Medical Hypotheses 164 (2022) 110859

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Medical Hypotheses
journal homepage: www.elsevier.com/locate/mehy

Hypothesis: Hypermobile Ehlers Danlos Syndrome is a determinant of fetal

and young infant bone strength
Marvin Miller a, b, *
a
Department of Pediatrics and Ob/Gyn, Wright State University Boonshoft School of Medicine, Dayton, OH, United States
b
Department of Medical Genetics, Dayton Children’s Hospital, United States

A R T I C L E I N F O A B S T R A C T

Keywords: Several studies have demonstrated that young infants who present with unexplained fractures have a higher
Joint hypermobility frequency of joint hypermobility, either in themselves or their parents, compared to the general population. The
Ehlers Danlos Syndrome, hypermobile form joint hypermobility is often associated with the autosomal dominant hypermobile form of Ehlers Danlos Syn­
Fetal bone loading
drome (h-EDS) in which the mother is far more likely the affected parent. Most of these infants have metabolic
Fragility fractures
Utah paradigm
bone disease as their radiographs often show poor bone mineralization. Some have alleged these infants were
abused, while others have stated infants who have h-EDS or a parent with h-EDS are at increased risk to fracture
as a result of a permanent, intrinsic connective tissue abnormality in the bone of the infant with h-EDS.
If these infants were not abused and the fractures were from an intrinsic bone abnormality with an increased
risk to a fracture, this increased fracture risk would be expected to persist throughout the lifetime of the affected
infant. However, this is not the case as the propensity to fracture in these infants is transient with few fractures
after 6 months of age. This observation begs for another explanation for the etiology of the increased fracture risk
as an infant, but much less so after 6 months of age.
I believe there is a different mechanism to explain this transient, increased fracture risk in infants with joint
hypermobility from h-EDS born to mothers with h-EDS. In such a mother-infant pair with h-EDS the infant has
joint hypermobility and the mother’s uterus has hyperelasticity. I hypothesize that both of these factors cause
diminished fetal bone loading when the infant with joint hypermobility strikes the uterus with hyperelasticity.
Simple principles of physics are used to demonstrate this. Diminished fetal bone loading causes diminished fetal
and young infant bone strength for the first 6 months of life that begins to normalize after about 6 months of age.
This hypothesis would explain the transient nature of the increased fracture risk for once born, these factors
would cease to be present in the postnatal time period, but their influence would last for about 6 months. This
finding has important implications in child abuse investigations of infants with unexplained fractures.

Background cells: osteocytes, osteoblasts, and osteoclasts. Osteocytes are the

mechanosensory cells that detect the load the bone experiences and are
a. Utah Paradigm and Fetal Bone Strength. the mechanostat of the bone. The osteocyte is able to signal the effector
cells, the osteoblasts and osteoclasts, to change bone strength if there is
The Utah Paradigm is the contemporary model of bone physiology some change in the load the bone experiences. These changes in bone
that can be used to understand factors that can promote bone strength strength can occur by changes in bone density, bone architecture, or
and weakness [1]. This model recognizes the importance of the essential bone quality.
nutrients that produce bone including calcium, phosphate, vitamin D, The Utah Paradigm also applies to the fetus as this system for regu­
and protein, but the centerpiece of the Utah Paradigm is the concept that lating bone strength is established and fully functional during the second
bone loading is the critical determinant of bone strength. The Utah and third trimesters of pregnancy [1,2]. Using the Utah Paradigm to
Paradigm postulates a regulatory system within bone that produces a analyze risk factors in young infants with unexplained fractures,
bone strength that is appropriate for the load placed on the bone. This is important determinants of both fetal and young infant bone strength
done through a coordination of activities between the 3 types of bone have been appreciated over the past 25 years [3,4].

* Address: Dayton Children’s Hospital, Department of Medical Genetics, 1 Children’s Plaza, Dayton, OH 45404, United States.
E-mail address: [email protected].

https://doi.org/10.1016/j.mehy.2022.110859
Received 30 January 2022; Received in revised form 10 April 2022; Accepted 13 April 2022
Available online 18 April 2022
0306-9877/© 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).
M. Miller Medical Hypotheses 164 (2022) 110859

Table 1
Studies that demonstrate fetal bone loading is an important determinant of fetal/young infant bone strength*.
First author Subjects Methodology Used Conclusion
[reference]

Rodriguez-a 11 Newborns Radiographic and histology analysis Reduction of intrauterine movement causes bone fragility
[6] with CNMD
Rodriguez-b 11 Newborns Quantitative bone parameters related Fetal immobilization produces fetal osteoporosis
[7] with CNMD to bone strength
Rodriguez-c Fetal akinesia Histological study of curare induced Fetal immobilization in utero produces fetal osteoporosis
[8] immobilization in fetal rat bones
Miller [2] Premature Theoretical comparison of bone Prematurity is associated with decreased bone loading; Intrauterine environment is more
infants loading in premature versus term infant favorable than the extrauterine environment in promoting bone strength
Miller [3] Infants with CT bone density compared to controls Infants with TBBD had lower CT bone density compared to controls
TBBD
Varghese [9] Infants with Bone architecture of radius determined and Infants with TBBD had less favorable bone architecture for
TBBD compared to controls bone strength compared to controls
Chan [10] Newborns – DEXA; compared to controls with normal Newborns with SUC have lower bone mass
SUC length
Tshorny [11] Newborns – TBUV compared to controls Newborns born in breech have decreased TBUV
breech
Ireland [12] Newborns DEXA; compared to control vertex Newborns born in breech have decreased bone density
–breech
Gursoy [13] Newborns – TBUV; compared to control singletons Newborn twins have lower TBUV
twins
Littner [14] Newborns TBUV; compared to control AGA Newborns who are LGA have lower TBUV
–LGA
Litmanovitz [15] Premature TBUV; compared to controls – no PT Minimal PT (bone loading) increases TBUV
infants
who receive PT
*
Abbreviations
CNMD = Congenital Neuromuscular Disorders
CT = Computed Tomography
TBBD = Temporary Brittle Bone Disease
DEXA = Dual Energy X-ray Absorptiometry
SUC = Short Umbilical Cord
TBUV = Tibial Bone Ultrasound Velocity
LGA = Large for Gestational Age
AGA = Appropriate for Gestational Age
PT = Physical Therapy.

The bone strength of the fetus and that of the infant in the first underestimate the true number of fetal movements [18].
several months of postnatal life is, in part, determined by fetal bone In a normal pregnancy the fetus is moving in a pool of amniotic fluid
loading through fetal movement [3]. Other factors that can also influ­ in which the amniotic fluid volume relative to fetal volume is much
ence fetal/young infant bone strength are maternal provision of essen­ greater in the early part of the second trimester and progressively de­
tial bone nutrients (calcium, phosphate, vitamin D, and protein to the creases as the pregnancy approaches term gestation. Thus, fetal
fetus), prenatal exposure to drugs that can unfavorably influence bone crowding occurs in the latter weeks of a normal pregnancy.
strength, gestational diabetes, and gestational age [4]. When there is a
deficiency of fetal bone loading or essential nutrients for bone forma­ c. How Fetal Movement Affects Fetal Bone Strength.
tion, fetal bone weakness can result, and this condition has been called
Metabolic Bone Disease of Infancy (MBDI) [4]. At an earlier time period The elegance of bone is its integrated composition of both a brittle
in the 1990 and early 2000s when the determinants of fetal bone material (mineral) and an elastic one (type 1 collagen). This composite
strength were less well-understood, this entity of transient infantile bone make-up affords bones, especially long bones, the ability to bend when
weakness was called Temporary Brittle Bone Disease (TBBD) [3,5]. Bone even the slightest force is applied to them.
loading through fetal movement is likely the most important determi­ The osteocyte is the “brain” of the regulatory system that controls
nant of fetal/young infant bone strength, and multiple studies using bone strength to keep it in line with the load placed on the bone [1]. The
various techniques and approaches have confirmed this as listed in osteocyte is buried in lacunae within bone and has multiple, thin cellular
Table 1 [2,3,6–15]. projections bathed in fluid that can detect even the slightest change in
strain. Strain is the proportional change in length (change in length/
b. Fetal Movement. length) caused by a load that can be from compression, tension, or
shearing loads.
Most primigravida mothers first appreciate fetal movement at 18 to A force that is applied to the fetal skeleton generates a strain which
20 weeks, and most multipara mothers at 16 to 18 weeks. Fetal move­ registers within the osteocyte. Strain is the proportional change in
ments include whole-body movements, trunk movements, limb move­ length (change in length/length) caused by a load and can be from
ments, breathing movements, hiccups, and stretching [16]. The healthy compression, tension, or shearing loads. If a bone is stretched by 1% of
fetus has between 4 and 100 movements/hour with an average of about its length, then it is undergoing a strain of 1%, or 10,000 microstrain. If a
40 movements/hour [17]. Thus, the estimated total number of fetal bone is compressed by 0.1% of its original length so that it is now 99.9%
movements between 20 and 40 weeks in a normal term pregnancy is the of its original length, then it is undergoing a strain of 1000 microstrain.
(number of days) × (number of hours/day) × (number of movements/ Loads will cause strains even when the loads are small.
hour) = 140 × 24 × 40 = 134,400 fetal movements. It is estimated a This regulatory system that determines bone strength is functional
mother appreciates only 40% of fetal movements, so this number may during the fetal time period. Human fetal bone histology specimens

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M. Miller Medical Hypotheses 164 (2022) 110859

Table 2 quality. During the first six months of life, the diameter of a long bone such
Studies describing an association between joint hypermobility and infant bone as the femur increases by about 50%, while the bone cortex thickness of the
fragility. femur slightly decreases. The total bone mineral density of the femur,
Study Subjects Findings including both the cortical and trabecular bone density, decreases by
[reference] about 30% with the cortical bone density decreasing by only 7% [23].
1. Paterson [5] 39 infants with 66% of parents had joint laxity With these bone density and bone geometry changes, bone strength at 6
TBBD months of age is 3× greater than that at birth, thus emphasizing the critical
2. Miller [25] 60 infants with 6 infants (10%) had EDS influence of bone geometry on bone strength [24].
TBBD
3. Paterson 81 infants with 40 infants (49%) had at least one parent with
[26] TBBD Beighton score >4 Hypotheses
4. Holick [27] 72 infants with 67 infants (93%) had evidence of h-EDS
MUF 1. Effect of Joint Hypermobility on Fetal Bone Loading.
5. Miller [4] 75 infants with 15 cases (20%) with JH/h-EDS in either
MBDI parent or infant
A common risk factor that has been appreciated in infants with un­
TBBD = Temporary Brittle Bone Disease. explained fractures in the first 6 months of life (infants with TBBD or
MUF = Multiple Unexplained Fractures. MBDI) is joint hypermobility in either the parents and/or the infant. The
MBDI = Metabolic Bone Disease of Infancy. joint hypermobility can be isolated, but is most often associated with the
JH = Joint Hypermobility.
hypermobile type of Ehlers Danlos Syndrome (h-EDS).
EDS = Ehlers Danlos Syndrome.
Table 2 summarizes 5 studies that describe the association between
h-EDS = hypermobile form of Ehlers Danlos Syndrome.
joint hypermobility and fragility fractures in young infants [4,5,25–27].
Paterson and Miller have independently described an increased frequency
taken as early as 20 weeks gestational age show the presence of all 3 of joint hypermobility in the child abuse-mimic Temporary Brittle Bone
bone cell types (osteocytes, osteoblasts, and osteoclasts) [19]. Moreover, Disease (TBBD), and Holick reported h-EDS was prevalent in contested
the Rodriguez studies and experimental studies using knockout mice cases of child abuse. In both TBBD and MBDI the fracture susceptibility is
with absent muscle show that this system is functional during the fetal in the first 6 months of life, suggesting the risk factors for these two con­
time period in mice, rats, and humans [6–8,20]. ditions were primarily fetal in origin. It appears that the h-EDS risk factor
There are likely 3 sources of forces during the fetal time period that also only influences bone strength in the first 6 months of life, an obser­
can produce strains on bone and thus osteocyte activation to promote vation which is, in part, the basis of the two hypotheses below.
maintaining or increasing bone strength: h-EDS is a systemic connective tissue disorder that is inherited in an
autosomal dominant fashion. However, the idea that h-EDS is a distinct,
1. The main source of fetal bone loading is from the force on the fetal single gene disorder has never been shown, and, at best, one can say h-
skeleton that occurs when the fetus hits the uterine wall from fetal EDS is multifactorial in origin with individuals having a 50% risk for
movement. Extremity strikes against the wall of the uterus are likely inheriting all or some of the features of h-EDS from an affected parent
the most efficient fetal movement to promote fetal bone strength. Of [28]. When h-EDS is familial, mothers are far more likely to be the
the greater than 100,000 fetal movements during a term pregnancy, transmitting parent than fathers with some studies showing up to 90% of
extremity strikes of the arms and legs vary depending on the gesta­ affected individuals with h-EDS being female [28].
tional age of the fetus. Hayat et al. showed that in the second Some have contended that the association between infants with MUF
trimester when the amniotic fluid volume is 70% of the intrauterine and h-EDS is based on abnormal bone quality or low bone density
volume, the median frequency of arm movements was 35% and leg leading to an intrinsic postnatal bone weakness, especially when vitamin
movements was 38%. Toward the end of the pregnancy when the D deficiency is also present as a risk factor for bone weakness [27].
fetal volume is 70% of the intrauterine volume, the median fre­ Studies of individuals with h-EDS have shown modestly lower bone
quency of arm movements was 20% and leg movements was 15% density and modestly increased risk for fractures in older children and
[21]. The relative decrease in extremity strikes as the pregnancy adults, but no dramatically increased risk for long bone and rib fractures
moves toward term is likely a result of the relative intrauterine in infants like there is in osteogenesis imperfecta [29]. However, the
confinement from an increasing fetal volume and stable amniotic increased risk for fractures in young infants with h-EDS appears real, and
fluid volume. like the other risk factors for MBDI, appears to be transient and not
2. Muscle contractions can also produce strains on the bones that the significantly affecting bone strength after 6 months of life. Infants with
muscle is attached to. Because muscle strength will also increase with MBDI would have an average of 10 fractures at an average age of 9
fetal movements and strikes against the uterine wall, muscle strength weeks and then none after 6 months of life [4]. This suggests the risk
and bone strength are intricately and positively correlated with each factor of joint hypermobility, like bone loading from fetal movement,
other [20]. may have its effect during the fetal time period.
3. Like swimming, a fetus moving in amniotic fluid for some 20 weeks Others have suggested that there is no increased risk for bone
may also experience a drag force which could also theoretically cause fragility in young infants with unexplained fractures in which child
bone strains and osteocyte activation [22]. abuse is alleged and in which the infant and/or parents have joint
hypermobility or h-EDS [30].
The bone strength of the fetus at the time of delivery will, in great
part, determine young infant bone strength and the risk for fragility Hypothesis 1. I hypothesize that fetal joint hypermobility affects fetal
fractures of the young infant in the first 6 months of life. Situations that bone loading. Herein I present a qualitative analysis of the force that is
decease fetal movement will decrease fetal bone strength, and include generated from fetal bone loading on the skeleton in the fetus with
intrauterine confinement, fetal exposure to drugs that decrease move­ normal joint laxity compared to that of the fetus with joint
ment, and fetal immobilization from congenital neuromuscular disor­ hypermobility.
ders. Noteworthy, factors that diminish bone strength have their
greatest influence when the rate of bone growth is the greatest, and the 2. Effect of uterine hyperelasticity on fetal bone loading
fetal time period is the period of time of the highest rate of bone growth
in the human [4]. The uterus has 3 layers – the endometrium, myometrium, and peri­
Bone strength is determined by bone density, bone geometry, and bone metrium. The myometrium is the middle layer and contains muscle,

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M. Miller Medical Hypotheses 164 (2022) 110859

Fig. 1. Leg Strike of Fetus with Normal Joint Mobility (NM) Against Uterine Wall Compared to Fetus with Joint Hypermobility (H)
Definitions:

M = Mass of Fetus; V = Velocity of Fetus When Hits the Uterine wall; UW = Uterine Wall; θ = Initial Angle of Flexion of Knee, same for NM and H; θ-NM = Angle of
Flexion of NM Knee After Strike; θ-H = Angle of Flexion of H Knee After Strike
Fig. 1a. Fetus with Normal Joint Mobility
Fig. 1a-1. The leg of a fetus with normal joint mobility is shown just before the leg hits the maternal uterine wall. The fetal body is represented by the large rectangle,
the 3 joints of the leg (hip, knee, and ankle) are shown by red arrows, and the maternal uterine wall is shown by the narrow rectangle. The hip, knee, and foot all have
angles of flexion while at rest. Only the flexion angle of rest for the knee is shown, angle θ.
Fig. 1a-2. When the fetus hits the maternal wall with velocity = V, the force of hitting the uterine wall causes all 3 leg joints to incur slight additional flexion. This is
only shown for the knee which now is at an angle of θ-NM, just slightly less than θ. The hip and ankle would also experience slight additional flexion, but this is not
shown in the figure.
Because the ankle, knee, and hip joints are of normal strength and mobility, there is minimal additional flexion of these joints, and the fetus immediately rebounds
from the uterine wall with a relatively short time required for deceleration and with the leg in almost the same position as when it hit the uterine wall. The total time
spent in contact with the uterine wall is the Deceleration Time = DT.
Fig. 1a-3. The fetus is now about to fully recoil from hitting the maternal uterine wall with the knee still at angle θ-NM.
Fig. 1a-4. The fetus is now fully recoiled and heading in the opposite direction with the knee now back to the resting flexion angle of θ.
Fig. 1b. Fetus with Joint Hypermobility
Fig. 1b-1. The leg of a fetus with joint hypermobility is shown just before the leg hits the maternal uterine wall. Except for the joint hypermobility, all factors are
initially identical to those in Figure 1a with the fetus having the same mass = M and the leg hitting the maternal uterine wall with the same velocity = V and the same
at-rest angles of flexion for all 3 leg joints.
Fig. 1b-2. When the fetus with joint hypermobility hits the maternal wall, the force of hitting the uterine wall causes all 3 leg joints to incur greater flexion of all 3 leg
joints compared to the fetus with normal joint mobility. The greater the flexion of the knee, the smaller than angle on impact with the uterine wall. For the knee joint
the flexion is θ-H, such that θ-H < θ-NM.
Most importantly, the time that the foot spends against the maternal uterine wall in the fetus with joint hypermobility will be greater than that in the fetus with
normal joint mobility. Thus, the deceleration time in the fetus with joint hypermobility, DT-H, is greater than that in the fetus with normal joint mobility DT-H
> DTNM.
Fig. 1b-3. The fetus is now about to fully recoil from hitting the maternal uterine wall with the knee still at angle θ-H.
Fig. 1b-4. The fetus is now fully recoiled and heading in the opposite direction with the knee now back to the resting flexion angle of θ.
The Figures show the 3 leg joints, but only shows the flexion angle for the knee. The hip and ankle would show similar changes in flexion angle as the for the knee.
Moreover, the same process and thinking applies to the 3 joints of the arm (shoulder, elbow, and wrist). The fetus with joint hypermobility will have a greater decel­
eration time for all 3 arm joints when the arm hits the uterine wall compared to the fetus with normal joint mobility.
The significance of DT-H > DT-NM is that it indicates the force that a fetal skeleton realizes when it strikes the uterine wall is greater in the fetus with normal joint
mobility compared to that of the fetus with joint hypermobility, as indicated from the following analysis:

F = Force on fetal skeleton upon hitting maternal uterine wall; M = Mass of fetus; V = Velocity of strike of fetus against maternal uterine wall; DT = Deceleration
time; F = (M) (A) = (M) (V)/(DT)
F (normal joint mobility fetus) = (M) (V)/DT-NM; F (joint hypermobility fetus) = (M) (V)/DT-H
M and V are the same for both the fetus with normal joint mobility and the fetus with joint hypermobility.
DT-H > DT-NM; therefore
F (NM fetus) > F (H fetus)
Bone loading (NM fetus) > Bone loading (H fetus)

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M. Miller Medical Hypotheses 164 (2022) 110859

collagen and elastic fibers. The myometrium undergoes great change force (F) that results from an extremity kick of the fetus with joint
during the pregnancy to accommodate the growing fetus with the hypermobility against the wall of a uterus with hyperelasticity as shown
collagen content increasing 7 fold and the elastin content increasing 4–5 in Fig. 3.
fold during pregnancy [31].
Most instances of joint hypermobility in infants with unexplained Predicted effect on the fetus.
fractures involve h-EDS with the mother most often being the affected
parent. h-EDS is a systemic disorder. Like the skin which is softer than a. Joint Hypermobility versus Normal Mobility.
normal in h-EDS and tendons and ligaments which are more hyperelastic
in h-EDS than normal, it is likely the uterus in h-EDS is softer and more Upon hitting the maternal uterine wall the analysis indicates that the
hyperelastic than the normal uterus. The following observations support extremity (arm or leg) of the fetus with joint hypermobility will have a
this idea: greater deceleration time than the fetus with normal joint mobility. This
arises because the joints of the extremity (arm = wrist, elbow, and
a. Scanning electron microscopy has demonstrated that the uterine wall shoulder; leg = foot, knee, and hip) in the fetus with joint hypermobility
contains elastic fibers in two forms: fibrils and thin sheets of elastic must all flex to a greater degree than the fetus normal joint mobility
membranes arranged in a honeycomb fashion. It is thought that the before the extremity fully rebounds from the uterine wall, thus requiring
elastin allows for normal expansion of the uterus during pregnancy additional time for this additional flexion compared to the fetus with
so that the feus can occupy unencumbered intrauterine space. The normal joint mobility.
elastin fibers are present in a spongelike matrix that contains flat A greater time for deceleration translates into a smaller force on the
sheets, or lamellae [32]. fetus, and thus a smaller force/load that is transmitted to the osteocytes
b. Transmission electron microscopy of the skin of patients with h-EDS of the skeletal system.
show abnormalities in both collagen fibers and elastin fibers [33,34]
c. Transcriptome studies and cell culture studies indicate the patho­ Force appreciated by osteocytes = F = M × V/Deceleration Time.
genesis of h-EDS is likely a result of abnormalities in connective F (Normal joint mobility) > F (Joint Hypermobility).
tissue, most likely elastin and/or collagen and the interaction of
these structural proteins with the extracellular matrix [35]. Thus, on striking the uterine wall, fetal bone loading is less in a fetus
with joint hypermobility compared to the fetus with normal joint
mobility.
Hypothesis 2. I hypothesize that the composition and elasticity of the
b. Uterus with Hyperelasticity versus Uterus with Normal Elasticity.
uterine wall also affects fetal bone loading. Herein I present a qualitative
analysis of the force that is generated from fetal bone loading on the
A uterus that is hyperelastic will dampen the force of a fetal ex­
skeleton in the uterus with normal elasticity compared to that of the
tremity strike, and similar to fetal joint hypermobility, will increase the
fetus with softness and hyperelasticity.
time for deceleration and thus decrease fetal bone loading.
Thus, on striking the uterine wall, fetal bone loading is less in the
Theoretical considerations. hyperelastic uterus of a woman with h-EDS compared to that of a woman
with a uterus of normal elasticity.
a. Joint Hypermobility versus Normal Joint Mobility
c. Fetus with Joint Hypermobility in Uterus with Hyperelasticity as in
Using the basic physics equation F = MA, I calculated the relative h-EDS.
force (F) that results from an extremity kick against the wall of the uterus
in the fetus with normal joint mobility compared to that of the fetus with A pregnancy in which both the mother and fetus have h-EDS will
joint hypermobility as shown in Fig. 1a and b respectively in which. have both of these factors that diminish fetal bone loading, and this
situation will be the most extreme for causing bone fragility in the im­
M = the mass of the fetus. mediate postnatal period of time.
A = the acceleration/deceleration when the fetus hits the uterine
wall. Discussion
A = V/DT.
V = the velocity of the fetus hitting the wall of the uterus. The following conclusions can be drawn from our application of
DT = the deceleration time, the time the fetal foot spends against the basic physics principles to how fetal joint hypermobility and uterine
wall of the uterus before it recoils in the opposite direction. hyperelasticity affects fetal bone loading:
F is thus is the load that the fetal skeleton would sense from a single
extremity kick that would activate osteocytes that experienced a 1. a fetus with joint hypermobility reared in a normal elasticity uterus
strain from this load. experiences less fetal bone loading than a fetus with normal joint
mobility reared in a normal elasticity uterus.
b. Uterus with Hyperelasticity versus Uterus with Normal Elasticity 2. a fetus with normal joint mobility reared in a hyperelastic uterus
experiences less fetal bone loading than a fetus with normal joint
Using the same approach described above, I calculated the relative mobility reared in a normal elasticity uterus.
force (F) that results from an extremity kick of the fetus against the wall 3. a fetus with joint hypermobility gestated in a hyperelastic uterus,
of a uterus with normal elasticity compared to the uterus of a mother such as occurs in a fetus and mother with-EDS, experiences signifi­
with h-EDS in which the uterus has relative hyperelasticity and softness cantly less fetal bone loading than described above in 1 and 2. The
as shown in Fig. 2a and b. effects are likely additive.

c. Fetus with joint hypermobility in uterus with hyperelasticity as in h- These are not empirical results, but rather possible explanations for
EDS the published observations in Table 2 in which there has been a striking
association between joint hypermobility and infant bone fragility.
Using the same approach described above, I calculated the relative If the hypothesis of diminished bone loading related to fetal

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M. Miller Medical Hypotheses 164 (2022) 110859

Fig. 2. Leg Strike of Fetus Against Uterine Wall of Normal Elasticity (NE) Compared to Uterus with Hyperelasticity (UH)
2a. Uterus with Normal Elasticity
Fig. 2a-1. The leg of the fetus with normal joint mobility hits a uterine wall of normal tissue elasticity (NE).
Fig. 2a-2. Because of the normal elasticity of the uterus there is no significant compression of the uterine tissue, so that the uterine wall remains essentially un­
changed with a thickness of D. Moreover, the fetus has normal joint mobility so that the flexion of the 3 leg joints in hitting the uterus is minimal and the angle of
flexion of the knee of θ-NE is just slightly less than θ.
Fig. 2a-3. The fetus then begins to recoil.
Fig. 2a-4. The fetus is fully recoiled and heading in the opposite direction.
2b. Uterus with Hyperelasticity
Fig. 2b-1. The leg of the fetus hits a uterine wall with tissue hyperelasticity in which the uterine wall thickness is initially D.
Fig. 2b-2. Because of the tissue hyperelasticity, there is compression of the uterine tissue so that the uterine wall thickness is now decreased to thickness d, a
thickness that is less than the initial thickness of D.
Fig. 2b-3. The fetus then begins to recoil.
Fig. 2b-4. On fully recoiling the uterine compression is released, and the uterine wall thickness returns to D.
The time for this deceleration is DT-UH.
Noteworthy DT-UH > DT-NE
Like the fetal joint hypermobility analysis, the significance of DT-UH > DT-NE is the force that a fetal skeleton realizes when it strikes the uterine wall of normal
elasticity is greater compared to that of the fetus who strikes a uterine wall of tissue hyperelasticity such as is seen in h-EDS.
F (normal uterine wall elasticity) = (M) (V)/ DT-NE
F (uterine wall hyperelasticity) = (M) (V)/ DT-UH
M and V are the same for both the fetus with normal joint mobility and the fetus with joint hypermobility.
DT-UH > DT-NE; therefore
F (NE) > F (UH)
Bone loading (NE) > Bone loading (UH)

hypermobility is correct, this would be a possible explanation for the bone strength in the newborn at the time of birth, and this can be
observed association between infant and/or parental joint laxity (usu­ analyzed from both a quantitative and qualitative perspective.
ally h-EDS with affected mother) and unexplained fractures in infants. While the actual number of fetal movements is a quantitative
In the 5 studies noted in Table 2 the infant fractures are likely determinant of fetal bone loading, the biomechanics of the interaction of
fragility fractures as there is almost always no bruising, no swelling, and fetal movement with the uterine wall is a qualitative determinant of fetal
no functional impairment unless they are long bone fractures. Moreover, bone loading. Fetal joint laxity and uterine hyperelasticity can affect the
in 2 of the series the authors note the frequency of infants with 4 or more load that a bone realizes when the fetus hits the uterine wall.
rib fractures and no severe internal thoracic injury with respiratory Hayat et al studied fetal movements at various gestational ages from
distress – in Miller [3] it was 17/26 (65%), and in Miller [4] it was 36/75 18 weeks gestation age to term using MRI and found the following [21]:
(48%). This observation is further compelling evidence that these are
fragility fractures as severe internal thoracic injury and respiratory 1. The frequency of all movement patterns including lower limb
distress would be expected in infants who had normal strength ribs [36]. movements decreased with increasing gestational age.
Thus, fetal movement is the primary cause of developing normal

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M. Miller Medical Hypotheses 164 (2022) 110859

Fig. 3. Fetus with Joint Hypermobility Strikes Uterus with Hyperealsticity

Fig. 3-1. The leg of the fetus with joint hypermobility hits a uterine wall with tissue hyperelasticity in which the uterine all thickness is initially D.
Fig. 3-2. The additive effects of BOTH (B) the fetal joint hypermobility and uterine hyperelasticity cause the knee angle, θ-B, to be significantly less than either θ-H or
θ-UH, and the uterine wall is compressed to d.
Fig. 3-3. The fetus then begins to recoil.
Fig. 3-4. On fully recoiling the uterine compression is released, the uterine wall thickness returns to D, and the knee joint angle returns to the pre-strike angle, θ.
The time for this deceleration is DT-B.
Noteworthy DT-B > DT-H ≈ DT-HU > DT-N; Therefore
Bone loading (N) > Bone loading (H) ≈ Bone loading (UH) > Bone loading (B)
This combination of a fetus with joint hypermobility striking a uterine wall with hyperelasticity occurs in h-EDS.

2. There was a significant reduction in lower limb movement from 30 hypermobile fetus compared to the normal mobility fetus in their ability
weeks gestational age to term that was associated with a high degree to promote bone strength are the direct extremity hits of the fetus
of flexion at the hip and knee joints against the uterine wall. In the second trimester and early third trimester
3. The fetal volume/total intrauterine volume doubled across this these extremity strikes are likely direct with no intrauterine confine­
gestational range which likely explains the difference in the quantity ment. However, in the latter part of the third trimester the extremity
and quality of movements. strikes occur in an environment of relative intrauterine confinement
(Total intrauterine volume = fetal volume + amniotic fluid where the various joints of the extremities will be more flexed compared
volume) to earlier gestational ages as a result of the more limited space. This
degree of flexion at different gestational ages will likely be less in the
The different fetal movements will have different likelihoods of fetus with normal joint mobility compared to the fetus with
promoting fetal bone strength. Hiccups and stretching will have little hypermobility.
effect on causing a strain that the osteocyte will appreciate. Trunk and During a normal, full term pregnancy the tens of thousands of
whole body movements are appreciated as being strong movements by effective fetal movements that cause osetocyte activation are the critical
the mother and will likely cause local strains that may be transmitted quantitative determinant of fetal bone loading and strength. The inter­
more distally. These movements clearly can promote bone strength, but action of fetal movement with the uterine wall is a qualitative deter­
are likely no different in fetuses with normal joint mobility compared to minant of fetal bone loading and strength. Not only is the quantity of
those with joint hypermobility. fetal movement critical in determining fetal bone strength, but also the
The fetal movements that are likely to be different in the quality of the movement.

7
M. Miller Medical Hypotheses 164 (2022) 110859

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Ehlers-Danlos/hypermobility syndrome and or vitamin D deficiency: a case series
Declaration of Competing Interest of 72 infants whose parents were accused of child buse and neglect. Dermato-
endocrinology 2017;9(1):e1279768.
[28] Tinkle B, Castori M, Berglund B, Cohen H, Grahame R, Kazkaz H, et al.
The authors declare that they have no known competing financial
Hypermobile Ehlers–Danlos syndrome (aka Ehlers–Danlos syndrome Type III and
interests or personal relationships that could have appeared to influence Ehlers–Danlos syndrome hypermobility type): Clinical description and natural
the work reported in this paper. history. In American Journal of Medical Genetics Part C: Seminars in Medical
Genetics (Vol. 175, No. 1, pp. 48-69). 2017;9.
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