Medically Assisted Reproduction and the Risk of Adverse Perinatal Outcomes

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Chapter
Medically Assisted Reproduction
and the Risk of Adverse Perinatal
Outcomes
Jessica Gorgui and Anick Bérard
Abstract
Over 5 million children have been born through in vitro fertilization (IVF) across
the world. IVF is only one of the many methods of assisted reproduction, which can
be used to achieve pregnancy in the context of infertility or subfertility. Since the
birth of the first IVF child, Louise Brown, in 1978, a number of researchers have
started to study the various impacts of the conception through these methods, on
both mothers and children. A growing body of evidence suggests that conception
through medically assisted reproduction (MAR) is not without risk. Given that
MAR is relatively new and that our look back period is short, there is limited
evidence on the risks associated to these procedures, both for the mother and the
child. In this chapter, we aim to explore the association between MARs and adverse
perinatal outcomes specifically. We will first provide you with an overview of the
prevalence and trends of use of these methods around the world, and then delve
into the associations between MARs and the risk of perinatal outcomes, namely
prematurity, being born with low birth weight and/or small for gestational age, and
lastly the impact of MARs on cognitive functions including cerebral palsy, behav-
ioral problems, and autism, which are identified later in the child’s life.
Keywords: medically assisted reproduction, prematurity, low birth weight, small
for gestational age, delay in cognitive function
1. Introduction
1.1 Infertility and subfertility
Infertility is defined as failure to conceive within 12 months of the first
pregnancy attempt [1], while subfertility describes any form or grade of reduced
fertility [2, 3].
The National Survey of Family Growth interviewed over 12,000 women of
childbearing age (15–44 years old) to estimate the prevalence of infertility in the
United States (US) [4]. A woman was considered infertile if she reported she and
her partner were continuously cohabiting during the previous 12 months or longer,
were sexually active each month, had not used contraception, and had not become
pregnant [4]. From 1982 to 2006–2010, the percentage of infertile women based on
this definition fell from 8.5 to 6.0% [4]. These estimates are lower than the 12–18%
incidence of infertility in the US [5]. The frequency of infertility in nulliparous
1

women (i.e., primary infertility) increased with age and was reported to be: 7.3–
9.1% in women 15–34 years old, 25% in the 35–39 year olds, and 30% in the 40–
44 year olds [4].
Infertility and subfertility may be due to conditions originating from the male
and/or female reproductive systems [6]. Between 8 and 20% of couples will experi-
ence difficulty conceiving [6–9]. Between 1982–1985, the World Health Organization
(WHO) performed a multicenter study where they attributed 20% of infertility cases
to male factors, 38% to female factors, 27% to causal factors identified in both
partners, and 15% could not be attributed to either partner [10]. In the following
section, we will provide you with an overview of the main causes of infertility.
1.1.1 Male infertility
A cross-sectional survey of men in the United States aged between 15–44 years
showed a prevalence of male infertility of 12% [11]. Male infertility accounts for 19–
57% of the identified causes of infertility in couples [9]. In about 30–40% of cases of
male infertility, the cause remains unknown [11, 12]. Male infertility can be classified
into four main categories which we will briefly describe in the following section.
1.1.1.1 Testicular disease: endocrine and systemic disorders
Testicular diseases including primary testicular defects account for 30–40% of
male infertility [13]. Primary testicular defects can be further classified into: (1)
congenital disorders including Klinefelter syndrome [14] and (2) acquired disorders
which can be due to infections (e.g., chlamydia) [15] and smoking [16]. Hypotha-
lamic pituitary diseases account for 1–2% for male infertility [13]. Secondary
hypogonadism can cause gonadotropin deficiencies, which in turn leads to infertil-
ity [13]. Secondary hypogonadism can be (1) congenital [17], (2) acquired (e.g.,
tumors of the pituitary gland [18]) or (3) systemic (e.g., obesity [19]).
1.1.1.2 Genetic disorders of spermatogenesis
Genetic disorders affecting spermatogenesis can be identified in 10–20% of male
infertility cases [13]. With the increasing use of genome-wide association studies,
genetic disorders have been linked to male infertility [12, 20]. Specifically,
microdeletions and substitutions on the Y chromosome are increasingly recognized
as genetic causes of azoospermia (i.e., semen without sperm) and severe
oligozoospermia (i.e., semen with a sperm concentration <15 million sperm/mL
compared to the norm of >48 million sperm/mL [20]. Additionally, mutations
linked to the X chromosome in men have also been linked to azoospermia [21–23].
1.1.1.3 Posttesticular defects
Posttesticular defects lead to disorders of sperm transport, which account for
10–20% of male infertility cases [13]. The epididymis is an important site for sperm
maturation and essential to the sperm transport system. The vas deferens transports
sperm from the epididymis to the urethra, where they are diluted by secretions
from the seminal vesicles and prostate. Abnormalities at any of these sites, particu-
larly the epididymis and vas deferens, can lead to infertility [13]. The causes of
these abnormalities include congenital obstructions of the vas deferens and
obstruction following an infection (e.g., chlamydia). Additionally, given that
sperm must be ejaculated, any disorder of the ejaculatory ducts can also lead to
infertility [13].
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1.1.1.4 Idiopathic
In 30–40% of male infertility cases, the cause is classified as idiopathic [13]. In
these cases, despite attempting to identify potential mechanisms at play, a cause for
abnormal sperm number, morphology, or function cannot be identified [13]. Idio-
pathic causes should be distinguished from unknown causes which is where men
with normal semen analysis and no other identified cause for infertility are unable
to impregnate an apparently clinically normal female partner.
1.1.2 Female infertility
In terms of female infertility, the main causes of infertility are ovulatory disor-
ders which account for 21–32%, tubal disorders for 14–26%, while endometriosis is
responsible in 5–6% of the cases of infertility [6, 9]. Approximately 30% of couples
will have both male and female factors contributing to their infertility [6, 9]. When
the cause is identified, a treatment plan can be put in place with the physician. The
concern however, is that 8–30% of infertility will remain unexplained, which makes
the choice of the course of fertility treatment difficult [24]. In the section below, we
have provided you with an overview of the main causes attributed to female infer-
tility.
1.1.2.1 Ovaries
1.1.2.1.1 Ovulatory disorders
Infrequent ovulation (oligoovulation) or absent ovulation (anovulation) results in
infertility because an oocyte is not available every month for fertilization. WHO
classifies ovulatory disorders into three classes [42]:
•Class 1—Hypogonadotropic hypogonadal anovulation occurs in 5–10% of
cases. This would describe women with hypothalamic amenorrhea from
excessive exercise or low body weight.
•Class 2—Normogonadotropic normoestrogenic anovulation accounts for 70–85%
of cases and includes women with polycystic ovary syndrome (PCOS) and hyper/
hypothyroidism.
•Class 3—Hypergonadotropic hypoestrogenic anovulation occurs in 10–30% of
cases and characterizes women with premature ovarian failure.
1.1.2.1.2 Oocyte aging
Maternal aging is a known factor of female infertility [25]. The decrease in
fecundability with aging could be due to a decline in both the quantity and quality
of the oocytes [25, 26].
1.1.2.2 Fallopian tubes
Tubal disease and pelvic adhesions prevent normal transport of the oocyte and
sperm through the fallopian tube [27]. The primary cause of tubal factor infertility
is pelvic inflammatory disease caused by pathogens such as chlamydia or gonorrhea
[28]. Tubal and pelvic adhesions could also be a consequence of endometriosis [27].
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1.1.2.3 Uterus
Conditions that distort the uterine cavity can result in implantation failure,
which may lead to infertility or recurrent pregnancy loss [29]. The most common
malformation, a septate uterus, was associated with pregnancy losses >60% and
fetal survival rates of 6–28% [30, 31].
1.1.2.4 Endometriosis
Adhesions within the uterus, the fallopian tubes, and/or the pelvic floor caused
by endometriosis could be a cause of infertility [27]. This could be mediated
through ovulatory dysfunction, defective implantation, alternations within the
oocyte, or impaired fertilization among other hypotheses [32].
1.1.2.5 Obesity
Evidence has demonstrated that obese women are at an increased risk of sub-
fecundity and infertility [33]. It has been shown that the pathway through which
obesity could be a precursor to subfertility/infertility may involve a dysregulation in
the hypothalamic-pituitary-ovarian axis as well as decreased oocyte quality and
endometrial receptivity [33]. Studies have demonstrated a correlation between
higher body mass index (BMI) and poor fertility [33].
1.2. Medically assisted reproduction
Fertility treatments are procedures and/or medication interventions used to
initiate a pregnancy. MARs include assisted reproductive techniques (ART) as well
as ovarian stimulators (OS). In Figure 1, we provide you with a visual classification
of MAR techniques as a whole, which we have briefly described below.
1.2.1 Assisted reproductive techniques
ART are defined as procedures that include handling of the oocytes and/or
sperm, or embryos to generate a pregnancy [1]. ART methods can be categorized
as follows:
1.2.1.1 Intrauterine insemination (IUI)
Intrauterine insemination (IUI) is a procedure in which processed and concen-
trated motile sperm are placed directly into the uterine cavity, and will often be
used when the cause of infertility is related to the male [1].
1.2.1.2 In vitro fertilization (IVF)
In vitro fertilization (IVF) with or without in vitro maturation (IVM) is a cycle of
procedures in which oocytes are retrieved from ovarian follicles, fertilized in vitro
then subsequently the resulting embryo(s) are transferred into the uterus [1]. The
number of embryos transferred into the uterus largely depends on the common
practice imposed by the country where the procedure is performed. A more recent
practice is to perform single embryo transfers (SET). This practice was put in place
to decrease the odds of producing multiple embryos per pregnancy. However,
through the Canadian ART register’s (CARTR) last reports in 2012, it was shown
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Infertility, Assisted Reproductive Technologies and Hormone Assays

that SET has yet to become common practice. Australia/New Zealand and Sweden
used SET in >70% of the reported ART cycles involving transfers, compared to
44% in Canada and 14% in Germany [34, 35]. These numbers translated into
different rates of multiple pregnancy per country: Australia/New Zealand and Swe-
den had the lowest rates at 6.9% and 5.9%, respectively, while Canada was at 16.5%
and Germany had the highest rates of all reported countries at 32.5% [34, 35]. IVF
procedures can be categorized as follows:
•Intra cytoplasmic sperm injection (ICSI) is an in vitro procedure in which a
single spermatozoon is injected into the oocyte cytoplasm [1].
•Assisted hatching (AH) an in vitro procedure in which the zona pellucida of an
embryo is either thinned or perforated chemically, mechanically or by laser in
order to assist the separation of the blastocyst. The blastocyst is the stage that
the embryo reaches 5–6 days following fertilization [1].
•Gamete intrafallopian transfer (GIFT) is an in vitro procedure in which both
gametes (oocyte and sperm) are transferred into the fallopian tube [1].
•Zygote intrafallopian transfer (ZIFT) is an in vitro procedure in which the
zygote(s) is/are transferred into the fallopian tube [1].
Figure 1.
Overview of the classification of methods of assisted reproduction. Assisted reproductive techniques (ART) are
defined as procedures that include handling the oocytes and/or sperm, or embryos to generate a pregnancy (i.e.,
IVF, ICSI, IUI, in vitro maturation [IVM], assisted hatching [AH], zygote intrafallopian transfer [ZIFT],
gamete IFT [GIFT]), while MAR techniques include ART and OS [1]. Depending on the indication of the use
of fertility treatments, women will either be given a course of OS, undergo ART procedures alone or will be
subjected to a combination of both OS and ART.
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1.2.2 Ovarian stimulators
Ovarian stimulators (OS) are used to promote the development and ovulation of
more than one mature follicle among subfertile women mainly to increase the
likelihood of conception [36]. This treatment can be used alone or in combination
with IUI, wherein we increase the number of oocytes and sperms together. OS can
also be used with other ARTs, described above [1, 37]. In many cases, OS will be
used as first line therapy when aiming to treat infertility/subfertility in women or
couples. OS alone are more likely to be used in the context of unexplained infertility
and age-related subfertility in women [36, 38, 39]. Depending on the underlying
cause of infertility, different OS may be used. Mainly, OS can be classified as having
two roles as they are either used to induce ovulation (i.e., clomiphene, gonadotro-
pins) or to assist with maturation and/or the release of the oocyte (i.e., human
chorionic gonadotropin [hCG], gonadotropin-releasing hormone [GnRH]).
1.2.2.1 Ovulation induction
Infrequent or irregular ovulation (i.e., oligoovulation) unrelated to ovarian fail-
ure can usually be treated successfully with ovulation induction (OI); women
treated with OI agents achieve fecundability nearly equivalent to that of couples not
suffering with infertility or subfertility (i.e., 15–25% probability of achieving a
pregnancy in one menstrual cycle) [40]. Agents used for OI tend to be used as a
first-line treatment to stimulate the development and ovulation of >1 mature
oocyte in women with unexplained or age-related subfertility/infertility [36, 39,
41]. OI agents include clomiphene and gonadotropins. Clomiphene is a selective
estrogen receptor modulator with both estrogen antagonist and agonist effects that
increases gonadotropin release [42]. It is known to be effective in women with
normal gonadotropin and estrogen levels but who still have ovulatory dysfunction
(WHO Class 2) [42]. Gonadotropins are used in women with WHO class 2 who
have not been able to ovulate using clomiphene or an insulin sensitizing agent such
as metformin (used in women with PCOS). This therapy may also be used in
women classified as WHO Class 1 [42].
1.2.2.2 Ovulation maturation and release
Agents used for final ovulation maturation and release are known as trigger
shots. The gold standard agent to induce follicular maturation has been hCG which
mimics the surge of luteinizing hormone that occurs mid-cycle and allows for the
release of the oocyte [43]. GnRH may also be used to replace hCG. Current evidence
suggests that GnRH may be used as a first-line treatment in egg donors [43].
2. Trends in medically assisted reproduction use
It has been speculated that fecundability has declined over the years, but results
need to be replicated at the scale of large populations in order to be confirmed
[44, 45]. Nonetheless, the number of women resorting to fertility treatments
remains on the rise. As reported by CARTR, the use of ART has increased steadily
over the years, having more than tripled in the last decade [34]. From the partici-
pating fertility clinics in the CARTR reports over the years (n = 28–32), 16,315 ART
cycles had been performed in 2009 compared to 27,356 cycles in 2012 across Canada
[34]. In 2012, Canada had the second lowest number of ART cycles after Sweden
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Infertility, Assisted Reproductive Technologies and Hormone Assays

(n = 17,628), while the US had the highest number with 176,247 ART cycles
performed as reported by the American Society for Reproductive Medicine [34, 35].
Over 5 million children have been born through IVF specifically worldwide [46].
At present, 1–3% of all children in industrialized countries including France, Ger-
many, Italy, Scandinavian countries, and the United States are born through ART
[47–49]. Over 1.5 million IVF cycles are performed every year, yielding over
350,000 children annually in Europe, as reported by the European Society of
Human Reproduction and Embryology [46].
Between 2010 and 2014, the province of Quebec was the first Canadian province
to put in place an assisted reproduction program which provided universal reim-
bursement for MARs. This program aimed to: (1) reduce multiple pregnancies with
the practice of SET, (2) help subfertile/infertile couples to have children, and (3)
increase Quebec’s birth rate [50]. Following the start of the reimbursement pro-
gram, reports have shown that MAR represented approximately 2% of all pregnan-
cies [50], of which 43% were from OS without any other ART [51]. Another 20% of
women were exposed to OS in combination with IUI, and 33% conceived through
IVF [50, 51]. Due to the fact that OS tend to be used the first-line fertility treatment
and that it is prescribed with most ARTs, it is the most prevalent exposure [52].
3. Medically assisted reproduction and perinatal outcomes
Since Louise Brown, the first IVF baby, was born in the United Kingdom in 1978,
over 5 million children have been born with IVF worldwide [46]. General concerns
about the safety of pregnancies resulting from MARs and the health implications of
these methods on the resulting child remain, as there is a growing body of evidence
supporting the association between these methods and adverse perinatal outcomes
[53, 54].
The association between MARs and multiple pregnancies has been studied
extensively and is known [51, 55–58]. ART alone and OS use alone have both been
associated to increase multiple pregnancies, which occur for two different reasons
[57, 59, 60]. On the one hand, ART alone may lead to the transfer of multiple
embryos as described above, while on the other hand OS use may lead ovarian
hyperstimulation [57, 59–61]. Indeed, ovarian hyperstimulation occurs in more than
40% of stimulated cycles [62]. In the context of ovarian stimulation, it is more
difficult to prevent multiple gestations with OS use because it involves the stimula-
tion of ovulation which leads to an unpredictable follicular growth number [61]. As
we have described above, the rate of multiple pregnancies associated with ART
around the world varies from 5.9 to 32.5% [19, 20]. In a systematic review and
meta-analysis performed by Chaabane et al. [63] looking at the association between
OS use and multiple pregnancies, they pooled a total of nine studies that had
estimates ranging from 1.01 to 50.20 [63]. They calculated a pooled relative risk
(RR) of 8.80 with a 95% confidence interval (CI) ranging from 5.09 to 15.20. To put
these numbers in context, the rate of multiple pregnancies in the general population
is about 3% around the world [64]. These estimates therefore suggest that OS use
alone leads to an approximate multiple pregnancy rate of 26% among its’users [46].
ART has also been associated with increased perinatal morbidity and mortality,
which the scientific community mainly attributes to the increased risk of multiple
births, the use of these technologies themselves, as well as the underlying condition
for which these methods are used, which is the infertility factor [54, 65–70]. In fact,
it is generally well accepted that multiple pregnancies occurring in the context of
fertility treatments due to the transfer of multiple embryos are associated with
being born premature (<37 weeks of gestation) or at a low birth weight (LBW;
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<2500 g at birth) [71]. These complications, among others, carry long-term impacts
on the child, which we will explore throughout this chapter.
Researchers have been making an effort to evaluate adverse risks associated with
MARs in singleton babies specifically. In fact, MAR-conceived singletons have been
shown to be at increased risk of very preterm (28 to <32 gestational weeks) and
moderately preterm birth (32 to <37 gestational weeks), LBW, small for gestational
age (SGA; weight below the 10th percentile for their gestational age), neonatal
intensive care unit (ICU) admissions (odds ratio [OR], 1.27; 95%CI, 1.16–1.40), and
overall perinatal mortality (OR, 1.68; 95%CI, 1.11–2.55) compared to spontaneously
conceived singletons [72, 73]. In line with these findings, IVF-conceived children
tend to be hospitalized for longer (n = 9.5 days versus 3.6 days in non-IVF children),
and use more in-patient care than their non-IVF counterparts in the neonatal period
and later in life due to increased risk of asthma, cerebral palsy, congenital
malformations, and infections [74]. It could be speculated that these results are due
to prematurity or multiplicity, but this observation persisted when restricted to
term infants and singletons, respectively [74].
A growing body of evidence suggests that children conceived through ART are
phenotypically and biochemically different from naturally conceived children [75].
Indeed, MAR involves hyperstimulation, manipulation, and culture of gametes/
embryos at the most vulnerable stage of development [76, 77]. ART has been
implied to affect the epigenetic control in early embryogenesis [78, 79]. In fact,
MARs have been associated with an increased risk of imprinting disorders both in
experimental and epidemiological studies [80, 81]. Furthermore, we must take into
consideration the impact of iatrogenic factors including gamete manipulations and
ovulation hyperstimulation, as well as the initial underlying cause of infertility as
discussed above.
In the following section of the chapter, we will present the associations between MARs
and the risks of the main perinatal outcomes (i.e., prematurity, LBW, SGA) as well as
long-term cognitive outcomes.
3.1 Prematurity
In the previous section, we discussed the known association between MARs
and the risk of multiplicity. Multiplicity has been shown to increase the risk of
preterm birth by 6-fold [82]. More recently, efforts have been made by the scien-
tific community to evaluate the contribution of MARs on the risk of prematurity
among singletons specifically. As such, we are able to tease out the role of multi-
plicity in the association between the MARs themselves and the risk of prematu-
rity [83, 84].
Evidence from a systematic review of matched controlled studies showed that
MAR-conceived singletons were at an increased risk for very preterm (28 to
<32 weeks’gestation) and moderately preterm birth (32 to <37 weeks’gestation),
compared to spontaneously conceived singletons [72, 73]. The RRs reported for 13
studies ranged from 0.57 (0.21–1.56) performed among 118 women [85] to 8.00
(1.87–34.2) performed among 240 women [86]. The general consensus among these
13 matched studies was that the risk of preterm birth was doubled [72]. Most studies
included in this systematic review adjusted for maternal age and parity by design
(i.e., matched case-control studies), but most failed to perform adjustments for
confounding variables such as smoking, socio-economic status, and pre-existing
chronic conditions [72]. Further supporting these results, ART users were 3.27 times
more at risk of prematurity than non-ART users (RR, 3.27; 95%CI, 2.03–5.28). ART
was also associated with a doubling of the risk of delivering moderately preterm
(RR, 2.05; 95%CI, 1.71–2.47) [87–89]. To put these results in context, the prevalence
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of prematurity is of 7.8% in Canada and 10% in the USA [90]. These results indicate
that among MAR-conceived children, the prevalence of prematurity could be esti-
mated at 15% or higher.
We found that the current literature does not appropriately take into account the
different fertility treatments separately and do not create the necessary distinction
between OS and ART [72, 87–89]. MARs are either pooled all together or only IVF
or ICSI are considered in analyses. Further studies are required to explore the
biological mechanisms through which these methods could cause premature birth/
delivery, which will only be possible once we have assessed each MAR distinctively.
3.2 Low birth weight
ART conceptions have been associated with being born LBW. Results have
mainly been attributed to higher rates of multiple pregnancies and prematurity
among MAR conceptions [91]. Recent meta-analyses have shown that the higher
rates of LBW are observed in both IVF singletons as well as twins, respectively,
compared to natural conceptions [92, 93]. When comparing singleton ART-
conceived children to those who were spontaneously conceived, we observed a
1.70-fold increase in the risk of LBW among ART singletons (RR, 1.70; 95%CI, 1.50–
1.92) [72]. In Canada, the prevalence of LBW was of 6.2% in 2013 [94] which is
lower than the prevalence reported in the USA in 2016, which was of approximately
8% [95]. To put these numbers into context, this would mean that among ART-
conceived children, the prevalence of LBW would be between 11 and 13%. Addi-
tionally, when comparing singletons conceived through ART to those who were
naturally conceived, the meta-analysis showed a 3-fold increase in the risk of being
born very LBW which is defined as a birth weight of <1500 g (RR, 3.00; 95%CI,
2.07–4.36) [72].
A number of studies have shown that IVF-conceived singletons were at an
increased risk of being born LBW, even following adjustment for gestational age
which is a known confounder [96–102], while two large prospective studies and one
matched case-control did not observe any differences following adjustments
[85, 103, 104]. Through they did not all adjust for the same variables, the two
prospective studies took into account maternal age, gestational age, education,
marital status, BMI, intrauterine exposure to smoking/alcohol/coffee as well as the
sex of the child, parity, and time since last pregnancy [103, 104].
Aside from the body of evidence examining the association between ART and
LBW, the exposure to OS has also been associated with LBW when compared with
spontaneous conceptions in conceptions with [68, 105, 106] and without IVF
[101, 107].
It has been hypothesized in this context that an alteration in oocyte quality,
decreased receptivity of the endometrium or the production of a poor implantation
environment may play a role in this observation [101, 107]. These could in part be
mediated through the increased levels of estradiol which could impair the implan-
tation process and this hypothesis has been confirmed in animal studies [91].
3.3 Small for gestational age
In the context of infertility treatments, we have discussed the negative implica-
tions of OS on the uterine environment. As such, oocyte manipulation as well as
hormonal triggers during implantation could be key players in the mother’s
response to growth factors [107]. In fact, the capacity of the placental system to
transfer nutrients to the fetus as well as the condition of the maternal endocrine
system will determine, along with genetics, whether or not the fetus will follow an
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expectedly normal growth curve during the gestational period [108]. Being born
SGA describes newborns who are smaller than the norm for their gestational age
established by the average growth curve [109]. It is important to note that defini-
tions of SGA are population-dependent as growth curves differ from one country to
another [109].
Limited evidence exists on the association between MARs and SGA. How-
ever, when comparing singleton IVF-conceived children to those who were
spontaneously conceived, studies observed a 1.4–1.6 fold increase in the risk of
SGA among IVF singletons [72, 110, 111]. An additional study published by the
United Kingdom government looked at this association and found a significant
increased risk of SGA when comparing IVF to spontaneous conception (RR,
1.98; 95%CI, 1.21–3.24) and also when comparing OS use alone to spontaneous
conception (RR, 1.71; 95%CI, 1.09–2.69) [112]. In low- to middle income coun-
tries, the prevalence of SGA births is of approximately 27% while in industrial-
ized countries, the prevalence ranges around 5–10% [113]. Based on these
prevalences, this would indicate that prevalences of SGA among IVF-conceived
children could range from 8.5–45%.
Current evidence is suggestive of an association between MARs and conceiving
babies that are SGA. Mechanisms leading to growth restriction in utero are those
discussed above when describing the probable etiology for the increased risk of
LBW [91]. Additional large-scale epidemiological studies are required to confirm
these results, as well as to generate further hypotheses to be tested in mechanistic
animal studies.
3.4 Long-term cognitive outcomes
Environmental factors that come into play in the early stages of embryonic
development can interact with the genotype and alter the capacity of the organism
to cope with this environment later in life, therefore modulating a child’s suscepti-
bility to disease [114, 115]. Evidence suggests that MAR-conceived children are
phenotypically and biochemically different from the spontaneously conceived [75].
MAR involves hyperstimulation, manipulation, and culture of gametes/embryos at
the most vulnerable stage of development [76, 77]. However, increased risk of
neurodevelopmental disorders in MAR-conceived children may be unrelated to the
procedure/treatment itself; MAR has been associated with increased risk of multiple
gestation [63], which in turn increases the risk of PTB, LBW, and SGA newborns as
we have described in detail in previous sections of the chapter [104, 111, 116]. These
adverse outcomes are strongly associated with a range of long-term child outcomes,
including vision impairment, cerebral palsy (CP), and neurodevelopmental deficits
[46, 117–120]. With the current state of the evidence, results support the hypothesis
that MARs could be a contributing factor to the recent increase in the prevalence of
neurodevelopmental disorders.
3.4.1 Cerebral palsy
CP is the most common motor disability in childhood. Approximately 1 in 323
children (0.3%) has been identified with CP according to estimates from CDC’s
Autism and Developmental Disabilities Monitoring Network. Population-based
studies worldwide report prevalence estimates of CP ranging from 1.5 to more than
4 per 1000 live births or children of a defined age range [121–124].
Very few groups have evaluated the association between MARs and CP. Most
available results stem from studies performed within large registries available in the
Scandinavian countries, namely Denmark, Finland, and Sweden. In 2009,
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Infertility, Assisted Reproductive Technologies and Hormone Assays

Hvidtjørn et al. performed a systematic review and meta-analysis to provide an
overview of the results pertaining to this association [125]. A total of nine studies
were included in this review [74, 126–133]. They were conscious to separate results
by parity (e.g., all children combined, singletons, twins, and triplets) and to isolate
estimates that had been adjusted for PTD, as it is a known risk factor for CP [125].
The outcome was defined by appropriate diagnostic codes of the International
Statistical Classification of Diseases, 10th Revision (ICD-10). Only two studies used
records from rehabilitations centers, one from questionnaires which were later
confirmed by discharge registers. All other studies obtained their information on CP
diagnoses from hospital discharge registers.
Among studies looking at all children combined, adjusted ORs ranged between
0.88 and 3.7 [74, 126, 127, 129, 132]. The strongest reported association was that of
Strömberg et al. with a significant 3.7-fold increased CP risk when comparing IVF to
non-IVF children [132]. After adjusting for PTD, the point estimate was reduced to
2.9 but remained significant [132]. Other studies found no significant association
when they adjusted for PTD. Among singleton studies, the tendency was towards an
increased CP risk among IVF singletons when compared to their non-IVF counter-
parts [126–128, 132]. The results of the meta-analysis showed an overall significant
1.8-fold increase (OR, 1.82; 95%CI, [1.31–2.52]) in CP when comparing IVF
singletons to non-IVF singletons [125].
Among studies including twins and triplets, the ORs were variable and ranged
from 0.6 and 1.5, and most results were not significant [126, 127, 130–133]. Despite
their large sample sizes, they had a low number of MAR-conceived children with
CP, with numbers ranging from 3 to 15. Additionally, studies did not take into
account PTD which could potentially be biasing these results [126, 127, 130–133].
Overall, this systematic review of the literature and meta-analysis suggests that
there is evidence supporting the implication of MARs, specifically IVF, in the
increased risk of CP. To put these results in context, CP remains a rare outcome
with a prevalence of 0.3% on average. These results would suggest that among
MAR-conceived children, the prevalence of CP could range between 0.6% and 1%.
The increased risk of CP among IVF-born children could be in part explained by the
known association between IVF and PTD [125]. Indeed, a more recent study
published in 2012 indicates that among MAR-conceived children, the risk of
neurodevelopmental outcomes, including CP, is more pronounced among those
that are born extremely preterm (22–26 weeks’gestation) [134].
3.4.2 Autism
As discussed above, ART-conceived children are phenotypically and biochemi-
cally different from naturally conceived children, likely due to the manipulation of
gametes and embryos at such a vulnerable stage of development [75–77]. MARs
have been associated with an increased risk of imprinting disorders, which in turn
can lead to ASD [80, 81]. Studies have shown that ASD risk is 1.5 to 2 times higher
among MAR-conceived children compared with their spontaneously conceived
counterparts [125, 135–138]. However, these associations were reduced after
adjustments for sociodemographic and perinatal variables including multiplicity,
PTD, SGA, maternal diabetes, hypertension and preeclampsia, and cesarean deliver.
One small case-control study (n = 942) performed in India looked at the association
between exposure to OS and the risk of ASD (measured through questionnaires),
and identified a 2-fold increased risk of ASD when compared to their
spontaneously-conceived counterparts [139]. To put these results in context, the
estimated prevalence of ASD has increased over time from 0.05% in the 1960s
[140] to 1.46% today in the USA [141] and is reported to be 1.36% in Quebec,
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DOI: http://dx.doi.org/10.5772/intechopen.81337

Canada [142]. This would indicate that among IVF-conceived children, the preva-
lence of ASD could be of approximately 2%.
On the contrary, other groups have yielded reassuring results when considering
ASD as an outcome [143, 144]. Overall, findings remain inconsistent as risk esti-
mate ranges are wide and variable across studies [145]. It is important to note that a
number of differences among these studies have been identified, and could there-
fore explain the disparity among results. Specifically, studies were performed in
small populations, which makes it especially difficult to study a rare outcome such
as ASD [125, 139, 145]. Additionally, ASD definitions were variable across studies,
and were often non-specific which could be due to differences in diagnostic criteria.
Some studies used questionnaires which are subject to recall bias, while other
studies used diagnostic codes through a registry. However, it is also important to
note that over the years, diagnostic criteria used to define ASD have changed
between versions of the Diagnostic and Statistical Manual of Mental Disorders (4th
versus 5th editions) [146, 147]. Lastly, we have identified that there is a lack of
evidence and consideration of the immediate and long-term effect of OS alone as
most studies focused on IVF or MARs in general without including the pharmaco-
logical approach [125, 145].
Throughout this chapter, we have seen that MARs increase the risk of multiple
gestation, prematurity, being born with LBW, and SGA. As such, the observed
increased risk of ASD in MAR-conceived children may be due to reasons unrelated
to the procedure or treatment itself. As we know, MAR has been associated with
increased risk for multiple gestations [63], which in turn increase the risk for
prematurity, LBW, and SGA babies [104, 111, 116]. We know that these are major
risk factors for neurodevelopmental deficits, including ASD [46, 117]. The main
question that remains is how MAR techniques contribute to the increased ASD risk.
The identified limitations as well as the inconsistency of results underline the
importance to produce more evidence on this association by including all exposures
to MARs as identified through this chapter.
3.4.3 Behavioral problems
Most studies presented herein measured behavioral problems through a ques-
tionnaire which included a Strengths and Difficulties Questionnaire (SDQ). The
SDQ is a validated tool comprised of 25 items which aims to assess the psychological
adjustment of children and youths [148]. Based on this questionnaire, behavioral
problems were defined as having emotional symptoms, hyperactivity, conduct
problems, prosocial behavior, and problems with their peers [148]. Depending on
the study group, the mother, the teacher or the child themselves (i.e., later as an
adult) had filled out the questionnaire to assess the outcome.
The rationale for the evaluation of this association is that couples who undergo a
long waiting time before being able to conceive and/or who have had to undergo
lengthy fertility treatments tend to experience significant amounts of stress and
anxiety during the process. Studies have shown that this increased period of stress
may affect their ability to adapt to their new parenting role, which in consequence
may influence their children’s behavioral and emotional development [149–151].
Animal studies suggest that this response may be largely due to the activity of the
stress-responsive hypothalamic-pituitary-adrenal axis and its end-product, which is
cortisol [151]. Higher levels of cortisol in the mother during the pregnancy are
translated into higher levels in the offspring, which in turn can influence the child’s
behavior [151]. Further supporting this theory, studies found that women who
suffered with symptoms of anxiety late in their pregnancy (32+ weeks’gestation)
had higher levels of cortisol in their blood following adjustments for
12
Infertility, Assisted Reproductive Technologies and Hormone Assays

sociodemographic status, gestational age, parity, and lifestyle factors (i.e., smoking
and alcohol consumption) [152, 153].
At both 5 and 7 years of age, the mean behavioral difficulties score was signif-
icantly higher in the ART-children when compared to children born through
spontaneous conception, even after adjusting for other confounding variables
[154]. Indeed, a study performed in the Millenium Cohort comprised of 18,552
women, ART-conceived children had double the risk of having children with peer
problems at 5 years of age (OR, 2.56; 95%CI, 1.14–5.77—model adjusted for
maternal age, age of the child, sex of the child, household socioeconomic status,
family type, maternal qualifications) [154]. A weaker association was observed at
age 7 and was non-significant. It was also shown that at the age of 5, ART-
conceived children seem to have increased emotional difficulties when compared
to those who were spontaneously conceived (adjusted OR, 1.80; 95%CI, 0.86,
3.79). Additionally at age 7, increased peer problems remained (adjusted OR, 1.90;
95%CI, 0.90, 3.98) [154]. Studies have shown that children conceived spontane-
ously, whether or not mothers/couples struggled with infertility, had similar
behavioral patterns [155–159]. These results therefore suggest that the underlying
cause of infertility in the parents is unlikely related to resulting behavioral patters
in children [159].
To put these results in context, it is estimated that 1 in 10 individuals (10%) will
suffer with behavioral problems throughout their life [160]. These results suggest
that among MAR-conceived children, the prevalence of behavioral problems could
be estimated at 20%.
On the contrary, other studies performed among ART-conceived children did
not exhibit any more behavioral problems than their naturally conceived counter-
parts [125, 155–158]. Some of these studies, unlike the others we have presented,
even suggested a more positive relationship between parents and ART-conceived
children [159, 161, 162]. Contrary to the previous theory about higher levels of
stress among these parents, these results are explained by the fact that ART-
conceived children may have a higher desirability factor than their spontaneously
conceived counterparts (i.e., planned and unplanned) [159].
Despite the differences in observed results, there seems to be a trend towards an
implication of MARs in the development of behavioral problems later in life. The
current evidence on behavioral problems suggests that there is a need for the
development of long-term surveillance programs (i.e., registries and databases) for
MAR-conceived children as of the age of 5 and until early adulthood.
4. Conclusions
The prevalence of MAR use around the world has been increased over the last
years. With a noticeable surge of infertility/subfertility among women of childbear-
ing age, these numbers are expected to remain on the rise. Through this chapter, we
evaluated the current state of the literature and showed that MARs have been associ-
ated with a number of significant adverse perinatal outcomes, which have repercus-
sions on the child later in life, but also on their parents, and society. MAR-conceived
children seem to have poorer health overall with increased healthcare utilization
largely due to an increased prevalence of prematurity, being born LBW or SGA, and
later in life, being more at risk for behavioral problems, cerebral palsy, and autism
among other neurodevelopmental outcomes. Decision makers as well as healthcare
professionals should be aware of the repercussions that these methods could have on
the mother as well as the child, and appropriately inform mothers and couples
seeking these therapies to achieve pregnancy in the context of infertility. Further
13
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DOI: http://dx.doi.org/10.5772/intechopen.81337

stufies are needed to present more evidence to strenghten the findings related to
perinatal outcomes when conceiving through MARs.
Acknowledgements
Dr. Bérard is the recipient of a career award from the Fonds de la Recherche en
Santé du Québec (FRQS) and is on the endowment Research Chair of the Famille
Louis-Boivin, which funds research on Medications, Pregnancy, and Lactation at
the Faculty of Pharmacy of the University of Montreal. Jessica Gorgui is the recip-
ient of the Sainte-Justine Hospital Foundation/Foundation of the Stars doctoral
scholarship as well as the FRQS doctoral award.
Conflict of interest
JG and AB have no conflicts of interest to report.
Author details
Jessica Gorgui
1,2
and Anick Bérard
1,2
*
1 Research Center, CHU Sainte-Justine, Montreal, Quebec, Canada
2 Faculty of Pharmacy, University of Montreal, Montreal, Quebec, Canada
*Address all correspondence to: anick.berard@umontreal.ca
© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms
of the Creative Commons Attribution License (http://creativecommons.org/licenses/
by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,
provided the original work is properly cited.
14
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