INTRODUCTION — Assisted reproductive technology (ART), which encompasses in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), has become increasingly successful. As a result, indications for use of ART have expanded and concerns about the outcome of these pregnancies have accompanied their increasing prevalence. Most individuals undergoing IVF and their resulting offspring are healthy; generally, the most favorable outcomes occur with singleton pregnancy. However, research in this field is complicated by the need to distinguish between the effects of ART on outcomes in offspring versus multiple other confounding or mediating factors, including selection bias related to maternal age and other conditions linked to infertility, technological changes in the performance of ART, number of fetuses produced, and changes in obstetric and neonatal care.
The impact of ART on infant and child outcomes will be discussed here. In-depth discussions of pregnancy and maternal outcomes, as well as IVF and ICSI procedures, can be found separately.
●(See "Assisted reproductive technology: Pregnancy and maternal outcomes".)
●(See "In vitro fertilization: Overview of clinical issues and questions".)
●(See "Intracytoplasmic sperm injection".)
In this topic, when discussing study results, we will use the terms "woman/en" or "patient(s)" as they are used in the studies presented. However, we encourage the reader to consider the specific counseling and treatment needs of transgender and gender diverse individuals.
ART TERMINOLOGY AND IMPACT
●Terminology – ART includes "all interventions that include the in vitro handling of both human oocytes and sperm or of embryos for the purpose of reproduction. This includes, but is not limited to, in vitro fertilization (IVF) and embryo transfer, intracytoplasmic sperm injection (ICSI), embryo biopsy, preimplantation genetic testing (PGT), assisted hatching, gamete intrafallopian transfer (GIFT), zygote intrafallopian transfer (ZIFT), gamete and embryo cryopreservation, semen, oocyte and embryo donation, and gestational carrier cycles. Thus, ART does not, and ART-only registries do not, include assisted insemination using sperm from either a woman's partner or a sperm donor" [1]. Additional terminology for fertility and related therapies are presented separately. (See "In vitro fertilization: Overview of clinical issues and questions", section on 'Terminology'.)
●Impact of ART – The first birth of an IVF baby was reported in 1978 [2]. Since then, there have been more than eight million pregnancies worldwide [3], and another 500,000 deliveries are being added annually by IVF and its modifications [4]. Live birth rates after IVF and ICSI are presented in detail in related content.
•(See "Intracytoplasmic sperm injection", section on 'Pregnancy'.)
PREGNANCY AND BIRTH RATES — Pregnancy rates after ART are influenced by a variety of factors, which are discussed in detail separately. (See "In vitro fertilization: Overview of clinical issues and questions", section on 'What factors impact IVF success?'.)
SUMMARY — Outcomes for infants and children born using ART are generally reassuring and the vast majority of babies born after ART are normal.
NEONATAL OUTCOMES
Chromosomal and genetic alterations — Although data are sparse, studies that have adjusted for maternal age have not reported a higher prevalence of karyotype abnormalities in offspring of IVF conceived pregnancies compared with unassisted conceptions [5,6].
However, there is concern that use of sperm from subfertile men and the intracytoplasmic sperm injection (ICSI) procedure itself [7] may increase the risk of chromosomal and gene abnormalities in children conceived by ART. Subfertile men (and individuals) are more likely than fertile individuals to have chromosomal abnormalities (eg, aneuploidies, structural abnormalities, gene mutations, microdeletions) that may contribute to their subfertility and may be passed to their offspring. Additionally, there is a concern that ICSI may interfere with genomic imprinting during germ cell development and preimplantation. These and related issues are discussed in separate content. (See "Intracytoplasmic sperm injection", section on 'Genetic alterations and congenital anomalies'.)
Congenital anomalies
Overall risk — Individuals who undergo ART appear to be at increased risk of delivering offspring with congenital anomalies compared with fertile individuals with unassisted conceptions [8-10] (table 1), but the reason for this increase is unclear. Additionally, subfertile couples who conceive without assistance may also have a somewhat elevated risk compared with those with normal fertility [11]. The higher risk of congenital anomalies may be related to infertility itself, to factors related to ART procedures, or both. Regardless, patients can be reassured that the absolute risk of having a child with a congenital anomaly is low; the population baseline risk of 2 to 4 percent is potentially increased by approximately one-third with ART [12-15].
●(See "Birth defects: Epidemiology, types, and patterns".)
●(See "Birth defects: Causes".)
Supporting data — Both observational studies and meta-analyses have reported increased risk of congenital anomalies of similar magnitude [8-10].
The largest study used national registry data to compare birth defects in children conceived by IVF and/or ICSI (n = 135,051 infants, 78,362 singletons, and 56,689 twins) with spontaneously conceived siblings of the ART-conceived children (n = 23,647 infants, 22,301 singletons, and 1346 twins) [8].
Major findings include [8]:
●Main results and the role of chance – Overall, among 68,908 singleton children born in 2017 by ART, there was an estimated excess of 386 born with a major birth defect. Further breakdown of the data includes:
•18 percent increased risk of a major nonchromosomal birth defect in singleton infants conceived with ART without ICSI (approximately 36 percent of ART births)
•30 percent increased risk of a major nonchromosomal birth defect with ICSI without male factor (approximately 33 percent of ART births)
•42 percent increased risk of a major nonchromosomal birth defect with ICSI and male factor (approximately 31 percent of ART births)
●Overall risk of congenital anomalies
•Incidence of birth defects – A total of 21,998 singleton children (1.9 percent) and 3037 twin children (3.3 percent) had a major birth defect.
•Comparison of ART singleton pregnancies (conceived from autologous oocytes, fresh embryos) with unassisted singleton pregnancies:
-Without ICSI – These children had increased risks of a major nonchromosomal birth defect (adjusted odds ratio [aOR] 1.18, 95% 1.05-1.32), cardiovascular defects (aOR 1.20, 95% CI 1.03-1.40), and any birth defect (aOR 1.18, 95% CI 1.09-1.27).
-With ICSI – The risks were increased for a major nonchromosomal birth defect (aOR 1.30, 95% CI 1.16-1.45 without male factor diagnosis; aOR 1.42, 95% CI 1.28-1.57 with male factor diagnosis); blastogenesis defects (aOR 1.49, 95% CI 1.08-2.05 without male factor; aOR 1.56, 95% CI 1.17-2.08 with male factor); cardiovascular defects (aOR 1.28, 95% CI 1.10-1.48 without male factor; aOR 1.45, 95% CI 1.27-1.66 with male factor). In addition, the risk for musculoskeletal defects was increased (aOR 1.34, 95% CI 1.01-1.78 without male factor) and the risk for genitourinary defects in male infants was increased (aOR 1.33, 95% CI 1.08-1.65 with male factor).
●Relative risk of IVF and ICSI compared with unassisted singleton children:
•IVF without ICSI – ART-conceived singletons (autologous oocytes, fresh embryos, no ICSI) had small increased risks of major nonchromosomal birth defects (adjusted odds ratio [aOR] 1.18, 95% CI 1.05-1.32), cardiovascular defects (aOR 1.20, 95% CI 1.03-1.4), and risks of any birth defect (aOR 1.18, 95% CI 1.09-1.27).
•IVF with ICSI – ART-conceived singletons (autologous oocytes, fresh embryos, with ICSI) had a further increased risk of major nonchromosomal birth defects (without male factor diagnosis: aOR 1.30, 95% CI 1.16-1.45; with male factor diagnosis 1.42, 95% CI 1.28-1.57) as well as increased risks of blastogenesis defects (aOR 1.65, 95% CI 1.08-2.51), gastrointestinal defects (aOR 2.21, 95% CI 1.28-3.82), and any birth defect (aOR 1.11, 95% CI 1.01-1.22).
●Sibling comparison – Compared with children conceived without ART, singleton siblings conceived with ART had increased risks of musculoskeletal defects (aOR 1.32, 95% CI 1.04-1.67) and any defect (aOR 1.15, 95% CI 1.08-1.23). Twins conceived via ART (conceived with autologous oocytes, fresh embryos, without ICSI) were at increased risk of chromosomal defects (aOR 1.89, 95% CI 1.10-3.24) and risk of any defect (aOR 1.26, 95% CI 1.01-1.57).
Additional contributing factors — There are numerous factors that could increase the rate of congenital anomalies, including age of mother (or egg donor), cause of infertility, prior treatment for infertility, duration of infertility, environmental exposures, risk behaviors such as alcohol use and smoking, and ART techniques (eg, extended culture, type of culture media). These patient factors should be discussed with patients prior to fertility therapy. Discussion of the impact of ART on pregnancy and maternal outcomes is presented in related content. (See "Assisted reproductive technology: Pregnancy and maternal outcomes".)
Stillbirth and perinatal mortality — Stillbirth [16,17] and perinatal mortality [18] rates appear to be increased as much as fourfold when compared with births from unassisted conception due, in part, to multiple gestation, low birth weight, and obstetric complications (eg, hypertensive disorders of pregnancy). However, the significance of this finding is unclear as the preferred comparator may be pregnancies in patients with subfertility who conceived without medical assistance [19].
●Stillbirth – In the United States, the stillbirth rate after IVF is approximately 0.6 percent [20]. A national cohort study from Denmark of low-risk ART pregnancies reported stillbirth rates of 0.1 percent following IVF and 0.3 percent after ICSI [17]. For low-risk patients, it is not known if the increased stillbirth risk is related to the treatment or the underlying subfertility.
●Impact of racial and ethnic disparities – Racial and ethnic disparities in infant health outcomes appear to be further exacerbated for children conceived with ART [21-23]. In a US population-based study comparing infant mortality for singleton births between 2016 to 2017, infant mortality rates of non-Hispanic Black patients were double those of non-Hispanic White patients for unassisted conceptions and rose to four times greater for ART-conceived pregnancies (adjusted rate ratio [aRR] 1.9, 95% CI 1.8-1.9 and aRR 4.1, 95% CI 2.9-5.9, respectively) [24]. The infant mortality differences could not be accounted for by available maternal demographic data and underlying medical conditions alone.
Detailed information on stillbirth and perinatal mortality can be found separately.
●(See "Stillbirth: Incidence, risk factors, etiology, and prevention".)
●(See "Perinatal mortality".)
Imprinting disorders — Available evidence indicates an increase in a subset of genomic imprinting disorders among children conceived by ART, but the absolute number is still very low given the very rare incidence of these disorders. (See "Intracytoplasmic sperm injection", section on 'Genetic alterations and congenital anomalies'.)
●Description of process – Genomic imprinting is a process by which genes from only one parental allele are expressed. These genes involve early embryonic growth, placental development and neurodevelopment. Generally, specific imprinted genes promoting fetal development are often active from only the maternal allele, while other imprinted genes promoting placental growth are active from only the paternal allele. (See "Principles of epigenetics", section on 'Terminology and basic concepts'.)
●Supporting data – Imprinting syndromes are rare (fewer than 1 in 12,000 births), thus even large increases in relative risk represents a small absolute risk and would be difficult to detect. Given the rarity of these disorders, it is difficult to determine whether they may be related to some aspect of the ART procedure or subfertility itself or a combination of factors [25]. As examples:
•A review of epidemiological studies concluded that Beckwith-Wiedemann syndrome (BWS) was significantly associated with IVF/ICSI, Silver-Russell syndrome was probably associated with IVF/ICSI, and Angelman and Prader-Willi syndrome were not associated with IVF/ICSI [26]. The authors noted that the incidences of Angelman syndrome and Prader-Willi syndrome were positively associated with subfertility and concluded that, "there are no indications for a causal relationship between ART and imprinted diseases in humans."
•A subsequent study that assessed the prevalence of BWS after ART or natural conception in Piedmont, Italy reported that BWS birth prevalence was notably higher in the ART group than the natural conception group (birth prevalence of 1:1126 versus 1:12,254, respectively) [27]. However, definitive conclusions are again limited by the small number of affected children in the study groups.
Detailed reviews on the association between ART and defects of genomic imprinting can be found separately [28-33].
●(See "Beckwith-Wiedemann syndrome".)
●(See "Causes of short stature", section on 'Silver-Russell syndrome'.)
●(See "Prader-Willi syndrome: Clinical features and diagnosis".)
●(See "Intracytoplasmic sperm injection", section on 'Genetic alterations and congenital anomalies'.)
LONG-TERM ISSUES
General health — Outcomes among ART offspring up to 28 years of age have been reported and are generally reassuring. A study comparing 253 ART-conceived adolescents (born between 1982 and 1993) with case-matched controls reported no detectable differences between groups for general health, mental health, or cognitive ability upon review of military preinduction screening records (performed at ages 16 to 17 years) [34].
●Chronic illness – While the evidence is not conclusive, studies are suggesting that children conceived by ART may be at a slightly increased risk of metabolic syndrome, type 2 diabetes, and cardiovascular disease later in life [35,36]. One study reporting this association controlled for maternal obesity, polycystic ovarian syndrome, fetal growth restriction, and preeclampsia, all of which may impact childhood outcomes [35].
●Cardiovascular changes – While initial small observational studies described vascular dysfunction in children conceived by ART, population-level data has not supported an increase in clinically relevant cardiovascular disease [35,37-39]. For example, a case-control study of 122 children reported greater carotid media thickness for ART-conceived compared with control children, but a population-based study including over 7.6 million children did not report increased risk of any cardiovascular disease for those conceived with ART compared with those conceived spontaneously (adjusted hazard ratio [aHR] 1.02, 95% CI 0.86-1.22, duration of follow-up six to eight years) [37,39]. The association between ART and cardiovascular changes may be related to confounders, such as intrauterine growth restriction and prematurity, and the long-term clinical impact of these findings, if any, is not yet known.
●Asthma – Some studies have reported an increased risk of asthma in children conceived by ART [40-42]. One study of two Norwegian databases reported a 20 percent increased risk of asthma in children born through ART compared with spontaneously conceived children [43]. However, the association does not necessarily reflect causality and biologic mechanisms are not known. At least part of the association seems to be attributable to subfertility, neonatal morbidity related to prematurity, and maternal asthma.
Reproductive potential — The prevalence of subfertility among children born from IVF does not appear to be greater than the population risk. However, one expiation may be children born to fathers with very low sperm counts who needed ICSI for IVF [44]. There is persistent controversy as to whether this relationship between previous ICSI due to male factor and infertility in a child conceived with IVF or ICSI holds true.
Depression and anxiety — Use of ART for conception does not appear to negatively impact mental health of offspring [34,45]. A prospective Swedish national birth cohort study including over 1.2 million individuals aged 12 to 25 years reported, in adjusted analysis, those conceived by ART (n = 31,565, 2.6 percent) had no increased risk of having a diagnostic code for depression, anxiety (other than obsessive-compulsive disorder [OCD]), or suicidal behavior compared with all others [45]. While an increased risk of OCD was reported when ART-conceived adolescents were compared with all others, the association became nonsignificant after adjustment for parental characteristics (aHR 1.10, 95% CI 0.98-1.24) and for known infertility (aHR 1.02, 95% CI 0.89-1.17). Type of fertilization method (standard in vitro fertilization versus intracytoplasmic sperm injection) also had no association with measured outcomes. Median age of follow-up was 18 years (interquartile range, 15 to 21 years). Factors considered in adjusted analysis included parental demographics, health conditions, and psychiatric history. A study strength was the use of a large, national data base; a study limitation was the reliance on billing codes as markers for clinical diagnoses.
Neurodevelopment
Summary — While some data suggest a small increased risk of neurodevelopmental problems in children conceived with ART, the bulk of available evidence suggests that the neurodevelopmental outcomes of singleton children conceived after medically assisted reproduction are similar to those of children conceived naturally [46-55]. However, the procedure does result in more multiple gestations, which are at high risk of preterm birth, low birth weight, and small for gestational age infants, all of which are important risk factors for neurodevelopmental sequelae. Neurodevelopmental outcomes include psychomotor, cognitive, behavioral, and socioemotional development, as well as mental disorders (eg, intellectual disability, autism spectrum disorder, attention deficit hyperactivity disorder).
Data by developmental age group — A 2013 systematic review analyzed data from 80 studies comparing the neurodevelopmental outcome of children born after ART and controls conceived naturally; the studies included between 31 and 2,446,044 children [56]. The authors concluded:
●Infant – Studies of the psychomotor development of infants showed no deficits, but data on cognitive or behavioral development were limited.
●Toddler – Studies on toddlers consistently reported normal cognitive, behavioral, socioemotional, and psychomotor development.
●Middle childhood – Studies on children in middle childhood generally reported normal development, but there were fewer studies with follow-up at this age.
●Teen – Studies on neurodevelopmental outcomes in teens were inconclusive, but very few studies have been published.
Confounders
●Impact of infertility on neurodevelopment – The impact of infertility itself on neurodevelopment is not known. In a study that assessed early intervention program enrollment by type of pregnancy, singleton children conceived through ART and children of subfertile mothers both had elevated risks of early intervention enrollment compared with singleton children born to mothers with normal fertility [57]. This finding could also be the result of increased vigilance on the part of parents of children born after subfertility and point to a potential diagnosis bias.
●Methodologic challenges – In addition to the small number of children followed to school age and beyond, these studies are limited by methodologic issues such as possible selection biases, inadequate control groups, and potentially confounding preexisting parental factors. For example, the etiology of subfertility, parental medical conditions, and socioeconomic and behavioral characteristics of couples who undertake ART could account for the differences in neurodevelopmental outcomes between their children and those conceived naturally reported in some studies, and these characteristics may also mask some true differences between the two groups. Large, well-controlled studies with long-term follow-up based on blinded and validated assessments are needed.
Puberty — Pubertal development in children conceived using ART does not appear to differ from those conceived spontaneously [58,59]. A longitudinal study of a cohort of ICSI-conceived teenagers compared pubertal development at age 14 years in this cohort with a spontaneously conceived control group [58]. Menarche, genital development in males, and pubic hair development in males and females was comparable in both groups, while breast developmental was less advanced in ICSI females compared with spontaneously conceived peers, even after adjustment for known potential confounders. (See "Normal puberty".)
Cancer risk — While the risk of cancer in offspring conceived through ART has been debated and the overall absolute risk may be slightly higher than that of the general population, it is difficult to separate the impact of the treatment from that of the underlying fertility disorder and association does not establish causality [60-64]. In addition, the choice of comparator has been debated; while initial comparisons were often made with fertile individuals, subsequent studies included subfertile individuals who achieved pregnancy without ART in attempts to clarify the impact of the disease (infertility) from that of the treatment [62,65,66].
Study examples include:
●In a 2022 Taiwanese population cohort study including over 2.3 million parent-child triads with children born between 2004 and 2017 who were followed for a median of six years, ART-assisted conception was associated with an increased risk of pediatric cancer compared with conception associated with subfertility but without ART assist (hazard ratio [HR] 1.42, 95% CI 1.04-1.95) and unassisted conception (HR 1.58, 95% CI 1.17-2.12) [67]. Compared with conception associated with subfertility but without ART assist, ART-assisted conception was specifically associated with increased risk of leukemias (HR 1.88, 95% CI 1.03-3.43) and hepatic tumors (HR 2.41, 95% CI 1.05-5.52). No significant differences in cancer risk were noted when comparing children born from unassisted conception with children born to subfertile parents but without ART assist, which suggests that the increased cancer risk may be related to the ART intervention.
•Study exclusion criteria included parental substance use, history of cancer, conceptions using donor sperm or oocytes, and birth of another child in the same calendar year.
•Analysis was adjusted for maternal age, parity, and abortion history; paternal age; child's birth year and sex; household income at birth; and residential urbanization level.
●A 2019 retrospective Danish cohort study of over one million children born between 1996 and 2012 reported similar numbers of overall cancer cases for children born to individuals with or without infertility (17.6 versus 17.5 per 100,000 children-years [also known as person-years], HR 1.02, 95% CI 0.91-1.15) [63].
•Fresh embryo transfer and ICSI – For children conceived using fresh embryo IVF (n = 19,448) and ICSI (n = 13,417), the risk of cancer was not increased (incidence rate of 17.1 and 23.1 per 100,000 children-years) [63].
•Frozen embryo transfer – For children born following frozen embryo transfer (FET), the childhood cancer risk was more than double that of children born to fertile individuals (44.4 per 100,000 children-years, HR 2.45, 95% CI 1.44-4.11) [63]. The risk of childhood cancer was not associated with non-FET fertility treatments, use of any fertility drug, or use of specific fertility drugs.
Concerns for possible increased risk of childhood cancer following FET must be balanced against the benefits, including facilitating single embryo transfer, with its resultant reduction of multiple gestation, preterm birth, low birth weight, growth restriction, and perinatal mortality. Cryopreservation of embryos is presented in detail elsewhere.
-(See "In vitro fertilization: Overview of clinical issues and questions".)
-(See "In vitro fertilization: Procedure".)
●In a 2019 United States population-based cohort study that matched over 275,000 children of IVF pregnancies with over 2.2 million children of spontaneous pregnancies, the overall cancer rate per 1,000,000 person-years was slightly higher, but not statistically significant, for children conceived by IVF (251.9 for the IVF group versus 192.7 for the non-IVF group, HR 1.17, 95% CI 1.00-1.36) [61]. The only cancer rate that differed between the two groups was for hepatic tumors (18.7 for IVF versus 5.7 for spontaneous, HR 2.46, 95% CI 1.29-4.70). However, it could not be determined if this increase was attributable to IVF, infertility, or some other process.
It remains unclear whether the risks observed are related to one or more aspects of fertility treatment itself or to personal factors associated with or causing subfertility. The low absolute risk of cancer after fertility therapy should also be considered [61]. If the 1.31 increase in relative risk of cancer described in the meta-analysis is applied to the Danish population, 4.4 cases of childhood cancer in Denmark each year (2.9 percent of all cases of childhood cancer) could be attributed to medically assisted reproduction, and treatment of 4236 Danish individuals would be required to result in one excess case of childhood cancer.
The possibility of an increase in the risk of ovarian and breast cancer in individuals receiving gonadotropin or clomiphene therapy is discussed elsewhere. (See "Overview of ovulation induction".)
RESOURCES FOR PATIENTS AND CLINICIANS
●European Society of Human Reproduction and Embryology (ESHRE).
●The Society for Assisted Reproductive Technology (SART) has information for both patients and providers, including an ART success predictor tool.
●Centers for Disease Control and Prevention (CDC).
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Female infertility" and "Society guideline links: Male infertility or hypogonadism".)
SUMMARY AND RECOMMENDATIONS
●Summary – Outcomes for infants and children born using assisted reproductive technology (ART) are generally reassuring and the vast majority of babies born after ART are normal.
●Neonatal – Neonates conceived with ART appear to have a modest increased risk of congenital anomalies, stillbirth, and, in some cases, imprinting disorders, but not chromosomal abnormalities. ART impacts the male-to-female sex ratio at birth based on procedure type. (See 'Neonatal outcomes' above.)
●Childhood and beyond – Health outcomes of children conceived through ART have been studied into young adulthood and are generally reassuring. Neurologic and pubertal development do not appear to be impacted. The risk of cancer in offspring conceived through ART has been debated and, while the overall absolute risk may be slightly higher than that of the general population, it is difficult to separate the impact of the treatment from that of the underlying fertility disorder. (See 'Long-term issues' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Richard Paulson, MD, MS, who contributed to earlier versions of this topic review.
