ART-conceived Children Research Articles

A Scoping Review: Risk of Autism in Children Born from Assisted Reproductive Technology

Background/Objectives: As the incidence of autism spectrum disorder (ASD) and use of assisted reproductive technologies (ART) continue to rise in tandem, their relationship to one another, as well as the general risks of ART, are increasingly being explored. The purpose of this review is to summarize the literature on ASD risk, as well as the risks for other neurological and neurodevelopmental disorders, in children born following the implementation of ART. Methods: Here we review studies published between 2000−2023 that elucidate relationships between ASD and some of the most common forms of ART, including in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), using fresh vs. frozen embryo transfer. Articles were identified by searching Google Scholar and PubMed databases. Results: Though some studies report adverse neurodevelopmental outcomes in ART-conceived children, such as ASD, attention-deficit/hyperactivity disorder (ADHD), and cerebral palsy, a majority of studies do not show a significant association between ART and neurodevelopmental disorders. Additionally, many confounding factors like multiple and preterm births, underlying infertility, and advanced parental age have been discussed, highlighting the need for studies that effectively control for these confounders. Potential mechanisms implicated in the pathogenesis of ASD, including epigenetic mechanisms of gene expression, that may be related to ART procedures, are also discussed. Conclusion: ART may pose a low additional risk to development of ASD, but confounding factors likely account for most of this risk. Several steps in the process of ART may cause epigenetic changes that are implicated in the development of ASD.

Sex differences in DNA methylation variations according to ART conception-evidence from the Norwegian mother, father, and child cohort study

Previous studies have shown cord-blood DNA methylation differences in newborns conceived using assisted reproductive technologies (ART) compared to those conceived naturally. However, whether these ART-related DNA methylation differences vary with children’s sex is unknown. We hypothesize that the DNA methylation differences in cord blood between ART-conceived and naturally conceived newborns also varies by the sex of the child, with distinct patterns of differential methylation present in males and females. We investigated sex differences in cord-blood DNA methylation variation according to conception by ART using the Illumina MethylationEPIC platform, comparing 456 ART-conceived versus 507 naturally-conceived girls, and 503 ART-conceived and 473 naturally-conceived boys. We identified 37 differentially methylated CpGs according to ART-conception among girls, and 70 differentially methylated CpGs according to ART-conception among boys, when we used a 1% false discovery rate to account for multiple testing. Ten CpGs were differentially methylated according to conception by ART in both sexes. Among the genes that were associated with these CpGs, we found the BRCA1; NBR2 gene (two CpGs) was hypermethylated in girls while the APC2 (two CpGs) and NECAB3;ACTL10, (four CpGs) related to cellular signaling were hypomethylated in boys. These findings confirm the presence of sex-specific epigenetic differences, illustrating the nuanced impact of ART on the fetal epigenome. There is a need for further explorations into the implications for sex-specific developmental trajectories and health outcomes in ART-conceived children.

The impact of assisted reproductive technologies on ADHD: A systematic review and meta-analysis

BackgroundThe escalating utilization of assisted reproductive technology (ART) in response to global infertility rates has spurred research into its complications. Short-term and long-term outcomes have been extensively studied, particularly the neurological concerns surrounding attention-deficit/hyperactivity disorder (ADHD) among ART-conceived children. This study aims investigate the association between ART and ADHD. MethodsMedline, Embase, Scopus, and Web of Science databases were searched through April 4, 2023. Cohort, case-control, and cross-sectional studies were eligible for inclusion. primary summary measures included the unadjusted relative risk (RR) and adjusted hazard ratio (HR) with 95 % confidence intervals. Both fixed-effects and random-effects models were utilized for meta-analysis data pooling to determine the overall effect size. The onset of ADHD in children conceived through ART compared to those conceived naturally. ResultsThe systematic search yielded 8 studies with 10,176,148 individuals included in the meta-analysis. The meta-analysis revealed a pooled RR of 0.93 (0.68–1.26) for cohort studies and a pooled RR of 0.97 (0.41–2.29) for cross-sectional studies, along with a pooled HR of 1.08 (1.03–1.13) for ADHD in the ART group compared to the non-ART group. ConclusionWhile this study identifies some potential association between ART and ADHD, the limited effect size and inherent heterogeneity underscore the need for cautious interpretation.

The risk of asthma in singletons conceived by ART: a retrospective cohort study.

Do singleton children conceived by ART have a higher asthma risk than naturally conceived (NC) singletons? The asthma risk was similar for ART-conceived singletons and NC singletons, and there were no clear differences between the various types of ART. Whether ART increases asthma risk in offspring is questionable. The evidence is inconsistent and limited by ethnicity, geographic distribution, inadequate confounder adjustment, unsatisfactory control groups, and specific methods of ART. Furthermore, the mediating effects of obstetric and neonatal outcomes on the association between ART and asthma remain unclear. This observational, single-centre study was conducted at a reproductive centre of an affiliated university hospital between September 2009 and April 2023. A total of 3227 singletons aged 3-6 years conceived by IVF versus ICSI or fresh versus frozen embryo transfer were retrospectively enrolled, and a total of 1206 NC singletons of the same age were subsequently recruited. Asthma was defined as a self-reported physician diagnosis or wheezing in the past 12 months. We performed multivariable logistic regression analyses to examine associations between asthma in offspring and ART use, adjusting for parental characteristics (age, education level, occupation type, BMI, asthma), smoking exposure, residence type, child sex, child age, and year of follow-up. Mediating effects were explored using longitudinal mediation structural equation modelling. Asthma was reported for 51 (4.2%) of the 1206 NC singletons (median [interquartile range] age 5 [4-5] years; 48.1% females) and 169 (5.2%) of the 3227 ART-conceived singletons (5 [5-5] years; 47.6% females). We found that risks of childhood asthma in singletons conceived by ART were, overall, similar to those of NC singletons before (odds ratio [OR], 1.25 [95% CI, 0.92-1.74]; P = 0.170) and after adjustment (adjusted OR [aOR], 0.66 [95% CI, 0.44-1.03]; P = 0.126). The results were similar in multiple sensitivity analyses, and there were no clear differences in asthma risks according to the method of ART. Mediation analysis revealed a significant positive indirect effect of neonatal intensive care unit (NICU) admission (standard path coefficient, b = 0.025, P < 0.05) and a negative indirect effect of breastfeeding (b = -0.012, P < 0.05) on the association between ART and asthma in singleton offspring. This study is limited to singletons only and cannot be generalized. The study is also limited by its retrospective observational single-centre nature and sample size. Mediation analyses were exploratory. Therefore, the findings need to be interpreted with caution. These findings can help infertile couples undergoing ART be reassured about the risk of childhood asthma in singleton offspring. Breastfeeding is recommended as a potentially feasible intervention to reduce the asthma risks in ART-conceived children who are at increased potential risk of asthma, such as those with NICU admissions. This work was supported by the Key Research and Development Program of Zhejiang Province (2021C03100), the National Key Research and Development Program of China (2021YFC2700603), and the Program for Key Subjects of Zhejiang Province in Medicine and Hygiene to Y. Z., the Zhejiang Province Natural Science Foundation (No. LQ22H040006) and the National Natural Science Foundation of China (No.82101759) to M.T., and the National Natural Science Foundation of China (No. 82201860) to J.Y. The authors declare no competing interests. ChiCTR2300069906.

The role of multiple birth and birth complications in the association between assisted reproductive technology conception and autism diagnosis.

In recent decades, the use of assisted reproductive technology (ART) has increased rapidly. To assess the relationship between ART and autism diagnosis, we linked California birth records from 2000 through 2016 with contemporaneous records from the National ART Surveillance System (NASS) and autism caseload records from California's Department of Developmental Services from 2000 through November 2019. All 95 149 birth records that were successfully linked to a NASS record, indicating an ART birth, were matched 1:1 using propensity scores to non-ART births. We calculated the hazard risk ratio for autism diagnosis and the proportions of the relationship between ART conception and autism diagnosis mediated by multiple birth pregnancy and related birth complications. The hazard risk ratio for autism diagnosis following ART compared with non-ART conception is 1.26 (95% CI, 1.17-1.35). Multiple birth, preterm birth, and cesarean delivery jointly mediate 77.9% of the relationship between ART conception and autism diagnosis. Thus, increased use of single embryo transfer in the United States to reduce multiple births and related birth complications may be a strategy to address the risk of autism diagnosis among ART-conceived children.

Effect of development speed and quality of blastocyst on singleton birthweight in single frozen-thawed blastocyst transfer cycles.

Assisted reproductive technology (ART) has revolutionized infertility treatment, leading to a surge in ART-conceived children. Despite its success, ART-born offspring face higher risks of preterm birth (PTB), low birth weight (LBW), and small for gestational age (SGA). The mechanisms behind these outcomes remain unclear, partly attributed to multiple embryo transfers. Recent advancements advocate single blastocyst transfers for improved outcomes. However, the influence of blastocyst quality and development speed on neonatal outcomes is underexplored. This study investigated whether blastocyst development speed and quality affect singleton birthweight when the blastocyst is selected for single frozen-thawed blastocyst transfer (FBT). Data from patients who performed an FBT cycle at our center from July 2011 to June 2021 were collected and analyzed. Based on the inclusion and exclusion criteria, 420 single FBT cycles were assessed. The women were divided into four groups, Group A (day 5, good-quality blastocysts), Group B (day 5, non-good-quality blastocysts), Group C (day 6, good-quality blastocysts), and Group D (day 6, non-good-quality blastocysts) according to the developmental speed and quality of the transferred blastocyst. The birthweight was relatively the highest in Group A, which developed rapidly and transferred good quality blastocysts. However, no significant difference existed among the groups (P>0.05). The prevalence of premature birth (PTB), low birth weight (LBW), very low birth weight (VLBW), or high birth weight (HBW) was similar among the four groups (P > 0.05). No correlation existed between birth weight and blastocyst development speed or quality after adjusting for possible confounders (P > 0.05 respectively). However, the difference in the proportion of males born among the four groups was significant, especially in Group D, which was significantly lower than that in Group A (adjusted odds ratio = 0.461, 95% confidence interval: 0.230-0.921, P< 0.05). This retrospective cohort study suggests that the combined effect of blastocyst development speed and quality on neonatal birthweight is insignificant. The transfer of slow-growing, non-good-quality blastocysts increases the chance of a female baby being born.

Increased Y Chromosome Microdeletions in Cord Blood of Male Newborns From Assisted Reproductive Technology Compared to Natural Conception

ObjectivesTo investigate the incidence of Y chromosome microdeletions in male newborns conceived by intracytoplasmic sperm injection (ICSI), in vitro fertilization (IVF), and natural conception (NC). MethodsA total of 186 male newborns were recruited, including 35 conceived by ICSI, 37 conceived by IVF, and 114 conceived naturally. DNA was extracted from umbilical cord blood after birth. The Yq genetic status of the newborns was determined according to 18 Y-specific sequence tagging sites (STS) markers covering 3 azoospermia factor (AZF) sub-regions and internal control sequences. ResultsPartial AZF microdeletions were identified in 8 of 35 (22.9%) ICSI newborns, 4 of 37 (10.8%) IVF newborns, and 1 of 114 (0.9%) NC newborns. There was a statistically significant difference in the proportion of newborns with partial Y chromosome microdeletions between the ICSI, IVF, and NC groups. When analyzed individually, only the SY114 and SY152 STS markers showed a statistically significant difference in incidence between the 3 cohorts. ConclusionsOur study indicates that the population of male children conceived through assisted reproductive technologies (ART), particularly ICSI, is at an increased risk of genetic defect in the form of partial Y chromosome microdeletions. The growing population of ART-conceived children emphasizes the importance of studying the genetic repercussions of these procedures regarding the future fertility of males conceived in vitro.

#299 : Sex Ratio in Children Born After Assisted Reproduction and After Spontaneous Conception in the Czech Republic

Background and Aims: Various authors described slight differences in the sex ratio in the children born after the use of various assisted reproduction techniques (ART). Our goal was to investigate this trend using population-wide datasets from the official medical registries of the Czech Republic. Method: We have used data from the official medical registries run by the Institute of Health Information and Statistics of the Czech Republic, namely the National Registry of Congenital Anomalies and the National Registry of Assisted Reproduction. The registration process in the Czech Republic is population-wide and the reporting is compulsory by the national law. We analyzed the number of births of children depending on the method of conception, the presence of a congenital defect, the twinning rate, and maternal age. Study period: 2013–2020. Results: A total of 881,975 children were born in the study period, 853,131 were born after spontaneous conception, and 28,844 after ART. The frequency of males was 50,89% in the spontaneously conceived children and 50.3% in the ART-conceived children, but the difference is not statistically significant. Among the children born with some kind of congenital anomaly, the males were more frequent, but again the difference was not statistically significant. Analyzing the different subgroups according to the twinning rate also did not identify any statistically significant trend. Conclusion: Using the population-wide data we have confirmed changes in the sex ratio in children born after ART conception (especially analyzing different study subgroups according to the presence/absence of congenital anomaly and according to the twinning rate). None of the trends was classified as statistically significant. Supported by Ministry of Health, Czech Republic – conceptual development of research organization (Thomayer University Hospital - TUH, 00064190)

#298 : Congenital Anomalies in Children Born after Assisted Reproduction in the Czech Republic

Background and Aims: The number of children conceived by assisted reproduction techniques (ART) is increasing in the Czech Republic. However, several studies reported an increased incidence of congenital anomalies in ART-conceived children. The main goal of this study was to evaluate this theoretical risk using population-based data from Czech medical registries. Method: The retrospective epidemiological analysis was performed using data from the National Registry of Congenital Anomalies and the National Registry of Newborns, run by the Institute of Health Information and Statistics of the Czech Republic. All diagnoses of congenital anomalies (Q00-Q99) were included. The registration process is population-wide and compulsory by Czech law. We compared the incidences of congenital anomalies in naturally conceived children and ART-conceived children born in the Czech Republic for 8 years period (2013–2020). Statistical analysis was performed by Fisher’s exact test. Results: In our study, we demonstrated a higher incidence of congenital anomalies in the children born after ART (4.35%) compared to the incidence in the group of children born after spontaneous conception (3.90%). This difference was statically significant (p &lt; 0.05). In the group of children born after ART, congenital defects of the central nervous system, congenital heart defects, and congenital defects of the gastrointestinal tract were diagnosed more frequently. In some groups of congenital defects, a higher proportion of males compared to females and a higher representation of cases with a congenital defect in children born from multiple pregnancies were also found. Conclusion: The results from our population-based study confirm that the incidence of selected groups of congenital anomalies may be higher in children born after ART.

Risk for Congenital Anomalies in Children Conceived With Medically Assisted Fertility Treatment : A Population-Based Cohort Study.

More than 2 million children are conceived annually using assisted reproductive technologies (ARTs), with a similar number conceived using ovulation induction and intrauterine insemination (OI/IUI). Previous studies suggest that ART-conceived children are at increased risk for congenital anomalies (CAs). However, the role of underlying infertility in this risk remains unclear, and ART clinical and laboratory practices have changed drastically over time, particularly there has been an increase in intracytoplasmic sperm injection (ICSI) and cryopreservation. To investigate the role of underlying infertility and fertility treatment on CA risks in the first 2 years of life. Propensity score-weighted population-based cohort study. New South Wales, Australia. 851 984 infants (828099 singletons and 23885 plural children) delivered between 2009 and 2017. Adjusted risk difference (aRD) in CAs of infants conceived through fertility treatment compared with 2 naturally conceived (NC) control groups-those with and without a parental history of infertility (NC-infertile and NC-fertile). The overall incidence of CAs was 459 per 10 000 singleton births and 757 per 10 000 plural births. Compared with NC-fertile singleton control infants (n= 747 018), ART-conceived singleton infants (n= 31256) had an elevated risk for major genitourinary abnormalities (aRD, 19.0 cases per 10 000 births [95% CI, 2.3 to 35.6]); the risk remained unchanged (aRD, 22 cases per 10 000 births [CI, 4.6 to 39.4]) when compared with NC-infertile singleton control infants (n= 36251) (that is, after accounting for parental infertility), indicating that ART remained an independent risk. After accounting for parental infertility, ICSI in couples without male infertility was associated with an increased risk for major genitourinary abnormalities (aRD, 47.8 cases per 10 000 singleton births [CI, 12.6 to 83.1]). There was some suggestion of increased risk for CAs after fresh embryo transfer, although estimates were imprecise and inconsistent. There were no increased risks for CAs among OI/IUI-conceived infants (n= 13574). This study measured the risk for CAs only in those children who were born at or after 20 weeks' gestation. Observational study design precludes causal inference. Many estimates were imprecise. Patients should be counseled on the small increased risk for genitourinary abnormalities after ART, particularly after ICSI, which should be avoided in couples without problems of male infertility. Australian National Health and Medical Research Council.

The association between type of conception through medically assisted reproduction and childhood cognition: a Danish population-wide cohort study.

Previous research has indicated that children conceived through medically assisted reproduction (MAR) generally have cognitive outcomes comparable to or better than naturally conceived children. However, previous studies have been limited in their ability to examine this relationship at a population level and consider variations across different types of MAR. This study utilizes data from all live births in Denmark between 2006 and 2009 (n = 259 608), including a subset of births resulting from MAR conceptions (n = 13 566). The dependent variable is the standardized test scores obtained in the second and third grades of primary schools. A comparison is made between the test scores of children spontaneously conceived (SC) and those conceived through intrauterine insemination (IUI) and assisted reproductive technologies (ART). Ordinary least squares regressions are employed, with a baseline model adjusted only for birth year, as well as models that additionally account for conception-related confounders and sociodemographic family characteristics. In the baseline analysis, ART- and IUI-conceived children displayed better test scores compared with their SC peers. However, after adjusting for relevant factors, ART-conceived children performed worse than SC peers, while IUI-conceived children performed equally well as SC peers and better than ART-conceived children. These results likely reflect differences in the selection process of potential parents into the type of MAR, as well as the consequences of variations in fecundability. Nevertheless, the differences observed across conception types were overshadowed by test score disparities in socioeconomic background.

P-779 School performance of children conceived by assisted reproductive technology

Abstract Study question Does elementary school performance differ between children conceived through assisted reproductive technology (ART) compared to children born to subfertile couples not conceived by ART? Summary answer Children born after ART perform equally well at age 12 (end of elementary school) compared to children born to subfertile couples not conceived by ART. What is known already It is well established that pregnancies conceived by ART are at higher risk of adverse outcomes, such as pre-term birth and a lower birth weight, also when restricted to singleton pregnancies. However, whether ART also affects outcomes in later life, such as school performance, is less clear. Although some studies indicate that there might be subtle differences in the school performance of ART and spontaneously conceived children, it remains unclear whether this is due to the ART treatment, parental factors or a combination of both. Study design, size, duration Data were used from the OMEGA-cohort, a historical nationwide cohort with prospective follow-up in the Netherlands. The cohort comprises all offspring of women who were treated in one of the 13 IVF clinics or 2 regional fertility centers in 1983-2010. Of 89,249 live-born children, 54,417 were ART-conceived and 37,832 were not ART-conceived (conceived naturally with or without ovarian stimulation) by subfertile women. Participants/materials, setting, methods Data on type of fertility treatment and maternal risk factors were available from medical records of the mothers and through the national perinatal registry. The OMEGA-cohort was linked to the education dataset of Statistics Netherlands, including school performance data for the period 2006-2017, leaving 24,806 children in the analytical cohort. The overall test Z-score and Z-scores on the separate domains (Dutch language and mathematics) between ART and non-ART children were compared using multivariable linear regression. Main results and the role of chance The cohort comprises 14,958 ART-conceived children and 9,848 non-ART children with test scores around age 12 in 2006-2017. The mean overall score was 536,5 (SD = 9.7), with scores of 536.4 (SD = 9.9) in ART-conceived children and 536.6 (SD = 9.5) in non-ART children. After adjustment for maternal age and maternal and paternal educational level, in a multivariable linear regression model, the overall test Z-score was also not different among ART-children compared to non-ART children from subfertile parents (β=-0.02, 95% CI=-0.04-0.01). Overall test Z-scores were not different according to different ART treatment modalities, IVF (β=-0.02, 95%CI=-0.05-0.01), ICSI (β=-0.01, 95% CI=-0.05-0.02) and frozen embryo transfer (β = 0.07, 95%CI=-0.01-0.14) when compared to children born to subfertile couples not using ART. ART children performed equally well on mathematics and Dutch language compared to children born to subfertile couples not conceived by ART. Limitations, reasons for caution Although the current analyses include a large proportion of the ART children in the Netherlands with data on school performance and our study had sufficient power to address the research question, it is not clear to which extent our results are generalizable to other countries. Wider implications of the findings Reassuringly, based on first results, children born after ART had comparable test scores at the end of elementary school compared to children from subfertile couples not conceived by ART. Trial registration number Not applicable

The X-factor in ART: does the use of assisted reproductive technologies influence DNA methylation on the X chromosome?

BackgroundAssisted reproductive technologies (ART) may perturb DNA methylation (DNAm) in early embryonic development. Although a handful of epigenome-wide association studies of ART have been published, none have investigated CpGs on the X chromosome. To bridge this knowledge gap, we leveraged one of the largest collections of mother–father–newborn trios of ART and non-ART (natural) conceptions to date to investigate sex-specific DNAm differences on the X chromosome. The discovery cohort consisted of 982 ART and 963 non-ART trios from the Norwegian Mother, Father, and Child Cohort Study (MoBa). To verify our results from the MoBa cohort, we used an external cohort of 149 ART and 58 non-ART neonates from the Australian ‘Clinical review of the Health of adults conceived following Assisted Reproductive Technologies’ (CHART) study. The Illumina EPIC array was used to measure DNAm in both datasets. In the MoBa cohort, we performed a set of X-chromosome-wide association studies (‘XWASs’ hereafter) to search for sex-specific DNAm differences between ART and non-ART newborns. We tested several models to investigate the influence of various confounders, including parental DNAm. We also searched for differentially methylated regions (DMRs) and regions of co-methylation flanking the most significant CpGs. Additionally, we ran an analogous model to our main model on the external CHART dataset.ResultsIn the MoBa cohort, we found more differentially methylated CpGs and DMRs in girls than boys. Most of the associations persisted after controlling for parental DNAm and other confounders. Many of the significant CpGs and DMRs were in gene-promoter regions, and several of the genes linked to these CpGs are expressed in tissues relevant for both ART and sex (testis, placenta, and fallopian tube). We found no support for parental DNAm-dependent features as an explanation for the observed associations in the newborns. The most significant CpG in the boys-only analysis was in UBE2DNL, which is expressed in testes but with unknown function. The most significant CpGs in the girls-only analysis were in EIF2S3 and AMOT. These three loci also displayed differential DNAm in the CHART cohort.ConclusionsGenes that co-localized with the significant CpGs and DMRs associated with ART are implicated in several key biological processes (e.g., neurodevelopment) and disorders (e.g., intellectual disability and autism). These connections are particularly compelling in light of previous findings indicating that neurodevelopmental outcomes differ in ART-conceived children compared to those naturally conceived.

The Risks of Birth Defects and Childhood Cancer With Conception by Assisted Reproductive Technology

ABSTRACT As the proportion of births conceived with assisted reproductive technology (ART) continues to increase, a growing body of literature continues to examine the risks involved such as the higher risk of birth defects. Recently, several studies have suggested that ART-conceived children may have a greater risk of childhood cancer. This population-based cohort study aimed to evaluate the risk of childhood cancer as a function of birth defect status and method of conception. Data were obtained from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System, birth certificates (2004–2013), birth defect registries, and cancer registries in 4 states. The Society for Assisted Reproductive Technology Clinic Outcome Reporting System contains comprehensive information on ART procedures from 86% of all clinics and more than 92% of all ART cycles in the United States. Assisted reproductive technology cycles reported from January 2004 to December 2017 that resulted in live births were included in this study. For each ART-conceived delivery, the subsequent 10 deliveries were selected as the non-ART comparison group, and siblings of each ART birth were selected as the ART sibling group. The ART group was divided into 4 subgroups based on the combination of oocyte source (autologous or donor) and embryo state (fresh or thawed). A host of independent variables with established associations on birth defects, cancer, and/or ART were selected a priori for inclusion in statistical models. The total study population included 165,125 ART-conceived children, 31,524 non-ART siblings, 12,451 children born as a result of infertility treatment without ART (ovulation induction/intrauterine insemination [OI/IUI]), and 1,353,440 naturally conceived children. A total of 29,571 singleton children (2.0%) and 3753 twin children (3.5%) had a major birth defect. Compared with naturally conceived children, risks for defects were increased for all other groups for nonchromosomal (adjusted odds ratios [AORs] ranged from 1.20 to 1.24, except for donor-fresh), blastogenesis (AORs, 1.22–1.74), cardiovascular (AORs, 1.04–1.26), gastrointestinal (AORs, 1.28–2.01), musculoskeletal (AORs, 1.10–1.48), and genitourinary among male children (AORs, 1.15–1.40, except for donor-fresh). Orofacial defects were increased in the OI/IUI and autologous-fresh and autologous-thawed groups (AORs, 1.26–1.42). The risk of any cancer was increased among ART autologous-fresh and non-ART siblings (hazard ratios [HRs], 1.31 and 1.34, respectively). A total of 127 children had both birth defects and cancer, with 53 (42%) of these children having leukemia. A Cox proportional hazards regression model identified 2 components for the risk of cancer: method of conception and type and number of birth defects. The presence of chromosomal defects was strongly associated with cancer risk (HRs, 8.70 for all cancers and 21.90 for leukemia), and this was further increased in the presence of both chromosomal and nonchromosomal defects (HRs, 21.29 for all cancers, 64.83 for leukemia, and 4.71 for embryonal tumors). The results of this study demonstrate that compared with naturally conceived children a significantly increased risk of nonchromosomal birth defects was found among children conceived with infertility treatment and that the risk of cancer was increased by greater than 30% among non-ART siblings and ART children born from autologous-fresh cycles. Among both naturally conceived and ART-conceived children, the presence of birth defects was associated with a greater risk of cancer.

Metabolomic Profile of Children Conceived With Medically Assisted Technologies.

Assisted reproductive technologies (ART) and non-in vitro fertilization fertility treatments (NIFT) are treatments for infertility. These technologies may have long-term health effects in children such as increased hypertension, glucose intolerance, and hypertriglyceridemia. Few studies have compared children born following ART and NIFT to those conceived spontaneously by subfertile couples. This work aimed to describe metabolic differences in children conceived by ART and NIFT compared to children conceived spontaneously by infertile couples. Children conceived by parent(s) receiving infertility care at the University of California, San Francisco, between 2000 and 2017 were invited to participate in the Developmental Epidemiological Study of Children born through Reproductive Technology (DESCRT). Serum metabolomic analyses were conducted using samples from 143 enrolled children (age range 4-12 years, 43% female) conceived using NIFT or ART (with fresh or frozen embryos with and without intracytoplasmic sperm injection [ICSI]) and children conceived spontaneously by subfertile couples. Principal component analysis and multivariable regression were used to compare the distribution of metabolites between groups. There was no separation in metabolites based on treatment or sex. NIFT-conceived children showed no differences compared to spontaneously conceived controls. Only spontaneously conceived children had different metabolomics profiles from children conceived from fresh ART, frozen ART, and all ICSI. Pantoate and propionylglycine levels were elevated in fresh ART compared to the spontaneous group (P < .001). Propionylglycine levels were elevated in the ICSI (both fresh and frozen) vs the spontaneous group (P < .001). Finally, 5-oxoproline levels were decreased in frozen ART compared to the spontaneous group (P < .001). NIFT-conceived children did not show any metabolic differences compared with spontaneously conceived children. The metabolic differences between ART-conceived children and children conceived spontaneously were small but unlikely to be clinically significant but should be examined in future studies.

Puberty disorders among ART-conceived singletons: a Nordic register study from the CoNARTaS group.

STUDY QUESTIONDo ART-conceived children have an increased risk for puberty disorders?SUMMARY ANSWERBoth ART-conceived boys and girls had a higher risk of puberty disorders; early puberty was more common among girls and late puberty among boys.WHAT IS KNOWN ALREADYSome physiological differences in growth and metabolism have been reported for ART-conceived children compared to non-ART-conceived children. Knowledge on pubertal development and disorders in ART-conceived children is limited.STUDY DESIGN, SIZE, DURATIONA register-based cohort study was carried out including data from 1985 to 2015. The Committee of Nordic Assisted Reproductive Technology and Safety (CoNARTaS) study population consists of all live and stillborn children, as well as their mothers, registered in the Medical Birth Registers during the study period in Denmark, Sweden, Finland and Norway.PARTICIPANTS/MATERIALS, SETTING, METHODSA total of 122 321 ART-conceived singletons and 6 576 410 non-ART singletons born in Denmark (1994–2014), Finland (1990–2014), Norway (2002–2015) and Sweden (1985–2015) were included. Puberty disorders were defined using International Classification of Diseases and Related Health Problems (ICD)-9/ICD-10 codes and classified in the following groups: late puberty (6268/E30.0), early puberty (2591 and 2958/E30.1 and E30.8) and unspecified disorders (V212 and V579/E30.9 and Z00.3 as well as Z51.80 for Finland). The results in Cox regression were adjusted for maternal age, parity, smoking, gestational diabetes, chronic hypertension, hypertensive disorders during pregnancy and country, and further for either gestational age, birthweight, small for gestational age or large for gestational age.MAIN RESULTS AND THE ROLE OF CHANCEThere were 37 869 children with diagnoses related to puberty disorders, and 603 of them were born after ART. ART-conceived children had higher risks for early (adjusted hazard ratio (aHR) 1.45, 95% CI: 1.29–1.64) and late puberty (aHR 1.47, 95% CI: 1.21–1.77). Girls had more diagnoses related to early puberty (aHR 1.46, 95% CI: 1.29–1.66) and boys with late puberty (aHR 1.55, 95% CI: 1.24–1.95).LIMITATIONS, REASONS FOR CAUTIONUsing reported puberty disorders with ICD codes in health care registers might vary, which may affect the numbers of cases found in the registers. Register data may give an underestimation both among ART and non-ART-conceived children, especially among non-ART children, who may not be as carefully followed as ART-conceived children. Adjustment for causes and duration of infertility, mothers’ own puberty characteristics and BMI, as well as children’s BMI, was not possible because data were not available or data were missing for the early years. It was also not possible to compare ART to non-ART siblings or to study the pubertal disorders by cause of subfertility owing to a small number of discordant sibling pairs and a large proportion of missing data on cause of subfertility.WIDER IMPLICATIONS OF THE FINDINGSThis large, register-based study suggests that ART-conceived children have a higher risk for puberty disorders. However, the mechanisms of infertility and pubertal onset are complex, and ART is a rapidly advancing field with various treatment options. Studying the pubertal disorders of ART-conceived offspring is a continuing challenge.STUDY FUNDING/COMPETING INTEREST(S)This work was supported by the Nordic Trial Alliance: a pilot project jointly funded by the Nordic Council of Ministers and NordForsk (71450), the Central Norway Regional Health Authorities (46045000), the Nordic Federation of Obstetrics and Gynaecology (NF13041, NF15058, NF16026 and NF17043), the Interreg Öresund-Kattegat-Skagerrak European Regional Development Fund (ReproUnion project), the Research Council of Norway’s Centre of Excellence funding scheme (262700), the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (ALFGBG-70940) and FLUX Consortium ‘Family Formation in Flux—Causes, Consequences and Possible Futures’, funded by the Strategic Research Council, Academy of Finland (DEMOGRAPHY 345130). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. The authors have no conflicts of interest to disclose.TRIAL REGISTRATION NUMBERN/A.

Sperm cryopreservation and DNA methylation: possible implications for ART success and the health of offspring.

Despite the beneficial effects of sperm cryopreservation, increased reactive oxygen species (ROS) production during this process can affect spermatozoon structure and function. Moreover, ROS production is associated with elevated DNA damage and alterations in DNA methylation. There is little information about the effects of cryopreservation on epigenetic modulation in sperm and the health of children born with frozen spermatozoa. Considering the potential consequences of cryopreservation in ART-conceived children, it is necessary to assure that cryopreservation does not modify sperm DNA methylation status. This review summarizes reports on epigenetic modifications of spermatozoa during cryopreservation and the probable effects of this process on offspring health. Contradictory results have reported the influence of sperm cryopreservation on DNA methylation in imprinted genes. Multiclinical studies with larger sample sizes under the same conditions of cryopreservation and DNA methylation analysis are needed to make any definitive conclusion about the effect of the cryopreservation process on sperm DNA methylation.

Evaluation of Bone Mineral Density in Children Conceived via Assisted Reproductive Technology.

ObjectivesTo investigate bone mineral density (BMD) differences between assisted reproductive technology (ART)-conceived children and naturally conceived (NC) children.Study DesignThis retrospective cohort study included ART-conceived children and controls aged 1 to 12 years assessed with a follow-up protocol. Maternal and paternal background, birth condition, and growth and development indicators were analyzed.ResultsThe ART and NC groups exhibited differences in maternal and paternal childbearing age; maternal weight; maternal body mass index (BMI); maternal alcohol consumption; paternal smoking; delivery method; and serum zinc, iron, and lead levels. Multifactor analysis adjusted for relevant factors showed that paternal childbearing age and group significantly affected the BMD Z score. In the subgroup analysis, in vitro fertilization (IVF) (p=0.026) or intracytoplasmic sperm injection (ICSI) (p=0.008) had a positive impact on the BMD Z score. Male infertility only (p=0.010) or male infertility combined with polycystic ovary syndrome (PCOS) (p=0.026) may affect the BMD Z score. In the embryo transfer cycle subgroup analysis, compared with natural conception, both stimulation cycle fresh embryo transfer (p=0.019) and natural cycle frozen embryo transfer (p=0.006) had a positive effect on the BMD Z score.ConclusionsThe BMD levels of the ART and control groups were generally in the normal range. Paternal childbearing age and the use of ART independently affected the BMD Z score of the offspring.

Analyses of child cardiometabolic phenotype following assisted reproductive technologies using a pragmatic trial emulation approach

Assisted reproductive technologies (ART) are increasingly used, however little is known about the long-term health of ART-conceived offspring. Weak selection of comparison groups and poorly characterized mechanisms impede current understanding. In a prospective cohort (Growing Up in Singapore Towards healthy Outcomes; GUSTO; Clinical Trials ID: NCT01174875) including 83 ART-conceived and 1095 spontaneously-conceived singletons, we estimate effects of ART on anthropometry, blood pressure, serum metabolic biomarkers, and cord tissue DNA methylation by emulating a pragmatic trial supported by machine learning-based estimators. We find ART-conceived children to be shorter (−0.5 SD [95% CI: −0.7, −0.2]), lighter (−0.6 SD [−0.9, −0.3]) and have lower skinfold thicknesses (e.g. −14% [−24%, −3%] suprailiac), and blood pressure (−3 mmHg [−6, −0.5] systolic) at 6-6.5 years, with no strong differences in metabolic biomarkers. Differences are not explained by parental anthropometry or comorbidities, polygenic risk score, breastfeeding, or illnesses. Our simulations demonstrate ART is strongly associated with lower NECAB3 DNA methylation, with negative control analyses suggesting these estimates are unbiased. However, methylation changes do not appear to mediate observed differences in child phenotype.

O-077 Cancer risk in a nationwide cohort of children and young adults conceived by assisted reproductive technology in 1983-2012

Abstract Study question Are children conceived by assisted reproductive technology (ART) at increased cancer risk, compared with the general population and with non-ART conceived offspring from subfertile women? Summary answer Overall cancer risk was not increased in ART-conceived offspring compared with non-ART conceived offspring from subfertile women (median follow-up, 17 years). What is known already There is growing evidence that ART procedures could perturb epigenetic processes during the pre-implantation period. Although the results of most studies are reassuring for children born after in vitro fertilization (IVF), recent studies showed (non-)significantly increased cancer risks after intracytoplasmic sperm injection (ICSI) and frozen embryo transfer (FET). Since the proportion of children born after these techniques increased dramatically over the past decades, it is important from a public health perspective to investigate cancer risk after ICSI and FET in larger studies. Study design, size, duration Data were used from the OMEGA-cohort, a historical nationwide cohort with prospective follow-up in the Netherlands. Offspring of women who were treated in one of the 13 IVF clinics or 2 regional fertility centers between 1983-2012 were included. Of 98,165 live-born children, 53,154 were ART-conceived and 45,211 were non-ART conceived (conceived naturally with or without ovarian hyperstimulation) by subfertile women. Participants/materials, setting, methods Data on type of fertility treatment and maternal risk factors were available from medical records from the mothers and the Dutch Perinatal registry. Cancer incidence was ascertained through linkage with the Netherlands Cancer Registry. Cancer risk in ART-conceived children was compared with risk in children not conceived by ART from subfertile women (hazard ratios [HRs]) and with children from the general population (standardized incidence ratios [SIRs]). Main results and the role of chance The median age at end of follow-up was 17 years and was shorter in ART-conceived children (16.1 years) compared with non-ART children (19.1 years). In total, 382 cancers were observed, 166 in the ART group and 222 in the non-ART group. In preliminary analyses, overall cancer risk was not increased in ART-conceived children, neither compared with children not conceived by ART from subfertile women (HR:0.98, 95% confidence interval (CI) = 0.79-1.22) nor compared with the general population (SIR:0.98, 95% CI = 0.81-1.11). Risks were also not significantly increased in children conceived by ICSI or FET (HR:1.20, 95%CI = 0.85-1.70; 1.25, 95%CI = 0.68-2.43, respectively). From 18 years of age onwards, the HR of cancer in ART-conceived versus non-ART individuals was 1.22 (95%CI = 0.86-1.74). There were no significantly increased site-specific cancer risks in ART-conceived children compared with non-ART children and the general population. Risk of lymphoblastic leukaemia was not increased in the ART group compared with the non-ART group (HR: 1.03, 95% CI = 0.58-1.82). Limitations, reasons for caution Despite the large cohort and long-term follow-up the number of cancer cases was limited which hampered some subgroup analyses, especially for analyses according to specific cancer types and children born after FET. Wider implications of the findings The results from this study importantly contribute to the current knowledge about health risks in ART-offspring. Physicians may inform parents who consider ART about potential health risks for ART-conceived children. Furthermore, pediatric oncologists caring for ART-conceived children/adolescents with cancer need evidence-based information about the association between ART and cancer risk. Trial registration number n.a.