Developmental and Genetic Outcomes in Children Conceived Through Assisted Reproductive Technologies

Congenital malformations after assisted reproduction: risks and implications for prenatal diagnosis and fetal medicine

Assisted Reproductive Technology and Major Birth Defects in Western Australia

Do assisted reproductive technologies cause adverse fetal outcomes?

When Darine El-Chaar began her residency in obstetrics and gynecology at the University of Ottawa five years ago, she grew curious about the potential health repercussions of assisted reproductive technologies (ART), the catchall term for procedures used to help couples artificially conceive a child. ART involves surgically removing eggs from a woman’s ovaries, combining them with sperm in the laboratory, and returning them to the womb.1 Women undergoing ART take “fertility drugs” such as clomiphene citrate and gonadotropins to stimulate the production of many eggs rather than the single egg that would normally grow during their monthly menstrual cycle.2 El-Chaar wondered about the influence that ART procedures, as well as the underlying infertility itself, might have on the health of children conceived. She is one of many researchers working to answer the fundamental question of whether introducing fertility drugs and manipulating eggs and sperm in a laboratory setting—in essence, altering the primal environment—sets the stage for adverse health effects in children. Artist’s rendering of intracytoplasmic sperm injection, in which a single sperm is inserted into an egg. Although some research indicates such a risk exists, there haven’t been enough large-scale studies to ascertain if the potential effects are severe enough over the long term to deter couples from seeking infertility treatments. Meanwhile, some findings are pointing the way toward possible refinements to improve health outcomes for ART babies.

Background:Multiple pregnancies occur more frequently in assisted reproductive technology (ART) compared tonormal conception (NC). It is known that the risk of congenital malformations in a multiple pregnancy are higher thansingle pregnancy. The aim of this study is to compare congenital malformations in singleton infants conceived by ARTto singleton infants conceived naturally.Materials and Methods:In this historical cohort study, we performed a historical cohort study of major congenital malformations(MCM) in 820 singleton births from January 2012 to December 2014. The data for this analysis were derived fromTehran’s ART linked data file. The risk of congenital malformations was compared in 164 ART infants and 656 NC infants. Weperformed multiple logistic regression analyses for the independent association of ART on each outcome.Results:We found 40 infants with MCM 29 (4.4%) NC infants and 14 (8.3%) ART infants. In comparison with NCinfants, ART infants had a significant 2-fold increased risk of MCM (P=0.046). After adjusting individually for maternalage, infant gender, prior stillbirth, mother’s history of spontaneous abortion, and type of delivery, we did not find any differencein risk. In this study the majority (95.1%) of all infants were normal but 4.9% of infants had at least one MCM.We found a difference in risk of MCMs between in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI).We excluded the possible role of genotype and other unknown factors in causing more malformations in ART infants.Conclusion:This study reported a higher risk of MCMs in ART singleton infants than in NC singleton infants. Congenitalheart disease, developmental dysplasia of the hip (DDH), and urogenital malformations were the most reportedmajor malformations in singleton ART infants according to organ and system classification.

Round spermatid nucleus injection (ROSNI)

Does cervical conization add an additional risk of preterm birth (PTB) in assisted reproduction technology (ART) singleton and twin pregnancies? Cervical conization doubles the risk of preterm and very PTB in ART twin pregnancies. ART and cervical conization are both risk factors for PTB. In this national population-based controlled cohort study, we included all ART singletons and twin deliveries from 1995 to 2009 in Denmark by cross-linkage of maternal and child data from the National IVF register and the Medical Birth register. Furthermore, control groups of naturally conceived (NC) singletons and twins were extracted. Cervical diagnoses were obtained from the Danish Pathology register. Cervical conization included both cold knife cone and LEEP (loop electrosurgical excision procedure) but not cervical biopsies. The main outcomes measures were PTB (PTB ≤ 37 + 0 gestational weeks), very preterm birth (VPTB ≤ 32 + 0 gestational weeks) and preterm premature rupture of membranes (PPROM). In all 16 923 ART singletons and 4829 ART twin deliveries were included. A random sample of NC singletons, 2-fold the size of the ART singleton group matched by date and year of birth (n = 33 835) and all NC twin deliveries (n = 15 112), was also extracted. Multiple logistic regression analyses were performed to adjust for the following confounders: maternal age, parity, year of child birth and sex of child. Cervical morbidity (dysplasia and conization) was more often observed in ART pregnancies (6.2% of ART singletons and 5.4% ART twins) than in NC pregnancies (4.2% for NC singletons and 4.5% for NC twins), both for singletons and twins. In ART singleton deliveries, the PTB rate was 13.1 versus 8.2% in women with and without conization, respectively, with an adjusted odds ratio (aOR) of 1.56 [95% confidence interval (CI) 1.21-2.01]. In ART twin deliveries, the prevalence of PTB was 58.2 versus 41.3% in women with and without conization, respectively, with an aOR 1.94 (95% CI 1.36-2.77), and the risk of VPTB was also doubled. Furthermore, previous dysplasia (without conization) increased the risk of VPTB in ART twins (aOR 1.74, 95% CI 1.04-2.94). Cervical dysplasia did not increase the risk of any of the other adverse outcomes in ART singletons or twins. The risk of PPROM was increased in both in ART and NC singleton deliveries with conization versus no conization; however, this increased risk of PPROM after conization was not observed in either ART or NC twin pregnancies. We were not able to adjust for the height of the cervical cone or the severity of the cervical intraepithelial neoplasia (CIN) or the time window between diagnosis of CIN and ART treatment. The finding on an increased risk of VPTB in ART twin pregnancies after dysplasia without conization may be random as we found no other increased risk after dysplasia alone either in singletons or in twins. After ART and prior conization, 58% of twin pregnancies versus 13% of ART singleton pregnancies result in PTB. There is a doubled risk of preterm delivery in ART twins with conization versus ART twins with no prior conization. Single-embryo transfer should always be recommended in women with prior conization irrespective of female age, embryo quality and prior number of ART attempts. No external funding was achieved for this project.

Severity of prematurity risk in spontaneous and in vitro fertilization twins: does conception mode serve as a risk factor?

Background: Assisted reproductive technologies (ARTs) have made great progress. However, whether tube baby born after ART were at an increased risk of birth defects is not clear. Objective: To assess whether the ART increases the risk of birth defects in children born after ART. Search strategy: Medline, Google Scholar, and the Cochrane Library were searched. Selection criteria: Clinical trials that evaluate the risk of birth defect in children born after in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) and natural conceptions (NC) were included. The primary outcome was the prevalence of birth defects. Data collection and analysis: The relative risk was used as the summary measure with random effects model. We assessed heterogeneity between studies using the I 2 index. Main results: Totally 46 studies were included. The pooled relative risk (RR) estimated suggested there was an increased risk of birth defects in ART compared with the NC group (RR: 1.40; 95% CI 1.31–1.49). Twenty and fifteen studies were included to compare the risk of birth defects between NC and IVF/ICSI, respectively. The results indicated that both IVF and ICSI increase the risk of birth defects (IVF: RR 1.25; 95% CI 1.12–1.40; ICSI: RR 1.29; 95% CI 1.14–1.45). When subgroup according to plurality, 22 studies assessed the risk of birth defects after ART or NC in singletons and 15 studies evaluated the risk of birth defects in twins. The pooled RRs were 1.41 (95% CI 1.30–1.52) and 1.18 (95% CI 0.98–1.42), respectively. Conclusions: Children born after ART were at an increased risk of birth defects compared with NC. There was no difference in birth defects risk between ART twins and NC twins.

Novel technologies for selecting the best sperm for in vitro fertilization and intracytoplasmic sperm injection

The possible excess of congenital malformations in infants born after in vitro fertilization (IVF) has been much discussed in the literature, with controversial conclusions. This population based study is aimed at analyzing the presence of congenital malformations in a large group of infants born after IVF and to compare malformation risk both with that of all infants born and according to IVF method used. Infants born after IVF during the period 1982-2001 were ascertained from all IVF clinics in Sweden. The presence of congenital malformations was identified from three national health registers: the Swedish Medical Birth Register, the Swedish Registry of Congenital Malformations, and the Swedish Hospital Discharge Register. The IVF children were compared with all children born in Sweden during the same period and recorded in the Swedish Medical Birth Register. Among 16,280 IVF children (30% conceived after intracytoplasmatic sperm injection [ICSI]) a 42% excess of any congenital malformation was found, explainable by parental characteristics and in some cases by the high rate of multiple births. Among these children, 8% had a congenital malformation, and 5% had a relatively severe condition. For neural tube defects, choanal atresia, and alimentary tract atresia, an additional risk increase was seen. There was no difference in malformation rate according to IVF method except for an excess of hypospadias after ICSI. An increased risk for congenital malformations occurs after IVF, similar for the different IVF techniques used, and mainly a consequence of parental characteristics. A few specific conditions show an extra increase in risk.

Globally, the number of assisted reproductive technology (ART) infants has surpassed 10 million, with its utilization steadily increasing. Numerous studies have shown that ART pregnancies are more prone to adverse pregnancy outcomes. ART infants are at a higher risk for adverse birth outcomes. However, the differences in growth between ART and natural pregnancy (NP) infants remain controversial. This study aims to explore differences in pregnancy outcomes, birth outcomes, and growth rates between ART and NP infants during the first year of life, and to analyze the association between ART and rapid growth. Birth records of the Nantong area, China, from January 2020 to June 2021 were extracted. A total of 29 886 pregnant women and 30 051 infants were included in the characteristic analysis. Based on the use of ART recorded in the database, the pregnant women and infants were categorized into ART and NP groups, with the NP serving as the control group. For the growth analysis, 29 447 singleton infants were included. Growth within 12 months was examined using the LMS method. The association between reproductive methods, perinatal sociodemographic characteristics, infant birth characteristics, and rapid growth was analyzed using GEE model. To further explore the association between ART and rapid growth, we performed subgroup analyses based on infants' sex, birth weight, and perinatal residence, which were statistically associated with rapid growth in the multivariate GEE model. ART infants had higher rates of preterm birth (7.4% vs. 4.8%) and cesarean section (57.7% vs. 49.1%; p < 0.001 for both). Growth analysis displayed faster overall growth rates and higher rapid growth incidence in ART singleton infants. Multivariate GEE analysis showed that ART was associated with a higher incidence of rapid growth in both length (OR = 1.415, 95% CI: 1.316-1.521) and weight (OR = 1.236, 95% CI: 1.134-1.348). ART singleton infants demonstrated a greater likelihood of experiencing rapid growth, despite being at higher risk of SGA, and achieved growth trajectories comparable to NP singleton infants. The findings suggest that ART may not influence postnatal growth. These results underscore the importance of tailored clinical monitoring and interventions for ART infants to ensure optimal growth and long-term health.

World collaborative report on in vitro fertilization, 2000

The effect of infertility and assisted reproduction on first-trimester placental and fetal development

To survey birth defects of neonates conceived by using various types of in vitro fertilization and embryo transfer (IVF-ET) between 1998 and 2007 in Shanghai. From 1998 to 2007, 8507 neonates from 6551 pregnancies conceived through assistant reproductive technology (ART) from 7 reproductive medicine center in Shanghai were enrolled in this retrospective study, including Shanghai Ji-Ai Genetics and IVF Institute, Shanghai Jiaotong University School of Medicine affiliated Renji Hospital, Ruijin Hospital, China Welfare Institute International Maternal and Infant Health Hospital, Shanghai First Maternity and Infant Health Hospital, Shanghai the Ninth People's Hospital and the Second Military Medical University affiliated Changhai Hospital. The clinical data about the type and incidence of birth defect were analyzed. Meanwhile, the factors associated with birth defect were investigated, such as various ART, gender, mother age, numbers of gestational sac, the source and quality of sperm. The birth defect rate was 1.08% (92/8507) and the most remarkable malformation occurred in circulation system [34% (31/92)]. The rates of major congenital malformations were 1.21% (34/2799) in fresh conventional IVF-ET, 1.07% (20/1871) in IVF-frozen-thawed embryo transfer (IVF-FET), 1.04% (23/2212) in fresh intracyto plasmic sperm injection (ICSI)-ET and 0.92% (15/1625) in ICSI-FET, which did not show statistical difference (P > 0.05). There was also no significantly different incidence of malformations between 1.12% (49/4371) in male neonates and 1.02% (42/4136) in female neonates (P > 0.05). However, the occurrence of congenital malformation is positively related with maternal age, the rates were 0.84%(41/4884) in mother's age less than 30 years and 1.77% (16/902) in mother' age more than 35 years, which reached statistical difference (P < 0.05). It also showed remarkable different incidence among 0.53% (25/4679) in singletons, 1.59% (57/3576) in twins and 3.97% (10/252) in triplets (P < 0.05). No remarkable difference of malformation rate among sperm sources used in fertilization were observed, including 1.09% (81/7419) in ejaculated sperm, 1.21% (7/579) in percutaneous epididymal aspiration (PESA) and 0.79% (4/509) in donor sperm (P > 0.05). The overall incidence of birth defect in neonates from ART is similar to those conceived naturally and is not associated with different types of IVF-ET, embryo cryopreservation, sperm sources. However, maternal age and multiple pregnancies confer the higher possibility of birth defect.