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Preconception folic acid supplement use is a well-known method of primary prevention of neural tube defects (NTDs). Obese women are at a higher risk for having a child with a NTD. As different international recommendations on folic acid supplement use for obese women before and during pregnancy exist, this narrative review provides an overview of epidemiology of folate deficiency in obese (pre)pregnant women, elaborates on potential mechanisms underlying folate deficiency, and discusses considerations for the usage of higher doses of folic acid supplements. Women with obesity more often suffer from an absolute folate deficiency, as they are less compliant to periconceptional folic acid supplement use recommendations. In addition, their dietary folate intake is limited due to an unbalanced diet (relative malnutrition). The association of obesity and NTDs also seems to be independent of folate intake, with studies suggesting an increased need of folate (relative deficiency) due to derangements involved in other pathways. The relative folate deficiency, as a result of an increased metabolic need for folate in obese women, can be due to: (1) low-grade chronic inflammation (2) insulin resistance, (3) inositol, and (4) dysbiotic gut microbiome, which plays a role in folate production and uptake. In all these pathways, the folate-dependent one-carbon metabolism is involved. In conclusion, scientific evidence of the involvement of several folate-related pathways implies to increase the recommended folic acid supplementation in obese women. However, the physiological uptake of synthetic folic acid is limited and side-effects of unmetabolized folic acid in mothers and offspring, in particular variations in epigenetic (re)programming with long-term health effects, cannot be excluded. Therefore, we emphasize on the urgent need for further research and preconception personalized counseling on folate status

Inadequate nutrition and lifestyle behaviors, particularly during the periconception period, are associated with a negative impact on embryonic and subsequent fetal development. We investigated the associations between parental nutritional and lifestyle factors and pre-implantation embryo development. A total of 113 women and 41 partners, with a corresponding 490 embryos, who underwent intracytoplasmic sperm injection (ICSI) treatment subscribed to the mHealth coaching platform “Smarter Pregnancy.” At baseline, nutrition and lifestyle behaviors (intake of fruits, vegetables, folic acid, and smoking and alcohol use) were identified and risk scores were calculated. A lower risk score represents healthier behavior. As outcome measure, a time-lapse morphokinetic selection algorithm (KIDScore) was used to rank pre-implantation embryo quality on a scale from 1 (poor) to 5 (good) after being cultured in the Embryoscope™ time-lapse incubator until embryonic day 3. To study the association between the nutritional and lifestyle risk scores and the KIDScore in men and women, we used a proportional odds model. In women, the dietary risk score (DRS), a combination of the risk score of fruits, vegetables, and folic acid, was negatively associated with the KIDScore (OR 0.86 (95% CI 0.76 to 0.98), p = 0.02). This could mainly be attributed to an inadequate vegetable intake (OR 0.76 (95% CI 0.59 to 0.96), p = 0.02). In men, smoking was negatively associated with the KIDscore (OR 0.53 (95% CI 0.33 to 0.85), p < 0.01). We conclude that inadequate periconceptional maternal vegetable intake and paternal smoking significantly reduce the implantation potential of embryos after ICSI treatment. Identifying modifiable lifestyle risk factors can contribute to directed, personalized, and individual recommendations that can potentially increase the chance of a healthy pregnancy.

Background Preterm birth is the leading cause of child mortality globally, with many survivors experiencing long-term adverse consequences. Preliminary evidence suggests that numbers of preterm births greatly reduced following implementation of policy measures aimed at mitigating the effects of the COVID-19 pandemic. We aimed to study the impact of the COVID-19 mitigation measures implemented in the Netherlands in a stepwise fashion on March 9, March 15, and March 23, 2020, on the incidence of preterm birth. Methods We used a national quasi-experimental difference-in-regression-discontinuity approach. We used data from the

Antimicrobial prophylaxis during surgery aims to prevent post-operative site infections. For fetal surgery, this includes the fetal and amniotic compartments. Both are deep compartments as drug equilibrium with maternal blood is achieved relatively late. Despite prophylaxis, chorio-amnionitis or endometritis following ex utero intrapartum treatment or fetoscopy occur in 4.13% and 1.45% respectively of the interventions. This review summarizes the observations on two commonly administered antimicrobials (cefazolin, clindamycin) for surgical prophylaxis during pregnancy, with emphasis on the deep compartments. For both compounds, antimicrobial exposure is on target when we consider the maternal and fetal plasma compartment. In contrast, amniotic fluid concentrations-time profiles display a delayed and much more blunted pattern, behaving as deep compartment. For cefazolin, there are data that document further dilution in the setting of polyhydramnios. Along this deep compartment concept, there is some accumulation during repeated administration, modeled for cefazolin and observed for clindamycin. The relative underexposure to antimicrobials in amniotic fluid may be reflected in the pattern of maternal-fetal complications after fetal surgery, and suggest that antimicrobial prophylaxis practices for fetal surgery should be reconsidered. Further studies should be designed by a multidisciplinary team (fetal surgeons, clinical pharmacologists and microbiologists) to facilitate efficient evaluation of antimicrobial prophylaxis.

This case illustrates the importance of multidisciplinary counselling and management of pregnancies in women with complex medical conditions, especially concerning women with cognitive impairment. We present a woman with hyperinsulinism/hyperammonaemia (HI/HA) syndrome. This syndrome is characterised by recurrent episodes of hypoglycaemia and elevated ammonia levels, which are potentially harmful to both the patient and a developing fetus. We describe a successful multidisciplinary approach during the pregnancy of a mentally challenged patient with HI/HA syndrome. This case illustrates the importance of personalised counselling during the preconception period and emphasises to include all disciplines involved in the medical and daily care of such a patient. In our case, the extensive multidisciplinary care during the preconception period, pregnancy, delivery and postpartum period resulted in a good maternal and neonatal outcome.

We present a case of a 38+1 weeks pregnant patient (G1P0) with a proven COVID-19 infection, who was planned for induction of labour because of pre-existent hypertension, systemic lupus erythematosus, respiratory problem of coughing and mild dyspnoea without fever during the COVID-19 pandemic in March 2020. To estimate the risk of vertical transmission of Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) during labour and delivery, we collected oropharyngeal, vaginal, urinary, placental and neonatal PCRs for SARSCoV-2 during the period of admission. All PCRs, except for the oropharyngeal, were negative and vertical transmission was not observed. Labour and delivery were uncomplicated and the patient and neonate were discharged the next day. We give a short overview of the known literature about SARS-CoV-2-related infection during pregnancy, delivery and outcome of the neonate.

Scope: The effectiveness of maternal folate in reducing the risk of congenital malformations during pregnancy is well established. However, the role of the paternal folate status is scarcely investigated. The aim of this study is to investigate the evidence of associations between the paternal folate status and sperm quality, sperm epigenome, and pregnancy outcomes. Methods and results: Databases are searched up to December 2017 resulting in 3682 articles, of which 23 are retrieved for full-text assessment. Four out of thirteen human and two out of four animal studies show positive associations between folate concentrations and sperm parameters. An additional meta-analysis of four randomized controlled trials in subfertile men shows that the sperm concentration increases (3.54 95% confidence interval (CI) [−1.40 to 8.48]) after 3–6 months of 5 mg folic acid use per day compared to controls. Moreover, two out of two animal and one out of three human studies show significant alterations in the overall methylation of the sperm epigenome. One animal and one human study show associations between low folate intake and an increased risk of congenital malformations. Conclusions: This systematic review and meta-analysis shows evidence of associations between paternal folate status and sperm quality, fertility, congenital malformations, and placental weight.

Background: The phosphodiesterase-5 inhibitor (PDE5) sildenafil has emerged as a promising treatment for preeclampsia (PE). However, a sildenafil trial was recently halted due to lack of effect and increased neonatal morbidity. Methods: Ex vivo dual-sided perfusion of an isolated cotyledon and wire-myography on chorionic plate arteries were performed to study the effects of sildenafil and the non-selective PDE inhibitor vinpocetine on the response to the NO donor sodium nitroprusside (SNP) under healthy and PE conditions. Ex vivo perfusion was also used to study placental transfer of sildenafil in 6 healthy and 2 PE placentas. Furthermore, placental mRNA and protein levels of eNOS, iNOS, PDE5 and PDE1 were quantified. Findings: Sildenafil and vinpocetine significantly enhanced SNP responses in chorionic plate arteries of healthy, but not PE placentas. Only sildenafil acutely decreased baseline tension in arteries of both healthy and PE placentas. At steady state, the foetal-to-maternal transfer ratio of sildenafil was 0·37 ± 0·03 in healthy placentas versus 0·66 and 0·47 in the 2 PE placentas. mRNA and protein levels of PDE5, eNOS and iNOS were

The preconceptional presence of microbiota in the female and male reproductive organs suggests that fertilization is taking place in a nonsterile environment and contributes to reproductive success. The concept of embryonic development in a sterile uterus has also been challenged with recent reports of the existence of a microbiome of the placenta, amniotic fluid and the fetal gut in normal, uncomplicated pregnancies. The maternal origins of the microbiota colonising the fetus and its surroundings are unknown as are the mechanisms of maternal-to-fetal transfer. In this review, we aim to highlight the preconception male and female microbiome, the maternal vaginal and gut microbiome during pregnancy and the fetal microbiome, including their possible roles in reproduction, and maternal and neonatal pregnancy outcome.

Background: During the last decade, research has shown that besides the known predictive factors, such as duration of subfertility, a women's age, the body mass index, also the microbiome might affect fertility. Micro-organisms together with their genetic information and the milieu in which they interact are called the microbiome. Studies have shown that the presence of certain microbiota during assisted reproductive technology (ART) has a positive impact on the outcome. However, the potential role of using the microbiome as a predictor for outcome of ART has not yet been investigated. Methods: In a prospective study, 300 women of reproductive age and with an indication for in-vitro Fertilization (IVF) with or without Intra Cytoplasmic Sperm Injection (ICSI) treatment will be included. Prior to the IVF or IVF-ICSI treatment, these women provided a midstream urine sample and a vaginal swab. The composition of the urinary and vaginal microbiome will be analysed with both Next Generation Sequencing and the IS-pro technique. The endpoints of the study are pregnancy achieved after fresh embryo transfer (ET) and within the subsequent year after inclusion. External validation of the findings will take place in an additional cohort of 50 women with an IVF or IVF-ICSI indication. Discussion: In the proposed study, the predictive accuracy of the composition of the urinary and vaginal microbiome for IVF or IVF-ICSI outcome will be only validated for fresh ET. Follow-up has to show whether the predictive accuracy will be similar during the consecutive frozen ET's as part of the IVF or IVF-ICSI treatment or for subsequent stimulated or natural cycles. In addition, external validation will take place in another cohort and hospital. Predictive knowledge of the microbiome profile may enable couples to make a more substantiated decision on whether to continue treatment or not. Hence, the unnecessary physical and emotional burden of a failed IVF or IVF-ICSI treatment can be avoided.

The preconceptional presence of microbiota in the female and male reproductive organs suggests that fertilization is taking place in a nonsterile environment and contributes to reproductive success. The concept of embryonic development in a sterile uterus has also been challenged with recent reports of the existence of a microbiome of the placenta, amniotic fluid a

Background: In mammalian meiotic prophase, homologous chromosome recognition is aided by formation and repair of programmed DNA double-strand breaks (DSBs). Subsequently, stable associations form through homologous chromosome synapsis. In male mouse meiosis, the largely heterologous X and Y chromosomes synapse only in their short pseudoautosomal regions (PARs), and DSBs persist along the unsynapsed non-homologous arms of these sex chromosomes. Asynapsis of these arms and the persistent DSBs then trigger transcriptional silencing through meiotic sex chromosome inactivation (MSCI), resulting in formation of the XY body. This inactive state is partially maintained in post-meiotic haploid spermatids (postmeiotic sex chromatin repression, PSCR). For the human, establishment of MSCI and PSCR have also been reported, but X-linked gene silencing appears to be more variable compared to mouse. To gain more insight into the regulation and significance of MSCI and PSCR among different eutherian species, we have performed a global analysis of XY pairing dynamics, DSB repair, MSCI and PSCR in the domestic dog (Canis lupus familiaris), for which the complete genome sequence has recently become available, allowing a thorough comparative analyses. Results: In addition to PAR synapsis between X and Y, we observed extensive self-synapsis of part of the dog X chromosome, and rapid loss of known markers of DSB repair from that part of the X. Sequencing of RNA from purified spermatocytes and spermatids revealed establishment of MSCI. However, the self-synapsing region of the X displayed higher X-linked gene expression compared to the unsynapsed area in spermatocytes, and was post-meiotically reactivated in spermatids. In contrast, genes in the PAR, which are expected to escape MSCI, were expressed at very low levels in both spermatocytes and spermatids. Our comparative analysis was then used to identify two X-linked genes that may escape MSCI in spermatocytes, and 21 that are specificall

Although influenza A/H1N1pdm09 is not causing a pandemic anymore, we recently observed two critically ill pregnant women infected by this virus. We present these cases to illustrate the possible severe complications of an - at that moment - seasonal influenza in pregnancy. We discuss the epidemiological differences between the pandemic and post pandemic phase and try to explain the high virulence of influenza A/H1N1pdm09 -infections in pregnancy by discussing insights in immunology during pregnancy. We conclude that although influenza A/H1N1pdm09 is in the post pandemic phase, infection by this influenza virus still needs to be considered in pregnant women with progressive respiratory dysfunction.

In mammalian meiotic prophase, the initial steps in repair of SPO11-induced DNA double-strand breaks (DSBs) are required to obtain stable homologous chromosome pairing and synapsis. The X and Y chromosomes pair and synapse only in the short pseudo-autosomal regions. The rest of the chromatin of the sex chromosomes remain unsynapsed, contains persistent meiotic DSBs, and the whole so-called XY body undergoes meiotic sex chromosome inactivation (MSCI). A more general mechanism, named meiotic silencing of unsynapsed chromatin (MSUC), is activated when autosomes fail to synapse. In the absence of SPO11, many chromosomal regions remain unsynapsed, but MSUC takes place only on part of the unsynapsed chromatin. We asked if spontaneous DSBs occur in meiocytes that lack a functional SPO11 protein, and if these might be involved in targeting the MSUC response to part of the unsynapsed chromatin. We generated mice carrying a point mutation that disrupts the predicted catalytic site of SPO11 (Spo11YF/YF), and blocks its DSB-inducing activity. Interestingly, we observed foci of proteins involved in the processing of DNA damage, such as RAD51, DMC1, and RPA, both in Spo11YF/YFand Spo11 knockout meiocytes. These foci preferentially localized to the areas that undergo MSUC and form the so-called pseudo XY body. In SPO11-deficient oocytes, the number o

During male meiotic prophase in mammals, X and Y are in a largely unsynapsed configuration, which is thought to trigger meiotic sex chromosome inactivation (MSCI). In avian species, females are ZW, and males ZZ. Although Z and W in chicken oocytes show complete, largely heterologous synapsis, they too undergo MSCI, albeit only transiently. The W chromosome is already inactive in early meiotic prophase, and inactive chromatin marks may spread on to the Z upon synapsis. Mammalian MSCI is considered as a specialised form of the general meiotic silencing mechanism, named meiotic silencing of unsynapsed chromatin (MSUC). Herein, we studied the avian form of MSUC, by analysing the behaviour of the peculiar germline restricted chromosome (GRC) that is present as a single copy in zebra finch spermatocytes. In the female germline, this chromosome is present in two copies, which normally synapse and recombine. In contrast, during male meiosis, the single GRC is always eliminated. We found that the GRC in the male germline is silenced from early leptotene onwards, similar to the W chromosome in avian oocytes. The GRC remains largely unsynapsed throughout meiotic prophase I, although patches of SYCP1 staining indicate that part of the GRC may self-synapse. In addition, the GRC is largely devoid of meiotic double strand breaks. We observed a lack of the inner centromere protein INCENP on the GRC and elimination of the GRC following metaphase I. Subsequently, the GRC forms a micronucleus in which the DNA is fragmented. We conclude that in contrast to MSUC in mammals, meiotic silencing of this single chromosome in the avian germline occurs prior to, and independent of DNA double strand breaks and chromosome pairing, hence we have named this phenomenon meiotic silencing prior to synapsis (MSPS).