Ovarian follicular function is not altered by SARS-CoV-2 infection or BNT162b2 mRNA COVID-19 vaccination.

STUDY QUESTION: Does the immune response to coronavirus disease 2019 (COVID-19) infection or the BNT162b2 mRNA vaccine involve the ovarian follicle, and does it affect its function? SUMMARY ANSWER: We were able to demonstrate anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) IgG in follicular fluid (FF) from both infected and vaccinated IVF patients, with no evidence for compromised follicular function. WHAT IS KNOWN ALREADY: No research data are available yet. STUDY DESIGN, SIZE, DURATION: This is a cohort study, composed of 32 consecutive IVF patients, either infected with COVID-19, vaccinated or non-exposed, conducted between 1 February and 10 March 2021 in a single university hospital-based IVF clinic. PARTICIPANTS/MATERIALS, SETTING, METHODS: A consecutive sample of female consenting patients undergoing oocyte retrieval was recruited and assigned to one of the three study groups: recovering from confirmed COVID-19 (n = 9); vaccinated (n = 9); and uninfected, non-vaccinated controls (n = 14). Serum and FF samples were taken and analyzed for anti-COVID IgG as well as estrogen, progesterone and heparan sulfate proteoglycan 2 concentration, as well as the number and maturity of aspirated oocytes and day of trigger estrogen and progesterone measurements. Main outcome measures were follicular function, including steroidogenesis, follicular response to the LH/hCG trigger, and oocyte quality biomarkers. MAIN RESULTS AND THE ROLE OF CHANCE: Both COVID-19 and the vaccine elicited anti-COVID IgG antibodies that were detected in the FF at levels proportional to the IgG serum concentration. No differences between the three groups were detected in any of the surrogate parameters for ovarian follicle quality. LIMITATIONS, REASONS FOR CAUTION: This is a small study, comprising a mixed fertile and infertile population, and its conclusions should be supported and validated by larger studies. WIDER IMPLICATIONS OF THE FINDINGS: This is the first study to examine the impact of SARS-Cov-2 infection and COVID-19 vaccination on ovarian function and these early findings suggest no measurable detrimental effect on function of the ovarian follicle. STUDY FUNDING/COMPETING INTEREST(S): The study was funded out of an internal budget. There are no conflicts of interest for any of the authors. TRIAL REGISTRATION NUMBER: CinicalTrials.gov registry number NCT04822012.

Prediction of severe adverse neonatal outcomes at the second stage of labour using machine learning: a retrospective cohort study.

OBJECTIVE: To create a personalised machine learning model for prediction of severe adverse neonatal outcomes (SANO) during the second stage of labour. DESIGN: Retrospective Electronic-Medical-Record (EMR) -based study. POPULATION: A cohort of 73 868 singleton, term deliveries that reached the second stage of labour, including 1346 (1.8%) deliveries with SANO. METHODS: A gradient boosting model was created, analysing 21 million data points from antepartum features (e.g. gravidity and parity) gathered at admission to the delivery unit, and intrapartum data (e.g. cervical dilatation and effacement) gathered during the first stage of labour. Deliveries were allocated to high-risk and low-risk groups based on the Youden index to maximise sensitivity and specificity. MAIN OUTCOME MEASURES: SANO was defined as either umbilical cord pH levels ≤7.1 or 1-minute or 5-minute Apgar score ≤7. RESULTS: The model for prediction of SANO yielded an area under the receiver operating curve (AUC) of 0.761 (95% CI 0.748-0.774). A third of the cohort (33.5%, n = 24 721) were allocated to a high-risk group for SANO, which captured up to 72.1% of these cases (odds ratio 5.3, 95% CI 4.7-6.0; high-risk versus low-risk groups). CONCLUSIONS: Data acquired throughout the first stage of labour can be used to predict SANO during the second stage of labour using a machine learning model. Stratifying parturients at the beginning of the second stage of labour in a 'time out' session, can direct a personalised approach to management of this challenging aspect of labour, as well as improve allocation of staff and resources. TWEETABLE ABSTRACT: Personalised prediction score for severe adverse neonatal outcomes in labour using machine learning model.

Universal chromosomal microarray analysis reveals high proportion of copy-number variants in low-risk pregnancies.

OBJECTIVES: To evaluate the yield and utility of the routine use of chromosomal microarray analysis (CMA) for prenatal genetic diagnosis in a large cohort of pregnancies with normal ultrasound (US) at the time of genetic testing, compared with pregnancies with abnormal US findings. METHODS: We reviewed all prenatal CMA results in our center between November 2013 and December 2018. The prevalence of different CMA results in pregnancies with normal US at the time of genetic testing ('low-risk pregnancies'), was compared with that in pregnancies with abnormal US findings ('high-risk pregnancies'). Medical records were searched in order to evaluate subsequent US follow-up and the outcome of pregnancies with a clinically relevant copy-number variant (CNV), i.e. a pathogenic or likely pathogenic CNV or a susceptibility locus for disease with > 10% penetrance, related to early-onset disease in the low-risk group. RESULTS: In a cohort of 6431 low-risk pregnancies that underwent CMA, the prevalence of a clinically significant CNV related to early-onset disease was 1.1% (72/6431), which was significantly lower than the prevalence in high-risk pregnancies (4.9% (65/1326)). Of the low-risk pregnancies, 0.4% (27/6431) had a pathogenic or likely pathogenic CNV, and another 0.7% (45/6431) had a susceptibility locus with more than 10% penetrance. Follow-up of the low-risk pregnancies with a clinically significant early-onset CNV revealed that 31.9% (23/72) were terminated, while outcome data were missing in 26.4% (19/72). In 16.7% (12/72) of low-risk pregnancies, an US abnormality was discovered later on in gestation, after genetic testing had been performed. CONCLUSION: Although the background risk of identifying a clinically significant early-onset abnormal CMA result in pregnancies with a low a-priori risk is lower than that observed in high-risk pregnancies, the risk is substantial and should be conveyed to all pregnant women. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Fetal cardiac evaluation services for low-risk pregnancies: how can we improve?

Linked Comment: Ultrasound Obstet Gynecol 2020; 55:747-757.

Planned induction versus spontaneous delivery among women using prophylactic anticoagulation therapy: a retrospective study.

OBJECTIVES: To examine the outcomes of planned induction of labour versus spontaneous onset of labour among women using prophylactic-dose low-molecular weight heparin (LMWH) therapy. DESIGN: Retrospective cohort study. SETTING: University hospital. POPULATION: Women receiving antepartum prophylactic LMWH therapy undergoing a trial of vaginal delivery. METHODS: Charts from 2018-2019 were reviewed. MAIN OUTCOME MEASURES: Duration of anticoagulation interruption and eligibility to receive neuraxial anaesthesia. RESULTS: Data from 199 women were analysed; 78 (39.2%) were admitted following spontaneous onset of labour and 121 (60.8%) underwent planned induction of labour. Compared to women who underwent planned induction of labour, women who presented with spontaneous onset of labour had a shorter median admission-to-delivery interval (4.7 versus 29.3 hours, P < 0.001). Similarly, intervals from the last LMWH injection to delivery (25.8 versus 48.2 hours, P < 0.001) and to the first postpartum LMWH injection (41.2 versus 63.7 hours, P < 0.001) were shorter. Among those with spontaneous onset of labour, 69 (88.5%) were eligible to receive neuraxial anaesthesia. Rates of postpartum haemorrhage and blood transfusion were similar between the groups. No thrombotic events were encountered in those with spontaneous onset of labour, but four (3.3%) women who delivered following induction of labour developed a postpartum thrombotic event. CONCLUSION: Planned induction of labour was associated with a higher risk of postpartum thrombotic events than was spontaneous onset of labour (4 of 121 [3.3%] versus 0 of 78 [0%]), presumably due to prolonged duration of anticoagulation interruption, although the difference was not statistically significant. Allowing spontaneous onset of labour was associated with comparable rates of bleeding complications, and only a low proportion (9 of 78, 11.5%) were not eligible to receive neuraxial anaesthesia. TWEETABLE ABSTRACT: Planned induction among women using prophylactic LMWH therapy might increase the risk of thromboembolic complications.

Deep microbial analysis of multiple placentas shows no evidence for a placental microbiome.

OBJECTIVES: To resolve the controversy regarding the presence of a microbiota in the placenta. DESIGN: Classical and molecular microbiological study. SETTING: All samples were collected during caesarean section. POPULATION: A total of 28 human placentas and six murine placentas. METHODS: All 28 human placentas were checked for 16S rRNA gene amplification products. Three locations from four selected human placentas and three 'environmental controls' for each placenta were placed in seven culture media. The four selected human placentas were further analysed using Gram stain, immunohistochemistry for bacteria, electron microscopy, and TaqMan RT-qPCR. Six placentas from three SPF mice were cut into four pieces each, and further analysed for 16S rRNA gene amplification. MAIN OUTCOME MEASURES: Microbiological and molecular evidence of bacteria. RESULTS: None of the placental cultures used for the full analysis, or their environmental cultures, was positive for bacterial growth. None of the other methods showed any evidence of bacteria. Immunohistochemistry showed negligible bacterial counts. None of the murine placentas showed evidence of 16S rRNA gene amplification. CONCLUSIONS: Our results support that the fetal environment in the womb is sterile. Based on the immunohistochemistry and the limit of detection of the other methods used, if a placental microbiome exists, it is of extreme low biomass, and thus its effect on clinical phenotypes is probably minor, if it exists at all. TWEETABLE ABSTRACT: Using several microbiological and molecular methods in parallel, we found no compelling evidence of bacteria in human and mouse placentas.

Single-nucleotide polymorphism-based chromosomal microarray analysis provides clues and insights into disease mechanisms.

OBJECTIVE: Chromosomal microarray analysis (CMA) is the modality of choice for prenatal diagnosis in pregnancy with fetal malformation, as it has a high diagnostic yield for microdeletion/duplication syndromes. The aim of this study was to demonstrate the additional utility of single-nucleotide polymorphism (SNP)-based CMA in diagnosing monogenic diseases, imprinting disorders and uniparental disomy (UPD). METHODS: CMA was performed using Affymetrix CytoScan array, for all indications in 6995 pregnancies, at a tertiary referral hospital from November 2013 to June 2018. We describe four cases that had a CMA result that provided a more comprehensive understanding of the complex genetic mechanisms underlying the clinical presentation. RESULTS: In the first fetus, CMA was performed due to intrauterine growth restriction and revealed a 75 kbp maternally inherited microdeletion encompassing the Bloom syndrome gene (BLM). A diagnosis of Bloom syndrome was made upon identifying a paternally inherited common Ashkenazi founder mutation. In the second case, CMA was performed due to severely abnormal maternal serum analytes and revealed a deletion in 14q32.2q32.31 on the maternally inherited copy, leading to a diagnosis of Kagami-Ogata syndrome, which is an imprinting disorder. In the third case, amniocentesis was performed because of late-onset fetal macrosomia and mild polyhydramnios. CMA detected a deletion encompassing the locus of Prader-Willi/Angelman syndrome. In the fourth case, amniocentesis was performed due to maternal cytomegalovirus seroconversion. Maternal UPD of the entire long arm of chromosome 11 was detected. CONCLUSION: Prenatal CMA, based on oligo and SNP platforms, increases the diagnostic yield and enables a wider spectrum of disorders to be detected through the identification of complex genetic etiologies beyond only copy number variants. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Role of late amniocentesis in the era of modern genomic technologies.

OBJECTIVE: Traditionally, amniocentesis is performed between 17 and 23 weeks of gestation. This enables decisions regarding the course of pregnancy to be made before viability. Less frequently, amniocentesis is performed in the third trimester. Advanced genomic technologies such as chromosomal microarray analysis (CMA) provide more detailed information about the fetus compared with traditional G-banded chromosomal analysis. The aim of this study was to assess the indications for and safety of late amniocentesis, genetic-test results (especially in the context of CMA technology) and outcome of pregnancies that underwent the procedure after 24 weeks. METHODS: Medical records were analyzed retrospectively of all women in whom amniocentesis was performed at a gestational age of 24 + 0 to 38 + 6 weeks, at Hadassah Medical Center, between June 2013 and March 2017. Parameters investigated included indications for late amniocentesis, complications, CMA results and pregnancy outcome. RESULTS: During the study period, 291 women (303 fetuses, 277 singleton and 14 twin pregnancies; in two twin pairs, one fetus was terminated before amniocentesis) underwent late amniocentesis. CMA was performed in all instances of amniocentesis. The most frequent indication was abnormal sonographic finding(s) (204/303 fetuses, 67%). Preterm delivery occurred in 1.7% and 5.1% of pregnancies within the first week and within 1 month following the procedure, respectively. Aneuploidy was detected in nine (3%) fetuses and nine (3%) others had a pathogenic/likely pathogenic copy number variant, suggesting that CMA doubled the diagnostic yield of traditional karyotyping. Maximal diagnostic yield (17.5%) was achieved for the subgroup of fetuses referred with abnormal sonographic findings in two or more fetal anatomical systems. Variants of uncertain significance or susceptibility loci were found in another nine (3%) fetuses. CONCLUSIONS: In pregnancies undergoing late amniocentesis, CMA increased detection rates of fetal abnormalities and had a shorter turnaround time compared with traditional chromosomal analysis; therefore, late amniocentesis may serve as a helpful tool for detecting fetal abnormalities or reassuring parents following late-appearing abnormal sonographic findings. However, CMA may expose findings of uncertain significance, about which the couple should be precounseled. The procedure appears to be safe. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

History-indicated cervical cerclage in management of twin pregnancy.

OBJECTIVE: Cervical cerclage, when performed in twin gestation, has been reported to be associated with poor outcome. However, the role of first-trimester history-indicated cerclage among women with a twin pregnancy and a history of preterm birth has not been evaluated. The aim of this study was to assess pregnancy outcomes among women with a twin pregnancy who underwent first-trimester history-indicated cervical cerclage compared with outcomes in those managed expectantly. METHODS: This was a retrospective matched case-control study. The study group comprised all women with a twin pregnancy who had undergone first-trimester history-indicated cerclage during the period 2006 to 2017 at Hadassah-Hebrew University Medical Center. A control group of women with a twin pregnancy who were managed expectantly was established by matching age, history of spontaneous preterm birth (20-36 weeks' gestation) and year of delivery. Pregnancy and delivery characteristics and neonatal outcomes were compared between the two groups. RESULTS: Data from 82 women with a twin gestation were analyzed, of whom 41 underwent first-trimester history-indicated cerclage and 41 were matched controls who were managed expectantly. Gestational age at delivery was higher in the cerclage group than in those managed expectantly (median 35 vs 30 weeks; P < 0.0001). Rates of spontaneous preterm birth before 24 weeks (2.4% vs 19.5%; odds ratio (OR), 0.10 (95% CI, 0.01-0.87); P = 0.03), before 28 weeks (12.2% vs 34.1%; OR, 0.27 (95% CI, 0.09-0.84); P = 0.03), before 32 weeks (22.0% vs 56.1%; OR, 0.22 (95% CI, 0.08-0.58); P = 0.003) and before 34 weeks (34.1% vs 82.9%; OR, 0.11 (95% CI, 0.04-0.30); P < 0.0001) were significantly lower in the cerclage group than in the control group. Median birth weight was higher in the cerclage group (2072 g vs 1750 g; P = 0.003), with lower rates of low birth weight (< 2500 g) (65.0% vs 89.4%; P = 0.001) and very low birth weight (< 1500 g) (21.3% vs 37.9%; P = 0.03) than in the group managed expectantly. Rates were also lower in the cerclage group for stillbirth, admission to the neonatal intensive care unit, respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis, sepsis, neonatal mortality and composite adverse neonatal outcome. CONCLUSIONS: History-indicated cerclage performed in the first trimester, as compared with expectant management, in women with a twin pregnancy had an overall positive effect on pregnancy and neonatal outcomes. These findings suggest the need for adequate randomized trials on cerclage placement in this subset of women. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.