Does the epigenetic control of imprinted genes and transposable elements at birth differ according to time to conception in natural conception and after intrauterine insemination (IUI)? A total of 144 singletons were included in four groups: 50 natural pregnancies obtained within 6 months after stopping contraception (group 1); 34 natural pregnancies with infertility period between 6 and 12 months (group 2); 36 pregnancies with an infertility period of more than 12 months (group 3) and 24 pregnancies obtained after IUI (group 4). The placental DNA methylation levels of H19/IGF2 and KCNQ1OT1 were lower in groups 2, 3 and 4 than in group 1 (P = 0.025 in the overall comparison). The DNA methylation rate for LINE-1 was higher in placentas from group 2 than in group 1 (P = 0.022). In cord blood, DNA methylation levels were not significantly different between groups except for H19/IGF2 for which the DNA methylation levels were higher in group 2 than in group 1 (H19/IGF2-seq1 and seq2: P = 0.023 and P = 0.002, respectively). In placenta tissue, compared with group 1, relative expression for SNRPN and for LINE-1 was significantly higher in group 2 (P = 0.002 and P < 0.001, respectively). The relative expression of KCNQ1 in placenta was lower in group 4 than in group 1 (P = 0.013). In cord blood, compared with group 1, the relative expression for H19 was significantly higher in group 3 (P = 0.026), and the relative expression of LINE-1 was higher in groups 2 and 3 and in group 4 (P < 0.001). Infertility itself, and not only ART techniques, could contribute to potential epigenetic risks for children.
To examine birth outcomes between children conceived with in vitro fertilization (IVF) or intrauterine insemination (IUI) and sibling births from unassisted conceptions. Retrospective sibling cohort. Live born children conceived via IVF, with or without intracytoplasmic sperm injection, or IUI at the Utah Center for Reproductive Medicine, 1999-2018, and sibling births from unassisted conceptions (born 1985-2018). The main analysis included singleton births (460 IVF, 666 IUI, and 1,579 unassisted siblings). Exposure: In vitro fertilization, with or without intracytoplasmic sperm injection, or IUI. Preterm birth, low birth weight, small for gestational age, large for gestational age (LGA), and major congenital anomalies. Compared with unassisted siblings, singleton children conceived via IVF had gestational ages shorter by nearly half a week (95% confidence interval [CI], -0.6 to -0.3), birth weights of 72.1 g lower (95% CI, -118.8 to -25.4), and higher proportions of preterm birth (IVF, 11.1%; IUI, 8.7%; unassisted siblings, 6.8%), LGA (IVF, 9.1%; IUI, 4.5%; unassisted siblings, 5.9%), and major congenital anomalies (IVF, 3.7%; IUI, 2.0%; unassisted siblings, 1.4%). Models adjusted for maternal age, infant sex, infant birth year, previous pregnancy, and birth order showed that children conceived via IVF were more likely to be preterm (adjusted risk ratio [aRR], 1.6; 95% CI, 1.2-2.2; absolute difference, 4.3%) and LGA (aRR, 1.8; 95% CI, 1.2-2.5; absolute difference, 3.2%). Children conceived via IVF had a higher risk of major congenital anomalies than unassisted siblings adjusted for maternal age, infant sex, and birth order (aRR, 1.9; 95% CI, 1.0-3.8; absolute difference, 2.3%). Children conceived via IUI had birth weights 55.8 g lower (95% CI, -95.6 to -15.9) than unassisted siblings. We observed an increased risk of preterm birth, low birth weight, LGA, and major congenital anomalies among singleton children conceived with IVF compared with that among unassisted siblings; however, absolute differences remain small. For children conceived via IUI, lower birth weights were observed. These results suggest that treatment-related factors in addition to underlying subfertility may contribute to adverse birth outcomes.
Abstract What are the obstetric and neonatal clinical implications of large-for-gestational age (LGA) babies conceived after a frozen-thawed embryo transfer (FET)? Besides a lower risk of neonatal hypoglycaemia, obstetric and neonatal risks for FET LGA babies were comparable to those conceived spontaneously or after fresh ET. It has been shown that conception after a FET is an independent risk factor for LGA babies. The underlying physiologic mechanism is still unclear but is likely different to the mechanisms that lead to LGA after fresh embryo transfers or spontaneous conception. As the freeze-all strategy and FETs are becoming increasingly popular, an important clinical question revolves around the significance of this complication both for the mother and the baby and whether the obstetric and neonatal risks differ between LGA babies conceived following FET compared to those conceived after fresh embryo transfer (Fresh) and spontaneously conceived babies (SC). Study design, size, duration
This population-based cohort study is based on the Medically Assisted Reproduction data linkage which is a bespoke data linkage of the Australian ART registry to nine population health datasets including births, hospital admissions, medical services, medications, and deaths. All singleton LGA babies in New South Wales (2009-2017) and the Australian Capital Territory (2009-2016) (N = 81,075) conceived either spontaneously or after fresh or frozen-thawed embryo ART were included. Participants/materials, setting, The LGA births were divided into those conceived a) spontaneously without history of subfertility (SC) (n = 73,321), b) spontaneously with history of subfertility (SC-SubFert) (n = 4,516), c) after fresh ET (Fresh) (n = 1,461) d) after FET (n = 1,777). Relevant obstetric and neonatal outcome data were compared between LGA deliveries following FET and those following Fresh, SC and SC-SubFert while adjusting for important confounders including preexisting comorbidities (diabetes mellitus) and stratified by mode of delivery (vaginal birth-VB vs. cesarean section-CS). Main The caesarean section rate was similar between FET (58.2%) and Fresh LGA babies (57.9%) but significantly higher compared to the SC (39.1%) and SC-SubFert (49.9%) cohorts (p < 0.001). The use of forceps was also significantly (p < 0.001) higher in FET (4.6%) and Fresh (4.7%) LGA babies compared to the SC (3.5%) and SC-SubFert (2.1%) cohorts. Mean APGAR Scores at 1min (range: 8.3-8.4) and 5min (8.9 for all groups) after birth were similar between the four groups (p > 0.05).
In VB, the adjusted risk ratios (aRR) for perineal tear, shoulder dystocia and postpartum haemorrhage, neonatal resuscitation, respiratory distress, transient tachypnea, admission to the NICU, perinatal death and hospitalization in the first 2 years of life were not significantly different between the four groups. The risk of neonatal hypoglycaemia was significantly elevated in the Fresh (aRR: 1.87, 95% CI: 1.16-3.01), SC-SubFert (aRR: 1.55, 95% CI: 1.03-2.34) and SC (aRR: 1.63, 95% CI: 1.11-2.40) compared to the FET LGA babies.
In CS births, no significant differences were detected between the groups compared regarding all outcomes evaluated, apart from neonatal hypoglycaemia where SC LGA babies had significantly elevated risk compared to FET LGA babies (aRR: 1.22, 95% CI: 1.02-1.45). Limitations, As data were sourced from population health registries, some risk of misclassification might be present, although this is unlikely to be systematically different between groups compared. Despite controlling for important confounders, including maternal age at delivery, nulliparity, history of diabetes mellitus and socioeconomic variables, residual bias may still be present. This is the first study evaluating the clinical implications of FET LGA babies, suggesting largely similar risks to other LGA babies. However, the difference in risk of hypoglycemia supports a different pathophysiological mechanism for LGA after FET compared to the one of LGA babies conceived spontaneously and following fresh ET. No
To determine the association between fertility treatment, socioeconomic status (SES), and neonatal and post-neonatal mortality. Retrospective cohort study of all births (19,350,344) and infant deaths from 2014-2018 in the United States. The exposure was mode of conception-spontaneous vs fertility treatment. The outcome was neonatal (<28d), and post-neonatal (28d-1y) mortality. Multivariable logistic models were stratified by SES. The fertility treatment group had statistically significantly higher odds of neonatal mortality (high SES OR 1.59; CI [1.5, 1.68], low SES OR 2.11; CI [1.79, 2.48]) and lower odds of post-neonatal mortality (high SES OR 0.87, CI [0.76, 0.996], low SES OR 0.6, CI [0.38, 0.95]). SES significantly modified the effect of ART/NIFT on neonatal and post-neonatal mortality. Fertility treatment is associated with higher neonatal and lower post-neonatal mortality and SES modifies this effect. Socioeconomic policies and support for vulnerable families may help reduce rates of infant mortality.
Assisted Reproductive Technology (ART) has made great strides in the past forty-years, but no medical treatment comes without side effects. Despite several studies reporting high incidences of perinatal complications, the association is inconclusive. Also, the effect of racially and ethnically distinguished Asian population undergoing ART on perinatal outcomes is not well studied. Therefore, this study attempts to compare various perinatal outcome parameters in ART, and spontaneously conceived singleton pregnancies from a single high-volume tertiary care center. This is a retrospective cohort study from a single tertiary infertility center, carried out from January 2011 to September 2020. The study included 1,125 IVF conceived babies (AB group) and 7,193 spontaneous conceived babies (SB group). The groups were compared using the Pearson Chi-square test and adjusted odds ratio, calculated using the multivariate analysis. Most of the perinatal complications, such as preterm birth (PTB), early preterm birth, low birth weight (LBW), extremely low birth weight, small for gestational age, large for gestational age babies, neonatal intensive care unit (NICU) admission, need for surfactant, meconium aspiration syndrome, neonatal seizures, intraventricular hemorrhage, hypoxic-ischemic encephalopathy, and patent ductus arteriosus was significantly increased in the AB group when compared to the SB group (p<0.05). In-vitro fertilization (IVF) independently increases the risk of LBW (aOR 2.530; 95% CI 2.194-2.917), PTB (aOR 4.004; 95% CI 3.496-4.587), NICU admission (aOR 2.003; 95% CI 1.610-2.492) and neonatal seizures (aOR 9.805; 95% CI 5.755-16.706).Conclusions: All ART-conceived pregnant patients should receive antenatal counselling regarding perinatal complications and should deliver at a tertiary care center with appropriate NICU support.