The greater incidence of small for gestational age newborns after gonadotropin-stimulated in vitro fertilization with a supra-physiological estradiol level on ovulation trigger day.

INTRODUCTION Reproductive scientists have postulated various risk factors for lower birthweight following conventional gonadotropin stimulated in vitro fertilization compared to spontaneously conceived children: parental factors (age, health, duration of subfertility, and smoking habits); ovarian stimulation; laboratory procedures; the number of oocytes retrieved; and the number of embryos transferred. Our aim was to investigate the impact of gonadotropin stimulation and serum estradiol level on the risk of a newborn's being small for gestational age. MATERIAL AND METHODS We conducted a cohort study (2010-2016) of singletons (n = 155) born either after conventional gonadotropin stimulated in vitro fertilization (using ≥150 IU/d human gonadotropin for stimulation) or after natural cycle in vitro fertilization without any stimulation. We analyzed perinatal outcomes using birthweight percentiles, as they adjust for gestational age and sex. RESULTS The proportion of small for gestational age was 11.8% following conventional gonadotropin stimulated in vitro fertilization, and 2.9% after natural-cycle in vitro fertilization (P = 0.058). The odds of small for gestational age were significantly higher with supra-physiological estradiol levels in maternal serum on ovulation trigger day (unadjusted odds ratio 4.58; 95% confidence interval 1.35 to 15.55; P = 0.015). It remained significant after adjusting for maternal height, age, and body mass index (adjusted odds ratio 3.83; 95% confidence interval 1.06 to 13.82; P = 0.041). CONCLUSIONS We found an associated risk of children being born small for gestational age after conventional gonadotropin stimulated in vitro fertilization compared to natural-cycle in vitro fertilization. This higher risk is significantly associated with supra-physiological estradiol levels. We propose a reduction in the dosage of gonadotropin to minimize the risk of small for gestational age and future health consequences. This article is protected by copyright. All rights reserved

Perinatal outcomes in singletons after fresh IVF/ICSI: results of two cohorts and the birth registry.

RESEARCH QUESTION How are perinatal outcomes of live-born singletons after stimulated and unstimulated IVF different from perinatal outcomes in (i) children born in a tertiary centre and (ii) all children born in Switzerland? METHODS This cohort study compared the perinatal outcomes of two birth cohorts and the national live birth registry. Relative risks were calculated using modified Poisson regression and clustering for siblings and adjustment for maternal age, parity and childs sex. RESULTS Of the 636,639 live births, 311 were in the Bern IVF Cohort (144 stimulated, 167 unstimulated), 2332 in the tertiary centre and 633,996 in the Swiss Live Birth Registry (SLBR). Perinatal outcomes following IVF did not differ compared with births in the SLBR (adjusted relative risk [aRR]; 95% confidence interval [CI]), with the exception of the increased risk of small for gestational age (1.31; 1.01 to 1.70, P = 0.04; aRR 1.12; 0.87 to 1.45, P = 0.39). Children born following stimulated IVF had a higher risk of low birthweight (2.17; 1.27 to 3.69, P < 0.01; aRR 1.72; 1.01 to 2.93, P = 0.05), and of being small for gestational age (1.50; 1.05 to 2.14, P = 0.03; aRR 1.31; 0.92 to 1.87; P = 0.13), whereas children born after unstimulated IVF had no increased risks compared with the SLBR. Higher Caesarean rate after IVF was mainly associated with higher maternal age. CONCLUSION Singletons in the Bern IVF Cohort do not show less favourable perinatal outcomes. Gonadotrophin stimulation seems to have an effect, because lower risks were associated with unstimulated IVF

Perinatal outcomes after in vitro fertilization – a comparison of the national live birth registry with a tertiary cohort and an IVF cohort.

Introduction: In vitro fertilization (IVF) treatment is performed increasingly in Switzerland. Conception by IVF negatively affects obstetric and perinatal outcomes. Possible risk factors are parental health and subfertility, gonadotropin stimulation, gamete manipulation or culture of the embryo. Our primary aim was to assess the impact of IVF on perinatal outcomes in comparison to i) children born in tertiary care (university hospital), ii) all children born in Switzerland in the same time; and secondary, to address the effect of gonadotropin stimulation. Methods: We performed IVF using 75IU-300IU gonadotropin per day to stimulate ovarian growth, or in the unstimulated natural cycle, where we collected the single oocyte. Fresh cleavage embryos were transferred on day 2 or 3. We recruited tertiary care births during first trimester check-up. We assessed differences in continuous perinatal outcomes, birthweight and gestational age, using linear regression; and the relative risk (RR) for preterm delivery (<37 GW), small for gestational age (<10th percentile) and low birthweight (<2500 g) using Poisson regression with robust error variance. We clustered for siblings and adjusted for maternal age, parity and foetal sex. Results: Of the 636'639 live births from 2010–2018, 311 were in the Bern IVF Cohort (167 unstimulated, 144 stimulated), 2332 in tertiary care and 633'996 from the Swiss Live Birth Registry (SLBR). IVF mothers were on average 3.6 years (95%CI 3.2, 4.1) older and more often primiparous (76 vs. 49%; p<0,001). Perinatal outcomes (RR or adjusted RR (aRR); 95% CI) after IVF did not differ compared to SLBR, beside the crude risk for being born small for gestational age (1.31; 1.01, 1.70; aRR 1.12; 0.87, 1.45). Children born following stimulated IVF had lower crude mean birthweight (−115 g; −212 g, −17 g) and higher risk for low birthweight (RR 2.17; 1.27, 3.69; aRR 1.72; 1.01, 2.93) and small for gestational age (RR 1.50; 1.05, 2.14; aRR 1.31; 0.92, 1.87) whereas the children born after natural IVF cycles had no increased risks compared to the LBR. Gestational age and birthweight were lower in tertiary care born children and their risk was increased for preterm birth (RR 1.19; 1.02, 1.40), low birthweight (RR 1.29; 1.09, 1.52), and small for gestational age (RR 1.11; 1.00, 1.24) compared to LBR. Cesarean delivery rate was 42% in IVF deliveries whereas it was 36% (p=0,03) in tertiary care and the Swiss average is 32%. Higher maternal age is mainly associated with higher section rate in IVF mothers (aRR for CS: 1.04; 0.89, 1.22). Discussion: IVF seems not to be a risk factor for adverse perinatal outcome in IVF births. Gonadotropin stimulation seems to affect birthweight and increased the risk for low birthweight and small for gestational age compared to the LBR. A strength of our study are the data quality and completeness. Selection bias for the tertiary care singletons with higher risk pregnancies explains worse outcome compared to SLBR

The greater incidence of small‐for‐gestational‐age newborns after gonadotropin‐stimulated in vitro fertilization with a supraphysiological estradiol level on ovulation trigger day

INTRODUCTION Reproductive scientists have postulated various risk factors for lower birthweight following conventional gonadotropin stimulated in vitro fertilization compared to spontaneously conceived children: parental factors (age, health, duration of subfertility, and smoking habits); ovarian stimulation; laboratory procedures; the number of oocytes retrieved; and the number of embryos transferred. Our aim was to investigate the impact of gonadotropin stimulation and serum estradiol level on the risk of a newborn's being small for gestational age. MATERIAL AND METHODS We conducted a cohort study (2010-2016) of singletons (n = 155) born either after conventional gonadotropin stimulated in vitro fertilization (using ≥150 IU/d human gonadotropin for stimulation) or after natural cycle in vitro fertilization without any stimulation. We analyzed perinatal outcomes using birthweight percentiles, as they adjust for gestational age and sex. RESULTS The proportion of small for gestational age was 11.8% following conventional gonadotropin stimulated in vitro fertilization, and 2.9% after natural-cycle in vitro fertilization (P = 0.058). The odds of small for gestational age were significantly higher with supra-physiological estradiol levels in maternal serum on ovulation trigger day (unadjusted odds ratio 4.58; 95% confidence interval 1.35 to 15.55; P = 0.015). It remained significant after adjusting for maternal height, age, and body mass index (adjusted odds ratio 3.83; 95% confidence interval 1.06 to 13.82; P = 0.041). CONCLUSIONS We found an associated risk of children being born small for gestational age after conventional gonadotropin stimulated in vitro fertilization compared to natural-cycle in vitro fertilization. This higher risk is significantly associated with supra-physiological estradiol levels. We propose a reduction in the dosage of gonadotropin to minimize the risk of small for gestational age and future health consequences. This article is protected by copyright. All rights reserved

Further delineation of the rare GDACCF (global developmental delay, absent or hypoplastic corpus callosum, dysmorphic facies syndrome): genotype and phenotype of 22 patients with ZNF148 mutations.

BACKGROUND Pathogenic variants in the zinc finger protein coding genes are rare causes of intellectual disability and congenital malformations. Mutations in the ZNF148 gene causing GDACCF syndrome (global developmental delay, absent or hypoplastic corpus callosum, dysmorphic facies; MIM #617260) have been reported in five individuals so far. METHODS As a result of an international collaboration using GeneMatcher Phenome Central Repository and personal communications, here we describe the clinical and molecular genetic characteristics of 22 previously unreported individuals. RESULTS The core clinical phenotype is characterised by developmental delay particularly in the domain of speech development, postnatal growth retardation, microcephaly and facial dysmorphism. Corpus callosum abnormalities appear less frequently than suggested by previous observations. The identified mutations concerned nonsense or frameshift variants that were mainly located in the last exon of the ZNF148 gene. Heterozygous deletion including the entire ZNF148 gene was found in only one case. Most mutations occurred de novo, but were inherited from an affected parent in two families. CONCLUSION The GDACCF syndrome is clinically diverse, and a genotype-first approach, that is, exome sequencing is recommended for establishing a genetic diagnosis rather than a phenotype-first approach. However, the syndrome may be suspected based on some recurrent, recognisable features. Corpus callosum anomalies were not as constant as previously suggested, we therefore recommend to replace the term 'GDACCF syndrome' with 'ZNF148-related neurodevelopmental disorder'