Higher incidence of embryonic defects in mouse offspring conceived with assisted reproduction from fathers with sperm epimutations.

Assisted reproductive technologies (ART) account for 1-6% of births in developed countries. While most children conceived are healthy, increases in birth and genomic imprinting defects have been reported; such abnormal outcomes have been attributed to underlying parental infertility and/or the ART used. Here, we assessed whether paternal genetic and lifestyle factors, that are associated with male infertility and affect the sperm epigenome, can influence ART outcomes. We examined how paternal factors, haploinsufficiency for Dnmt3L, an important co-factor for DNA methylation reactions, and/or diet-induced obesity, in combination with ART (superovulation, in vitro fertilization, embryo culture and embryo transfer), could adversely influence embryo development and DNA methylation patterning in mice. While male mice fed high-fat diets (HFD) gained weight and showed perturbed metabolic health, their sperm DNA methylation was minimally affected by the diet. In contrast, Dnmt3L haploinsufficiency induced a marked loss of DNA methylation in sperm; notably, regions affected were associated with neurodevelopmental pathways and enriched in young retrotransposons, sequences that can have functional consequences in the next generation. Following ART, placental imprinted gene methylation and growth parameters were impacted by one or both paternal factors. For embryos conceived by natural conception, abnormality rates were similar for WT and Dnmt3L+/- fathers. In contrast, paternal Dnmt3L+/- genotype, as compared to WT fathers, resulted in a 3-fold increase in the incidence of morphological abnormalities in embryos generated by ART. Together, the results indicate that embryonic morphological and epigenetic defects associated with ART may be exacerbated in offspring conceived by fathers with sperm epimutations.

Association of Assisted Reproductive Technology and Stroke During Hospitalization for Delivery in the United States.

INTRODUCTION: Infertility treatment with assisted reproductive technologies (ARTs) has been associated with adverse vascular events in some but not all previous studies. Endothelial damage, prothrombotic factor release, and a higher prevalence of cardiovascular risk factors in those receiving ART have been invoked to explain this association. We sought to explore the relationship between ART and stroke risk using population-level data. METHODS: We conducted a retrospective cohort study using data from the National Inpatient Sample registry from 2015 to 2020, including all delivery hospitalizations for patients aged 15 to 55 years. The study exposure was use of ART. The primary end point was any stroke defined as ischemic stroke, subarachnoid hemorrhage, intracerebral hemorrhage, or cerebral venous thrombosis during index delivery hospitalization. Individual stroke subtypes (ischemic stroke, subarachnoid hemorrhage, intracerebral hemorrhage, and cerebral venous thrombosis) were evaluated as secondary end points. Standard International Classification of Diseases, Tenth Revision, Clinical Modification algorithms were used to define study exposure, comorbidities, and prespecified end points. In addition to reporting population-level estimates, propensity score adjustment by inverse probability weighting was used to mimic the effects of randomization by balancing baseline clinical characteristics associated with stroke between ART and non-ART users. RESULTS: Among 19 123 125 delivery hospitalizations identified, patients with prior ART (n=202 815, 1.1%) experienced significantly higher rates of any stroke (27.1/100 000 versus 9.1/100 000), ischemic stroke (9.9/100 000 versus 3.3/100 000), subarachnoid hemorrhage (7.4/100 000 versus 1.6/100 000), intracerebral hemorrhage (7.4/100 000 versus 2.0/100 000), and cerebral venous thrombosis (7.4/100 000 versus 2.7/100 000) in comparison to non-ART users (all P<0.001 for all unadjusted comparisons). Following inverse probability weighting analysis, ART was associated with increased odds of any stroke (adjusted odds ratios, 2.14 (95% CI, 2.02-2.26); P<0.001). CONCLUSIONS: Using population-level data among patients hospitalized for delivery in the United States, we found an association between ART and stroke after adjustment for measured confounders.

Cardiovascular autonomic nervous function in children conceived by assisted reproductive technology with frozen or fresh embryo transfer.

As a result of epigenetic changes, children conceived by assisted reproduction may be at risk of premature cardiovascular aging with notably increased blood pressures. Their cardiovascular autonomic nervous function is unknown. Therefore, this study investigated the cardiovascular autonomic nervous function in 8-12-yr-old children (51% girls) conceived naturally (n = 33) or by assisted reproduction with frozen (n = 34) or fresh (n = 38) embryo transfer by evaluating heart rate variability, during rest; from provocation maneuvers; and from baroreflex function. Heart rate and blood pressure response to provocation maneuvers and baroreflex function were comparable between children conceived naturally or by assisted reproduction. The mean RR-interval and high-frequency component of heart rate variability were lower in children conceived by assisted reproduction than in children conceived naturally. Children conceived by fresh embryo transfer had ∼17% lower heart rate-corrected standard deviation of normal-to-normal R-R intervals; ∼22% lower heart rate-corrected square root of the mean of the squared difference between successive R-R intervals; and ∼37% higher low-frequency/high-frequency ratio than naturally conceived children. Children conceived by assisted reproduction still had lower heart rate variability and vagal modulation than naturally conceived children after adjustment for confounders. Thus, these results raise the possibility of sympathetic predominance in children conceived by assisted reproduction. Therefore, it is important to reproduce these results in larger and older cohorts as sympathetic predominance relates with cardiovascular and metabolic diseases.NEW & NOTEWORTHY We observed that children conceived by assisted reproductive technology (both frozen and fresh embryo transfer) had lowered heart rate variability during rest as compared with children conceived naturally. During physiological stress maneuvers, however, the cardiovascular autonomic nervous regulation was comparable between children conceived by assisted reproductive technologies and naturally. Our findings highlight the potential that lowered heart rate variability during rest in children conceived by assisted reproductive technologies may precede premature hypertension.

Estimating the impact of bias in causal epidemiological studies: the case of health outcomes following assisted reproduction.

Researchers interested in causal questions must deal with two sources of error: random error (random deviation from the true mean value of a distribution), and bias (systematic deviance from the true mean value due to extraneous factors). For some causal questions, randomization is not feasible, and observational studies are necessary. Bias poses a substantial threat to the validity of observational research and can have important consequences for health policy developed from the findings. The current piece describes bias and its sources, outlines proposed methods to estimate its impacts in an observational study, and demonstrates how these methods may be used to inform debate on the causal relationship between medically assisted reproduction (MAR) and health outcomes, using cancer as an example. In doing so, we aim to enlighten researchers who work with observational data, especially regarding the health effects of MAR and infertility, on the pitfalls of bias, and how to address them. We hope that, in combination with the provided example, we can convince readers that estimating the impact of bias in causal epidemiologic research is not only important but necessary to inform the development of robust health policy and clinical practice recommendations.

Infertility treatments and cyanotic congenital heart defects among livebirths in the USA: findings from a contemporary cohort.

STUDY QUESTION: Is there an elevated risk of cyanotic congenital heart defects (CCHD) among livebirths following infertility treatments? SUMMARY ANSWER: In this population-based study of single livebirths, infertility treatment (either ART or non-ART) was associated with a higher prevalence of CCHD among livebirths. WHAT IS KNOWN ALREADY: The use of infertility treatment has been on the rise over the past few decades. However, there are limited studies assessing the risk of major cardiac defects following infertility treatments. STUDY DESIGN, SIZE, DURATION: A retrospective cohort study of livebirth data from the National Vital Statistics System (NVSS) was conducted, comprising of 9.6 million singleton livebirths among first-time mothers aged 15-49 years from 2016 to 2022. PARTICIPANTS/MATERIALS, SETTING, METHODS: Information on infertility treatment use and CCHD was obtained from the health and medical information section of birth certificates, which was completed by healthcare staff after reviewing medical records. Logistic regression models were used to estimate odds ratios (OR) and 95% CI. Entropy balancing weighting analysis and probabilistic bias analysis were also performed. MAIN RESULTS AND THE ROLE OF CHANCE: The proportion of births following infertility treatment increased from 1.9% (27 116) to 3.1% (43 510) during the study period. Overall, there were 5287 cases of CCHD resulting in a prevalence of 0.6 per 1000 livebirths. The prevalence was 1.2 per 1000 live births among infertility treatment users (ART: 1.1 per 1000 livebirths; non-ART: 1.3 per 1000 livebirths) while that for naturally conceived births was 0.5 per 1000 livebirths. Compared to naturally conceived births, the use of any infertility treatment (OR: 2.06, 95% CI: 1.82-2.33), either ART (OR: 2.02, 95% CI: 1.73-2.36) or other infertility treatments (OR: 2.12, 95% CI: 1.74-2.33), was associated with higher odds of CCHD after adjusting for maternal and paternal age, race and ethnicity, and education, as well as maternal nativity, marital status, source of payment, smoking status, and pre-pregnancy measures of BMI, hypertension and diabetes. This association did not differ by the type of infertility treatment (ART versus other infertility treatments) (OR: 1.04, 95% CI: 0.82-1.33, P = 0.712), and was robust to the presence of exposure and outcome misclassification bias and residual confounding. LIMITATIONS, REASONS FOR CAUTION: The findings are only limited to livebirths. We did not have the capacity to examine termination data, but differential termination by mode of conception has not been supported by previous studies designed to consider it. Infertility treatment use was self-reported, leading to the potential for selection bias and misclassification for infertility treatment and CCHD. However, the association persisted when systematic bias as well as exposure and outcome misclassification bias were accounted for in the analyses. Information on the underlying etiology of infertility relating to either maternal, paternal, or both factors, data on specific types of ART and other infertility treatments, as well as information on subtypes of CCHD, were all not available. WIDER IMPLICATIONS OF THE FINDINGS: In light of the increasing trend in the use of infertility treatment in the USA, and elsewhere, the finding of the current study holds significant importance for the clinical and public health of reproductive-aged individuals. The data show that the use of infertility treatment may expose offspring to elevated odds of severe congenital heart defects such as CCHD studied here. These findings cannot be interpreted causally. While our findings can assist in preconception counseling and prenatal care for pregnancies conceived by either ART or other infertility treatments, they also support some current recommendations that pregnancies resulting from infertility treatments undergo fetal echocardiography screening. STUDY FUNDING/COMPETING INTEREST(S): No funding was sought for the study. The authors declare that they have no conflict of interest. TRIAL REGISTRAION NUMBER: N/A.

Shedding light on the ART laboratory.

This commentary examines the impact of light conditions in the assisted reproductive technology (ART) laboratory, specifically considering gametes and embryo culture. While these processes traditionally occur in the absence of light within the female reproductive tract, laboratory conditions often involve exposure to varying wavelengths, intensities and light sources. Although literature reports describe potential detrimental effects of certain wavelengths of light on biological material, these findings are often based on experiments that might not reflect actual laboratory conditions. Current ART laboratory practices aim to minimize light exposure; however, some procedures necessitate light exposure, typically involving microscopy. Results from the authors' cross-sectional survey on light-intensity practices in ART laboratories revealed the frequent use of inadequate lighting, leading to errors and impacting staff well-being. A failure mode and effects analysis was used to identify potential failure modes and their impacts due to poor lighting. Overall, this manuscript stresses the importance of maintaining proper ambient lighting in the ART laboratory, balancing the potentially detrimental effects of light on gametes and embryos against the need for proper lighting for accurate procedures and staff well-being. Adequate lighting not only ensures the safety of reproductive cells, but also improves process management and the operators' psychological conditions.

Is infertility more common among patients with multiple sclerosis? Implications for utilization of assisted reproductive techniques.

RESEARCH QUESTION: Is fertility affected in women with multiple sclerosis (MS), and what is their usage of assisted reproductive technology (ART)? DESIGN: Data regarding multiple sclerosis and ART usage among patients with multiple sclerosis were extracted from the Israeli health maintenance organization Clalit Health Service database. Data regarding the diagnosis and treatment of multiple sclerosis, cause of infertility and use of fertility treatments were collected for all female multiple sclerosis patients aged 18-45 years between 2005 and 2021. Each patient was matched by age in a 1:10 ratio with reference women from the general population. The prevalence of infertility was compared between the two groups. Univariate and multivariate statistical tests were used to analyse the association between multiple sclerosis and fertility treatments including IVF and ovarian stimulation. RESULTS: During the study period, 1309 multiple sclerosis patients were compared with 13,090 controls from the general population matched for age. The mean age was 29 ± 7.8 years. The overall prevalence of infertility was 15.4% (202/1309) among the multiple sclerosis patients, similar to the general population (16.3%; 2129/13090) (P = 0.436). The prevalence of IVF and ovarian stimulation was similar among multiple sclerosis patients and matched controls from the general population (8.1% versus 7.2%, P = 0.240; 13.8% versus 14.3%; P = 0.624, respectively). CONCLUSIONS: The results show similar rates of infertility and fertility treatments among multiple sclerosis patients and the general population. This provides reassurance that fertility among women with multiple sclerosis does not differ from that of women in the general population, and indicates there is no excessive usage of ART.

Type of infertility and prevalence of congenital malformations.

BACKGROUND: Children conceived with assisted reproductive technologies (ART) or after a long waiting time have a higher prevalence of congenital malformations, but few studies have examined the contribution of type of infertility. OBJECTIVES: To quantify the association between causes of infertility and prevalence of malformations. METHODS: We compared the prevalence at birth of all and severe malformations diagnosed up to age 2 between 6656 children born in 1996-2017 to parents who had previously been assessed for infertility a an academic fertility clinic ("exposed") and 10,382 children born in the same period to parents with no recent medical history of infertility ("reference"). We estimated prevalence ratios (PR) and prevalence differences (PD), by infertility status, type of treatment (non-ART, ART), and infertility diagnosis, in all children and among singletons. RESULTS: Compared with children of parents with no infertility, children of parents with infertility had a higher prevalence of malformations (both definitions), particularly following ART conceptions. After accounting for treatment, ovulatory disorders were associated with a higher prevalence of both all (PR 1.49, 95% confidence interval (CI) 1.15, 1.93; PD 3.8, 95% CI 1.0, 6.6) and severe (PR 1.53, 95% CI 1.02, 2.29; PD 1.8, 95% CI -0.2, 3.7) malformations (the estimates refer to exposed children conceived without treatment). Unexplained and male factor infertility were associated with all and severe malformations, respectively. Estimates among singletons were similar. A diagnosis of ovulatory disorders was associated with all malformations also in analyses restricted to exposed children, regardless of treatment (we did not examine severe malformations, due to limited power). CONCLUSIONS: In this study, ovulatory disorders were consistently associated with a higher prevalence of congenital malformations (including severe malformations) among live births, regardless of mode of conception.

Assisted Reproductive Technology in the Presence of Polycystic Ovary Syndrome: Current Evidence and Knowledge Gaps.

OBJECTIVE: In this narrative review, we discuss the current evidence as well as the knowledge gaps concerning assisted reproductive technology (ART) indications, protocols, and results in the presence of polycystic ovary syndrome (PCOS). METHODS: An electronic literature search was performed for English-language publications in the last decade in databases such as PubMed, Medline, the Web of Sciences, Embase, and Scopus. RESULTS: We found evidence that ovarian steroidogenesis and folliculogenesis are deeply altered by PCOS; however, the oocyte quality and pregnancy rates after ART are not affected. Patients with PCOS are more sensitive to the action of exogenous gonadotropins and more likely to develop ovarian hyperstimulation syndrome. This risk can be mitigated by the adoption of the gonadotropin-releasing hormone antagonist protocols for pituitary blockade and ovarian stimulation, along with frozen embryo transfer, without compromising the odds of achieving a live birth. Pregnancy complications, such as miscarriage, gestational diabetes, preeclampsia, and very preterm birth, are more frequent in the presence of PCOS, requiring more intense prenatal care. It remains uncertain whether weight reduction or insulin sensitizers used before ART are beneficial for the treatment outcomes. CONCLUSION: Although PCOS is not a drawback for ART treatments, the patients need special care to avoid complications. More in-depth studies are needed to uncover the mechanisms of follicular growth, gamete maturation, and endometrial differentiation during ART procedures in the presence of PCOS.

Is Assisted Reproductive Technology Linked to Fetal Asphyxia? A Retrospective Italian Case-Control Study.

Several risk factors are associated with fetal asphyxia. The main aim of this retrospective, analytical, case-control study was to determine whether assisted reproductive technologies (ART) could be considered one of these factors. In total, 162 cases of fetal asphyxia were compared to 361 controls where this event did not occur. We included 32 ART pregnancies, of which 12 were obtained through egg donations. Overall, 75% (24) of ART pregnancies experienced fetal asphyxia, suggesting ART increases the risk of fetal asphyxia by about 7 times. This finding is consistent with the literature. The pathogenesis of fetal asphyxia in ART pregnancies is currently unknown. Accordingly, this topic should be further investigated.

What is the impact of endometriosis and the AFS stage on cumulative pregnancy rates in IVF programs?

BACKGROUND: Endometriosis is commonly observed in infertile women and can be staged with regard to severity [e.g. according to the American Fertility Society (AFS) classification]. This condition can cause infertility through impaired oocyte quality, fertilization disorders, tubal lesions, adhesions, deep infiltration, and adenomyosis. Although women with endometriosis often turn to in vitro fertilization (IVF) programs, the literature data on IVF outcomes are sometimes contradictory (i.e. the same as in other etiologies of infertility, or worse). The objective of the present study was to assess and compare pregnancy rates in women with and without endometriosis and according to the endometriosis stage. METHODS: We retrospectively studied clinical and ongoing pregnancy rates in IVF and the cumulative pregnancy rates after frozen/thawed embryo transfers, in women without endometriosis (group A) or with endometriosis (group B). We further compared groups in which endometriosis was staged according to the revised AFS classification: stage 1/2 (group C), stage 3/4 (group D, without endometrioma), and endometrioma alone (group E). RESULTS: We documented 430 cycles in group A and 460 in group B (including 56 in group C, 88 in group D and 316 in group E). After fresh or frozen/thawed embryo transfers, the differences in ongoing pregnancy rates between groups A and B were not significant. However the cumulative rates per couple were significantly lower (p < 0.05) in group D. CONCLUSIONS: We recommend IVF for women with endometriosis because the pregnancy rates are similar to those observed for women with other types of infertility. This approach is in line with the international guidelines issued by assisted reproductive technology societies. These results again raise the question of whether surgical resection of deep infiltrating endometriosis (stage 3/4) should be recommended before admission to an IVF program. Trial registration This study was approved by an institutional review board (CPP Ouest VI, Brest, France): reference: B2020CE.43.

Miracles of science: Birth after uterus transplantation.

AIM: The concept of regaining childbearing ability via uterus transplantation (UTx) motivates many infertile women to pursue giving birth to their own children. This article provides insight into maternal and neonatal outcomes of the procedure globally and facilitates quality of care in related medical fields. METHODS: The authors searched ISI Web of Science, MEDLINE, non-PubMed-indexed journals, and common search engines to identify peer-review publications and unpublished sources in scientific reference databases. RESULTS: The feasibility of the procedure has been proven with 46 healthy children in 88 procedures so far. Success relies upon dedicated teamwork involving transplantation surgery, obstetrics and reproductive medicine, neonatology, pediatrics, psychology, and bioethics. However, challenges exist owing to donor, recipient, and fetus. Fetal growth in genetically foreign uterine allograft with altered feto-maternal interface and vascular anatomy, immunosuppressive exposure, lack of graft innervation leading to "unable-to-feel" uterine contractions and conception via assisted reproductive technology create notable risks during pregnancy. Significant portion of women are complicated by at least one or more obstetric problems. Preeclampsia, gestational hypertension and diabetes mellitus, elevated kidney indices, and preterm delivery are common complications. CONCLUSIONS: UTx has short- and long-term satisfying outcome. Advancements in the post-transplant management would undoubtedly lead this experimental procedure into mainstream clinical practice in the near future. However, both women and children of UTx need special consideration due to prematurity-related neonatal problems and the long-term effects of transplant pregnancy. Notable health risks for the recipient and fetus should be discussed with potential candidates for UTx.

The Association between Assisted Reproductive Technologies and Neurodevelopmental Disorders in Offspring: An Overview of Current Evidence.

The utilization of assisted reproductive technologies (ART) is on the rise, resulting in a growing population of ART-conceived offspring. The health concerns of this unique population have attracted significant attention. During ART procedures, gametes and early-stage embryos are exposed to various non-physiological conditions, such as manipulation, culture media, and cryopreservation, which may disrupt embryonic development and potentially impact the health of offspring. Notably, the potential impact of ART on neurodevelopment and its association with an increased risk of neurodevelopmental disorders (NDD) later in life remains a subject of debate. This review aims to summarize the current research advancements concerning the effects of ART on neurodevelopment, specifically focusing on the evidence of the relationship between ART, epigenetic modifications, and NDD, including autism spectrum disorder, intellectual disability, attention deficit hyperactivity disorder, and cerebral palsy. Future studies should prioritize large sample sizes, rigorous adjustment for confounding factors, and the use of interdisciplinary approaches to effectively monitor the neurodevelopmental outcomes of ART-conceived children.

Ultrasound evaluation of the cardiovascular system in offspring conceived through assisted reproductive technology.

With the widespread application of assisted reproductive technology, the health issues of offspring conceived through assisted reproductive technology have also received increasing attention. Animal experiments and clinical studies have found subclinical adverse changes in the cardiovascular system of assisted reproductive offspring. Assisted reproductive technology itself may be just one of the many factors contributing to this phenomenon, with epigenetics playing an important role. Ultrasound technology can be used to assess the morphological structure and function of the cardiovascular system in assisted reproductive offspring from the fetal stage, providing the possibility to study the potential cardiovascular damage in this large population. This review aims to explore the effects and mechanisms of assisted reproductive technology on the cardiovascular system of offspring and provide a review of the research progress in ultrasound technology in this area.

Combined effects of pre-pregnancy BMI and gestational weight gain on preterm birth: comparison between spontaneous and ART conception.

BACKGROUND: Inappropriate pre-pregnancy body mass index (BMI) and gestational weight gain (GWG) are both linked to preterm birth (PTB); however, which one plays a dominant role in PTB risk is not yet sure. We aimed to evaluate the combined effect of pre-pregnancy BMI and GWG on the risk of PTB in singleton pregnancies conceived both spontaneously and through assisted reproductive technology (ART). METHODS: The data included all mothers (n = 17,540,977) who had a live singleton birth from the US National Vital Statistics System (NVSS) 2015-2019. Logistic regression models, quantile-g-computation, and generalized additive model were used to analyze the combined association of pre-pregnancy BMI and GWG with PTB. RESULTS: The singleton PTB rate was significantly higher in ART pregnancies (11.5%) than in non-ART pregnancies (7.9%). When compared to those women with pre-pregnancy normal weight and GWG within Institute of Medicine (IOM) guidelines, the highest PTB risk was observed in non-ART women with pre-pregnancy underweight and GWG below IOM guidelines (aOR 2.56; 95% CI 2.53-2.60) and in ART women with pre-pregnancy obese and GWG below IOM guidelines (aOR 2.56; 95%CI 2.36-2.78). GWG dominated the combined effect with its joint effect coefficient of - 0.281 (P < 0.05) in non-ART women and - 0.108 (P < 0.05) in ART women. CONCLUSIONS: Inappropriate GWG played a dominant role in increasing the risk of PTB in both non-ART and ART populations. Counseling regarding pre-pregnancy BMI and especially GWG appears to be even more crucial for pregnancies conceived via ART, given their impact on PTB.

Maternal and neonatal outcomes of dichorionic twin pregnancies achieved with assisted reproductive technology: meta-analysis of contemporary data.

PURPOSE: Assisted reproductive technology (ART) is commonly used to achieve pregnancy and often results in dichorionic diamniotic (DCDA) twin pregnancies. However, the potential risks of ART on maternal and neonatal outcomes in these pregnancies are not well understood. The objective is to compare the maternal and neonatal outcomes in DCDA twin pregnancies between those achieved through ART and those spontaneously conceived (SC). METHODS: We carried out a systematic comprehensive search of electronic databases; namely, PubMed, Embase, Scopus, and the Cochrane Library, from inception to March 2023 with a study period of recruitment between 2003 and 2023. We included all studies comparing the maternal and neonatal outcomes of DCDA twin pregnancies between those achieved by ART and those SC. RESULTS: We analyzed data from 18 cohort studies involving 10,485 women with DCDA twin pregnancies. The meta-analysis showed that ART-conceived pregnancies had a significantly higher risk of preeclampsia or gestational hypertension (GH), gestational diabetes mellitus (GDM), placenta previa (PP), placental abruption (PA), postpartum hemorrhage (PPH), and elective and emergency cesarean sections than SC twin pregnancies. The absolute risks of these complications remained relatively low. We also found a slightly higher risk of respiratory distress syndrome (RDS) and congenital malformations in ART-conceived infants compared to the risks in SC infants. Finally, the risk of neonatal intensive care unit (NICU) admissions was significantly higher in ART-conceived infants than in SC infants, but with high heterogeneity. CONCLUSION: We found associations between DCDA twin pregnancies conceived through ART and increased frequencies of adverse maternal outcomes. However, the absolute risks of these complications remained low, and the benefits of ART for achieving successful pregnancies may well outweigh the potential risks. Additionally, ART-conceived DCDA twin pregnancies may pose higher risks of RDS, congenital malformations and NICU, admissions than SC DCDA twin pregnancies.

Long-term health risk of offspring born from assisted reproductive technologies.

Since the world's first in vitro fertilization baby was born in 1978, there have been more than 8 million children conceived through assisted reproductive technologies (ART) worldwide, and a significant proportion of them have reached puberty or young adulthood. Many studies have found that ART increases the risk of adverse perinatal outcomes, including preterm birth, low birth weight, small size for gestational age, perinatal mortality, and congenital anomalies. However, data regarding the long-term outcomes of ART offspring are limited. According to the developmental origins of health and disease theory, adverse environments during early life stages may induce adaptive changes and subsequently result in an increased risk of diseases in later life. Increasing evidence also suggests that ART offspring are predisposed to an increased risk of non-communicable diseases, such as malignancies, asthma, obesity, metabolic syndrome, diabetes, cardiovascular diseases, and neurodevelopmental and psychiatric disorders. In this review, we summarize the risks for long-term health in ART offspring, discuss the underlying mechanisms, including underlying parental infertility, epigenetic alterations, non-physiological hormone levels, and placental dysfunction, and propose potential strategies to optimize the management of ART and health care of parents and children to eliminate the associated risks. Further ongoing follow-up and research are warranted to determine the effects of ART on the long-term health of ART offspring in later life.

Pregnancy following assisted reproductive technology in morbidly obese patients: assessment of feto-maternal outcomes.

PURPOSE: To examine feto-maternal characteristics and outcomes of morbidly obese pregnant patients who conceived with assisted reproductive technology (ART). METHODS: This cross-sectional study queried the Healthcare Cost and Utilization Project's National Inpatient Sample. Study population was 48,365 patients with ART pregnancy from January 2012 to September 2015, including non-obesity (n = 45,125, 93.3%), class I-II obesity (n = 2445, 5.1%), and class III obesity (n = 795, 1.6%). Severe maternal morbidity at delivery per the Centers for Disease and Control Prevention definition was assessed with multivariable binary logistic regression model. RESULTS: Patients in the class III obesity group were more likely to have a hypertensive disorder (adjusted-odds ratio (aOR) 3.03, 95% confidence interval (CI) 2.61-3.52), diabetes mellitus (aOR 3.08, 95%CI 2.64-3.60), large for gestational age neonate (aOR 3.57, 95%CI 2.77-4.60), and intrauterine fetal demise (aOR 2.03, 95%CI 1.05-3.94) compared to those in the non-obesity group. Increased risks of hypertensive disease (aOR 1.35, 95%CI 1.14-1.60) and diabetes mellitus (aOR 1.39, 95%CI 1.17-1.66) in the class III obesity group remained robust even compared to the class I-II obesity group. After controlling for priori selected clinical, pregnancy, and delivery factors, patients with class III obesity were 70% more likely to have severe maternal morbidity at delivery compared to non-obese patients (8.2% vs 4.4%, aOR 1.70, 95%CI 1.30-2.22) whereas those with class I-II obesity were not (4.1% vs 4.4%, aOR 0.87, 95%CI 0.70-1.08). CONCLUSIONS: The results of this national-level analysis in the United States suggested that morbidly obese pregnant patients conceived with ART have increased risks of adverse fetal and maternal outcomes.

Ovulation induction and subfertile untreated conception groups offer improved options for interpreting risks associated with ART.

PURPOSE: To identify and characterise appropriate comparison groups for population studies of health outcomes in ART-conceived births: ovulation induction (OI), subfertile untreated and fertile natural conceptions. Our secondary objective was to examine whether known risks of pregnancy complications and adverse birth outcomes in ART births are elevated in comparison with subfertile (untreated and OI) conception groups. METHODS: We linked State and Commonwealth datasets to identify all live and stillbirths (≥ 20 weeks) in Western Australia from 2003 to 2014 by method of conception. Demographic characteristics, maternal pre-existing conditions, adverse obstetric history and pregnancy complications were compared across conception groups. Generalised estimating equations were used to estimate adjusted risk ratios (aRRs) and 95% confidence intervals (CI) for pregnancy complications and birth outcomes in singletons. RESULTS: We identified 9456 ART, 3870 OI, 11,484 subfertile untreated and 303,921 fertile naturally conceived deliveries. OI and subfertile untreated groups more closely resembled the ART group than the fertile group; however, some differences remained across parity, maternal age, pre-existing conditions and obstetric history. In multivariate analyses, ART singletons had greater risks of placental problems (e.g. placenta praevia aRR 2.42 (95% CI 1.82-3.20)) and adverse birth outcomes (e.g. preterm birth aRR 1.38 (95% CI 1.25-1.52)) than the subfertile untreated group, while OI singletons were more similar to the subfertile group with higher risk of preeclampsia and gestational diabetes. CONCLUSION: OI and subfertile untreated conception groups offer improved options for interpreting health outcomes in ART births. Pregnancy complications (particularly placental disorders) and adverse outcomes at delivery are more common following ART.

Assisted reproductive technology and the risk of fetal congenital heart disease: insights from a tertiary-care referral center.

PURPOSE: To investigate whether congenital heart diseases exhibit higher rates in pregnancies achieved through assisted reproductive technology (ART) compared to natural conception. METHODS: In this retrospective cohort study, multinomial logistic regression was employed to analyze the relationship between categories of congenital heart diseases and three conception groups (IVF, ICSI, and natural pregnancies). The main outcome measures are risks of congenital heart disease categories in IVF and ICSI groups using the natural group as reference. We selected fetuses referred for fetal echocardiography to IRCCS Policlinico Sant'Orsola, Bologna, between January 2005 and November 2023, diagnosed with congenital heart diseases. RESULTS: We categorized the congenital heart diseases into six groups based on anatomical and embryological criteria. The estimated risk of left ventricular outflow tract, valvular, conotruncal, and atrioventricular septal defects was lower in the IVF group compared to natural conception. The estimated risk of valvular and atrioventricular septal defects was lower in the ICSI group vs natural. Conversely, the risk for right heart anomalies was higher both in the IVF and ICSI groups compared to natural conception. Heart rhythm diseases were more frequent in IVF pregnancies. When comparing ART methods, valvular defects, conotruncal defects, and right heart anomalies were more frequently observed in the ICSI group, while atrioventricular septal defects were more common in the IVF group. CONCLUSION: Significant differences were found in the occurrence of congenital heart diseases in pregnancies conceived through IVF and ICSI, versus those conceived naturally, underscoring the importance of further studying the underlying mechanisms of these associations.