The environmental differences between twins in utero and their importance for downstream development: a need for standardized monitoring in obstetric research

Abstract

The journey from fertilization to birth is a hazardous one, in which development and environment interact. Twin studies are ideal for comparing measurable parameters along this journey and how these affect the developing fetuses, newborns, and children. However, although perinatal outcomes have been studied in relation to specific intrauterine factors, a sufficient breadth of factors has not been covered. Moreover, few studies have focused on outcomes beyond birth. In this chapter, we review studies of the multitude of developmental factors that come into play between fertilization and birth. In doing so, our aim is that such factors can be recorded and used to enrich longitudinal studies of the effect of prenatal experience on perinatal and postnatal health and disease.

Full text

CHAPTER
21
The environmental differences
between twins in utero and their
importance for downstream
development: a need for standardized
monitoring in obstetric research
Jeffrey M. Craig
1
, Emma K. Sutton
2
and Shayesteh Jahanfar
3
1
Centre for Molecular and Medical Research, School of Medicine, Deakin University, Geelong,
VIC, Australia
2
School of Medicine, Deakin University, Geelong, VIC, Australia
3
MPH Program, Central Michigan University, Mt Pleasant, MI, United States
OUTLINE
Rationale and aims 322
The developmental origins of health
and disease 322
The nonshared uterine environment
and the importance of twin data 323
The placenta 324
The fetoplacental unit and placenta
development 324
Twin placentation 324
Placental nonshared factors 325
Placenta examination 325
Placental placement and position 325
Placental pathology and growth
discordance 326
Placental lesions 328
The umbilical cord 329
Anastomoses 329
Atypical location of cord insertion 329
321
Developmental and Fetal Origins of Differences in Monozygotic Twins
DOI: https://doi.org/10.1016/B978-0-12-820047-6.00021-7 ©2020 Elsevier Inc. All rights reserved.

Cord diameter 331
Cord length 332
Other cord parameters 332
Predictive accuracy of birth weight
discordance in utero 333
Infection 334
Placental rupture and exposure to
hypoxia at birth 338
Birth order and birth interval 338
Discussion 339
References 340
Further Reading 343
Abstract
The journey from fertilization to birth is a hazardous one, in which development and environment interact.
Twin studies are ideal for comparing measurable parameters along this journey and how these affect the
developing fetuses, newborns, and children. However, although perinatal outcomes have been studied in
relation to specific intrauterine factors, a sufficient breadth of factors has not been covered. Moreover, few
studies have focused on outcomes beyond birth. In this chapter, we review studies of the multitude of
developmental factors that come into play between fertilization and birth. In doing so, our aim is that such
factors can be recorded and used to enrich longitudinal studies of the effect of prenatal experience on peri-
natal and postnatal health and disease.
Keywords: Twin; pregnancy; placenta; umbilical cord; environment; monitoring; ultrasound; perinatal out-
comes; birth
Rationale and aims
The aim of this chapter is to review the measurable differences in the uterine develop-
ment within pairs of twins and to discuss the medical relevance for offspring health at
birth and beyond. A better understanding of these factors will facilitate further studies
into the role of early life environment on lifelong health and disease. We focus on twins
because they provide a controlled model to measure the magnitude of these measurable
differences. However, most of the factors we identify are measurable and relevant in sin-
gletons. We start by discussing the evidence for the early life origins of health and disease,
then introduce the concept of nonshared, twin-specific factors. We go on to discuss twin-
specific effects relating to the placenta and umbilical cords. We also focus on inflamma-
tion, a clinically important nonshared factor, and birth weight, a proxy for an intrauterine
nonshared environment. We finish by recommending specific, measurable factors to
record in future studies of the early life origins of chronic disease.
The developmental origins of health and disease
Historically, fetal medicine has centered on the production of live births and the
minimization of morbidity and mortality. However, there has been a recent shift in
322 21. The environmental differences between twins in utero and their importance for downstream development
Developmental and Fetal Origins of Differences in Monozygotic Twins

this thinking toward a broader understanding of how intrauterine development and
fetal outcomes can be intermediates of future health outcomes throughout life (Barker,
1990). The interaction between genetics and prenatal environmental factors was first
proposed in the late 1990s by Barker and colleagues, who theorized that maternal mal-
nutrition could lead to “fetal programming,” which would permanently shape metabo-
lism, anatomical structure, and physiological function, and have lasting effects on later
disease risk (Barker, 1990; Knopik et al., 2016; Barker and Clark, 1997). Thus the reason
that studying such characteristics in twins is important is that by doing so, we gain
the potential to record and track their consequences in both twins during gestation, at
birth and during postnatal life into adulthood (Knopik et al., 2016; Stromswold, 2006).
In light of this realization, the measurements we are able to record during fetal develop-
ment now have lifelong implications. For example, it is well recognized that low birth
weight is associated with a higher risk of developing type 2 diabetes and cardiovascular
and metabolic disease (Godfrey and Barker, 2001). The current measurements and data
recorded during fetal development vary between hospitals and between professions (e.g.,
ultrasonographers and obstetricians and midwives). There is, therefore, a need to univer-
sally standardize a specific set of measurements to accurately add to a pool of data that
can be used to analyze ongoing trends in childhood and adult health that can be traced
back to characteristics of prenatal development.
The nonshared uterine environment and the importance of twin data
Classical twin models can estimate the proportion of variance of any phenotype due to
genetics, shared, and nonshared factors (Boomsma et al., 2002). During fetal development,
nonshared factors include a mix of stochastic developmental variation and twin-specific
environments (Knopik et al., 2016; Stromswold, 2006). Both types of nonshared factors are
relevant to this chapter with the implication that the former can influence the latter. For
example, natural variation in placental structure may influence fetal growth. Whether or
not a particular “environment” (e.g., antibiotics for infection) can be modified in utero,
will determine the extent to which prevention or intervention is possible once identified.
Known nonshared factors include, but are not limited to, placental placement and posi-
tioning, differences in cord formation and thickness, ascending vaginal infections, growth
patterns and parameters, birth order and birth intervals, exposure to hypoxic events, and
placental rupture during the birthing process (Antoniou et al., 2013; Tore et al., 2018). As
the multitude of physical, biochemical differences within monozygotic (MZ) twin pairs at
birth and beyond, nonshared factors can have a major effect on phenotype (Knopik et al.,
2016; Stromswold, 2006). Moreover, not only will we be able to use these findings to better
understand multiple gestations, but also the data we record in these cases can be studied
in singletons.
We will focus first on the placenta as part of the fetoplacental unit in twin pregnancies,
in the context of placental development.
323The nonshared uterine environment and the importance of twin data
Developmental and Fetal Origins of Differences in Monozygotic Twins

The placenta
The fetoplacental unit and placenta development
The fetalplacentalmaternal unit or simply the “fetoplacental unit” is a highly special-
ized group of organs unique to pregnancy and responsible for passing blood and its con-
tents through the placenta and umbilical cords, to and from mother and fetus, and for
regulating placental endocrine function (Wang and Zhao, 2010). Early in pregnancy, after
fertilization, the blastocyst segregates its outer cells from the small inner mass. The inner
cell mass will become the fetus, and the outer cells, or trophoblast, will develop into the
placenta. Over the next few days of development, the trophoblast invades into the uterine
layers, a process called implantation. Over the following few weeks, the placenta begins to
secrete hormones that control the basic physiology of the mother so that the fetus is sup-
plied with the essential nutrients and oxygen required for effective growth. The placenta
also removes carbon dioxide and other waste products from the fetus and releases meta-
bolic products into the fetomaternal circulations. The placenta also produces hormones
that not only mature the fetal organs in preparation for life outside of the uterus but also
releases hormones into the fetomaternal circulation to regulate fetal growth, parturition,
and other functions.
Twin placentation
The placenta is continuous with the chorion or outer sac. The amnion, or inner sac, sur-
rounds the amniotic fluid. Twins pregnancies have three types of chorionamnion
(McNamara et al., 2016).
Dichorionicdiamniotic (DCDA) twins with separate placentas, amniotic sacs and
umbilical cords can be either dizygotic (DZ) or monozygotic (MZ). DZ twins form a com-
bination of two separate eggs fertilized by two separate sperms. In this case, each embryo
will develop its own placenta. Sometimes, however, placentas may grow in proximity and
fuse. MZ twins form from a single egg and sperm, and within a few days of fertilization,
the early embryo undergoes splitting. Although we do not know the exact timing of split-
ting, we know that earlier splitting results in dichorionicdiamniotic twins, implanting
separately in the endometrium and developing separate placentas. Again, if the two sepa-
rate placentas grow in proximity, they may overlap and fuse.
Monochorionic-diamniotic (MCDA) twins, which are thought to split later than DCDA
twins, share the same placenta, usually have separate amniotic sacs, and always have their
own umbilical cords. They are usually MZ, with exceptions (McNamara et al., 2016), and
account for approximately one third of MZ twins. MCDA embryos will develop with a
single, shared placenta (MC). In most cases, these twins will develop individually, within
separate amnions (DA).
Monochorionicmonoamniotic (MCMA) twins are the rarest type of twins and occur in
approximately 1% of twin pregnancies. MCM twins share one placenta and one amniotic
sac and are always MZ. Both types of MC twins have a higher risk of complications com-
pared to DC twins (McNamara et al., 2016).
324 21. The environmental differences between twins in utero and their importance for downstream development
Developmental and Fetal Origins of Differences in Monozygotic Twins

Placental nonshared factors
Twin-specific developmental stochasticity influences placental growth, the extent to which
a single placenta is shared by MC twins, where the cord enters each placenta, and the vascu-
lature in each placenta. In extreme cases, unequal sharing of such factors can result in compli-
cations in twin pregnancies. For example, blood vessels from MC twin placentas can connect,
and result in blood sharing, sometimes unequally. Since MZ twins have the same blood type,
this is not a medical issue in itself. However, in approximately 15% of MC twin pairs, there is
an unequal sharing of blood, leading to twin to twin transfusion syndrome (TTTS), which if
not treated, can lead to the death of both twins (McNamara et al., 2016). Twins may also share
placental resources unequally, which affects the delivery of nutrients, gas exchange, and
waste removal, which may directly impact fetal growth (Lewi et al., 2007). Unequal placenta
sharing depends on where the cord is inserted into the placenta (e.g., center, margin, or mem-
branes), and how the resources are subsequently shared within a twin pair. This issue has an
impact on twin growth and development (Fick et al., 2006).
Placenta examination
Placenta examination, both gross and microscopic, is useful to uncover the nature of
intrauterine impairment of twin growth. Studies in singleton pregnancies have shown smal-
ler, lighter placentas with morphological changes in villus structure in placentas of fetuses
affected by intrauterine growth impairment (McFayden et al., 1986; Montenegro et al., 1997;
Doubilet et al., 1997; Salafia et al., 2006). Microscopic and macroscopic examination of the
placenta is, therefore, important in the evaluation of growth discordance (Kent and
Dahlstrom, 2006). Impaired fetal growth has been attributed to defective trophoblast inva-
sion (Sebire and Sepulveda, 2008) and placental infarcts (Eberle et al., 1993; Montenegro
et al., 1997) leading to impaired development of the uteroplacental circulation.
Placental placement and position
The blood supply to the uterus is not uniform and thus the positioning of the attached
placenta is important when assessing placental blood (Zia, 2013). An increasing number of
studies have looked at the association between placental positioning, pregnancy complica-
tions, and fetal outcomes. However, there have been few strong findings (Ebbing et al.,
2013). There are a few major locations at which the placenta can attach and develop. In pos-
terior and anterior attachment, the fertilized ovum attaches to the posterior (back) or the
anterior (front) walls of the uterus, respectively. In fundal attachment, the placenta attaches
the top part of the uterus. In the placenta previa, the placenta attaches at the lower end of
the uterus and grows toward the cervix (Ebbing et al., 2013; Ismail et al., 2017). Studies have
shown that the placement of the placenta may influence the presentation of the fetus and
thus determine the mode of delivery and likelihood for delivery complications (Ismail et al.,
2017; Hacker et al., 2015). For example, in some cases of placenta previa, the placenta grows
325Placental placement and position
Developmental and Fetal Origins of Differences in Monozygotic Twins

in such a way the cervix is blocked, which usually requires a cesarean section for safe
delivery. Some have found that a posterior placement is associated with preterm labor and
others that fundal placement increased the risk of premature rupture of the membranes
leading to a hypoxic risk for the fetus (Butler and Behrman, 2007). To our knowledge, no
studies have looked at the long-term influence of placenta position.
Placental pathology and growth discordance
Birth weight discordance (BWD) is calculated by dividing the difference between the
heavier and lighter twin by the weight of the heavier twin and expressing the result as a
percentage. Pathophysiological changes in the placenta in relation to BWD have been stud-
ied in the literature. Eberle et al. (1993) examined placental abnormalities of 147 structurally
normal twin pairs with cords labeled at delivery and significant BWD was defined as
.20%. The authors concluded that in DC twins, significant BWD was attributable not to dif-
ferences in placental weight but to a greater number of placental lesions in the lighter twin
than in the heavier twin (P,.05). This did not hold true for MC twins. Victoria et al. (2001)
studied 382 twin pregnancies with a cut-off of 25% for significant BWD. The strongest asso-
ciations with BWD were placental weight discordance and discordance in umbilical cord
abnormalities.
The studies above are limited by small numbers, inadequate control of confounding fac-
tors such as maternal morbidities, single stillbirth, and a failure to exclude twins with con-
genital anomalies. Moreover, in cases of multicenter studies, placenta examination was
carried out in different pathology laboratories that applied different approaches in exami-
nation of placentas and cords. This could lead to variation between pathology results.
To counteract these inaccuracies, SJ and colleagues conducted a study on twins to assess
pathological characteristics of placenta and cord in relation to BWD in a large cohort of
twin data (1571 twin pregnancies) collected over a 10-year period (Jahanfar and Lim,
2018). The advantage of this study over previously mentioned studies was the exclusion of
twins born with congenital anomalies, missing birth weight data, and those born at less
than 20 weeks of gestation. Moreover, cases with TTTS, twins with one single stillbirth,
twins lighter than 500 g, and those who underwent reduction procedures in utero were
excluded from the study. A standardized placental pathology examination was carried out
in one hospital. Pathology data were then linked to delivery outcome data such as gesta-
tional age and birth weight. To identify the trend of change in growth discordance, twins
were divided into four groups of BWD: 10% or less (reference category), 11%20% (mild),
21%30% (moderate), and .30% (severe; Table 21.1). Higher frequencies of unequal pla-
centa sharing were found in twins with moderate as well as severe growth discordance.
The relationship with BWD and unequal placenta sharing was also studied in a pro-
spective cohort of 522 MC/DC twin pregnancies using dye injection studies on fresh post-
partum placentas (Fick et al., 2006). The study revealed that 50% of the cases with
BWD .20% had unequal placenta sharing compared with 10.4% of the cases without
unequal placenta sharing (P5.01). The phenomenon of increasing placenta territory dis-
cordance leading to discordant growth is thought to result from unequal splitting of the
initial cell mass (Breathnach and Malone, 2012).
326 21. The environmental differences between twins in utero and their importance for downstream development
Developmental and Fetal Origins of Differences in Monozygotic Twins

TABLE 21.1 Comparisons of placenta and cord characteristics in groups with and without $20% BWD or
$30% growth discordance for twin gestations (1466 pairs, n52932).
BWD
Less than 20%
N52436
20% and more
N5496 Pvalue
Less than 30%
N52730
30% and more
N5194 P
Placenta
Chorionic villi inflammation 221 (9.1%) 43 (8.7%) 0.43 251 (9.2%) 13 (6.7%) 0.15
Chorionitis 179 (7.3%) 34 (6.9%) 0.39 206 (7.5%) 7 (3.6%) 0.02
Anastomosis 209 (8.6%) 54 (10.9%) 0.06 245 (8.9%) 18 (9.3%) 0.48
Unequal placenta sharing 74 (3.0%) 64 (12.9%) 0.01 114 (4.1%) 24 (12.4%) 0.02
Composite of inflammation 325 (14.4%) 63 (12.7%) 0.38 372 (13.6%) 16 (8.2%) 0.04
Composite placenta lesions 49 (2.0%) ,5 (0.2%) 0.08 53 (1.9%) ,5 (0.2%) 0.11
Cord composite 7 (0.3%) ,5 (0.2%) 0.59 7 (0.3%) ,5 (0.2%) 0.42
Placentation 33 (1.4%) ,5 (0.2%) 0.12 34 (1.2%) ,5 (0.2%) 0.57
Average placenta
weight, g
534.37 6228.00 538.62 6234.54 0.77 534.13 6230.36 550.07 6205.61 0.49
Average placenta
length, cm
22.02 65.14 22.3565.29 0.32 22.04 65.16 22.61 65.23 0.27
Average placenta
width, cm
16.98 63.96 17.16 64.05 0.48 17.00 63.99 17.14 63.84 0.73
Average placenta thickness,
cm
2.13 60.47 2.12 60.43 0.74 2.12 60.46 2.15 60.46 0.64
Cord
Cord length, cm 28.14 612.73 24.19 611.89 0.01 27.76 612.61 23.07 612.68 0.01
Cord distance from margin,
cm
4.61 62.24 4.63 62.45 0.54 4.63 62.29 4.39 62.31 0.09
Cord distance from
membrane, cm
6.54 63.84 6.90 64.62 0.81 6.63 63.93 6.25 64.69 0.22
Cord distance from the
other cord, cm
14.23 68.85 13.81 65.60 0.30 14.29 68.53 12.54 65.10 0.46
Cord insertion type
Marginal 1949 (80.0%) 377 (76.0%) 0.21 2176 (79.7%) 142 (73.1%) 0.01
Central 388 (15.9%) 93 (19.3%) 446 (16.3%) 35 (18.0%)
Velamentous 99 (4.1%) 26 (5.0%) 108 (3.9%) 17 (8.7%)
Velamentous vs marginal 99 (4.1%) 26 (5.2%) 0.39 108 (4.0%) 17 (8.8%) 0.01
Velamentous vs central 99 (4.1%) 26 (5.2%) 0.14 108 (4.0%) 17 (8.8%) 0.01
Marginal vs central 1688 (69.2%) 336 (67.7%) 0.08 1901 (69.6%) 123 (63.4%) 0.19
327Placental pathology and growth discordance
Developmental and Fetal Origins of Differences in Monozygotic Twins

Another small prospective study of 100 MC twins investigated the relationship between
placenta territory and BWD from pregnancies not complicated by TTTS. All samples were
from pregnancies with two live-born twins. Placental territory discordance was calculated
by dividing the venous surface area of the larger placental part by that of the smaller.
Unequal placental sharing was defined as a placental territory discordance of $1.5.
Placental territory discordance increased with BWD (P5.001) (Lewi et al., 2007). The
study showed that regardless of the level of BWD severity, a higher percentage of unequal
sharing of the placenta is expected among twins with BWD compared to concordant twins.
The relationship between BWD and degree of placenta sharing remained strong even after
adjustment for chorionicity (odds ratio 4.56 vs 4.26 for BWD $20% and 2.01 vs 2.00 for
BWD $30%, Table 21.2). Higher odds for the threshold level of $20% compared to
$30% could be the result of differences in the depth of the anastomosis or type of anasto-
mosis (arteryartery vs arteryvein).
Placental lesions
Singleton pregnancies have higher rates of morphological changes in villus structure in
the placentas of fetuses affected by intrauterine growth restriction (McFayden et al., 1987;
Montenegro et al., 1997;Salafia et al., 2006). The abnormalities in the villus structure are
due to defective trophoblastic development leading to impaired uteroplacental circulation.
An association between placental infarcts (obstruction to blood supply) and impaired uter-
oplacental circulation of growth restricted fetuses has been reported in singleton pregnan-
cies (Montenegro et al., 1997; Sebire and Sepulveda, 2008). In twin pregnancies, such a
relationship has also been previously studied (Victoria et al., 2001; Blickstein et al., 2006)
but publications on gross and histological placental examination of MC and DC twins are
rare. Two retrospective studies evaluating placenta histology have been limited by a small
sample size (Eberle et al., 1993; Victoria et al., 2001). A retrospective study of 147 twin
pairs (99 DC and 48 MC) suggested that in DC twins, BWD .20% is associated with a
greater number of placental lesions in the lighter twin than in the heavier twin (P,.05)
(Eberle et al., 1993). The other study included 388 DC and 89 MC twin pregnancies and
found significantly more vascular thrombotic lesions in the placental domains of the smal-
ler twin in DC pairs (Victoria et al., 2001).
TABLE 21.2 Unadjusted and adjusted odds of anastomosis and unequal placenta sharing in relation to
BWD .20% and .30%.
BWD $20% BWD $30%
Unadjusted Adjusted
a
Unadjusted Adjusted
a
Placenta
Anastomosis 1.30 (0.951.79) 0.92 (0.641.31) 0.96 (0.581.59) 0.57 (0.330.98)
a
Unequal placenta sharing 4.26 (2.706.70) 4.56 (2.706.70)
a
2.01 (1.083.72) 2.00 (1.073.76)
a
a
Adjusted for chorionicity.
328 21. The environmental differences between twins in utero and their importance for downstream development
Developmental and Fetal Origins of Differences in Monozygotic Twins

A prospective study of 668 twin pairs (21.1% MC and 78.9% DC) analyzed a composite
variable of placental pathology including evidence of infarction, retro-placental hemor-
rhage, chorangioma (hamartoma), subchorial fibrin, and abnormal villus maturation.
These histological abnormalities were more frequent in placentas of smaller twins of BWD
pairs (P5.02) and in the placentas of small for gestational age, defined as birth weight
less than the 10th percentile (P5.01). Such associations were observed in DC twins but
not in MC twins (Kent et al., 2012). Author SJ did not find such differences (Jahanfar and
Lim, 2019), potentially due to a smaller number of lesions in the study population, which
could be due to the retrospective nature of the data. The incidence of composite placenta
lesions was 13.2% with a slightly higher frequency in MC compared to DC twins (2.6% vs
1.6%), although this difference was not significant. Lower frequencies of inflammation of
chorion and composite inflammation were found in BWD of $30% compared to growth
concordant twins.
Another reason for differences between findings in a Canadian study (Jahanfar and Lim
2019) and the study of SJ described here could be greater sample size in the latter study as
well as specific differences in defining the composite variable, or measurement bias.
Composite placental pathological lesions included in the Canadian study were inclusive of
placental infarction, chorangioma, subchorial fibrin deposition, and retro-placental hematoma.
The umbilical cord
Anastomoses
Umbilical cord abnormalities are relatively common in MZ twins and can have serious con-
sequences on development. Interplacental vascular anastomoses are one of the common pre-
sentations in twins, with data suggesting it occurs in 90% of twin pregnancies (Hacker et al.,
2015). There are three kinds of anastomoses, with the most common being artery to artery to
artery (AA), then arterialvenous, and finally venousvenous (Hubinont et al., 2015). Such
vascular communication between the fetuses may cause a number of complications such as
fetal loss, hydramnios, fetal malformations, and TTTS. AA anastomoses can result in structural
malformation as the arterial blood from the donor twin enters the arterial circulation of the
recipient twin and vice versa. This may cause thrombosis within critical organs or closure of
vessels,partsofthecord,orevenorificessuchasthedevelopingearsduetotrophoblastic
embolization. The recipient twin, who is perfused in a reverse direction, also receives poorly
oxygenated blood and this can alter normal development (Hubinont et al., 2015).
Absence of one of the umbilical arteries occurs in up to 4% of twins compared to 1% in
singleton births. Thirty percent of such cases result in congenital abnormalities such as
failure to develop one or more of the fetal kidneys (Hacker et al., 2015).
Atypical location of cord insertion
Velamentous cord insertion (VCI), when the umbilical vessels fail to develop suffi-
ciently and insert into fetal membranes rather than the center of the placenta, occurs in 1%
329Atypical location of cord insertion
Developmental and Fetal Origins of Differences in Monozygotic Twins

of singleton pregnancies, 10% of twin pregnancies, and 50% of triplet pregnancies
(Feldman et al., 2002). In such circumstances, cords vessels travel within the chorion and
amnion to the placenta, leaving the vessels exposed and no longer protected by Wharton’s
jelly, which protects and insulates umbilical blood vessels. This makes the vessels vulnera-
ble to rupture, particularly if they are covering the cervix, which is a condition known as
vasa previa, the risk of which is also increased in multiple gestations (Loos et al., 2001;
Hacker et al., 2015). Similarly, marginal insertion of the cords (outer 50% of the placenta
radius) occurs when the vessel attaches away from the center of the placenta to a thinner
portion around the edge and consequentially, there is insufficient functioning of the
placenta resulting in a developmental deficit in the reliant fetus.
An association between VCI and compromised fetal growth in singleton pregnancies is
a longstanding discovery (Bjøro, 1983). In twin gestations, the effect of VCI is dependent
on chronicity. A high incidence of VCI in twins (21%) was reported to be significantly
more common in MC than DC twin pairs (18% vs 6%; P5.001) (Hanley et al., 2002).
Moreover, the effect of VCI on BWD has been reported to be 13.5 3greater for MC twin
gestations than for DC twins.
Another study (Costa-Castro et al., 2016) showed that the prevalence of VCI is higher in
MC twins than in DC twin pregnancies. VCI is not associated with the development of
TTTS but increases the risk of adverse outcomes. Both VCI and TTTS independently
increased the prevalence of intrauterine fetal death and lower gestational age at birth in a
similar way, showing that VCI is an important indicator of adverse perinatal outcome in
monochorionic twins.
In the Canadian study (Jahanfar and Lim, 2019), the VCI of one twin was associated
with BWD. Twins with severe discordance had a higher frequency of VCI compared with
both central (32.7% vs 19.5%, P5.02) and marginal (12.1% vs 5.4%, P5.01) insertions.
Severely growth discordant twins had higher odds of getting their nutrients from a pla-
centa with VCI than a placenta with a central cord. This finding has been reported in pre-
vious studies with a smaller sample size of MC twins (De Paepe et al., 2010). A matched
case-control study of 47 twin pairs compared the placental characteristics of MC placentas
from pregnancies with BWD .25% with a control group of MC placentas without BWD
matched for gestational age at birth. The rate of VCI was significantly different in BWD
twins compared with concordant ones (30% vs 16%, P5.036) (36).
In the Canadian study, a similar result was found even after adjusting for chorionicity
and gestational age (Jahanfar and Lim, 2019 unpublished). An ordinal regression analysis
of cord insertion type suggested that BWD $30% was related to type of cord insertion for
two comparisons: velamentous versus central (inner 50% of the placenta radius) and vela-
mentous versus marginal. If the twin pair had severe growth discordance ($30%), VCI
was more likely than marginal cord. Also, if a twin pair had severe growth discordance,
central cord insertion was more likely compared to VCI (Table 21.3). The above analysis
was repeated for BWD $20% with no significant results (data not shown).
A prospective study of 319 twins also found a higher frequency of VCI in twins with
BWD of $20% compared with growth concordant twins (22% vs 8%, P5.001) (Zhao
et al., 2015). A total of 369 MC placentas were analyzed in another study of MC placentas,
and the frequency of VCI was found to be 36% in BWD twins compared to 21% in normal
MC group (P5.06).
330 21. The environmental differences between twins in utero and their importance for downstream development
Developmental and Fetal Origins of Differences in Monozygotic Twins

A higher incidence of VCI has been reported in twins with TTTS compared with non-
TTTS placentas (Bosselmann and Mielke, 2015). In view of this finding, an etiologic role
for VCI in the impaired growth of fetus is linked with TTTS. The authors proposed that
TTTS could result from hemodynamic instability due to reduced blood flow to the donor
twin with a VCI, hence growth impairment in a donor twin. SJ’s study excluded twins
with TTTS and still found a relationship between VCI and BWD despite adjustment for
chorionicity (Jahanfar and Lim, 2018). This conclusion is in the light of the fact that we
were unable to show any association between VCI and placenta sharing, or other placenta
lesions. Thus the reason(s) for association between BWD and VCI remains unknown.
SJ’s study suggests that twins were more likely to show growth discordance at birth if
the cord was inserted into the placenta marginally rather than centrally in either twin
(Jahanfar and Lim, 2018). This finding is in agreement with the result of a study of 60 MC
twins in that when one placental cord insertion site was central and the other was mar-
ginal, 33% of twin pairs exhibited a BWD of at least 20% (Machin, 1997) The study did not
separate the marginal insertion and VCI due to low numbers.
A larger, prospective study of cord insertion type and growth discordance was also con-
ducted on a large population of 806 twin pairs (165 MC, 651 DC). MC twins had higher rates
of marginal (P5.0068) placental cord insertion. A significant association between noncentral
(combined marginal and velamentous) placental cord insertion sites and growth abnormali-
ties was reported in MC twins but not in DC twins (Kent et al., 2012). The Canadian study
finding (Jahanfar and Lim, 2019) is in agreement with this study because the ordinal regres-
sion model showed higher odds of BWD in marginal versus velamentous cord insertions.
These odds were adjusted for chorionicity, sex discordance, and gestational age.
Cord diameter
The diameter of the cord is also seldom measured but is theorized to play an impor-
tant role in the discordance growth patterns between monozygotic twins. Cord diameter
TABLE 21.3 Regression analysis of cord length and type of cord insertion, beta, significance of each term in
the model, and 95% confidence interval.
Dependent variable Independent variable Beta (SE) Pvalue 95% CI
Cord length BWD $30%
a
23.13 60.84 0.060 20.06 to 22.02
Chorionicity 0.98 60.53 0.001 0.89 to 3.12
Sex discordance 21.20 60.46 0.010 22.10 to 20.29
Gestational age 0.684 60.07 0.001 20.52 to 9.06
Marginal vs central BWD $30%
a
20.05 60.25 0.830 25.40 to 0.432
Velamentous vs central 0.86 60.17 0.001 0.537 to 1.185
Velamentous vs marginal 2.23 60.26 0.001 1.73 to 2.73
a
Adjusted for chorionicity (Ref 5MC), sex discordance, and gestational age.
331Cord diameter
Developmental and Fetal Origins of Differences in Monozygotic Twins

can also vary between twins during multiple gestations (Hubinont et al., 2015; Guo et al.,
2017). This can lead to unequal distribution of oxygen and nutrients between the twin pair
resulting in growth discordance (Guo et al., 2017). Uniquely, MCMA twins can experience a
forking of the cords from the placenta (Fraser et al., 1997). There is a high prevalence in this
case that one of the bifurcated cords has a significant difference in thickness compared to
the second twin’s cord, and this often results in TTTS and growth restriction of the twin
with the thinner cord (Guo et al., 2017).
Cord length
Cord length in twins can also vary, ranging from between 3570 cm. Anything outside
this range is seen to have a negative impact on the health and development of the fetus
(Bosselmann and Mielke, 2015). Twins are reported to have, on average, a 7.9 cm shorter
umbilical cord compared with singleton pregnancy (Soernes and Bakke, 1987). Shorter
cord length is associated with a high spontaneous abortion rate while longer cord length is
associated with knotting or looping of the cord as well as cord prolapse ( Balkawade and
Shinde, 2012;Antoniou et al., 2013;Bosselmann and Mielke, 2015).
A higher incidence of short umbilical cords (less than 35 cm in length) is also reported
in twins compared to single pregnancies (Loos et al., 2001). The relationship between
BWD and length of cord has been investigated in the literature controlling for the impact
of gestational age (Szyma´
nski et al., 2010). SJ’s study investigated such a relationship
(Jahanfar and Lim, 2018). Adjusted for gestational age, sex discordance, and chorionicity,
the BWD was statistically significantly related to cord length suggesting that shorter
cords by an average of 3.13 cm are associated with severe growth discordance.
Additionally, results from SJ study suggest that shorter cords yield lighter twins
(27.48 612.47 vs 25.25 612.03, P5.01). A lighter twin was defined as a twin who was
lighter than the cotwin within a growth discordant pair. The results for the lighter dis-
cordant twins (n5236) were compared to the combined group of heavier cotwins and
twins with concordant birth weight (n51214). Such a finding has not been reported in
the literature and it could be due to higher pressure needed to transfer blood to the
fetus, a physiological phenomenon that is absent in shorter cords with normal thickness.
A small study of 24 MC and 200 DC placentas (Umur et al., 2003) showed statistically
significant differences between the length of the umbilical cords in MC and DC twins.
Unlike the Canadian study, this study included TTTS cases in the analysis. No informa-
tion about BWD was reported in this study.
Other cord parameters
Within- and between-pair differences have been observed for cord coiling, and the
number of twists per unit cord length can impact upon the flow rate and thus the delivery
of oxygen and nutrients to the recipient fetus (Antoniou et al., 2011).
332 21. The environmental differences between twins in utero and their importance for downstream development
Developmental and Fetal Origins of Differences in Monozygotic Twins

Predictive accuracy of birth weight discordance in utero
There is a need for standardized monitoring of fetal growth parameters in obstetric
research, as the existing ultrasound screening is not optimal. Here, we report on system-
atic reviews that have illustrated this important point using standard diagnostic accuracy
methods.
A Cochrane diagnostic accuracy systematic review was conducted by SJ and colleagues
to estimate the diagnostic accuracy of different estimated biometric ultrasound measures
and to provide readers with a summary of the predictive accuracy of ultrasound measures
for the diagnosis of BWD in twin gestations (Jahanfar et al., 2017a, b). The authors used 20%
and 25% thresholds with actual BWD as the reference standard compared with estimated
BWD measured in utero (e.g., abdominal circumference or femural length measurements).
The justification for this review was that guidelines provide conflicting advice about the
time, frequency and type of measures reliable to diagnose growth discordance in
American (Wenstrom et al., 2004) and Canadian (Okun et al., 2000) Obstetrics and
Gynecology Guidelines.
The American College of Obstetricians and Gynecologists (ACOG) recommends screen-
ing ultrasounds in MC twins every 2 to 3 weeks from 16 weeks’ gestation (Packham 2011).
For DC twins, issues related to fetoplacental perfusion leading to growth discordance can
be clarified by such screens. However, there are no guidelines on the optimal gestation at
which to start screening, or the frequency and gestational ages for subsequent screenings.
Moreover, sex was found to be an important factor that has interaction with BWD and
perinatal outcomes (Melamed et al., 2009). Identifying the sex of the fetus by ultrasound
improves predictability of prenatal outcomes (Di Renzo et al., 2007). Thus the accuracy of
ultrasound to identify sex is also crucial.
The variation in guideline recommendations arises from the fact that the ability to esti-
mate abnormal growth is challenging. Estimated fetal weight (EFW) is calculated as the
weight of the heavier twin minus weight of the lighter twin, divided by the weight of the
heavier twin. It is not clear whether the prenatal prediction of a critical BWD by the EFW
formula 2 to 3 weeks prior to delivery (Caravello et al., 1997), provides an accurate estima-
tion of actual BWD (Kalish et al., 2003; Klam et al., 2005; Lewi et al., 2008). The pooled
detection rate of BWD of $25%, in three studies, was 63% for a false positive rate of 2%
(Caravello et al., 1997;Diaz-Garcia et al., 2010).
The existing uncertainties are further complicated by several factors including (1) an
inconclusive predictive value of early (first and second trimester) versus late (2 to 3 weeks
prior to delivery) measurement of growth discordance; (2) the use of different sonographic
estimates (AC versus EFW); and (3) reliance on the retrospective nature of study designs
and small sample sizes of existing literature. Literature suggests that biometric prediction
of BWD at early gestation or during the second trimester has significantly different preci-
sion (Banks et al., 2008). Moreover, the efficacy of a single biometric measurement, such as
crown-rump length (CRL) or abdominal circumference (AC) with or without other mea-
surement(s), in predicting BWD, is controversial (Bhide et al., 2009). The most popular cur-
rent methods for predicting BWD in twin gestations have limited accuracy when held to a
standard for discordance that requires a within-twin pair BWD of at least 20% as sonogra-
phy tends to underestimate the degree of discordance.
333Predictive accuracy of birth weight discordance in utero
Developmental and Fetal Origins of Differences in Monozygotic Twins

Ruling out BWD will eliminate the need for further clinical intervention as clinicians
often use this measure as an indication for cesarean section. It is believed that a combina-
tion of estimated BWD and parameters such as amniotic fluid index (an estimate of amni-
otic fluid volume) and umbilical artery Doppler can be useful in a clinical setting.
Improving the selection of pregnancies, which might benefit from early delivery, would be
of considerable benefit to neonates, mothers, families, and to the community.
The Cochrane systematic review by SJ and colleague screened 3253 articles (manuscript
under review). After removing duplicates, irrelevant outcomes, inappropriate compari-
sons, or unrelated population, the review included 15,747 pregnancies from 76 eligible
studies. Twenty-two studies estimated fetal BWD (20% cut-off) by ultrasound measures
(abdominal circumference, femural length, etc.). Among these studies, sensitivities ranged
between 16% and 100% whereas the specificities ranged between 66% and 99% (Fig. 21.1).
Using the bivariate model, the summary estimate of sensitivity was 0.50 (95% CI 0.41 to
0.59), and the summary estimate of specificity was 0.92 (95% CI 0.88 to 0.94; Fig. 21.1).
Fig. 21.2 shows 16 studies that estimated sensitivity and specificity of fetal weight dis-
cordance by ultrasound measures provided data using a cut-off of 25%. The sensitivities
ranged between 1% and 100% whereas the specificities ranged between 60% and 100%.
Using the bivariate model, the summary estimate of sensitivity was 0.45 (95% CI 0.26 to
0.66), and the summary estimate of specificity was 0.93 (95% CI 0.89 to 0.96; Fig. 21.2).
A non-Cochrane review of diagnostic accuracy of ultrasound in predicting BWD in twin
pregnancy was conducted by Leombroni et al. (Leombroni et al., 2017). They studied fewer
databases and found 22 relevant studies (including 5826 twin pregnancies). EFW discordance,
measured by femural length or AC, of $20% had a sensitivity of 0.65 and specificity of 0.98 in
predicting BWD $20%. The predictive performance of ultrasound performed within 1 month,
2 weeks, and 3 days before birth was 0.61, 0.73, and 0.78, respectively. Estimated fetal growth
discordance $25% had a sensitivity of 0.57 and specificity of 0.95 in predicting BW discor-
dance $25%. The sensitivity of EFW discordance $25% detected within 1 month, 2 weeks,
and 3 days before birth was 0.60, 0.75, and 0.63, respectively, while the corresponding values
for specificity were 0.98, 0.96, and 0.87, respectively. These authors were not able to produce a
forest plot for AC due to lack of numbers and concluded that ultrasound EFW discordance
has an overall moderate accuracy in predicting BWD in twin pregnancy.
The findings of both systematic reviews show that ultrasound has a moderate diagnostic
performance in detecting discordance in fetal size prenatally. Clinically, predictive accuracy
is better when the interval between ultrasound assessment and birth is minimal. It is well
known that the late second and early third trimesters of pregnancy represent the optimal
time to identify growth discordance (Jahanfar et al., 2017a, b). Twins affected by a higher
degree of growth discrepancy are at increased risk of perinatal mortality. However, given the
moderate diagnostic accuracy, weight discordance per se should not be used as the primary
indication for delivery, as many of these pregnancies will not be affected by perinatal loss.
Infection
The incidence of maternal or placental infection during pregnancy is estimated to be
around 1525% (Hacker et al., 2015). Infection via viruses, bacteria, and parasites during
334 21. The environmental differences between twins in utero and their importance for downstream development
Developmental and Fetal Origins of Differences in Monozygotic Twins

Study
Bimson 2014a 17 0.35 [0.22, 0.50]
0.74 [0.60, 0.85]
0.43 [0.23, 0.66]
0.43 [0.18, 0.71]
0.69 [0.62, 0.76]
0.56 [0.30, 0.80]
0.53 [0.48, 0.58]
0.67 [0.56, 0.76]
0.37 [0.23, 0.52]
0.83 [0.59, 0.96]
0.64 [0.35, 0.87]
0.16 [0.12, 0.21]
0.25 [0.05, 0.57]
0.47 [0.32, 0.62]
0.32 [0.20, 0.45]
0.25 [0.07, 0.52]
0.36 [0.11, 0.69]
0.60 [0.32, 0.84]
0.80 [0.44, 0.97]
0.63 [0.46, 0.78]
1.00 [0.66, 1.00]
0.63 [0.42, 0.81]
0.96 [0.86, 1.00]
0.84 [0.75, 0.91]
0.66 [0.56, 0.76]
0.90 [0.81, 0.96]
0.93 [0.91, 0.94]
0.87 [0.77, 0.94]
0.85 [0.83, 0.86]
0.88 [0.83, 0.92]
0.95 [0.92, 0.97]
0.90 [0.74, 0.98]
0.91 [0.80, 0.97]
0.92 [0.90, 0.93]
0.89 [0.82, 0.94]
0.95 [0.91, 0.97]
0.99 [0.97, 1.00]
0.87 [0.78, 0.94]
0.94 [0.83, 0.99]
0.87 [0.79, 0.93]
0.93 [0.76, 0.99]
0.93 [0.88, 0.96]
0.98 [0.90, 1.00]
0.94 [0.85, 0.98]
0.2 0.4 0.6 0.8 10 0.2 0.4 0.6 0.8 10
232 47
40 14 14 74
40 14 14 65
67864
119 76 53 1009
229 266 203 1463
60 23 30 170
18 13 31 244
15 3 3 28
95549
3 13 9 105
41012 69
43747
913 6 90
82226
91050
17 4 10 63
24 18 14 224
21 11 24 197
19 1 41 160
16 142 242 1563
910 7 66
Bimson 2014b
Blickstein 1996
Chamberlain 1991
Chauhan 1995
D'Antonio 2013a
Diaz-Garcia 2010
Fox 2011
Hill 1994
Jenson 1995
Johansen 2014
Kalish 2003
Kim 2015
Machado 2007
MacLean 1992
Secher 1985
Shahshahan 2011
Storlazzi 1987
van de Waarsenburg 2015
vanMieghem 2009
Watson 1991
Chang 2006
TP FP FN TN Sensitivity (95% Cl) Specificity (95% Cl) Sensitivity (95% Cl) Specificity (95% Cl)
FIGURE 21.1 Sensitivity and specificity of diagnostic performance of ultrasound in identifying actual birth weight using 20% cut-off (n522
studies).

Study
10 0.40 [0.21, 0.61]
0.89 [0.71, 0.98]
0.20 [0.04, 0.48]
0.11 [0.05, 0.20]
0.38 [0.09, 0.76]
0.75 [0.65, 0.83]
1.00 [0.66, 1.00]
0.47 [0.43, 0.51]
0.52 [0.38, 0.66]
0.67 [0.54, 0.79]
0.59 [0.39, 0.78]
0.36 [0.27, 0.46]
0.32 [0.15, 0.54]
0.14 [0.32, 0.58]
0.80 [0.52, 0.96]
0.01 [0.00, 0.02]
0.78 [0.40, 0.97]
0.29 [0.04, 0.71]
0.98 [0.90, 1.00]
0.83 [0.59, 0.96]
0.60 [0.50, 0.68]
0.93 [0.87, 0.96]
0.91 [0.82, 0.96]
0.96 [0.95, 0.97]
1.00 [0.97, 1.00]
0.90 [0.89, 0.92]
0.88 [0.83, 0.92]
0.91 [0.87, 0.95]
0.88 [0.82, 0.92]
0.94 [0.91, 0.96]
0.95 [0.89, 0.98]
0.93 [0.87, 0.97]
0.92 [0.82, 0.97]
0.79 [0.59, 0.92]
0.98 [0.90, 1.00]
1.00 [0.96, 1.00]
0.2 0.4 0.6 0.8 10 0.2 0.4 0.6 0.8 10
115 50
24 3 3 15
40 50 12 74
9 12 71 150
37570
9 0 0 126
253 157 287 1464
28 26 26 198
41 19 20 203
16 21 11 148
8 5 17 96
4 6 566 22
71250
20582
1 8 6 105
12 5 3 58
39 25 70 369
68 46 23 1120
Bimson 2014a
Bimson 2014b
Blickstein 1996
Chamberlain 1991
Caravello 1997
D'Antonio 2013a
Danon 2008
Diaz-Garcia 2010
Hoopmann 2011
Klam 2005
Nakayama 2014
Reberdao 2010
Sayegh 1993
Simoes 2011
Zipori 2016
VanMieghem 2009
Chang 2006
Crane 1980
TP FP FN TN Sensitivity (95% Cl) Specificity (95% Cl) Sensitivity (95% Cl) Specificity (95% Cl)
FIGURE 21.2 Sensitivity and specificity of diagnostic performance of ultrasound in identifying actual birth weight using 25% cut-off (n516
studies).

pregnancy can be a cause of preterm labor or spontaneous abortion, growth defects, and
delays and mental deficiency. During pregnancy, a woman’s immune system undergoes a
series of changes to maintain immunity for themselves and their fetus. This protects
against foreign substances and intruders while preventing the mother’s immune system
from detecting the fetal cells as foreign and attacking them as well (Smith et al., 2002;
Goering 2019). However, this process is poorly understood. Because of these changes to
maternal immunity, pregnant women are at higher risk of worsening or reactivation of
existing infections as well as severe infection or death due to specific pathogens such as
hepatitis, influenza, listeria, gonorrhea, salmonella, and malaria (Hacker et al., 2015;
Goering 2019). When compared with nonpregnant women, this seems to be related to the
selective immune mechanisms.
The placenta has immune functions and acts to protect the fetus from microorganisms cir-
culating in the maternal blood stream; similarly, the fetal membranes function to shield the
fetus from genital tract infections (Goering 2019). Asymptomatic ascending infections are
associated with many mid-pregnancy losses and cervical incompetence (Hacker et al., 2015).
This mode of infection has been identified as a possible cause of premature membrane rup-
ture as well as a consequential risk risks to fetal development. Group B Streptococci are con-
sidered part of the normal flora in the vagina and cervix and colonize 15%40% of
pregnant women. Of these colonized women, only one third will be heavily colonized
enough to be at risk of a transmissible infection putting her pregnancy at risk or transferring
to the fetus during delivery, increasing the risk of neonatal sepsis (12 per 1000 births),
respiratory distress and pneumonia, and meningitis (30% of cases) (Hacker et al., 2015).
Bacterial infections such as syphilis can cross the placenta from the mother to the fetus at
any gestational age and can lead to developmental defects such as deafness, dental defects,
failure to thrive, hepatitis, skin lesion, and death (Hacker et al., 2015; Goering 2019).
In a twin pregnancy, there is a unique situation in which one twin may be more likely
to be exposed to an infection when compared to the other (Dickinson et al., 2006). For
example, during recent Zika virus outbreaks, there were reported cases of discordance
between twin transmission and fetal outcomes post vertical Zika exposure (Linden et al.,
2017). Affected twins showed severe central nervous system damage, while the other twin
was free of such damage. Similar effects have been seen in infections involving cytomega-
lovirus and toxoplasmosis, although the transmission process in each of these cases is not
well understood (Linden et al., 2017). In another example of unequal infection exposure,
one twin may be closer to, or completely cover, the cervix, and thus at a higher risk of
being exposed to an ascending infection (Phung et al., 2002). In cases of DCDA twins,
transplacental transfer may occur in one placental unit at differing levels to the other. In
these circumstances, the impact to each twin differs (Hacker et al., 2015). Similarly, in late
pregnancy if there is perforation of the amniotic sac fetal infection often occurs, but in dia-
mniotic twins this may have differing consequences (Goering 2019).
Funisitis is an inflammation of the umbilical cord and an also have detrimental effects
on the developing fetus by reducing nutrient supply, and is associated with an increased
risk for cerebral palsy (Phung et al., 2002). Chorioamnionitis is the inflammation due to
bacterial infection of one or more of the following: the chorion, amnion or amniotic fluid
that surrounds the fetus, associated with an increased incidence of fetal meningitis and
pneumonia (Phung et al., 2002). Both funisitis and chorioamnionitis have been shown to
337Infection
Developmental and Fetal Origins of Differences in Monozygotic Twins

affect twins unequally. The presenting twin (Twin A) is often at greater risk for chorioam-
nionitis. However, while some studies show that twin B is at higher risk for funisitis, others
argue twin A is at the greater risk (Phung et al., 2002).
Placental rupture and exposure to hypoxia at birth
Oxygen consumption of the developing fetus is twice that of an adult and the amount
transfused to the fetus and the oxygen reserve is only enough to meet the fetal metabolic
demand for about one to two minutes (Hacker et al., 2015). This is why even momentary
disruption to adequate flow of oxygen via the placenta can have huge detrimental out-
comes to fetal development. Perinatal asphyxia relates to a prolonged lack of oxygen to
the fetus due to a lack of blood flow or gas exchange. This can occur immediately before,
during, or after birth. The consequences of this oxygen deprivation can result in profound
systemic (muscle liver heart and ultimately brain) oxygen debt, metabolic acidosis, and
neurological sequelae such as neonatal hypoxic-ischemic encephalopathy in which a lack
of oxygen and glucose to the brain results in cell swelling and lysis leading to a cascade of
further damage and poor long-term outcomes (Hacker et al., 2015).
Premature placental rupture can occur at any stage of a pregnancy and has a range of
consequences to the health of the developing fetus and the mother (Butler and Behrman,
2007). Other risks associated with prolonged rupture of membrane include maternal-fetal
infection, cord prolapse, fetal deformation, and pulmonary hypoplasia (incomplete devel-
opment of the lungs). These depend on gestational age at the time of the rupture and in
some cases, membrane rupture can lead to abruptio placentae. Abruptio placentae from a
normally implanted placenta occurs in roughly 1 in 120 pregnancies, the complications of
which can be severe enough to cause fetal death in 1 in 500 births (Hacker et al., 2015;
Butler and Behrman, 2007). The perinatal mortality rate for premature membrane rupture
is around 35% and accounts for 15% of all third trimester stillbirths. Fifteen percent of
live-born infants exposed to these hypoxic conditions develop a range of neurological defi-
cits (Hacker et al., 2015; Ismail et al., 2017).
The cause of the placental separation is unclear. The separation forms a hemorrhage,
which can be missed if the blood travels up toward the fundus and is covered by the pla-
centa and is known as a concealed hemorrhage. Clinically, it is therefore much easier to
evaluate an external hemorrhage in which the blood travels down toward the cervix
resulting in external blood loss and in some women is associated with pain. As ultraso-
nography can only accurately diagnose 2% of abruptio placentae, health practitioners
must rely on clinical presentation (Hacker et al., 2015). In these situations, intensive moni-
toring is critical as the blood loss could cause the fetus to become hypoxic or for the
mother to go into shock.
Birth order and birth interval
It is not only the pregnancy itself that poses greater morbidity and mortality risk in
multiple gestations but also the delivery (Young et al., 1985). Birth order relates to the
338 21. The environmental differences between twins in utero and their importance for downstream development
Developmental and Fetal Origins of Differences in Monozygotic Twins

order in which each twin is born. In a twin pregnancy, the position of the twins informs
the mode of delivery (vaginal or cesarean) as well as the birthing order (Hacker et al.,
2015; Yokoyama et al., 2016). Cephalic (head first) presentation is the optimal position for
a vaginal delivery. Breech (bottom-first)-breech or breech-vertex presentations in twins are
usually delivered via cesarean section. However, in the case of vertex-breech or vertex-
transverse (sideways) there is no current evidence to suggest a cesarean section is superior
and the choice lies with the obstetrician and mother (Hacker et al., 2015). However, the
difficult delivery of the second twin does increase the risk of umbilical cord prolapse,
head entrapment, neck injury, and asphyxia, which results in many of these births being a
planned cesarean (Smith et al., 2007;Smith et al., 2002;Rossi et al., 2011).
One of the major contributors to the increased risk of morbidity and mortality in twin
pregnancies compared to singleton pregnancies is birth asphyxia. In twins, birthing inter-
val relates to the time between twin A’s birth and twin B’s birth. Twin B is at double the
risk of asphyxia compared to twin A in vaginal births (Leung et al., 2002; Hacker et al.,
2015). This is mainly due to increased risk of cord prolapse, premature placental separa-
tion, hypoxia, and fetal distress in the second twin after the delivery of the first (Leung
et al., 2002). There is a lack of consensus in the literature about the time interval impacting
on the risk these negative birthing outcomes, with some papers suggesting the longer the
time interval between births the greater the risk, and others suggesting there was no sig-
nificant difference overtime to the overall risk to the second twin (Florjanski et al., 2019;
Lindroos et al., 2018).
Another situation unique to some multiple births in the rare cases when one twin is
born vaginally, and the other is born via cesarean section (Engelbrechtsen et al., 2013).
This is an ideal control group study to see the developmental consequences downstream
of these differing birthing route and their long-term consequences. However, due to the
high morbidity and mortality in these rare cases, the time interval and increasing risks
might be a bias (Yokoyama et al., 2016).
Discussion
In this chapter, we have reviewed several of the nonshared factors twins may experi-
ence in utero and how these differences contribute to the discordance between twins.
These experiences within pairs of twins, and in many cases between singletons, may dif-
fer, ultimately leading to a range of prenatal outcomes that can be responsible for ongoing
consequences to health and development throughout the lifespan. We discussed why mea-
suring these differences can lead to a greater understanding of the association between in
utero development and longitudinal health outcomes.
A major gap in our clinical approach and understanding comes from monitoring of out-
comes at birth but not beyond this time, into childhood, adolescence, and adulthood. This
has resulted in a dearth of studies in the long-term implications of natural variations in
fetal experiences. In this chapter, we hope to inspire more collaborative clinical teamwork
to work toward such goals. Firstly, we suggest creating a universal standard of records
and measurements to be taken within specific timeframes based on the parameters out-
lined in this chapter. Secondly, we encourage collaboration and data sharing between
339Discussion
Developmental and Fetal Origins of Differences in Monozygotic Twins

obstetricians, ultrasonographers, placental pathologists, neonatologists, pediatricians, and
epidemiologists. Some of the difficulties faced in reaching this goal include motivating
hospitals to move away from existing variations in data collection protocols toward a stan-
dardized protocol for multiple gestations. We suggest that placental examination and sam-
ple archiving be mandatory for all twins due to the high value of the data to cohort
studies. We also encourage increase in accessibility and data linkage to antenatal and peri-
natal data to researchers and ultimately to an individual’s future health practitioners.
Other difficulties in reliability of data collection include data collection by nonclinically
trained staff, a lack of auditing data collected, and financial limitations of individual insti-
tutions (DiGiuseppe et al., 2002).
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Further Reading
Costa-Castro, T.; Zhao, D. P.; Lipa, M.; Haak, M. C.; Oepkes, D.; Severo, M.; Montenegro, N.; Matias, A.; Lopriore,
E. Velamentous Cord Insertion in Dichorionic and Monochorionic Twin Pregnancies: Does It Make a
Difference? Placenta. 2016 Jun, 42,8792. Available from: https://doi.org/10.1016/j.placenta.2016.04.007 Epub
2016 Apr 7.
Jahanfar, S.; Lim, K.; Oviedo-Joekes, E. Stillbirth Associated With Birth Weight Discordance in Twin Gestations.
J Obstet Gynaecol Can 2019 Jan, 41 (1), 5258. Available from: https://doi.org/10.1016/j.jogc.2018.02.017.
343Further Reading
Developmental and Fetal Origins of Differences in Monozygotic Twins