Assisted reproductive technologies and children's neurodevelopmental outcomes.
ABSTRACT Initial reports suggested that children conceived with assisted reproductive technologies (ART) may be at increased risk for a spectrum of developmental disabilities. Evolving evidence suggests that some of the early risks may have been overstated when not taking plurality of birth or gestational age at delivery into consideration, as both are independent risk factors for neurodevelopmental disabilities arising from alterations in structure and function or limitations in activities. Continued research is needed to overcome lingering data gaps in light of the equivocal literature for many neurodevelopmental disabilities relative to ART, increasing utilization of services, and changes in the clinical management of infecund couples such as the adoption of natural cycles or in vitro maturation treatment options. Population-based cohorts with longitudinal assessment of the multifaceted nature of neurodevelopment across critical and sensitive windows is paramount for the development of empirically based guidance for clinical and population health.
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ABSTRACT: Interrogating the association between assisted reproductive technologies (ART) and perinatal outcome is complicated but very important. This is an introduction to a series of articles that review this potential association with an eye toward etiology of risk, and what aspects of in vitro fertilization (IVF) can be modified to reduce this risk. When an association is not due to chance (i.e., statistically significant), one must also consider how the association may be affected due to bias or confounding. Despite lack of the perfect study, perinatal consequences of ART are apparent, even though the vast majority of children conceived with ART are healthy. Pregnancy after IVF is altered as evidenced by risk of preterm delivery, low birth weight among infants, and an alerted prevalence of preeclampsia. The long-term clinical implications of ART, such as childhood development and metabolism, have not been established and ongoing study is proceeding. The risk attributed to multiple births is iatrogenic and needs to be minimized. Optimizing the environment at the time a woman conceives will likely have an effect on gestation as well as the health of children. Reproduction effects health and health effects reproduction.Fertility and sterility 02/2013; 99(2):299-302. · 4.30 Impact Factor
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ABSTRACT: Are children born after assisted reproductive technology (ART) at increased risk of autism spectrum disorders (ASD)? There is no evidence that ART significantly increases the risk of ASD in the offspring. A few systematic reviews have explored the correlation between assisted conception and ASD with inconclusive results, partly due to the heterogeneity of diagnostic criteria and methodology in the different studies. Systematic review of 7 observational studies (2 cohort and 5 case-control) encompassing 9216 subjects diagnosed with ASD published since 2000. Literature searches were conducted to retrieve observational studies on the risk of ASD in ART population. Databases searched included PubMed, EMBASE and PsycINFO. In order to obtain more consistent results, we only included the studies in which (i) subjects with either infantile autism or ASD could be identified according to international classification systems and (ii) the diagnosis was obtained from hospital records. Seven studies matched the inclusion criteria. Four out of seven studies, including the two with the best quality scores, did not show an association between ART and ASD. The two papers supporting an increased risk of autism following ART had the lowest quality scores, due to major methodological limitations. Only one paper showed a protective role of ART. In spite of the strict inclusion criteria applied as to the diagnosis of ASD, the papers selected are heterogeneous in many aspects including study design, definitions of ART, data source and analysed confounders. At present, there is no evidence that ART is significantly associated with ASD and hence that current health policies should be modified. The divergent results of some of the studies suggest that further prospective, large and high-quality studies are still needed. This work was supported, in part, by the Italian Ministry of Health and by Tuscany Region. The authors have no competing interests to declare. TRIAL REGISTRATION NUMBER: N/A.Human Reproduction 10/2013; · 4.59 Impact Factor
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ABSTRACT: Critical data gaps remain regarding infertility treatment and child development. We assessed the utility of a birth certificate registry for developing a population cohort aimed at answering such questions. We utilised the Upstate New York livebirth registry (n = 201 063) to select births conceived with (n = 4024) infertility treatment or exposed infants, who were then frequency-matched by residence to a random sample of infants conceived without (n = 14 455) treatment or unexposed infants, 2008-10. Mothers were recruited at 2-4 months postpartum and queried about their reproductive histories, including infertility treatment for comparison with birth certificate data. Overall, 1297 (32%) mothers of exposed and 3692 of unexposed (26%) infants enrolled. Twins represented 22% of each infant group. The percentage of infants conceived with/without infertility treatment was similar whether derived from the birth registry or maternal report: 71% none, 16% drugs or intrauterine insemination, and 14% assisted reproductive technologies (ART). Concordant reporting between the two data sources was 93% for no treatment, 88% for ART, and 83% for fertility drugs, but differed by plurality. Exposed infants had slightly (P < 0.01) earlier gestations than unexposed infants (38.3 ± 2.8 and 38.7 ± 2.7 weeks, respectively) based upon birth certificates but not maternal report (38.7 ± 2.7 and 38.7 ± 2.9, respectively). Conversely, mean birthweight was comparable using birth certificates (3157 ± 704 and 3194 ± 679 g, respectively), but differed using maternal report (3167 ± 692 and 3224 ± 661, respectively P < 0.05). The birth certificate registry is a suitable sampling framework as measured by concordance with maternally reported infertility treatment. Future efforts should address the impact of factors associated with discordant reporting on research findings.Paediatric and Perinatal Epidemiology 03/2014; · 2.16 Impact Factor
technologies and children's
Mary L. Hediger, Ph.D.,aErin M. Bell, Ph.D.,bCharlotte M. Druschel, M.D.,b,c
and Germaine M. Buck Louis, Ph.D.a
aDivision of Epidemiology, Statistics and Prevention Research, Eunice Kennedy Shriver National Institute of Child Health
and Human Development, National Institutes of Health, Rockville, Maryland;bSchool of Public Health, University at
Albany, State University of New York, Rensselaer, New York; andcCongenital Malformations Registry, New York State
Department of Health, Albany, New York
developmental disabilities. Evolving evidence suggests that some of the early risks may have been overstated when not taking plurality
from alterations in structure and function or limitations in activities. Continued research is needed to overcome lingering data gaps in
in the clinical management of infecund couples such as the adoption of natural cycles or in vitro maturation treatment options.
Population-based cohorts with longitudinal assessment of the multifaceted nature of neurodevelopment across critical and sensitive
windows is paramount for the development of empirically based guidance for clinical and pop-
ulation health. (Fertil Steril?2013;99:311–7. ?2013 by American Society for Reproductive
Key Words: Assisted reproductive technology, children, epidemiology, neurodevelopment,
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of live births in the United States, but
more than 3% of live births in Connect-
icut, District of Columbia, Massachu-
setts, New Jersey, and New York (1).
These percentages are likely to increase
as treatment continues to advance and
services become covered by health
insurance. Of note is the additional
percentage of births that are assisted
hildren conceived using assisted
reproductive technology (ART)
represent currently about 1.4%
by other infertility treatments such as
ovulation stimulation by administra-
tion of clomiphene citrate (CC; e.g.,
alone or in combination with gonado-
tropins (e.g., FSH), and IUI. The impact
of ART on population health is notable,
including in the United States, largely
as a reflection of the greater percentage
births (33% vs. 12%), and low birth
weight (32% vs. 8%) infants conceived
with ART in comparison with the gen-
eral birth population, respectively (1).
These percentages vary tremendously
bounds. For example, 48% of ART
births in Puerto Rico were low birth
weight (<2,500 g) in comparison with
26% in Massachusetts, whereas pre-
term births (<37 weeks) varied from
47% in Wyoming to 21% in Vermont.
Given that infants conceived with
ART are more likely to be born preterm,
small-for-gestational age (SGA, <10th
percentile for reference) or as multiples
relative to children conceived without
treatment, they represent a population
at risk for mortality and morbidity,
including a spectrum of neurodevelop-
mental disabilities (NDDs) (2). Ques-
tions remain, however, whether the
disabilities or developmental differ-
ences can be attributed to the infertility
treatment and/or underlying parental
impaired fecundity, multiple gestation,
Received November 20, 2012; revised December 11, 2012; accepted December 17, 2012.
M.L.H. has nothing to disclose. E.M.B. reports grants and travel support from the Eunice Kennedy
Shriver National Institute of Child Health and Human Development. C.M.D. reports grants and
travel support from the Eunice Kennedy Shriver National Institute of Child Health and Human
Development. G.M.B.L. has nothing to disclose.
Supported in part by the Intramural Research Program, Eunice Kennedy Shriver National Institute of
Child Health and Human Development, National Institutes of Health (M.L.H., G.M.B.L.).
Reprint requests: MaryL.Hediger, Ph.D.,DivisionofEpidemiology,Statistics andPreventionResearch,
Eunice KennedyShriverNationalInstituteofChildHealthandHuman Development,NationalIn-
stitutes of Health, 6100 Executive Boulevard, Room 7B03, Rockville, Maryland 20852 (E-mail:
Fertility and Sterility® Vol. 99, No. 2, February 2013 0015-0282/$36.00
Copyright ©2013 American Society for Reproductive Medicine, Published by Elsevier Inc.
VOL. 99 NO. 2 / FEBRUARY 2013
or unmeasured environmental factors. There have been many
follow-up studies of children born from ART addressing their
neurodevelopmental status, which have been reviewed ex-
haustively (3–10), as practitioners have looked for answers
and information for counseling expectant couples. Evidence
on the long-term effects of infertility treatments remains
equivocal, with the main criticisms of existing studies being
that they frequently do not account for birth plurality and/
or chorionicity if twins are even included, have small sample
sizes, are rarely able to characterize the infertility treatment
protocols except broadly, rely on clinic-based populations,
inadequate selection of comparison children, or failure to ac-
count for known determinants of growth and development.
In practicality, the root causes of NDDs may not matter to
expectant couples, but the answer has implications for treat-
ment and obstetric management. At the population level,
NDDs carry tremendous socioeconomic costs and contribute
heavily to the global burden of disease, given the higher asso-
ciated mortality and long-term disability for children born
early or with reduced size (11). In fact, the US President's
Council on Bioethics called for improved monitoring of infer-
tility treatments and outcomes and long-term longitudinal
studies to assess child health concerns for better informed
decision-making on the part of practitioners and parents (12).
This article reviews the available data regarding the neu-
rodevelopmental status of children conceived with ART in
comparison with children conceived without such treatment.
For purposes of this article, we define ART as the manipula-
tion of gametes or embryos external to the body for purposes
of establishing a pregnancy (13). Furthermore, we use the
conceptual framework of the International Classification of
Functioning, Disability and Health that defines a disability
as difficulty with any or all of the three interrelated areas of
function: 1) impairments, defined as problems in body func-
tion or alterations in body structure (e.g., blindness, paraly-
sis); 2) activity limitations, defined as difficulties in
executing activities (e.g., eating, walking); and 3) participa-
tion restriction, defined as problems with involvement in
any aspect of life (e.g., employment discrimination) (11).
This article addresses impairments (i.e., autism, cerebral palsy
[CP], intellectual disability, sensory impairments) and activity
motor, verbal), but not participation restriction. Because
many investigators focus on multiple neurodevelopmental
outcomes using validated diagnostic instruments, we refer
to activity limitations as attention and other neurodevelop-
mental outcomes. We begin the article with a short review
ofART andperinatal outcomes, given thatthey are associated
with NDDs in general followed by a succinct review of the re-
cent literature for specific NDDs. Other important outcomes,
such as birth defects and cardiovascular health, are discussed
cussion of the methodological limitations underlying linger-
ing data gaps, and offer key research strategies aimed at
advancing our knowledge.
ADVERSE PERINATAL OUTCOMES
It has been well established that infertility treatment and ART
are associated withanincreasedriskof obstetriccomplications
and adverse perinatal outcomes. In a review of 17 matched
control studies published from 1985–2002, Helmerhorst and
colleagues (10) reported that after ART, singletons were at
significantly increased risk for very preterm (<32 weeks) and
moderately preterm delivery (32–36 weeks), SGA birth, and
perinatal mortality with relative risks ranging from 1.40 (95%
confidence interval [CI] 1.15–1.71) for SGA to 3.27 (95% CI
2.03–5.28) for very preterm delivery. Cesarean delivery and
neonatal intensive care unit (ICU) admissions were also in-
creased, and the eight nonmatched studies that were reviewed
showed similar patterns (10).
increased risk for either very preterm delivery or preterm de-
livery and SGA in comparison with twins conceived without
ART (10). In fact, ART twins were reported to have a 40%
reduction in risk of perinatal mortality (0.58; 95% CI
0.44–0.77), compared with twins conceived spontaneously.
However, unlike the findings for singletons, which have
been replicated and confirmed in a number of meta-
analyses and population-based studies (14–20), the picture
for twins is more complicated and less established (10, 21,
22). Specifically, ART twins are much more likely to be
dichorionic, dizygotic pairs, and therefore twins conceived
spontaneously are an inappropriate comparison group, as
monochorionic pairs who are likely to have worse outcomes
are included in the comparison. Using as the comparison
4,097 unlike-sex, spontaneously conceived twin pairs (i.e.,
no monochorionic, monozygotic pairs) the perinatal out-
comes for 700 ART twin pairs in Western Australia, surveyed
from 1994–2000, showed that adverse outcomes were indeed
2.5 (95% CI 1.6–3.7) and moderately preterm delivery was 1.9
(95% CI 1.3–2.2), with very low birth weight (<1,500 g) and
rable increased risk. Twins conceived by ART were also more
likely to be delivered by emergency cesarean, have longer
birth admissions, and more frequent hospitalizations in the
first 3 years of life than spontaneously conceived twins (22).
Finally, although less abundant, there is now some evi-
dence suggesting that ovulation stimulation apart from ART
may be associated with poor fetal growth. Comparing among
live born singleton infants conceived with ART, with ovula-
tion stimulation medications, and spontaneously in a sample
of 16,748 births in six States under surveillance by the Preg-
nancy Risk Assessment Monitoring System, D'Angelo and
colleagues (19) corroborated that singleton infants conceived
with ART are at risk for preterm delivery and SGA birth, with
adjusted odds ratios (AOR) of 1.91 (95% CI 1.31–2.80) for pre-
term delivery and 1.98 (95% CI 1.21–3.24) for SGA. Singleton
infants conceived with ovulation stimulation were not at risk
1.09–2.69). On the other hand, this study did not show effects
for two reasons: first, there were too few twins or triplets in
the treatment groups (n ¼ 285) and twins in the reference
(n ¼ 176) for meaningful comparison; and second, the refer-
known number of monochorionic pairs, which would have
attenuated the difference among the groups in terms of
VOL. 99 NO. 2 / FEBRUARY 2013
VIEWS AND REVIEWS
outcomes. In sum, the available weight of evidence to date
supports a shortened gestation and lighter birth size for
ART-conceived infants in comparison with infants conceived
without such treatment.
Little is known about the etiologic determinants of NDDs
making it difficult to specify statistical models inclusive of
relevant variates and known/potential confounders. With in-
creasing support for the early origins of health and disease
hypothesis (23), delineating periconceptional and in utero
influences on human development becomes essential for
understanding association studies focusing on ART and chil-
dren's development. Further complicating our understanding
is recognition of possible transgenerational exposures that
flecting a shared etiology (24, 25). Such data are absent and,
therefore, we focus on research that is assessing ART and
Concern has arisen as to whether children conceived by ART
may be at increased risk of autism and the autism spectrum
disorders (ASD), again either from a treatment effect or be-
cause of parental characteristics, such as older parental age.
Studies from Scandinavia (Finland, Denmark, Sweden), either
nosed from discharge registers have been inconsistent in their
findings, but at present, have been reassuring (26–28). An
early Swedish study looking at births from 1984–1997 (26),
showed an increased risk of ASD with infertility treatment,
although the findings did not achieve significance (odds
ratio [OR], 1.35; 95% CI 0.86–2.11). Among Finnish births
from 1996–1999 (27), ART was not associated with an
increased risk for behavioral disorders usually diagnosed in
childhood or adolescence, including ASD, among singletons
(OR, 1.05; 95% CI 0.57–1.91). On the other hand, a higher
but insignificant increased risk for these disorders was
observed for twins (OR, 3.05; 95% CI 0.70–13.29). Finally,
a Danish study (28) of children born from 1995–2000 after
assisted conception (IVF or ovulation induction) observed
a moderately decreased risk of ASD for twins (OR, 0.82;
95% CI 0.23–2.95). In the United States, Grether and
colleagues (29) reported no increased risk of ASD (AOR,
0.99; 95% CI 0.67–1.50) among 349 singleton cases born
between 1995 and 1998 in Northern California who were
compared with 1,847 control children in relation to parental
infertility using various indicators. A significantly increased
risk was observed for twins (OR, 3.9; 95% CI 1.2–13). These
findings for twins appear to corroborate the results of the
Finnish Study (27), but it is important to note that the
Grether and colleagues (29) analysis was based only on 21
twin cases and 54 twin controls.
Although earlier, smaller studies with short follow-up inter-
vals tended to report null findings for both IVF and
intracytoplasmic sperm injection (ICSI) techniques, a number
of large, primarily Scandinavian population-based cohort
studies based on registry data have reported a significant in-
crease in risk of CP for IVF children compared with those
spontaneously conceived (5, 26, 27, 30–34). The later
studies are prospective cohorts and obtained neurological
outcome data from physical examination, medical or
hospital records, and/or registry records. In general, they
found about a twofold increased risk in CP with IVF or ICSI
that is explained to some extent, but not all, by preterm
delivery and multiple births (34). However, with the number
of twin birthsfrom ART
Scandinavia, the rates of CP have likewise decreased (35).
Similarly, a recent study by Davies and colleagues (36)
from South Australia, 1986–2002, looked at CP in the context
of birth defects incidence in a cohort of 308,974 births, of
which 6,163 were from assisted conception (i.e., IVF and
ICSI). These investigators were able to adjust for a number
of parental and fetal factors, including maternal age, parity,
fetal sex, year of birth, maternal race/ethnicity, maternal
country of birth, maternal conditions of pregnancy, maternal
smoking, socioeconomic status, and maternal and paternal
occupation, but did not adjust for timing of delivery (i.e.,
very preterm or preterm). In the adjusted models, there was
an increased risk of CP overall (AOR, 2.66; 95% CI
1.79–3.94), with the effect being larger for singletons from
assisted conceptions (AOR, 2.22; 95% CI 1.35–3.63), than
for twins (AOR, 1.39; 95% CI 0.69–2.77) (36).
Researchers continue to assess the relation between ART
and CP in the context of other aspects of parental infertility.
sess whether the increased risk of CP noted with ART was due
to the effect of ART treatment or parental infertility. Zhu and
colleagues (34) identified cases of CP through the Danish
registry among children aged 4 years or older, and looked at
outcomes in relation to time-to-pregnancy (TTP, 0–2, 3–5,
6–12, >12 months), infertility treatment (IVF, ICSI, other),
and whether or not the pregnancy was planned. In the total
cohort of 90,203 children, 165 cases (0.18%) of CP were iden-
tified, and there was no association between TTP and the risk
of CP. Although subfecundity was not associated with CP, af-
ter adjusting for preterm delivery and multiple births, there
was a more than twofold risk associated with ART (adjusted
hazard ratio [AHR], 2.30; 95% CI 1.12–4.73).
Investigators have attempted to synthesize original re-
search using a weight of evidence approach for assessing
ART and CP. Specifically, a recent meta-analysis of 19,462
children conceived with IVF reported a twofold increased
odds of CP. However, the investigators identified important
methodological limitations that impact a more complete un-
derstanding of the association (6). These limitations included
limited sample sizes, particularly for rare outcomes such as
dity, and specific aspects of ART and other infertility-related
treatment such as ovulation stimulation.
decreasing over time in
Littleis knownwhether and how ARTmay affectthedevelop-
ing brain, and there have been virtually no studies that have
VOL. 99 NO. 2 / FEBRUARY 2013
Fertility and Sterility®
followed ART fetuses by ultrasound to delivery to chart the
development of the brain. After initial reports suggesting
that ICSI children were at significantly increased risk for
developmental delay in comparison to IVFand naturally con-
ceived children, recent evidence suggests comparable mental
development. A review summarizing nine previous studies
involving 969 ICSI children and 828 controls (343 IVF, 485
naturally conceived) concluded that most ICSI conceived
children had normal mental development, but that maternal
education and social class were important determinants of
children's developmental outcomes (37). Thus, proper model
specification regarding the inclusion of relevant confounders
is critical for assessing associations between ART and chil-
dren's intellectual development. Another systematic review
analyzed 59 studies including 23 registry-based and 14 con-
trolled studies and concluded that children born after IVF or
ICSI were not at increased risk of severe cognitive impairment
in comparison with naturally conceived children (5).
Sensory Impairments: Hearing and Vision
At present there have not been many studies focusing specif-
ically on sensory impairments or auditory and visual acuity,
despite their extreme relevancy for development. Ludwig
ICSI children and 273 children who were spontaneously
ported no differences across groups of children. An important
aware of children's hearing abnormalities as detected as part
of this study, suggesting that parental reporting may not be
a valid method for ascertaining children's sensory deficits.
An observational cohort of IVF children born from 1982–
2007 was assessed for eye malformation (n ¼ 32,091) and the
cohort born from 1985–2005 for severe visual impairment
(n ¼ 24,628) using all births and the Swedish health registers,
and the IVF cohorts were compared with all children born
during the time periods involved. Only 36 cases of ocular
malformation were identified, and this did not represent an
increased risk after adjusting for potential confounders
(AOR, 1.05; 95% CI 0.75–1.47). The 25 IVF cases of severe
visual impairment identified did represent a significant
increase (AOR, 1.55; 95% CI 1.04–2.32) compared with all
Children's development can be affected without altering
structure, function, or the so-called neurodevelopmental
impairments. Rather, developmental deficits may become
apparent particularly when assessed at developmentally ap-
propriate ages (e.g., preschool or school aged). Borrowing
from the literature for high-risk infants, such as those born
early, of diminished birth size or as multiples, it is important
tinue to identify deficits that may arise later in childhood or
adulthood. We briefly review neurodevelopmental outcomes
including attention deficit and hyperactivity.
In the largest study conducted to date and known to us,
28,158 children born after IVF were compared with
2,417,886 children from the Swedish population, 1982–
2005. Using prescription drug registries as the proxy for
diagnosis, children with attention deficit/hyperactivity were
compared with the children in the general population. An
elevated risk for attention deficit/hyperactivity disorder was
dren after adjusting for potential confounders (OR, 1.18; 95%
However, the association was no longer significant after
adjusting for length of involuntary childlessness, which the
investigators interpreted as offering weak evidence for an as-
sociation between IVF and attention deficit/hyperactivity
this area with conflicting findings, again primarily relating to
preterm. Most studies havereportedno significant differences
in cognition, mental, or psychomotor development between
ICSI and/or IVF children compared with spontaneously con-
ceived children (30, 41–49), but still some earlier studies did
report a developmental deficit in ART-conceived children
(50, 51). These studies were all prospective in design, with
the exception of two retrospective studies (45, 50), and
assessed developmental status through a variety of methods,
complicating comparison. Most studies on follow-up used
Development (42, 44), the Griffith Scale (47–49), or the
Wechsler Preschool and Primary Scale of Intelligence-
a nonstandardized neurologic examination (41), nationwide
registry data (30), or a list of developmental milestones
collected through interview (44). Furthermore, there are
other limitations to the existing studies that hamper the
generalizability and interpretation of findings. As indicated
earlier, criticisms of existing studies include not accounting
for plurality and chorionicity if twins are included,
restriction to singletons, small sample sizes, clinic-based
populations, failure to account for gestational age, and other
factors known to influence development.
Two recent studies, one with follow-up to 18 months (52)
and the other to 3 years (53), have tried to address some of the
concerns and are notable. Zhu and colleagues (52) followed
up to 18 months of age, 37,897 singleton infants from fertile
couples, 4,351 infants from subfertile couples (TTP >12
months), and 3,909 infants born after infertility treatment
(IVF, ICSI, IUI, hormonal treatment) in the Danish National
Cohort and evaluated them for gross and fine motor develop-
ment (milestones), cognitive, and language skills. They found
no effect of fertility or treatment on motor or attention skills,
but they did find, comparing the infertility treatment with the
subfertile group, that the infertility-treated group overall had
a slight delay (OR, 1.24; 95% CI 1.01–1.53) in achieving cog-
the global score (delay in meeting at least three milestones),
the children conceived with ICSI, compared with those born
from subfertile couples, did appear to be particularly prone
to delays in gross motor development (e.g., sitting without
VOL. 99 NO. 2 / FEBRUARY 2013
VIEWS AND REVIEWS
support at 9 months: AOR, 1.33; 95% CI 0.84–2.09; walking
without support at 16 months: AOR, 1.40; 95% CI 0.96–2.04).
However, in a more comprehensive study from the Mil-
lennium Cohort Study, 2000–2002, in England and Wales,
Carson and colleagues (53) followed up infants to 3 years of
age and found no differences in cognitive development after
ART. These investigators used the British Ability Scales II
Naming Vocabulary test and compared the 99 children from
ART singleton pregnancies with four groups from the cohort:
a sample of 198 singleton children matched for gender,
mother's age, and socioeconomic status; 402 singleton chil-
dren from planned pregnancies with a TTP more than 12
months; 5,556 singleton children from planned pregnancies
spontaneously conceived (53). For each comparison, the ART
children outperformed the comparison group in ability,
although no comparison was significant. The ability differ-
ence in the favor of the ART children was þ1.10 (95% CI
?2.47–4.68) with the matched group, þ1.44 (95% CI
?1.74–4.63) with a TTP more than 12 months, þ1.66 (95%
CI ?1.34–4.66) with a TTP less than 12 months, and þ1.84
(95% CI ?1.07–4.74) for any spontaneous conception. This
cohort was also assessed at 5 years of age, again, with no
evidence that ART adversely affected children's cognitive de-
velopment after adjusting for sociodemographic factors (54).
In conclusion, the most cited population-based study that
addressed neurodevelopmental outcomes among children
conceived from infertility treatment raised tremendous con-
cerns, finding that suspected developmental delay was in-
creased nearly fourfold in children born after IVF (30).
However, this study made it quite clear that the increased
risk was primarily attributable to the complications of twins
and to preterm delivery. Subsequently, although the picture
has been less clear, the evidence that has been accumulated
has been generally reassuring. Singleton children born at
term or near term with normal birth weights, irrespective of
conception mode (i.e., IVF, ICSI, ovulation stimulation,
spontaneous after a prolonged TTP), appear to be developing
normally. On the other hand, it will also be important to con-
regard to generalized health status and hospitalization. Previ-
ous reports have noted significantly more childhood illnesses,
surgeries, medical therapies, and hospital admissions for ART
children in comparison with children conceived without such
treatment (55, 56), although some of the increase in use of
medical services has been attributed to multiple or preterm
Insum,theavailable literature, although initiallysuspect,
now suggests that ART-conceived children do not have a uni-
formly higher risk of NDDs than children conceived without
such treatment. As such, the weight of evidence is reassuring,
particularly when accounting for multiple births and other
istics. The absence of increased risks for impairments and, to
to mean that follow-up is no longer warranted. As noted by
many investigators, continued monitoring and follow-up of
pacting the full interpretation of findings and an increasing
percentage of children born after treatment, which was esti-
research needs to move beyond select clinical or registry-
based research to ensure treatment and other relevant
exposures/confounders are ascertained in a valid and reliable
manner and that outcomes are assessed relative to the whole
child and not just one aspect of development. We suggest
a strategy for moving forward and filling lingering data gaps.
Advancing Knowledge: Overcoming
Using the many important findings from past research, our
future research strategy should address four overarching
methodological limitations if we are to overcome lingering
data gaps regarding the long-term developmental status of
and not restricted to particular ART clinics to ensure external
country-specific follow-up to address varying clinical
practices, especially single ET, in vitro maturation, and natu-
ral cycle IVF. Also with regard to sampling, it is important to
of the couple along with the child to better measure fecundity
and related impairments or treatments in addition to ART.
This step is important when considering a possible shared
lopmental status in the offspring, and in delineating the
causal model for fecundity, ART, and NDDs.
Second, because they are at higher risk for adverse out-
later child development, fetuses conceived with ART and by
ovulation stimulation should be followed longitudinally
through gestation to determine the nature of the growth re-
striction, if any, and minimize the risk of adverse outcomes.
This is especially important for twins, where it has been
shown that the smaller twin of a discordant pair will perform
less well on intelligence tests at age 3 years, yet achieving
a physical size comparable to the larger twin of the pair
(58). The timing of intrauterine growth restriction associated
with ART or ovulation stimulation is unknown, therefore
cases with growth restriction that is brain sparing are not dis-
tinguished from those who are not.
The third consideration is the need for postnatallongitudi-
dren's development including its transient unevenness. This
design will position researchers to assess the potential shared
etiology of impaired parental fecundity, ART, epigenetic
changes, and suboptimal fetal, infant, and child development.
that some comparison children are conceived by couples with
impaired fecundityorafterotherinfertility treatments. Ascer-
taining pregnancy intention or time required for conception
among planners may help provide insight regarding the un-
derlying fecundity status of couples. Many registry-based
studies involving large cohorts do not specifically address
this issue despite its relevancy for interpreting findings.
We are unaware of any research that has prospectively
followed ART-conceived and comparison infants from
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conception onward in the context of other environmental in-
fluences, such as diet, household quality, and chemical expo-
sures, to assess fetal growth and to assess growth and
development continuing through infancy and childhood.
Such strategies may help identify high-risk patterns and
trajectories for ART and non-ART pregnancies along with
the implications for infant and child health. Similarly, longi-
tudinal studies of ART births through key developmental
milestones that are the hallmark of childhood and adoles-
cence are noticeably absent. The Upstate KIDS Study is one
such attempt to longitudinally follow a population-based
cohort of children irrespective of their mode of conception
across sensitive windows of infant and child growth and de-
There are many population level changes affecting child-
bearing in the United States and in other countries including
a later age at first birth and smaller completed family size.
These factors have implications for both couple fecundity
(59) and fetal/infant growth and development. As such, there
is a continual need to establish prospective cohorts for mon-
itoring and assessment as we strive to understand how couple
fecundity or evolving ART treatment may or may not imprint
the next generation.
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