This chapter should be cited as follows:
Kjaer ASL, Pinborg A, et al, Glob. libr. women's med.,
ISSN: 1756-2228; DOI 10.3843/GLOWM.421173

The Continuous Textbook of Women’s Medicine Series – Gynecology Module

Volume 15

Reproductive medicine for the obstetrician and gynecologist

Volume Editors: Professor Luca Gianaroli, S.I.S.Me.R. Reproductive Medicine Institute, Italy; Director of Global Educational Programs, IFFS
Professor Edgar Mocanu, RCSI Associate Professor in Reproductive Medicine and Surgery, Rotunda Hospital, Ireland; President, IFFS
Professor Linda Giudice, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, USA; Immediate Past President, IFFS

Published in association with the
International Federation of
Fertility Societies

Chapter

Short- and Long-term Health in Children Born after ART

First published: November 2024

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INTRODUCTION

Worldwide more than 10 million children have been born after assisted reproductive technology (ART) fulfilling the family formation wishes for couples facing infertility and also their desire of having healthy children. Therefore, continuous surveillance of the short- and long-term health outcomes of ART procedures compared with natural conception (NC), is essential for informed decision-making in clinical practice for the future parents and clinicians working in the field.

This chapter explores the current literature on short- and long-term health outcomes of ART versus NC and the nuances of different ART procedures, including intracytoplasmic sperm injection (ICSI) versus in vitro fertilization (IVF), frozen embryo transfer (FET) versus fresh embryo transfer, blastocyst versus cleavage stage embryo transfer, and oocyte donation. Furthermore, the possible causes for altered short- and long-term outcomes in children born after ART is discussed (Figure 1).

SHORT-TERM HEALTH OUTCOMES FOLLOWING ASSISTED REPRODUCTIVE TECHNOLOGY

Assisted Reproductive Technology versus Natural Conception

Multiple Births

Multiple births are still a major concern in ART, due to the substantial elevated risks of adverse obstetric and perinatal outcomes with a greater risk of short- and long-term morbidity in the children such as neurodevelopmental diseases.^{1,2,3,4,5,6,7} Based on the Committee of Nordic ART and Safety (CoNARTaS), a recent multinational cohort study yielded that the risk of cerebral palsy (CP) among ART children was significantly reduced from the early 1990s to 2015 due to a lower risk of preterm birth (PTB) caused by the reduction in multiple births.⁸

In Europe, the twin birth rate after ART decreased from 28% to 15% between 1997 and 2016.^10,12 A similar trend occurred in the United States, where the twin birth rate dropped from 27% to 10% between 2000 and 2018.¹¹ In the Nordic countries, increased adoption of single embryo transfers resulted in a decrease in twin birth rates within the ART population, dropping from nearly 30% in 1994 to 4–13% in 2014 and now below 5% in all Nordic countries.^14,15

Based on data from the CoNARTaS cohort, it is evident that rates of placenta-mediated complications, PTB, low birth weight (LBW), and stillbirth have substantially decreased in the Nordic countries in parallel with the declining twin birth rates.¹⁶ However, despite the high survival rates of frozen/thawed embryos and the risks associated with twin pregnancies, double embryo transfer remains the standard procedure in many countries, even for couples with a favorable prognosis for achieving pregnancy and live birth.^11,12,13,17 Hence, there is still a crucial need to ensure the well-being of children born through ART by the widespread implementation of the "single embryo transfer" policy.^9,18

Singletons

Extensive cohort studies consistently reveal that even singleton pregnancies resulting from ART carry a slightly elevated risk of adverse outcomes compared with NC singletons.

In a recent systematic review and meta-analysis encompassing 52 cohort studies worldwide, data from over 180,000 singleton pregnancies after fresh and FET were analyzed.¹⁹ The analysis unveiled significant disparities in perinatal outcomes between ART and NC. The absolute differences in the prevalence of adverse perinatal outcomes between singletons born after ART and NC were 4.5% for PTB, 1.2% for very preterm birth (VPTB), 2.9% for LBW, 1.0% for very LBW (VLBW), 1.4% for small-for-gestational-age (SGA), 0.4% for perinatal mortality and 1.8% for congenital malformations; all values were statistically significant with P-values <0.001.¹⁹ Recently, a meta-analysis involving 19 cohort studies and 68,000 ART singleton pregnancies yielded an increased risk of stillbirth after ART, with a pooled risk of odds ratio (OR) 1.41 (95% CI 1.20–1.65) and the crude stillbirth rate being 4.44/1000 total births.²⁰ Another meta-analysis, comprising 22 cohort studies in singletons, reported an elevated relative risk (RR) of congenital malformations (RR 1.41, 95% CI 1.30–1.52) in ART versus NC singletons, but most studies included in their analysis focused on older birth cohorts, and none included data on birth cohorts born after 2010.²¹

Based on CoNARTaS data including more than 90,000 ART children born in the Nordic countries, the absolute prevalence of congenital malformations was 3.4% versus 2.9% in NC children and the RR of a congenital malformation remained similar over a four-decade period from 1988 to 2007.²² The adjusted risk for ART versus NC singletons in the Nordic countries over the full period being adjusted OR (aOR) 1.14 (95% CI 1.08–1.20).

Intracytoplasmic Sperm Injection versus In Vitro Fertilization

The comparison of outcomes following ICSI and IVF pregnancies is a topic of considerable interest. Most large cohort studies generally indicate similar or even lower risks of PTB, LBW, and perinatal mortality in singletons born after ICSI compared to IVF.^22,23 A meta-analysis based on five cohort studies showed a lower risk of PTB in ICSI versus IVF pregnancies (both fresh and FET) with an aOR of 0.80 (95% CI 0.69–0.93).²³ The cause of better perinatal outcomes after ICSI is most probably the effect of healthier mothers with no reproductive diseases. This is supported by a large cohort study based on the national HFEA data in the UK, where female causes of infertility were associated with a higher risk of PTB and LBW in singletons born after IVF/ICSI.²⁴ Whether the risk of congenital malformations differs between ICSI and IVF offspring remains the subject of ongoing debate.^25,26,27,28 A systematic review and meta-analysis on 19 studies found no increased risk of chromosome abnormalities in the adjusted data when comparing ICSI to either standard IVF (aOR 0.75, 95% CI 0.41–1.38) or NC (aOR 1.29, 95% CI 0.69–2.43).²⁶ In contrast, a recent register-based Nordic study by the CoNARTS group in 86,862 live-born singletons showed a slight but significantly higher risk of major congenital malformations, especially contributed to respiratory and chromosomal malformations, among fresh ICSI compared to fresh IVF (aOR 1.07, 95% CI 1.01–1.14). They found no difference when comparing ICSI used for male infertility factor and ICSI for other indications, except for the risk of hypospadias where the risk was significantly higher when male factor infertility was present.²⁵ These results indicate that hypospadias in the offspring may be related to intrinsic paternal factors and not the ART per se, while for the other malformations it seems that there is no relation to the low semen quality but rather the ICSI procedure.

Frozen Embryo Transfer versus Fresh Embryo Transfer

Initial systematic reviews and meta-analyses yielded promising results for FET pregnancies with a reduced risk of PTB, LBW, and SGA in FET offspring, while the risks of stillbirth and perinatal deaths were comparable to those after fresh cycles.^23,29,30,31 However, a Finnish cohort study in 2010, involving 2293 FET children, revealed a higher risk of large-for-gestational age (LGA) in FET children.³² A recent systematic review and meta-analysis encompassing 26 studies offered a more comprehensive understanding of FET outcomes, where pooled risk estimates confirmed a lower relative risk of PTB, LBW, and SGA in pregnancies following FET compared to fresh cycles.³³ Conversely, the risk of LGA offspring and a birth weight exceeding 4500 g as well as hypertensive disorders of pregnancy (HDP) was increased in FET pregnancies. In accordance, a recent Cochrane review on elective FET versus fresh embryo transfer found an increased risk of HDP (OR 2.15, 95% CI 1.42–3.25), LGA offspring (OR 1.96, 95% CI 1.51–2.55) and a higher birth weight (mean difference 127.4 g, 95% CI 77.1–177.8) of children born following the 'freeze all' strategy.³⁴ Additionally, convincing data have shown that programmed-FET cycles with endometrial preparation with sequential estradiol and progesterone without the creation of a corpus luteum in comparison with natural cycle FET (NC-FET) contribute to a higher risk of HDP, postpartum hemorrhage (PPH) and overgrowth in FET singletons.^35,36,37 In agreement, a recent systematic review showed significantly decreased risk of HDP (aOR 0.52, 95% CI 0.47–0.52), pre-eclampsia (PE) (aOR 0.43, 95% CI 0.37–0.51), LGA (aOR 0.87, 95% CI 0.80–0.93) and PPH (0.44, 95% CI 0.36–0.47) in the NC-FET group compared to programmed-FET.³⁸ In ART pregnancies the absence of a corpus luteum leads to undetectable levels of relaxin, which is a potent vasodilator. This may be a plausible explanation for the adverse outcomes observed in pregnancies without a corpus luteum.^39,40,41

Blastocyst versus Cleavage Stage Transfer

The practice of extending the culture time of embryos to the blastocyst stage before transfer in ART has sparked considerable scientific interest. This extended exposure of the in vitro cultured blastocyst to external stressors for 2–3 additional days, compared to cleavage stage embryos, has raised questions about its effects on embryo implantation, placentation, and early fetal development. The in vitro environment differs significantly from the uterine environment in terms of temperature, pH, oxygen concentration, and the mechanical processes involved, including pipetting. Moreover, the extended culture time means embryo development in vitro beyond the time of embryonic genome activation (occurring on day three after fertilization), making blastocysts potentially more sensitive to epigenetic changes. Finally, the culture media used for blastocyst embryos differs from that used for cleavage stage embryos.⁴² Emerging evidence suggests that the culture medium itself may influence specific gene expressions, perinatal outcomes, and the rate of monozygotic twinning (MZT);^43,44,45,46 however, not all studies on this subject find that the culture media plays an important role in offspring phenotype.⁴⁷ Additionally, the prolonged culture time reduces the window for communication between the embryo and endometrium before implantation, potentially compromising synchronization.

Despite these concerns, extended culture time has its advantages. It facilitates a more stringent selection of viable embryos, potentially leading to healthier pregnancies. In fresh cycles, waiting until day 5 or 6 for embryo transfer leads to an extended duration from ovarian stimulation and more normalized hormone levels. This results in an endometrial environment that more closely resembles that of a natural cycle.

A comprehensive meta-analysis by Marconi et al. from 2021 reviewed perinatal outcomes in children born after blastocyst and cleavage stage transfer, fresh and frozen.⁴⁸ The analysis included 35 cohort studies or randomized controlled trials with a total of 520,769 singleton pregnancies. When considering fresh blastocyst transfer, it was observed that singleton pregnancies exhibited a heightened risk of LGA with a RR of 1.14 (95% CI 1.05–1.24). Additionally, there was a higher risk of VPTB with an RR of 1.17 (95% CI 1.08–1.26) when compared to fresh cleavage stage transfer. Moreover, singleton pregnancies following frozen blastocyst transfer also displayed distinct trends. These pregnancies were associated with elevated risks of LGA (RR 1.17, 95% CI 1.08–1.27) and PTB (RR 1.13, 95% CI 1.03–1.24). However, they exhibited lower risks of being SGA (RR 0.84, 95% CI 0.74–0.95), as well as a reduced risk of perinatal mortality (RR 0.70, 95% CI 0.58–0.86). The increased risks of PTB following fresh blastocyst transfer and increased risk of LGA and PTB following frozen blastocyst transfer remained consistent in sensitivity analysis including adjustments for effect sizes of the included studies. A recent large cohort study from 2023 including 1290 sibling pairs was able to perform a sibship comparison on blastocyst and cleavage stage offspring. They confirmed the increased risk of LGA in fresh cycles after blastocyst transfer (RR 1.57, 95% CI 1.01–2.46).⁴⁹

Another meta-analysis from 2023 found no increased risk of congenital malformations after blastocyst transfer compared to cleavage stage transfer when including results from 10 studies and 192,442 liveborn neonates.⁵⁰ They did find a slightly higher probability of a male neonate with a RR of 1.072 (95% CI 1.055–1.088) based on 18 studies and 227,530 neonates. Some have hypothesized that a potentially accelerated growth of male embryos could contribute to the overrepresentation of male blastocysts and, consequently, a higher male-to-female ratio among offspring. One study supported this notion by demonstrating that male blastocysts achieved a higher embryo morphological score compared to female embryos.⁵¹ Another study proposed that abnormal X-chromosome inactivation might result in postimplantation fetal loss, thereby skewing the male-to-female ratio.⁵²

The association between blastocyst transfer and the risk of monozygotic twinning (MZT) has garnered considerable attention. A meta-analysis by Hviid et al. in 2018, incorporating 11 original articles and 88,565 pregnancies after blastocyst transfer, revealed a two-fold increased risk of MZT.⁴⁶ This risk is of particular concern due to the potential complications associated with multiple pregnancies and the development of twin-to-twin transfusion syndrome. Studies have suggested that the culture medium itself may contribute to the higher rate of MZT after blastocyst transfer, with glucose levels in the medium being a suspected factor. Elevated glucose levels in blastocyst media may lead to increased free radicals, apoptosis, and disruptions in the inner cell mass, potentially causing embryo splitting.⁴⁶

Oocyte Donation

The risk of several obstetric and perinatal adverse outcomes is increased in pregnancies with oocyte donation (OD) compared to ART with autologous oocytes and NC pregnancies. A recent systematic review and meta-analysis showed a pooled adjusted OR for PE of 2.67 (95% CI 2.28–3.13) in OD compared with ART with autologous oocytes.⁵³ The pooled prevalence of PE in singleton pregnancies after OD was 10.7% (95% CI 6.6–15.5) compared to 2.0% (95% CI 1.0–3.1) after NC and 4.1% (95% CI 2.7–5.6) after ART with autologous oocytes. The prevalence of PE in multiple births was 27.8% (95% CI 23.6–32.2) after OD, 7.5% (95% CI 7.2–7.8) after NC, and 9.7% (95% CI 6.2–13.9) after ART with autologous oocytes. Potential contributors to the increased risk of PE on pregnancies after OD are advanced maternal age, an amplified immunological response due to the genetically different fetus and the lack of a corpus luteum as most OD treatments are performed in programmed-FET cycles, as ovarian insufficiency in the patients makes induced ovulation impossible. Further, pregnancies with OD carry an increased risk of first-trimester bleeding, gestational diabetes and PPH.⁵⁴

Finally, some perinatal outcomes are less favorable after OD compared to ART with autologous oocytes such as PTB (OR 1.57, 95% CI 1.33–1.86) and LBW (OR 1.25, 95% CI 1.20–1.30), but in adjusted analysis they seem to be somewhat driven by the higher PE incidence.^55,56

As a precaution, it is therefore highly encouraged to perform only single embryo transfer and to prescribe prophylactic low-dose aspirin during pregnancies after OD to lower the risk of PE. Further, whenever possible OD should be performed in natural or stimulated FET cycles instead of programmed.

LONG-TERM HEALTH OUTCOMES IN OFFSPRING FOLLOWING ASSISTED REPRODUCTIVE TECHNOLOGY

The long-term implications for children being born through ART have been examined to varying extents, depending on the specific health outcomes. Studies focusing on the enduring health consequences in the offspring of different types of ART treatments are limited.

Neurodevelopmental Health

Cognitive Development

Since the inception of ART in the late 1970s, concerns have arisen regarding the cognitive development of ART children. These concerns primarily stem from the advanced techniques and the impaired perinatal outcomes that could affect fetal brain development.^57,58 Numerous studies have explored different aspects of cognitive development in ART children, particularly in pre-schoolers up to 5 years of age. Overall, these studies conclude that there is no difference in IQ, language development, or scholastic abilities.⁵⁹ Studies examining cognitive development in ART children have been incorporated into two systematic reviews and one meta-analysis.^60,61,62 The overarching conclusion drawn from these three meta studies is largely reassuring. Nevertheless, many of the existing studies are hampered by methodological limitations, such as low participation rates and small sample sizes with a high risk of selection bias. Additionally, the control cohorts in the studies often consist of highly selected individuals from generally healthy populations.

In recent years, larger cohort studies focusing on academic performance in ART children have emerged, contributing additional insights into ART children’s cognitive development. The first comprehensive study on school performance encompassed all ART singletons (n = 2836) born in Denmark between 1995 and 1998, evaluating mean school grades after 9 years of primary school.⁶³ The main outcome measure was the mean total score of four subjects. ART singletons were found to have a higher crude mean total score but a slightly lower adjusted mean total score of −0.15 (95% CI −0.29 to −0.02) compared to NC singletons. The authors concluded that a possible small negative effect of parental subfertility or ART treatment is counterbalanced by the higher educational level of the ART parents. The findings were replicated in a Swedish cohort study comprising 8323 singleton individuals conceived through ART between the years 1985 and 2001 in Sweden.⁶⁴ The unadjusted mean total score in ART-conceived children was higher than that in NC children, but the mean total score, after adjusting for confounding variables, exhibited a slight decrease of −0.72 (95% CI −1.31 to −0.12).⁶⁴

Subsequently, in 2020 a Danish cohort study, overlapping with the study from Spangmose et al. but including two more birth years, included new comparison groups: (1) an infertile cohort of firstborn ART adolescents, (2) a fertile cohort of firstborn NC adolescents born to mothers who never sought fertility treatment, and (3) a subfertile cohort of firstborn NC adolescents born to mothers who sought fertility treatment in their second pregnancy.⁶⁵ The inclusion of the subfertile cohort aimed to disentangle maternal factors from treatment-related factors. This study confirmed the findings and those of the first Danish study and the Swedish study:^63,64 crude mean test scores were higher in ART adolescents, but they were lower after adjustments for maternal/parental educational level and socioeconomic status. Interestingly, the adjusted analyses showed a lower mean test score in NC adolescents in the subfertile cohort than in NC adolescents in the fertile cohort, with an adjusted mean difference of −0.19 (95% CI −0.26 to −0.13). Furthermore, the mean test score was similar in ART adolescents and NC adolescents in the subfertile cohort. These results suggest that the underlying infertility (reproductive disease) rather than the ART procedures per se influences academic performance.⁶⁵

Owing to the invasiveness of the ICSI procedure and the randomized selection of spermatozoa, numerous studies have probed into the cognitive outcomes of children born as a result of ICSI. Two large cohort studies compared academic performance in ICSI and IVF adolescents and no differences were found.^63,66 In one cohort study, FET adolescents were found to exhibit academic performance similar to that of adolescents born following fresh embryo transfer.⁶⁷

Psychiatric Health

The risk of psychiatric disease in children and adolescents has primarily been investigated in Danish and Swedish cohorts. In three large Danish cohort studies and one Nordic study that included children up to their teenage years, no increased risk of mental retardation, autism, or Asperger's syndrome was found in children born after ART, whether singletons or twins.^68,69,70,71 A similar risk of autism in ART and NC children has been confirmed in a large cohort study from Massachusetts, including 10,147 ART children and 8072 children of subfertile parents.⁷² Likewise, a meta-analysis found no increased risk of intellectual disabilities or autism in ART children based on 5 (n = 45,263 ART children) and 6 studies (n = 59,075 ART children), respectively.⁶¹

One Danish study investigated mental disorders in 108,707 singletons of women with fertility problems born from 1969 to 2006.⁷³ These singletons exhibited an elevated risk for various mental health conditions, including schizophrenia (hazard ratio [HR] 1.16, 95% CI 1.06–1.27), mood (affective) disorders (HR 1.22, 95% CI 1.15–1.29), autism (HR 1.11, 95% CI 1.03–1.19), mental retardation (HR 1.19, 95% CI 1.08–1.32) as well as ADHD (HR 1.36, 95% CI 1.29–1.45) compared with singletons born to women without fertility problems. The risk estimates remained relatively consistent when the analysis was stratified into two age categories: mental disorders diagnosed during childhood (0–19 years) and those emerging in young adulthood (20–40 years). However, it is worth noting that no adjustments were made for socioeconomic status.⁷³ The elevated risk of ADHD in children born through ART compared with NC children has been substantiated by a recent 2022 Canadian study (adjusted HR [aHR] 1.17, 95% CI 1.07–1.28). Interestingly, also offspring born to infertile parents without fertility treatment had an increased risk of ADHD (aHR 1.12, 95% CI 1.16–1.23) compared with NC children.⁷⁴ This suggests a modest association between infertility and the risk of childhood ADHD, rather than a direct link to the use of fertility treatment itself. The study was able to consider critical factors associated with ADHD, including socioeconomic parameters.⁷⁴ A large Swedish study from 2011 including birth years 1982–2005 (ART children, n = 28,158)⁷⁵ and a large Nordic study from 2022 including singletons born in 1995–2014 in Denmark and Finland, 2005–2015 in Norway, and 1995–2015 in Sweden (ART children, n = 116,909)⁷¹ found a similar risk of ADHD in ART and NC singletons. Note that the Swedish cohort overlap in the two studies.^71,75

Cerebral Palsy

CP stands as the most prevalent motor disability in childhood, affecting a significant portion of the general child population, with an estimated prevalence ranging from 1.5 to 3.5 per 1000 live births,⁷⁶ the risk of CP increases significantly with the number of fetuses in a pregnancy, primarily due to the heightened risk of premature birth, which is the most prominent risk factor for CP.^1,3

Several cohort studies have revealed an approximately two-fold increased risk of CP in the overall ART population.^{3,27,77,78,79,80,81} While other studies show no elevated risk of CP among ART singletons.^{8,78,79,80,82,83} According to the CoNARTaS data, it was observed that the risk of CP decreased over time among children born through ART due to a reduction in the rate of multiple births.⁸ In the years 1990–1993, ART children had a significantly higher aOR for CP (aOR 2.76, 95% CI 2.03–3.67) compared to NC children. By 2011–2014, the risk had diminished and was only moderately increased (aOR 1.39, 95% CI 1.01–1.87). For singleton births during the period 2011–2014, the risk was no longer elevated (aOR 1.11, 95% CI 0.98–1.24).

In general, the literature on neurodevelopmental health in singletons born after ART is reassuring, but multiple pregnancies should be diminished to avoid the risks associated with PTB.

Cardiometabolic Health

Cardiovascular Health

ART children have been examined for cardiovascular health, including, elevated blood pressure^84,85,86 and suboptimal cardiac diastolic function.^87,88 However, many of these studies, summarized in systematic reviews, are based on small cohorts with low participation rates, resulting in a high risk of selection bias.^89,90 Guo et al. scrutinized the cardiovascular health of ART children, spanning from childhood to early adulthood.⁹⁰ Among 872 ART children, the study exhibited higher systolic and diastolic blood pressure with mean differences of 1.88 mmHg (95% CI 0.27–3.49) and 1.51 mmHg (95% CI 0.33–2.70), respectively, compared with NC children. However, stratification by birth year revealed that only ART children born between 1990 and 1999, but not from 2000 to 2009, displayed increased systolic and diastolic blood pressure. The included studies consistently showed suboptimal diastolic function in ART children, especially under stressful conditions like high altitudes. Furthermore, the thickness of the aortic and carotid intima-media was notably higher in the ART group, although a meta-analysis on this was not conducted due to a limited number of studies.⁹⁰ It should be emphasized that most of the studies in this area are small and carry a high risk of selection bias. Recent cohort studies, although still featuring small study populations, have not shown notable differences in cardiovascular profiles between ART and NC adolescents.^91,92,93 A few large studies have explored the association between ART and cardiovascular diseases. In a population-based cohort study encompassing individuals born in Denmark, Finland, Norway, and Sweden between 1984 and 2015, data from national ART and medical birth registers were cross-referenced with national patient registers and other population-based registers.⁹⁴ The study included 122,429 children born after ART. Of these, 135 (0.11%) children born after ART were diagnosed with various cardiovascular diseases (ischemic heart disease, cardiomyopathy, heart failure, or cerebrovascular disease). After adjustments, similar risks were observed for children born after ART and NC for any cardiovascular disease (aHR 1.02, 95% CI 0.86–1.22). Notably, the study's limitations included the relatively short follow-up period, 8.6 and 14.0 years for children born after ART and NC, respectively, and few events for some outcomes. Therefore, while the results were generally reassuring, continued monitoring and surveillance for these important diseases are crucial.

In summary, limited data suggest potentially elevated blood pressure in ART children. However, large register-based studies have not confirmed significant heightened risks for cardiovascular disease in ART children thus far.

Type 1 Diabetes

Three cohort studies have been conducted on the risk of type 1 diabetes (DM1) in children born following ART, two in Denmark and one in Sweden. These studies collectively found no significant association between ART and the risk of developing DM1 later in life.^95,96,97 However, in the Swedish study, they performed a subgroup analysis in children born after FET and found an increased risk of DM1 when compared to both children after fresh embryo transfer and NC children, with aHR values of 1.52 (95% CI 1.08–2.14) and 1.41 (95% CI 1.05–1.89), respectively.⁹⁷

A possible explanation for the increased risk of DM1 found in children born after FET might be the higher birth weight and higher rate of LGA associated with FET more than the FET procedure per se, as birth weight and LGA are independently associated with the risk of obesity and metabolic disease later in life.⁹⁸ A recent Nordic register-based study including 77,920 ART children and 4,511,667 non-ART-children found no increased risk of DM1 in the children born after ART – the results have at this point only been published in an abstract.⁹⁹

Growth and Body Composition

Two systematic reviews with accompanying meta-analyses explored differences in height, weight, and body mass index (BMI) between ART and NC children.^90,100 Their findings revealed a slight negative association between ART and childhood weight, although only apparent up to the age of five, and no significant association between ART and height or BMI.^90,100 Similarly, a cohort study including data from 26 population-based studies with anthropometric measures at several timepoints across childhood and adolescence found that offspring conceived after ART were smaller and had lower adiposity during early life than those who were NC, while differences diminished with advanced child age. However, they found a non-significant trend towards higher adiposity by early adulthood with ART conception (difference in fat mass index 0.23 SD units, 95% CI −0.04 to 0.50).¹⁰¹

Another Nordic retrospective cohort study including 122,429 children born after ART compared to NC children observed a small but significant increased risk of childhood obesity among children born after ART (aHR 1.14, 95% CI 1.06–1.23).⁹⁴ A recent Danish study compared anthropometric measures in children aged 7–10 years born after fresh embryo transfer, FET and NC. In a sex-stratified analysis, weight (presented as sex- and age-specific standard deviation scores (SDS) and height (SDS) were significantly higher in girls born after FET compared to NC while the fat percentage in girls born after FET was increased compared to fresh embryo transfer. No differences were seen for boys. Importantly, outcomes were adjusted for birth weight.¹⁰²

Overall, the data on growth and body composition in children born after ART seems reassuring as the identified differences in risk of obesity are only modest and seem to diminish with advancing age.

Cancer

The question of whether ART elevates the risk of cancer remains a topic of debate. It is important to note that the heightened risk has predominantly been observed in specific subgroups of ART children and for particular types of cancer.¹⁷ Two comprehensive systematic reviews with corresponding meta-analyses, one encompassing 13 cohort studies and the other including 11 case-control studies and 16 cohort studies, failed to reveal an increased risk of childhood cancer in ART children.^103,104 Though the largest meta-analysis did identify an elevated risk of childhood cancer in children born after FET when compared to NC children, based on findings from five studies involving 25,563 FET children yielding a RR of 1.37 (95% CI 1.04–1.81).¹⁰³

One of the first studies to note a slightly increased risk of any malignancy in children from FET compared to NC was a Danish population-based registry study. However, this finding was based on few cases.¹⁰⁵

More recently, a large Nordic registry-based cohort study, which included 171,774 children born after ART and 7,772,474 NC children, did not identify an overall elevated risk of childhood cancer in children born after ART.¹⁰⁶ However, a higher risk was observed in children born after FET (48 cases; incidence rate 30.1/100,000 person-years) when compared to both fresh embryo transfer (incidence rate 18.8/100,000 person-years, aHR 1.59, 95% CI 1.15–2.20) and children born after NC (aHR 1.65, 95% CI 1.24–2.19).¹⁰⁶ Leukemia was the most common type of cancer observed and was significantly increased both in children born after FET compared to fresh embryo transfer and in children born after FET compared to those born through NC. The exact mechanism behind the potentially increased risk in children born after FET is not clear. However, singletons born after FET are at a heightened risk of macrosomia, which itself has been associated with an increased risk of childhood cancer.¹⁰⁷

In summary, most studies provide reassurance by demonstrating no increased risk of overall cancer in children born after ART. Nevertheless, a slightly elevated risk was observed in children born after FET. Although the actual number of childhood cancer cases was relatively low, the study raises concerns regarding the significant rise in FET procedures, especially in cases where there are no clear medical justifications for using the freeze-all approach.

Imprinting Disorders

Imprinting disorders are caused by disruptions in epigenetic regulation at specific imprinted genetic loci, affecting aspects of growth, development, and metabolism.¹⁰⁸ The latest systematic review and meta-analysis focusing on imprinting disorders following ART unveiled that ART children exhibited an elevated risk of developing all four major imprinting disorder examined; Angelman (summary OR [sOR] 4.7, 95% CI 2.6–8.5, 4 studies), Beckwith-Wiedemann (sOR 5.8, 95% CI 3.1–11.1, 8 studies), Prader-Willi (sOR 2.2, 95% CI 1.6–3.0, 6 studies) and Silver-Russel Syndrome (sOR 11.3, 95% CI 4.5–28.5, 3 studies) compared with NC children.¹⁰⁹ However, a more recent cohort study, not included in the initial meta-analysis, scrutinized a cohort of nearly 75,000 ART children born in Denmark and Finland and found no overall increased risk of imprinting disorders after ART.¹¹⁰ However, the study did find an increased risk of Beckwith-Wiedemann syndrome, with an aOR of 2.84 (95% CI 1.34–6.01). It is worth noting that findings were derived from a relatively small number of cases with Beckwith-Wiedemann syndrome within the ART cohort.¹¹⁰ The precise causes of imprinting disorders remain only partially understood, and their diverse clinical manifestations pose challenges in the clinical diagnosis.

Differences in global epigenetic patterns in children born after ART compared to NC children have been shown in some studies but should be interpreted with caution as no functional or health-related consequence later in life has been shown.^111,112,113

Reproductive Health

In 2016, the first study was published examining semen quality in individuals conceived through ICSI.¹¹⁴ This study involved 54 young men, aged between 18 and 22 years, who were born between 1992 and 1996 as a result of ICSI due to severe male infertility. It was observed that, in comparison to men born through NC, the ICSI-conceived men exhibited significantly lower median sperm concentration, total sperm count, and total motile sperm count. These differences persisted even after adjusting for pertinent confounding factors.¹¹⁴ Current evidence does not indicate any significant alterations in the endocrine gonadal function of ICSI-conceived boys and young adults.¹¹⁵ Furthermore, in young women aged 18–22 years, who were conceived through ICSI due to male factor infertility (in total 71 individuals), the antral follicle count and circulating levels of reproductive hormones, including AMH (anti-Müllerian hormone), FSH (follicle stimulating hormone), LH (luteinizing hormone), and DHEAS (dehydroepiandrosterone), were found to be the same as in NC offspring.¹¹⁶

CONCLUSION

Knowledge of the short- and long-term health consequences of children born after ART procedures is vital for society, clinicians, and prospective parents. ART pregnancies carry unique risks compared to NC and the choice of ART procedure, such as ICSI versus IVF or FET versus fresh ET, requires careful consideration.

In light of the higher risks associated with ICSI, FET, programmed FET cycles, and blastocyst transfer, it is obvious that we should apply ART methods whenever they are needed to improve success rates, but we should never apply any add-on if it is not required. Hence ICSI should be performed by indication, and the same goes for FET and programmed FET. Regarding blastocyst transfer, the higher live birth rates by the longer in vitro culture and the selection procedure may outweigh the slightly higher risk after blastocyst transfer. Furthermore, new methods and culture media should be carefully registered to closely monitor the health of the offspring and to carefully plan treatment strategies according to the offspring’s health profiles of the treatments. All professionals in the field should bear in mind that the health of the offspring is the final goal of quality control in ART. With the declining birth rates and the increasing childbearing age worldwide, ART has become an important player in lifting the birth rates in society and will contribute to a significant proportion of future generations hence surveillance of their long-term health is crucial.

PRACTICE RECOMMENDATIONS

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