![Article
Antidepressants in Amniotic Fluid:
Another Route of Fetal Exposure
Ada M. Loughhead, B.S. Objective: Th e au th ors ’ goal was to ternal serum ratios were higher for ven-
determine the concentration of antide- lafaxine: 172% (SD=91%) (N=3). Of interest,
pressants in amniotic fluid during mater- the amniotic fluid to maternal serum ra-
Angela D. Fisher, B.S.
nal treatment of depression. tios for the metabolites (N=19) did not
demonstrate a consistent pattern com-
D. Jeffrey Newport, M.D., M.S., Method: Women treated with antide-
pared to the parent compound ratios. In
pressants undergoing amniocentesis for
M.Div. obstetrical reasons were enrolled. Anti- 10 subjects, the amniotic fluid to maternal
depressant concentrations in amniotic serum ratio for the metabolites was higher
James C. Ritchie, Ph.D. fluid and maternal serum were deter- than the parent compound and lower in
mined with high-performance liquid the remaining nine subjects.
Michael J. Owens, Ph.D. chromatography. Conclusions: The pattern of antidepres-
Results: Amniotic fluid was obtained sant concentrations in amniotic fluid is
C. Lindsay DeVane, Pharm.D. from 27 women, and the amniotic fluid’s similar to recent data for placental pas-
antidepressant concentrations were highly sage. Although the significance of amniotic
Zachary N. Stowe, M.D. variable. For the parent compounds, the fluid exposure remains to be determined,
amniotic fluid concentrations of selective these results demonstrate that maternally
serotonin uptake inhibitors averaged administered antidepressants are accessi-
11.6% (SD=9.9%) of maternal serum con- ble to the fetus in a manner not previously
centrations (N=22). Amniotic fluid to ma- appreciated.
(Am J Psychiatry 2006; 163:145–147)
A ntidepressant use during pregnancy has undergone
considerable scrutiny in the past decade. Despite increas-
Method
The present study is a naturalistic prospective investigation of
ing interest in defining drug transfer between mother and
antidepressant concentrations in the amniotic fluid of 27 women
fetus, some pathways of fetal exposure have been incom- treated with a fixed antidepressant dose (citalopram [N=1], esci-
pletely investigated. One route of fetal exposure for which talopram [N=1], fluoxetine [N=12], fluvoxamine [N=1], paroxetine
especially sparse information exists is amniotic fluid. Pre- [N=2], sertraline [N=6], and venlafaxine [N=4, including one set of
vious investigations have examined amniotic fluid con- twins]) for more than 4 weeks before amniocentesis. All women
underwent amniocentesis as part of recommended obstetrical
centrations of anticonvulsants (1, 2), antibiotics (3), and care and gave written informed consent for retention and analysis
nicotine (4), but only a single report exists on antidepres- of amniotic fluid and serum samples. Twenty-three women un-
sants (5), to our knowledge. derwent amniocentesis between 14 and 21 weeks’ gestation be-
cause of advanced maternal age. Amniocentesis was performed
One important consideration is that amniotic fluid
for four women proximate to delivery to verify fetal lung maturity
composition varies with gestational age and evolving rates before induction. Maternal serum was collected within 14 days of
of fetomaternal exchange. In early pregnancy, amniotic amniocentesis for the majority (N=25) of the 27 subjects. Obstetri-
fluid is predominantly an ultrafiltrate of maternal serum. cal outcome data were collected by self-report from all partici-
In later pregnancy, however, fetal urine is the principal pants who had delivered before preparation of this article. This
study was approved by the institutional review board of Emory
constituent of amniotic fluid. Amniotic fluid is not only University School of Medicine.
derived from varied sources, but it also reaches the fetus Isocratic high-performance liquid chromatography with ultra-
via several routes, including 1) inhalation into the respira- violet detection was used to quantify parent drug and active me-
tory tract, bypassing fetal first-pass hepatic metabolism; tabolite (norfluoxetine, desmethylsertraline, O-desmethylven-
2) swallowing into the gastrointestinal tract; and 3) possi- lafaxine) concentrations in paired maternal serum and amniotic
fluid samples. Metabolite concentrations for citalopram and
bly transcutaneous absorption. The fetus swallows 7 ml/ escitalopram were not determined in the present study second-
day of amniotic fluid at 16 weeks’ gestation, increasing to ary to the manufacturers declining to provide the internal stan-
16 ml/day by 20 weeks’ gestation, and peaking at 210–760 dards for such metabolites. After solid-phase extraction of sam-
ml/day by term (6). If amniotic fluid contains significant ples, high-performance liquid chromatography separation was
accomplished by using a 100×2-mm stainless steel Keystone Sci-
antidepressant quantities, amniotic fluid may represent a
entific (Bellefonte, Pa.) MOS-2 Hypersil (C8) reverse-phase col-
medium for continuous fetal exposure to maternally ad- umn of 3 µm particle size. Chromatographic data were analyzed
ministered drugs and metabolites. by using a computer-controlled Hewlett Packard (Palo Alto, Calif.)
Am J Psychiatry 163:1, January 2006 http://ajp.psychiatryonline.org 145](https://image.slidesharecdn.com/antidepressantsinamnioticfluidanotherrouteoffetalexposure-091015182018-phpapp02/85/Antidepressants-In-Amniotic-Fluid-Another-Route-Of-Fetal-Exposure-1-320.jpg)
Antidepressants In Amniotic Fluid Another Route Of Fetal Exposure
- 1. Article Antidepressants in Amniotic Fluid: Another Route of Fetal Exposure Ada M. Loughhead, B.S. Objective: Th e au th ors ’ goal was to ternal serum ratios were higher for ven- determine the concentration of antide- lafaxine: 172% (SD=91%) (N=3). Of interest, pressants in amniotic fluid during mater- the amniotic fluid to maternal serum ra- Angela D. Fisher, B.S. nal treatment of depression. tios for the metabolites (N=19) did not demonstrate a consistent pattern com- D. Jeffrey Newport, M.D., M.S., Method: Women treated with antide- pared to the parent compound ratios. In pressants undergoing amniocentesis for M.Div. obstetrical reasons were enrolled. Anti- 10 subjects, the amniotic fluid to maternal depressant concentrations in amniotic serum ratio for the metabolites was higher James C. Ritchie, Ph.D. fluid and maternal serum were deter- than the parent compound and lower in mined with high-performance liquid the remaining nine subjects. Michael J. Owens, Ph.D. chromatography. Conclusions: The pattern of antidepres- Results: Amniotic fluid was obtained sant concentrations in amniotic fluid is C. Lindsay DeVane, Pharm.D. from 27 women, and the amniotic fluid’s similar to recent data for placental pas- antidepressant concentrations were highly sage. Although the significance of amniotic Zachary N. Stowe, M.D. variable. For the parent compounds, the fluid exposure remains to be determined, amniotic fluid concentrations of selective these results demonstrate that maternally serotonin uptake inhibitors averaged administered antidepressants are accessi- 11.6% (SD=9.9%) of maternal serum con- ble to the fetus in a manner not previously centrations (N=22). Amniotic fluid to ma- appreciated. (Am J Psychiatry 2006; 163:145–147) A ntidepressant use during pregnancy has undergone considerable scrutiny in the past decade. Despite increas- Method The present study is a naturalistic prospective investigation of ing interest in defining drug transfer between mother and antidepressant concentrations in the amniotic fluid of 27 women fetus, some pathways of fetal exposure have been incom- treated with a fixed antidepressant dose (citalopram [N=1], esci- pletely investigated. One route of fetal exposure for which talopram [N=1], fluoxetine [N=12], fluvoxamine [N=1], paroxetine especially sparse information exists is amniotic fluid. Pre- [N=2], sertraline [N=6], and venlafaxine [N=4, including one set of vious investigations have examined amniotic fluid con- twins]) for more than 4 weeks before amniocentesis. All women underwent amniocentesis as part of recommended obstetrical centrations of anticonvulsants (1, 2), antibiotics (3), and care and gave written informed consent for retention and analysis nicotine (4), but only a single report exists on antidepres- of amniotic fluid and serum samples. Twenty-three women un- sants (5), to our knowledge. derwent amniocentesis between 14 and 21 weeks’ gestation be- cause of advanced maternal age. Amniocentesis was performed One important consideration is that amniotic fluid for four women proximate to delivery to verify fetal lung maturity composition varies with gestational age and evolving rates before induction. Maternal serum was collected within 14 days of of fetomaternal exchange. In early pregnancy, amniotic amniocentesis for the majority (N=25) of the 27 subjects. Obstetri- fluid is predominantly an ultrafiltrate of maternal serum. cal outcome data were collected by self-report from all partici- In later pregnancy, however, fetal urine is the principal pants who had delivered before preparation of this article. This study was approved by the institutional review board of Emory constituent of amniotic fluid. Amniotic fluid is not only University School of Medicine. derived from varied sources, but it also reaches the fetus Isocratic high-performance liquid chromatography with ultra- via several routes, including 1) inhalation into the respira- violet detection was used to quantify parent drug and active me- tory tract, bypassing fetal first-pass hepatic metabolism; tabolite (norfluoxetine, desmethylsertraline, O-desmethylven- 2) swallowing into the gastrointestinal tract; and 3) possi- lafaxine) concentrations in paired maternal serum and amniotic fluid samples. Metabolite concentrations for citalopram and bly transcutaneous absorption. The fetus swallows 7 ml/ escitalopram were not determined in the present study second- day of amniotic fluid at 16 weeks’ gestation, increasing to ary to the manufacturers declining to provide the internal stan- 16 ml/day by 20 weeks’ gestation, and peaking at 210–760 dards for such metabolites. After solid-phase extraction of sam- ml/day by term (6). If amniotic fluid contains significant ples, high-performance liquid chromatography separation was accomplished by using a 100×2-mm stainless steel Keystone Sci- antidepressant quantities, amniotic fluid may represent a entific (Bellefonte, Pa.) MOS-2 Hypersil (C8) reverse-phase col- medium for continuous fetal exposure to maternally ad- umn of 3 µm particle size. Chromatographic data were analyzed ministered drugs and metabolites. by using a computer-controlled Hewlett Packard (Palo Alto, Calif.) Am J Psychiatry 163:1, January 2006 http://ajp.psychiatryonline.org 145
- 2. ANTIDEPRESSANTS IN AMNIOTIC FLUID high-performance liquid chromatography chemstation incorpo- Discussion rating a degasser, an autosampler, and a diode array detector. The limit of detection was 2.0 ng/ml. Amniotic fluid concentra- Antidepressant pharmacotherapy during pregnancy is tions below the limit of detection were converted to 2.0 ng/ml to clouded by the unknown impact of the medication on the avoid underestimating fetal exposure. fetus. Fetal antidepressant exposure can be more clearly A descriptive analysis was conducted by the calculation of means, standard deviations, and ranges for the parent drug and defined by an improved understanding of the routes of fe- metabolite concentrations in both maternal serum and amniotic tal exposure and the factors that influence such pathways. fluid. Simple correlation analysis was performed to evaluate the For example, the amniotic fluid concentration of fluoxetine relationship between maternal serum and amniotic fluid concen- (mean=22.8 ng/ml, SD=17.7) and venlafaxine (mean=71.5 trations. The ratio of the medication (and metabolite) concentra- ng/ml, SD=68.2) would increase fetal oral ingestion by a tion in amniotic fluid versus that in maternal serum was also cal- modest 0.02 mg/day and 0.05 mg/day, respectively, during culated for paired samples (25 of 27). late gestation when the fetus swallows up to 760 ml amni- otic fluid per day. The significance of respiratory exposure Results to antidepressants in the fetus is unknown but can theoret- A total of 28 women were enrolled in the study. Data for ically be both significant and efficient and would bypass one participant, for whom the parent compound was unde- fetal hepatic metabolism before CNS exposure. The indi- tectable in both maternal serum and amniotic fluid, was ex- vidual variability and limited group size for particular cluded from analysis because medication compliance medications (citalopram, escitalopram, fluvoxamine, paroxetine, and venlafaxine) preclude definitive conclu- could not be confirmed. The remaining results are reported sions. These preliminary results suggest that higher protein on 27 subjects with confirmed antidepressant exposure binding may be associated with lower amniotic fluid con- (Table 1, published in the online version of this article). centrations, although additional study is warranted. Parent compounds were detected in all of the amniotic The ratio of the metabolite to parent drug concentration fluid samples for four of seven antidepressants (citalo- in either maternal serum or amniotic fluid reflects the rel- pram, escitalopram, fluvoxamine, and venlafaxine). Fluox- ative exposure to circulating antidepressant or its major etine was detectable in 11 of 12 fluid samples, paroxetine metabolite. A ratio of 1.0 means equal circulating concen- was detectable in one of two fluid samples, and sertraline trations at the time of sampling. A difference in the ratio was detectable in two of six fluid samples. Active metabo- between maternal serum or amniotic fluid would reflect a lites were also detected in amniotic fluid—nine of 12 nor- change in the overall exposure to parent drug or metabo- fluoxetine samples, four of six desmethylsertraline sam- lite between these two body compartments. These data do ples, and four of four O-desmethylvenlafaxine samples. not demonstrate any consistent pattern during compari- Analysis of paired amniotic fluid and maternal serum sons of metabolite to parent ratio between maternal se- concentrations excluded women with serum collection rum and amniotic fluid across different patients. The am- more than 2 weeks from the time of amniocentesis (sub- niotic fluid to maternal serum ratio for norfluoxetine was jects J and Y). In the remaining 25 women, the ratio of am- less than the parent compound ratio in six of 12 cases. niotic fluid to maternal serum concentrations for the par- Similarly, the amniotic fluid to maternal serum ratios for ent compound and the metabolite was calculated. The desmethylsertraline and O-desmethylvenlafaxine were amniotic fluid to maternal serum ratio for the different less than the parent ratio: two of six and one of three, re- parent compounds and the metabolites varied from 1.4% spectively. The significance of this observation is obscure. to 267.2% for the parent compound and 0.8% to 446.7% for It is plausible that the metabolites, by definition more po- the active metabolites. The maternal serum and amniotic lar than the parent compounds, are less likely to be filtered fluid concentrations and ratios for the individual medica- into amniotic fluid. It also raises a potential concern over tions are shown in Table 1 (online only). the fetal capacity to metabolize antidepressants because Obstetrical outcome data were available for all of the 28 of the contribution of fetal urine to the amniotic fluid infants (27 women and one set of twins). Obstetrical com- sample. The impact of pharmacogenetic differences be- plications included 1) nine of 28 who were preterm deliv- tween the mother and fetus on such results remains unex- eries (i.e., <37 weeks gestational age), 2) six of 28 infants plored. From the clinical perspective, such issues are of who were admitted to a special care nursery, and 3) one of concern when we administer medications with active me- 28 infants who had a low birthweight (i.e., <2.5 kg). The tabolites or metabolites that are potentially toxic (e.g., the majority of infants (27 of 28) left the hospital with their cis metabolite of nortriptyline). mothers. Obstetrical outcome data, although important, In the present study, no significant correlation was must be reviewed in the context of the subject group (e.g., found between the concentrations of parent compound advanced maternal age, obstetrical issues warranting fetal and/or metabolites in maternal serum and amniotic fluid. lung maturity assessment). The women undergoing third- This lack of correlation suggests that a more complex set trimester amniocentesis (subjects D, S, Z, and AA) ac- of variables may be involved in determining fetal exposure counted for three of the nine cases of preterm delivery. to antidepressant medications, such as placental and fetal 146 http://ajp.psychiatryonline.org Am J Psychiatry 163:1, January 2006
- 3. LOUGHHEAD, FISHER, NEWPORT, ET AL. metabolic capability. Overall, these data reflect the large Dr. DeVane is on the speakers’ bureau for GSK, Bristol-Myers Squibb, Janssen, and AstraZeneca and the advisory board for GSK, Sommer- variability in the factors that control not only the absolute set, and Eli Lilly. Dr. Stowe is on the speakers’ bureau for Pfizer, Wy- exposure of the fetus to drug and metabolite in amniotic eth, GlaxoSmithKline, and Eli Lilly and on the advisory board for GSK. fluid but also the relative exposure to drug or active me- See the online version of this article for supplemental data. tabolite in comparison to the more readily available ma- ternal serum from which blood samples can be drawn. Re- References gardless of the contribution of maternal and fetal hepatic elimination of antidepressants, these data suggest that fe- 1. 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Philadelphia, WB Saunders, Received April 29, 2005; revision received June 20, 2005; accepted 1991, pp 139–141 July 12, 2005. From the Department of Psychiatry and Behavioral Sci- 7. Hendrick V, Stowe ZN, Altshuler LL, Hwang S, Lee E, Haynes D: ences, the Department of Pathology and Laboratory Medicine, and Placental passage of antidepressant medications. Am J Psychi- the Department of Gynecology and Obstetrics, Emory University atry 2003; 160:993–996 School of Medicine, Atlanta; and the Department of Psychiatry and 8. Stowe ZN, Cohen LS, Hostetter A, Ritchie JC, Owens MJ, Nemer- Behavioral Sciences, Medical University of South Carolina, Charles- off CB: Paroxetine in human breast milk and nursing infants. ton. Address correspondence and reprint requests to Dr. Stowe, Em- Am J Psychiatry 2000; 157:185–189 ory Women’s Mental Health Program, 1365 Clifton Rd., N.E., Suite B6100, Atlanta, GA 30322; [email protected] (e-mail). 9. Hendrick V, Suri R, Stowe ZN, Hendrick V, Hostetter AL, Widaw- Supported by an unrestricted educational grant from Pfizer Phar- ski M, Altshuler LL: Estimates of nursing infant daily dose of flu- maceuticals, a research grant from GlaxoSmithKline (GSK), and an oxetine through breast milk. Biol Psychiatry 2002; 52:446–451 NIMH Specialized Center of Research grant (P50 MH-68036). 10. Stowe ZN, Hostetter A, Owens MJ, Ritchie JC, Sternberg K, Co- The authors thank Lilly, Pfizer, GSK, and Wyeth for providing appro- hen LS, Nemeroff CB: The pharmacokinetics of sertraline ex- priate internal standards for determination of metabolite concentra- cretion into human breast milk: determinants of infant serum tions, the Atlanta community obstetricians who collected these sam- concentrations. J Clin Psychiatry 2003; 64:73–80 ples, and the women who willingly participated in this study. 11. Fisher AD, Brown JS, Newport DJ, Owens MJ, Ritchie JC, Stowe Disclosure of competing interests: Dr. Newport is on the speakers’ bureau for GSK and Eli Lilly. Dr. Owens is a consultant for Bristol- ZN: Fetal CNS exposure after maternal SSRI: a rodent model, in Myers Squibb, Cielo Institute, Cypress Biosciences, and Pfizer; is on 2001 Annual Meeting New Research Program and Abstracts. the speakers’ bureau for Forest Labs, GSK, Pfizer, and Lundbeck; and Washington, DC, American Psychiatric Association, 2001, num- receives research support from Pfizer, GSK, Merck, and UCB Pharma. ber NR137 Am J Psychiatry 163:1, January 2006 http://ajp.psychiatryonline.org 147