs. Trials comparing aspart and lispro analogs reveal few
ation of hexamers determine the PK and PD profiles of this prepa- differences in blood glucose profiles, and the time of maximal
ration. NPH has an onset of action one to two hours following an reduction of plasma glucose (40–60 mins).106–109 Studies on glu-
injection, an intermediate duration of action (14 ± 3 hours) and lisine suggest a more rapid onset of action, especially in obese
a peak approximately four hours after injection.96 In a represent- patients.110,111 This may be due to an effect of the site of injection.
ative glucose-clamp study, significant interindividual variability Injections in the abdominal area produce the highest plasma insu-
was noted,96 likely due to inadequate suspension prior to injec- lin concentrations at the earliest time compared with injections in
tion.97 NPH is commonly administered twice daily. the arm, thighs, and buttocks; but without significantly altering
Insulin glargine is formed by replacing asparagine with gly- overall glycemic control.104,112 Overall, the rapid short-acting insu-
cine in the α-chain and lengthening the β-chain by adding two lin formulations are comparable and they are usually administered
arginines at the C terminus. These changes shift the isoelectric 5–15 minutes before a meal.
point from that of human insulin to a more neutral pH. Following
injection, the solution forms microprecipitates that must dissolve Insulin Clearance
before absorption can take place. Enzymatic removal of the two Despite the widespread use of insulin for glycemic control in
arginine amino acids, either at the injection site or in the circula- pregnancies complicated by diabetes, PK data for different ana-
tion, liberates metabolically active insulin. By comparison, insu- logs are limited and most dosing strategies are based on studies in
lin detemir’s formulation includes the addition of a fatty acid side nonpregnant adults. Insulin PK studies are also hampered by the
chain, which results in hexamer stabilization and hexamer-hex- limited availability of methods to measure and compare absolute
amer interaction. Slow breakdown of hexamers leads to meta- serum concentrations of different preparations.113,114
bolically active products. Detemir is also highly protein bound Insulin degradation is complex and incompletely understood.
(98.8%) in the interstitial tissues and plasma, which may contrib- First, it is necessary to distinguish between endogenous insulin,
ute to its prolonged duration of action.98 Detemir absorption is which is cleared following secretion into the portal circulation and
uniform, since it does not require re-suspension and does not form exogenous insulin, which is absorbed into the systemic circulation
microprecipitates. Long-acting insulin analogs have an onset of following subcutaneous injection.
action 90 minutes following injection, and a duration of action The liver is the primary site of endogenous insulin clear-
of 16–24 hours.96,99 Their time-action profile is longer and flatter ance.115,116 Approximately half of portal insulin is removed during
compared to NPH, allowing for once daily dosing. its first-pass across the liver. Hepatic uptake and degradation of
insulin is a receptor-mediated and nutrient-sensitive process.117
Short-Acting Insulin Analogs In general, glucose ingestion increases hepatic insulin uptake,
Short-acting formulations of insulin are meant to replace the post- presumably due to signals from the gut, since intraportal glucose
prandial insulin response. For this reason, they are usually admin- infusion does not have this effect. Several studies have suggested
istered close to meal intake. that the increase in circulating insulin in obesity and type 2 diabe-
The classic short-acting insulin is regular insulin. In solution, tes is due, at least in part, to a reduced hepatic clearance, although
it exists as an equilibrium mixture of monomers, dimers, tetram- not all studies agree.118,119 Others have suggested a correlation
ers, and zinc-containing hexamers.100 However, in pharmaceutical between hepatic insulin removal and hepatic insulin effects.120,121
preparations, the hexamers predominate. The large molecular size Since insulin administered by subcutaneous injection escapes
the hexamers is thought to delay absorption following subcutane- first-pass removal by the liver, the kidney has a more prominent
ous injection and the need for hexamer dissociation further delays role in this setting.122 Insulin clearance by the kidney occurs by
drug action,100 resulting in an onset of action at 30–60 minutes and two mechanisms: glomerular filtration and proximal tubular reab-
a duration of action of~3–4 hours. sorption and degradation.122 After entering the tubule lumen, more
Rapid-acting analogs include insulin lispro, insulin aspart, than 99% of the filtered insulin is reabsorbed by proximal tubule
and insulin glulisine. Their molecular structures include minor cells, primarily by endocytosis.46 Relatively small amounts of

CH03.indd 23 09/01/15 6:15 PM

 24 The Diabetes in Pregnancy Dilemma

intact insulin are excreted in urine. The kidney also clears insulin 2. Bonati M, Bortolus R, Marchetti F, et al. Drug use in pregnancy: an
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CONCLUSION Drug Deliv Rev. 1999;38(1):3–15.
Gestational changes in all of the processes regulating drug distribu- 16. Nagashige M, Ushigome F, Koyabu N, et al. Basal membrane
tion and elimination can lead to dramatic changes in pharmacokinet- localization of MRP1 in human placental trophoblast. Placenta.
ics and pharmacodynamics, requiring dosing strategies that differ 2003;24(10):951–958. doi: S014340040300170X.
from those in nonpregnant patients. Our understanding of the PK 17. Mylona P, Hoyland JA, Sibley CP. Sites of mRNA expression of the
cystic fibrosis (CF) and multidrug resistance (MDR1) genes in the
and PD of hypoglycemic drugs in diabetic pregnancy remain lim-
human placenta of early pregnancy: no evidence for complemen-
ited. The complexities of drug metabolism, distribution, and elim-
tary expression. Placenta. 1999;20(5–6):493–496. doi: 10.1053/
ination, including variations in enzymatic activity and transporter
plac.1999.0400.
expression, should be subjects of future research. Both glyburide
18. Meyer Zu Schwabedissen HE, Grube M, Heydrich B, et al.
and metformin clearances are increased during pregnancy, lead- Expression, localization, and function of MRP5 (ABCC5), a trans-
ing to lower plasma levels and perhaps limiting their hypoglyce- porter for cyclic nucleotides, in human placenta and cultured human
mic effects. Even with our limited current knowledge, it should no trophoblasts: effects of gestational age and cellular differentiation. Am
longer be acceptable to extrapolate pharmacological data from men J Pathol. 2005;166(1):39–48. doi: 10.1016/S0002-9440(10)62230-4.
and nonpregnant women when treating pregnant women. 19. Raggers RJ, van Helvoort A, Evers R, van Meer G. The human mul-
tidrug resistance protein MRP1 translocates sphingolipid analogs
across the plasma membrane. J Cell Sci. 1999;112 (pt 3):415–422.
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“Oh, if you will be so kind—as fast as you can go,” said Mary.
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a fright. It seems to have paralysed her whole being. I hope everything from
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want to try the shock of your appearance.”
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she recognised her mother—and it was evident that she had done so. But he
himself stood aloof, keeping his troubled looks out of their sight. And after
Mrs. Asquith had sat by her daughter’s side for hours, telling her everything
as if Hetty fully understood, saying a hundred things to her—news of home,
caresses, tendernesses without end—it presently became evident to all that
very little real advance had been made. Hetty said, “Mamma!” as she had
said, “Thank you,” but she did no more.
 CHAPTER XXII.

MARY’S INVESTIGATIONS.

M RS. ASQUITH kept to all appearance perfectly tranquil during the rest
of that evening. It was a strange and affecting sight to see her by the
side of Hetty’s chair, talking with a smiling countenance and every
appearance of ease and an unburdened heart. She kept telling all the nursery
stories, all the little family jokes, every kind of trifling happy circumstance,
the commonplaces of the family, to her daughter’s dulled and heavy ear. The
spectators could not understand this strange sight. They were anxious, but
she seemed free from care. They contemplated that little marble image of
poor little Hetty with piteous eyes, shaking their heads aside, and saying to
each other that, after all, the appearance of her mother had not done what
was hoped. But the mother sat and smiled and talked as if she had been
altogether unconscious that Hetty was not as she had been. Miss Hofland,
though she could not understand, though she could not approve, this strange
mode of action, got interested in spite of herself in all those unknown
children, and found herself softly laughing in the background at the tricks of
the boys, and Janey’s matronly demeanour, and the sweet little sayings of the
baby. It all looked so pretty, and tender, and sweet. But how that woman
could talk, and talk, and smile, and tell those stories with poor Hetty
blanched and unresponsive like marble, wax—anything that you can think of
which is most unlike flesh and blood, was what Miss Hofland could not
understand. She felt very angry. She said to herself, “That woman has so
many, she has no heart for this one;” and felt as if she loved poor Hetty
better than her mother did, who showed so little feeling. Rhoda, who had
stolen in when no one was looking, was, on the contrary, fascinated by Mrs.
Asquith. She crept closer and closer, and at last curled herself up on the skirt
of the stranger’s gown like a little dog, and listened, and laughed, and
clapped her hands at all those stories. “Oh, tell me a little more about little
Mary! Oh! what did baby say?” Rhoda cried, pushing closer and closer. Mrs.
Asquith put one arm round the child, though without looking at her. She
could think even of that strange child, who had been the cause of it all, with
Hetty lying motionless there!
But all this had no effect upon Hetty, the lookers-on thought. An
occasional faint smile came to the corners of her mouth, something so faint,
so evanescent, that it could scarcely be called a smile; a faint little colour,
almost imperceptible, came upon her marble paleness; now and then she
said, “Mamma!” quite inconsequently, not as an answer to anything, and the
tiny hands that had been folded in her lap were folded now in one of her
mother’s hands, which seemed to communicate a little warmth, a little life—
a poor result to have effected by the heroic measure of sending for her, and
admitting a stranger, against every rule, to this secluded house. The
housekeeper was very impatient of the whole business. “You did it against
everything I could say; and nothing has come of it,” she said.
“As for that, we can’t tell yet,” said the doctor, naturally taking his own
part; but he was very anxious, and did not seem to have taken much comfort
from the new arrival. He had gone into the library to talk it over with his
coadjutor, while Hetty was being conveyed to bed. The house was very
quiet, the room badly lighted, the lamp on the table bringing out the anxious
expression on the young man’s troubled face, and half showing the figure of
the housekeeper, who stood on the other side of the table. The light fell upon
her hands clasped in front, and showed her person vaguely, but her face was
in the shade.
“The right thing to do would have been to send the girl off to that man
who treats hysteria,” she said; “he would soon have brought her to her
senses. What good can the mother do?—a silly woman telling all that
nonsense that the girl can’t hear, and would not care for if she did! Rhoda
likes it, to be sure,” she said, with a short laugh; “and perhaps she thinks that
to make an impression upon Rhoda, who will be an heiress, is always worth
her while.”
“It is no part of your business, or mine either, to judge Mrs. Asquith,”
young Darrell said impatiently; but there could be little doubt that he was
disappointed too. The effect of the mother’s first appearance had not been
what he hoped.
“And here we’ve brought in, against all our promises, just the last person
in the world that ought to be admitted into this house.”
“I made no promises,” said the young doctor hurriedly. “How could I on
this subject? No one could have foreseen such a combination of
circumstances—a near relation when we expected a stranger.”
“Only a cousin,” the housekeeper said quickly; “but now the thing is to
get rid of her as soon as possible, and in the meantime to keep her
completely in the—— Good gracious! I beg your pardon, ma’am,” cried
Mrs. Mills, quickly stepping out of the way.
“I knocked, but you did not hear me,” said Mary. “You forget that I know
my way about this house.” She passed the housekeeper by, and came up to
where Darrell was sitting, and drew a chair to the table near him. “I have got
my poor child to bed. She looks as if she had fallen asleep; whether it is
sleep or stupor I can’t tell, but she is very quiet. Now will you tell me how it
happened?” Mary said. Her voice was very quiet, but very serious—not the
voice of one who was to be trifled with. Instinctively both the listeners
perceived this. Darrell cast an anxious, almost imploring glance into the
surrounding dimness of the half-lighted room, and the housekeeper stirred
from one foot to the other with an involuntary motion. She had not thought
much of Mrs. Asquith as an antagonist, but now she began to change her
mind.
“How it happened?” said the young doctor, faltering. “I am afraid it was a
fright. She got a—fright.”
“We cannot tell exactly how it happened,” said the housekeeper quickly,
“for it happened in the middle of the night.”
“But you must have some sort of understanding. A thing like that can’t
happen in a house without some one knowing. How was it? even if you can’t
tell me what it was.”
 “It all arose from this, ma’am,” said the housekeeper, “that Miss Asquith
would have her window open at night. Some people I know have fads on
that subject; if I asked her once, I asked her a dozen times not to do it, but
she would. She would not be guided by me.”
“She left her window open all night? Well, and what happened?” Mary
said.
Mr. Darrell cleared his throat. A kind of loathing of the glib woman, who
was so ready to answer for him, quickened his speech. “So far as we can tell,
something came into her room and frightened her,” he said.
“Something? Oh! this is trifling,” cried Mary impatiently. “Many, many a
night have I slept in this house with my window open. The windows were
always open. What is there about, to come in at an open window in the
middle of the night?”
The two culprits exchanged a glance across the table. The housekeeper
could see the doctor’s pale face full of revelations, but he could not see hers.
“That’s what we don’t know,” she said. “Miss Hofland will tell you that she
warned her just as I did. Supposing it was something quite innocent—as
harmless as you please—one of the sheep in the park, or a cow! A cow’s an
innocent thing, but it would give you a terrible fright in the middle of the
night; or even a rabbit or a squirrel,” continued Mrs. Mills, getting
confidence as she went on; “it was one of the animals about the place, for
anything we know.”
“What do you know? will you tell me exactly? What roused you first?
and when you went to her what did you see?”
The housekeeper shivered a little. “We found her lying on her bed, poor
dear! with her eyes staring, the bedclothes clenched in her hands as if she
had tried to cover her face. Oh, Mrs. Asquith! I thought the child was dead.”
She stopped with a half sob. “And the half of the French window wide open
—it’s not a sash window in that room—standing wide open, showing how it
had come in.”
“How what had come in?” said Mary huskily, scarcely able to command
her voice.
“How can I tell? Some wild creature out of the woods—some of the
animals that had got loose about the farm.”
“Was there any trace of an animal? There must have been some trace!”
 “Or it might,” said the housekeeper with a sob, the strong excitement of
the moment gaining upon her, “have been a tramp that had hidden about the
place.”
Mary pushed her chair from the table, and covered her face with her
hands. But it was only for a moment. She came back to herself, and to the
examination of these unwilling witnesses, before they could draw breath, but
not before a low indignant outcry, “No, no!” had burst from the young
doctor’s lips. She turned upon him with the speed of lightning. “Mr.
Darrell!” she cried, “was it a tramp that got into my child’s room in the
middle of the night? Speak the truth before God!”
What did she suspect or fear? The question flashed through his mind with
a shock of strange sensation. “No,” he said, looking at her, “it was no
tramp.”
“And you know who it was?”
She rose up and confronted him with her pale, set face, holding him with
her eyes, which were like Hetty’s eyes, in the strain of the horrible gaze that
had settled in them that night. He was helpless in her hands like a child.
“Yes,” he said, “I know.”
She could not speak, but she made him an imperative gesture to go on.
He was no longer the unwilling witness, he was the conscious criminal at the
bar.
“Mrs. Asquith,” he said, with a shiver of nervous emotion, “it needs a
long explanation. I would have to tell you many things to make you
understand.”
“Many things which you have no right to tell any one, Mr. Darrell,” the
housekeeper said.
Mary once more insisted with an imperious wave of her hand. The young
man made a nervous pause. “I have an—invalid gentleman under my
charge,” he said.
“Mr. Darrell!” cried the housekeeper again, “do you remember all you’ve
promised? You’ve no right to go against them that support you, them that
pay you.”
“What is that to me?” cried Mary quickly. “What do I want with your
secrets? Tell me about my child!”
“I will tell you everything,” he said. “It has been against my conscience
always. I’ll have this burden no longer. He wanders about at night, we can’t
help it, he slips from our hands. And I suppose he saw the open window. I—I
was too late to keep him back. I found him there. He thought she was his
child, whom he thinks he has lost. When I heard her scream I knew how it
was, and I got him away.”
“Is this the truth?” Mrs Asquith said; “is this all the truth?”
“It is everything,” cried the young man; “there is nothing more to tell
you, but there is more for me to do. I give up this charge, Mrs. Mills. I will
do it no more, it is against my conscience. If he only knew a little better he
could bring us both up for conspiracy. I will clear my conscience of it this
very day.”
“If you are such a fool!” the housekeeper said in her excitement. She
went round to him and caught him by the arm, and led him aside, talking
eagerly. “She’ll pay no attention. What does she care for anything but her
girl?” the woman said.
Mary had seated herself again suddenly, her brain swimming, her heart
beating. Thank God! she said to herself. She did not know what she had
feared, but something more dreadful, worse than this; her relief was greater
than words could say. She sat down to recover herself. What the housekeeper
said was true. She cared for nothing but her girl. What were their secrets to
her? If somebody was wronged Mary did not feel that it was her business to
set it right. It was her child or whom, and of whom alone, she was thinking;
and in all probability no further thoughts of the mysterious invalid would
have crossed her mind, but for this incident which now occurred, and which
for the moment was nothing but an annoyance to her, detaining her from
Hetty. There was a knock at the door, to which the others in their
preoccupation paid no attention. After a second knock the door was softly
opened, and one of the women servants came in, a tidy person, in the dark
gown and white cap and apron, which is a respectable maid-servant’s livery.
She hesitated for a moment, and then said, “Oh, please, is Mrs. Asquith
here?”
“Yes, I am here,” cried Mary, quickly getting up, with the idea that she
was being called to Hetty. The woman came in, hurried forward, and made
curtsey after curtsey—a little sniff of suppressed crying attending each
—“Oh, ma’am, don’t you know me? Oh, ma’am, I’ve never forgotten you!
Oh, please, I am Bessie Brown,” she said.
 “Are you indeed Bessie Brown? I am very glad to see you,” said Mrs.
Asquith. “And are you here in service? And how is it I never heard about
you from my Hetty? You were the first nurse she ever had.”
“Oh, ma’am, is that our baby? and me never to know! I never heard her
name right. I never knew. Oh, to think that poor young lady is our baby! And
the dreadful, dreadful fright she got! But oh! ma’am, perhaps now you’ve
come it is all for the best.”
“How can it be for the best that my child should be so ill?” said Mary.
“Oh, she is so ill! To see her is enough to break one’s heart.”
And in the softness of this sympathy, the first touch of the old naturalness
and familiarity which she had yet felt, Mary too began to cry in the fulness
of her heart.
“The house is dreadful changed, ma’am, and everything going wrong, I
think, though it mayn’t be a servant’s place to speak.”
“I am afraid,” Mrs. Asquith said, “I am selfish. I think too much of my
own. I can’t enter into the troubles of the new family. It’s only of the old I
can think when I am here.”
“But oh! it’s no new family, ma’am; it’s the same family, it’s your own,
own family,” cried Bessie Brown. “If you’re married ever so, you can’t give
your natural relations up.”
“My natural relations!” Mary cried.
But the conversation by this time had caught the watchful ear of the
housekeeper, who left Darrell and came back to see what was going on here.
“Brown,” she said, “what are you doing in this room? who told you to
come and talk to a lady who is paying a visit in the house? I hope, Mrs.
Asquith, you’ll excuse her. There is no rudeness meant,” the housekeeper
said.
“My natural relations,” Mary repeated. “I don’t know what you mean.
The house has passed into other hands. I don’t suppose there are any of my
relations here.”
“Brown, you had better go to your work. I’ll answer the lady’s questions.
We did not know till the other day that there was any relationship.”
“But,” said Mary bewildered, “it is Mrs. Rotherham——”
“Mrs. Prescott-Rotherham. My lady was an heiress. She married Mr.
Prescott——”
 The discovery was too bewildering and strange to convey itself distinctly
to Mary’s troubled brain. She said only something which she felt to be
entirely irrelevant.
“Who, then, is the invalid gentleman?” she cried.
 CHAPTER XXIII.

THE SICK-ROOM.

M RS. ASQUITH took her place in Hetty’s room to keep watch there,
with indescribable anxiety and alarm. She had been warned that every
night since that mysterious occurrence Hetty had seemed to go over
again in her dreams the midnight visit which had jarred her being. It had
been the effort of her nurses to soothe and silence her, to get her, if possible,
to forget; but every night the dreadful recollection had come back. Mary sat
down to watch, feeling that this moment of return upon the cause of all the
trouble might be the moment of recovery, if she but knew how to use it
aright. But that was the question, of far more importance for the moment
than those other wonders and anxieties which had arisen in her mind, and
which she had not been able to satisfy. How was she to act that this moment
might be the critical one, that she might be able to penetrate within the mist
that enveloped Hetty? She tried to think, tried to form for herself a plan of
action, but with trembling and doubt. The child’s life, the child’s reason,
might depend upon her own presence of mind, her power to touch the right
chord, her wisdom. Mary had never taken credit to herself for wisdom. She
had never had to face the intricate problems of human consciousness; how to
minister to a mind diseased had never been among her many duties. Out of
all the simple calls of her practical life, out of her nursery, where everything
was so innocent, how was she to reach at once to the height of such a crisis
as this? She tried to apply all her unused faculties to it; but they eluded her,
and ran into frightened anticipations, endeavours to realise what was about
to happen. She had no confidence that she would keep her self-possession, or
have her wits about her when the moment come. Oh, if Harry had but been
here! But then she remembered all he had to do, and was glad to think that
he would be quietly asleep and unconscious of what was going on; and that
after all, the fatigue, and the disquietude and dreadful fear that she would not
be equal to the necessities of the occasion, would be endured by herself
alone. He had plenty to trouble him, she reflected. He would be wretched
enough in his anxiety, without wishing him to share this vigil. And then
Mary appealed silently to the only One Who is never absent in trouble,
imploring Him to stand by her; and felt a little relief in that, and in the
softening tears that came with her prayer.
The room was very still, and so was the house, all wrapt in sleep and
silence. The housekeeper and Miss Hofland had both offered to sit up, but
she had rejected all companionship. She could not have borne the presence
of a stranger, or the possibility of any third person coming between her and
her child. A nightlight burned faintly in a corner; the light of the fire diffused
a soft glow. All was warm and still and breathless in the deep quiet of the
night. And as the hours passed on so still, bringing no change with them,
Mary’s thoughts wandered to the past, into which she seemed to have come
back when she entered this house. Her youth seemed to come back: the
familiar figures which she had not seen for years surrounded her once more.
Hetty slept, or seemed to sleep, not moving in her bed; and in Mary’s
thoughts the familiar room took back its old appearance. This was where the
mother of the house had sat with her basket of coloured worsteds and her
endless work, which was never done. And there the girls had their little
establishments: Anna with her music, Sophie with her little drawings.
Neither the drawings nor the music had been of high quality, but Mary’s
anxious heart went away to them in the midst of this vigil, and got a
moment’s refreshment and affectionate soft consolation out of their faded
memory. She had not been of much account in those days, but they had all
been good to her. And now they were both at the other end of the world,
knowing nothing of Mary, as Mary knew nothing of them. And Percy, where
was he, the handsome, careless fellow? And John, poor John? Ah! that struck
a different chord in her musings. Where was he, if this house was still his?
and who was the wife that had made him rich, and then left him, and left her
child in this mysterious way? Where was John? Was it true that he had lost
his wits (he had so few, dear fellow, at the best of times!), and was shut up
somewhere in a madhouse, as had been said? Shut up in a madhouse, he who
never would have hurt a fly, shut up—shut up!
Mary’s thoughts had run away with her, had made her forget for a
moment what was her chief object, her only object. The start she gave, when
a new and alarming idea thus came into her mind, brought her back to
herself. She had drifted towards that wondering suspicion, that undefined
alarm on the evening before, after Bessie’s revelation, and Mrs. Mills’
evident desire to stave off all further questions. Who was the invalid
gentleman? she had asked with an awakening of curiosity, of interest, and
wonder. But the housekeeper and the doctor had been called most
opportunely away, and she had got no answer to a question. She started
when it came back thus in sudden overwhelming force. But the very
keenness of the question, which felt almost like a discovery, brought her
back to herself with a guilty sensation, as if she had forgotten Hetty in thus
following out another train of thought. And what was all the world in
comparison with Hetty, whose well-being now hung in the balance, and
whom perhaps her mother, dreaming and thinking of others, might miss the
moment to save? She recovered herself in an instant, and brought herself
back with all her mind concentrated upon her child. Hetty lay still as in
depths of sleep; but from time to time her eyes were opened, though only to
close again, and the sight of those open eyes chilled the mother through and
through, and drove everything else out of her mind. It was now the most
ghostly depth of night, the darkest and the coldest, when morning seems to
begin to wake with a chill and shiver. Hetty’s eyes had closed again, and
Mrs. Asquith had resumed her seat to watch, with a nervous anticipation of
the crisis—when presently the bed shook with the nervous shuddering of the
little form that lay on it; and starting up, she found Hetty with her eyes wide
open, an agonised look upon her face, and her hands clutching the
bedclothes, as had been described to her. The mother’s dress brushing the
bed as she rose hastily, seemed to increase the dreamer’s horror. She began
to move from side to side, moaning as in a nightmare, struggling to rise. And
then a babble of broken words came to her lips. What was she saying? Mrs.
Asquith listened with keen anguish, her faculties sharpened to their utmost
strain. Was it some explanation, some complaint, that Hetty was trying to
utter, something that would make this mystery clear? Her mother made out
that it was the same thing over and over, now more now less clear. Her ears
made out the words at last by dint of repetition—Heaven knows, the most
innocent words!—“My child, my little darling! my child, my little darling!
have I found you at last?”
When this had gone on for some time, Mary in her excitement could bear
it no longer. She raised her child suddenly in her arms, clasping her close,
taking possession of her in a transport of love and pity. “Hetty!” she cried,
“Hetty!” almost with a shriek. “What is it? what is it? Tell me what it is!”
The girl uttered another cry, a wild and piercing shriek, as shrill as that
which on the former occasion had roused the house. She started up in her
bed, struggling, pushing Mrs. Asquith’s arms away, looking wildly round her
with the frantic gaze of terror. Then all at once the contrast seemed to reach
her stunned soul—not darkness and the awful visitant who had driven her
out of herself, but light and that beloved face which poor Hetty thought she
had not seen for years. She gave another cry of recognition, “Mother!” and
flung herself upon her mother’s breast. Mrs. Asquith trembled with the
shock, for Hetty plunged into her arms and buried her face as if she had fled
into some place of refuge; but if it had been the weight of the great house, as
well as that of Hetty, Mary could have borne it in the sudden hope and relief
of her soul.
“My dearest!” she said, “my sweet, my own Hetty, I’m here. There’s
nobody can touch you, I’m here! Don’t you know, my darling, your mother?
There’s nobody can touch you while I am here!”
Hetty made no response in words, but she suspended her whole weight
upon her mother, clinging to her, burrowing with her head on Mary’s bosom.
It was no ordinary embrace; it was the taking of sanctuary, the entry into a
city of refuge. So far as the child was aware, she had found her natural
protector for the first time. She hid herself in Mary, disappearing almost in
the close clasping arms, in the soft shield and shelter of her mother’s form.
Mary’s head was bowed down on Hetty’s; her shoulders curved about her;
the girl’s slim white figure almost disappeared, all pressed, folded, enclosed
in the mother’s embrace. This was what the housekeeper saw when she
rushed to the door, roused by the scream, expecting some repetition of the
former scene. Mary signed to her with her eyes, having no other part of her
free, to go away. She made the same sign to Miss Hofland, who appeared in
her nightdress, trembling and distressed, behind the well-clothed
housekeeper. Mary felt that she dared not speak to them, dared not even
move or say a word. The success of all depended on her being left alone with
her child.
Even the movement of this interruption, however, though hushed and full
of precaution, aided the clearing of Hetty’s brain. She raised her head for a
moment, gave a furtive glance round. “Is he—is he—gone, mamma?”
“Yes, my darling; there is no one here but you and I.”
Hetty moved a little more, and cast a tremulous glance, holding her
mother tighter and tighter, over her shoulders. “Is the window—shut? Is it
safe? Are you sure? Are you sure”—with another passionate strain, under
which Mary tottered, yet held up mechanically, she could not tell how
—“that he can’t come back?”
To Hetty’s bewildered mind the terrible moment of that midnight visit
had only just passed. She knew nothing of the interval; nor did she ask how
it was that, miraculously, when she was most wanted, her mother had come
to her; that is always natural in a child’s experience. She wanted no
explanation of that, but only to make sure that the cause of her terror had
disappeared.
“Darling, lie down and go to sleep. You are safe, quite safe. I am going to
stay with you, don’t you see? Could any harm happen to you and me here?”
Hetty raised her head and turned her face upward for her mother’s kiss. It
was warm and soft with returning life. “No!” she said, with a long-drawn
breath, with that profound conviction of childhood. She had turned into a
child after her trance, all other development disappearing for the moment.
But her hands seemed incapable of disengaging themselves. She could not
loosen her hold. “Oh, mamma, don’t let me go! oh, hold me fast! Oh, don’t
let any one come, mamma!”
“Nobody, my love; I won’t leave you, not for a moment—not for a
moment, Hetty.”
After a while the girl fell fast asleep, with her head upon her mother’s
shoulder, and her arms so soft, yet clenched like iron round Mary’s neck.
Hetty was far too profoundly dependent, too desperate in her absolute need,
to be capable of thinking of the comfort of her shield and guardian. Cramped
and aching, but happy and relieved beyond description in mind, Mary, too,
after a while dozed and slept. When she opened her eyes, the chill grey of
the morning was coming on. The night was over, with its dangers and fears.
Hetty’s desperate clinging had relaxed; her head was falling back; the soft
warmth and ease of sleep had softened all the rigidity of her trance away.
Mary laid her down softly upon her pillow with a light heart, though every
limb and every muscle was aching, and took her place once more by the
bedside, that she might be the first object on which her child’s waking eyes
should rest. And Hetty slept—how long she slept! Fatigue crept over Mrs.
Asquith; she dozed, and dreamed, and woke with a start, half-a-dozen times
before, in the full daylight, Hetty opened her eyes. There was a moment of
awful suspense—the blank look of her stupefied state seemed to waver for
an instant over her face, like a mist trembling, wavering, uncertain whether
to go or stay. Then light broke out, and love and meaning in the girl’s eager
look. “Oh, mamma!”
There had been by this time many anxious tappings at the door. Miss
Hofland had looked in with an anxious face; and little Rhoda, with eyes full
of awe, had peeped round the edge of the door; and the housekeeper, with
whispers and signs and that invariable cup of tea which is intended to be the
consolation of the watcher. But Mary would not be beguiled for a moment
from her child’s side; the danger was too near, the deliverance too great, to
be trifled with. And the other great questions which had almost distracted her
mind from Hetty came back as she waited. Hetty’s murmurs in the hour of
recollection had strangely, fantastically strengthened her suspicions. Could
she dare to recall Hetty, waking and restored to reason, to that awful
remembrance? Whatever happened she could not risk her child.
This question was put to rest later in the day by Hetty herself, who, very
weak, scarcely able to move with physical exhaustion, lay still in her bed,
regarding her mother with all a child’s beatitude. She had heard all the
nursery stories again, Rhoda assisting as before, and laughed and cried and
been happy in all the sweetness of convalescence over the little witticisms of
baby. But later, when Rhoda, was sent away, Hetty lay very silent for a time,
and then called her mother to her bedside.
“Mamma,” she said, growing paler and deeply serious, “I wanted to ask
you, could he take me for Rhoda? Could he be—could he be—Rhoda’s
father, mamma?”
“Hetty,” said Mary, taking her child’s hands, “could you repeat to me, my
darling, quietly, without exciting yourself, what you told me in the night?
What he said?”
The colour came in a flood to Hetty’s face, then ebbed away, leaving her
quite pale. She clasped her mother’s hands tight; and then she repeated
slowly, like a lesson, “Oh, my child, my little darling! have I found you at
latht?”
“Oh, Hetty! God bless you, my dearest! Why did you say ‘at latht’?”
Mary cried.
Hetty looked at her mother with startled eyes. “I don’t know what I said. I
said only what he said, mamma.”
“Hetty,” cried Mary in great agitation, “I think God has sent us here, both
you and me.”
 CHAPTER XXIV.

THE INVALID GENTLEMAN.

M ARY stole out in the afternoon, when the day was beginning to wane. It
was not only that as soon as her anxieties were relieved the spell of the
old associations came back: a far more serious pre-occupation was in
her mind, though all was mystery round her. The question that had sprung up
within her came back and back like a fitful wind through all the agitations
and happiness of the day. Her body was altogether worn out by excitement
and anxiety, and by the long vigil of that troubled night; but, as happens
sometimes in such a case, her mind was only the more eager and alive, her
senses keener to everything around. She had sat by Hetty’s bedside and
talked all the day, talked till her throat and breast seemed to be strained with
physical exertion, talked against time, against weariness, that her child’s
mind might be filled with the peaceful image of home, so as to leave no
room for those distracting images which had jarred her whole being. Mary
felt the strain of that monologue almost more than any other form of fatigue.
She was well used to it, as to all other forms of exhaustion. Talking to
children both her own and others, telling stories, giving lessons, the
sensation was not new to her; but it made the silence and sweet air very
grateful, as, leaving Hetty once more asleep, with Miss Hofland established
at her bedside, she stole out into the great quiet of nature, into the dewy park
and wonderful serenity of the spring afternoon, as it began to soften into
night.
 The grass had been growing all day, the flowers struggling, making their
way upward, the young leaves unrolling their tightly-bound folds out of their
sheaths; and now all seemed to have paused in the midst of that hopeful,
cheerful progress, to rest a little, to get strength for a warmer effort still.
Life, all thrilling through the awakened earth in every vein, in every pore,
paused in the midst of that warm impulse to rest. She felt in sympathy with
all the world, delivered from a terror beyond description,—from death, and
worse than death, her very exhaustion adding to the refreshment and
blessedness of that quiet and repose. For the moment, except for a vague
sense in her mind of an uneasiness which she held at arm’s length, she was
able to give herself up entirely to this tranquil sweetness. She wandered out,
going round the old house, with every line of which her eyes were familiar,
the dear old house, about which she had tripped in her childhood, when she
had been “only Mary,” running everybody’s errands, doing what everybody
told her—a little unconsidered happy creature, sent up and down, here and
there, but never unkindly, never untenderly, she said to herself with tears in
her eyes. Oh, never unkind! nothing but a little wholesome neglect, the
carelessness of familiarity which in its way was sweet. She had not been like
her own children, wrapped in love from their cradles, their little interests and
pleasures put above everything; but Mary knew that she had been as happy
as a lamb or a bird—creatures which have no special tendance, but to which
all nature is sweet. She had never known what harsh words were, or harsh
judgments. They had let her grow like a flower; they had kept her from the
colds and from the heats of life; covered her and sheltered her, and loved her
in their way. She looked back upon her young life with a tender gratitude,
more profound than if they had made her the chief object. She had not been
so to any one in Horton, but how much more, she said to herself, in
consequence, all their sweetness and kindness was. To make your own child
happy, upon whom your happiness depends, what is that but selfishness of
the most refined kind? But to make a little creature happy upon whom your
happiness does not depend—is not that true love, the charity of the Gospel?
She thought of them all who had been so good to her, so kind, so careless, so
indulgent, her heart swelling with tenderness and gratitude.
When she had got far enough off to take in the full view of the house, she
turned back, renewing as it were her acquaintance with it, following with
tender recollection every line and curve. It was changed in some respects.
The front of the house had been renovated, some parts of the architecture
carefully restored, the grounds about the house all put into luxurious order.
Altogether, she said to herself, it looked as if a wave of prosperity had
visited the place, as if there were no longer a deficiency of gardeners or of
servants to keep it in perfection, as there once was. The lawn looked as if it
were rolled every day; there was no sign of neglect anywhere—and once
there had been so many signs. Only one thing in which there was no change
met her eyes. The east wing was all shut up as of old, the windows closely
shuttered, every opening closed. All the same, and yet a little different. In
former days it had been evidently a natural expedient, the shutting up of a
portion of the house which the family was not numerous enough or wealthy
enough to keep up. Now it was different. It was an obvious breach of the
wealthy propriety of the place, about which there was no indication that such
an expedient could be necessary. Mary walked slowly round that side of the
house. The shutting up even was not as before. It was far more elaborate,
done with precaution, as if with the view of closing the interior from all
inspection. In the old times, no one had minded what loop-hole there might
be; appearances had not been thought of. And then her heart began to beat
loudly in her ears. Was it possible that this was a prison, a place of
confinement? and who was it that was shut up there?
Who was it that could be shut up there? By what right or wrong, without
warrant or authority, nobody knowing, nobody able to help! All the
questions that had been in Mary’s mind, suspended by her exhaustion, and
by the grateful quiet of which she had so much need, sprang up again in the
fullest force. The strange words which Hetty had murmured in her trance,
which she had repeated when in full possession of her mind, which had
evidently engraved themselves on her brain, and which had roused her
mother to one sudden gleam of enlightenment, came back to her again and
seemed to echo in her ears. She had put them away after that first
impression. How could it be? Why should it be? In those days such things
could not happen. Shut up the master of the house in his own habitation,
separate him from his child, conceal him from the world! How could it be?
Who could do it? The motives and the means seemed both wanting. But
Mary’s brain throbbed and whirled, even as she said all this to herself. She
forgot even Hetty in the gathering excitement of her mind. She walked up
and down, up and down, at the foot of the grassy slope on which those
barricaded windows opened. Yes, they had always been barricaded, but not
as they were now!
 The night began to darken round her; already the shrubberies, the distant
trees in the park, began to grow indistinct. The veil of the twilight dropped
slowly over the brightness of the sky. But Mary took no notice; her steps
made no sound upon the damp and mossy velvet of the turf; her mind grew
every moment less under her own control. What could she do to satisfy that
question? Was he there? Who was he? What could she do? She was but a
stranger, though a child of the house; she had nothing to prove that the
invalid gentleman of whom the doctor had spoken, the wanderer who had
broken in upon her child’s rest, had in reality any connection with the family,
or was one for whom she could interfere: and how could she interfere?—a
stranger, a poor woman, the mother of Miss Rotherham’s companion. That
was all Mary was to the servants and people about. And the invalid might be
a stranger too, for anything she could tell; he might be—anyone. What right
had she to jump to a conclusion, and decide thus who he was? But she could
not go in quietly and sit down, and take care of her child, and perhaps sleep,
while all the while, close to her, within her reach, might be shut up, deprived
of everything, one who perhaps was the rightful master of all. But how could
that be? How could that be? Why, and with what motive, could such a thing
be done? Her brain turned round more than ever, her mind was all confused,
hanging in the misery of doubt and helplessness, suspended between the how
and the why.
Suddenly she heard a stealthy sound behind her, as of an opened window
or door. She was at the end of the slope, and turned round quickly at this
indication of some one moving. At the end of the long range of windows she
saw a head put dimly forth, and then disappear. Mary divined that it was her
own appearance, vague as it must be in the twilight, which was the cause.
She changed her position, rapidly concealing herself behind a clump of
laurels, and waited. After a little interval there was a faint stir once more.
Almost afraid to breathe, she looked out between the thick leaves.
Something had come out into the dimness of the night. She felt only as Hetty
had done, a movement, a something that was human, a new breathing in the
still atmosphere. The leaves rustled now and then in the night air, and she
felt as if it must be she who did it, and put her hands upon the bough to keep
them still. A strange horror, half superstitious, came over her; something was
coming without any sound, with nothing but a consciousness in the tingling
atmosphere. She forgot the yielding of the turf, in which no footstep was
audible. It seemed to her that something incorporate, some vision sensible to
the mind alone, must be moving past unseen. Terror took possession of her
soul. Was it this then, and not any suffering human creature, some one who
had come back, some one out of the darkness of the grave, whose presence
should chill the blood in her veins, as he had chilled her child’s. Mary felt as
if she hung by her hands from the laurel boughs, which she had grasped to
keep them still. Then, with a sensation of utter horror, she felt herself slip
from them, her hands relaxing. It had passed; her heart stood still; the
surging blood went up and up in blinding circles to her brain. Then there was
a sudden calm in her being, and the common action of life was taken up
again in a moment. In front of her, going softly across the dim lawn, was a
long slim shadow, the head bent a little, the gait uncertain, swaying as if with
weakness. Mary’s superstitious terrors had vanished in a moment. It was a
man she saw; who he was no one could have told, in the faint evening, on
the noiseless grass; but at all events it was a man.
Mary’s faculties all came back. Suppose the guess she had made was
right, suppose it was he, with only herself in all the world to protect him!
She disengaged herself from the bushes, and gliding from one shelter to
another, sometimes dropping to the ground in her terror, lest he should be
alarmed and fly from her, she followed. The night was soft and dim,
wrapping all things in a ghostly shadow; but she never lost sight of the
vague, moving thing winding out and in among the bushes, avoiding with a
kind of strange skill the front of the house. He made a long round, and Mary
kept up mechanically, always following, her limbs failing under her. When
he had got round to the other side, he drew slowly near to the corresponding
range of windows in the western wing; and after various falterings mounted
the slope, and made his way along close to the house. The faltering, stealthy
figure stealing along, now with a foot upon the ledge of stone, now all
noiseless upon the turf, made her half shudder with terror, notwithstanding
the excitement, which was all of which she was now sensible, the only thing
that kept her up. Should anyone within catch a glimpse of the noiseless
shadow thus stealing round the house, what wonder if panic and maddening
terror should follow his steps! Mary, stumbling on, felt that she was going
through all that was preliminary to that midnight visit which had half crazed
her child. The gliding figure suddenly stopped. She saw it pause, turn
inward, put up two arms to the window. Thank God, it was no longer Hetty’s
window; the child was safe. And once more, once more—by what chance
who could tell?—the opening gave way. With a last effort of strength pulling
herself together, Mary climbed the slope.
It had become so dark without that the night had seemed far advanced,
but within lights were shining. The door of the room stood open, admitting a
cheerful glimmer; the sound of voices was audible. Mary came quickly in,
shutting the window behind her, her excitement risen to fever point. She
found herself confronting the ghostly figure, which stood bewildered in the
middle of the room. Even now, even here, sure as she was that it was a man,
and a helpless one, who stood before her, the horrible alternative, the wild
suggestion, that at her touch that shadow might dissolve and melt away, and
leave her mad with the awful encounter, flashed through Mary’s confused
brain. To stand by him in the dark room was somehow more appalling than
to follow through the free air and space. But it was only in that flash that she
remembered herself at all. The poor wanderer had known his way when he
was making that devious course round the house: he had come soberly with
an evident intention through the clumps and bosquets to this window—he
had meant all along to get here, to enter by it, to pursue his wild search for
his child. But the open door on the other side, the lights gleaming, the
sounds of the household, all active and awake, bewildered him. He stopped
short; perhaps he had already seen that there was no one in the bed. He stood
wavering, tremulous, diverted from his intention, looking wildly round him.
When he caught sight of Mary he shrank back, as if to escape. Trembling as
she was, her lips almost refusing to utter the words that came to them, her
limbs to support her, she tottered up to him, and caught him by the arm.
“Yes,” he said, retreating a little before her. “Don’t be angry—I wanted to
thee my little girl.”
“Oh, John!” cried Mary. “Cousin John!—oh, dear John, you that were
always so good, why won’t they let you live as you ought in your own
house?”
He stepped still further back, with a gesture of dismay. “Who is that?” he
said. “You’re not Mrs. Mills. I don’t know who you are.”
“Oh yes, John, you know me, if you will only think; I’m Mary. You
remember Mary, your little cousin, to whom you were always so good?”
“Mary?” he said. “I know your voice, and I know your name: but they
will not like it. They thay I’m not fit—Mary—I wonder if I would know you
if I thaw you. But don’t tell them I’m here; I daren’t go into the light.”
 “Cousin John,” said Mary, “tell me who you think I am.”
He drew back a little farther; it seemed to bewilder him to be so near her.
“I think,” he said, “you must be little Mary that used to be at home in the old
time, Mary that wath married to the curate. I wath very found of Mary. But
don’t tell them I’m here. I’ll go back—I’ll go back—to my own little place.”
“This is your place, John. Oh, dear John, who has done this to you? You
shall not go back; you shall stay in your own house, John.”
“It will only get you into trouble,” he said in a dreamy tone. “She thaid—
she told me——” his voice ran off into a murmur of sound; perhaps the
effect of that she, which he uttered with a sharp sibilation, was too much for
him; or perhaps the thought of her was too much. “Perhapth I had better go
back.”
“No,” cried Mary, grasping his arm with both her hands. “Come with me
and see your little girl.”
“Oh, my little girl: my little darling!” the poor fellow cried, and resisted
no more.
 CHAPTER XXV.

THE RESTORATION.

R HODA’S sitting-room was very warm and pleasant and quiet, the safest
and most comfortable place—the fire lighting it up with fitful gleams,
the windows still glimmering between the curtains with the dim twilight
which had not turned to dark, the pictures and mirrors on the walls giving
forth gleams of ruddy reflection. There were no longer flowers outside to
brighten the prospect, but within groups of plants in every corner, and a tall
pot of creamy, fragrant narcissus spreading its delicate spring scent through
the room. The warm flicker of the firelight seemed to draw out the sweetness
of the flowers, the deeper tints of colour, the reds and browns of the
furniture. There could not have been a woman’s apartment more entirely
breathing of women, and of comfort, and tranquillity, and peace. Hetty lay
on the sofa near the fire, the ruddy glow shedding a pink colour over her still
pale face. Rhoda sat at her feet, leaning against the sofa, holding up her
eager little face, asking questions in her eager way about Hetty’s home,
about the children, about baby, who was so funny. “Oh! I wish I could see
him. Oh, I wish I could go and play with them all!” Rhoda said. Hetty, who
had been removed here in her mother’s absence to join the little party once
more, in the sweetness of that convalescence, which was almost more than
coming back to health, lay smiling, answering the child’s questions in a little
broken voice of weakness and happiness. Miss Hofland sat on a low chair by
the fire, going through her usual little calculations, setting down all the
comforts on one side against the very curious condition of this house on the
other. All these things that had happened were very mysterious. The
whispers of the maids, which could scarcely fail to reach her, were full of
suggestions. It was not pleasant to live in a house where such strange things
were heard and seen; but then, on the other hand, it was very comfortable.
There was scarcely anything one wanted that one could not have. In some
families the treatment was very different. She was putting these things
meditatively against one another when the servant came in with the lamp.
There was an abundant supply of light, as of everything else—no stint of
anything—lamps and candles, it did not seem to matter how many were
used. It was very comfortable, enough to make up for the many unpleasant
circumstances which did not after all touch either her pupil or herself.
Just then the servant, going away after he had placed the lamp, uttered a
cry of alarm, and seemed to fall back against the wall, letting go the handle
of the door. Miss Hofland started up, feeling that if anything dreadful came
in here, into this warm and pleasant place, all the comfort would not make
up for such an interruption. She rose so hurriedly that her chair turned over,
coming down with a muffled sound on the carpet, and turned her startled
face towards the door. Mrs. Asquith had just come in, looking very pale and
excited, leaning upon the arm of—no, she was not leaning, she was guiding
him with her hand through his arm—a tall, slim man with a strange grey
coat, too large for him, and wrapping over his shadowy thinness, a long face,
with large projecting eyes, grizzled hair hanging wildly, a ragged beard, and
drooping, melancholy moustache hiding the outlines of the tremulous mouth.
He had a bewildered, dazed look, and turned his head slowly from side to
side, as if he scarcely saw, and did not know where he was.
And before a word could be said, almost before the attention of the girls
had been roused, or Miss Hofland’s cry of alarm got vent, the housekeeper
rushed into the room. She swept into it like a whirlwind, and placed herself
at the other side of that strange figure.
“Sir, sir!” she cried, “you must go back, you must go back—you must not
be seen here!”
“John!” cried Mrs. Asquith, “don’t give way to her; this is your house,
and here is your child.”
He turned his face from one side to the other, shrinking a little from the
housekeeper, yet making a step back as if in obedience—appealing to Mary,
yet drawing his arm away from hers in a self-contradictory movement,
opening his mouth but only with a gasp, saying nothing.
Mrs. Mills put her hand upon his sleeve.
“Come back, sir,” she said; “come back, oh! come back to your own
comfortable room, where things are fit and proper for you. My mistress
would break her heart if she thought you were here. Oh, sir, come back! You
know what my mistress would say, and that it’s all for your good. What does
she think of night and day but for your good?”
He gasped again as if for breath, and then drew away, retreating a little.
“Mary,” he said, “perhapth she’s right. I’ll be better in my own place.” As he
stood thus irresolute, feeble, with a woman on each side of him, a picture of
a bewildered soul cowed with long subjection, there came into the
movement of the strange little drama another unexpected actor. Hetty had
sprung up from her sofa, forgetting her weakness, putting out her hands at
first as if to keep away the sight; and her movement had disturbed Rhoda,
who sprang up too, and stood for a moment astonished, taking in the scene.
Then with a cry the little girl flung herself forward, clutching at the grey
coat, clinging to his knees. “Father!” she cried. Her little voice, shrill in its
childish tones, rang through the air like the ring of a pistol shot, clearing
away the mist. He gave a great, sobbing cry, shook himself clear, and
stooping down, gathered the child into his arms. They all stood round, a
group of hushed spectators, to watch that meeting. He seemed to grope for a
chair, and sat down and folded her to him. “My little girl, my darling! my
little girl, my darling! I’ve found you at latht!” Hetty tottered across the floor
to her mother, and caught her arm and clung to her, hiding her head upon
Mary’s shoulder. And behind them all young Darrell came in, and stood
looking on like the rest.
Even the housekeeper had been paralysed by
 “ ‘MY LITTLE GIRL, MY DARLING!’ ” (p. 374.)

this touching sight; she had not been able to speak or interfere, but at the
appearance of Darrell she recovered herself. “Doctor,” she said, going up to
him, “you know what our orders are, you know he’ll hurt himself by this,
you know it’s for his good—for his good. What were we put here for but for
his good? And who is this lady that has ventured to interfere? Doctor, call
Turner, call the man, and take him back. I order you,” cried the woman, “in
my mistress’s name, take him back. Sir, sir, Mr. Prescott! take the child from
him, take him back.”
No one paid any attention to her cries, and the woman was almost beside
herself. “Miss Hofland,” she said, “it’s as much as our places are worth. You
said yourself it was a comfortable house. Oh, for goodness’ sake take the
child from him, take the child from him! Don’t you know he’s off his head?
I’ve got my mistress’s authority. Turner—doctor—this moment, he must be
taken back!”
Little Rhoda here released herself from her father’s arms. She put herself
before him like a guardian spirit, not angel, for her eyes flashed fire, and her
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