Increase In Birth Defects Research Articles

6487 Hypercalcemia In Pregnancy Due To An Ectopic Parathyroid Adenoma: A Diagnostic Dilemma

Abstract Disclosure: S.S. Patel: None. M.B. Sharma: None. Introduction: Hypercalcemia is a rare complication of pregnancy, with the most common cause being primary hyperparathyroidism due to a parathyroid adenoma. Ultrasound is the primary modality used for localization, as sestamibi and computed tomography (CT) carry the risk of potential harm to the fetus. We present the case of hypercalcemia in a pregnant female that failed to resolve after two gland parathyroidectomy, necessitating a sestamibi parathyroid scan to localize an ectopic parathyroid adenoma. Case: A 40-year-old pregnant woman at 12 weeks of gestation presented with hypercalcemia, with a corrected calcium level of 12.5 mg/dL (8.7-10.4 mg/dL). She complained of nausea and vomiting but denied any personal or family history of hypercalcemia. Further evaluation revealed primary hyperparathyroidism as the etiology, with Intact PTH of 429.2 pg/mL (18.5-88.0 pg/mL), ionized calcium of 1.45 mmol/L (1.12-1.32 mmol/L), 25-OH vitamin D of 16.4 ng/mL (30-100 ng/mL), phosphorus of 1.3 mg/dL (2.4-5.1 mg/dL), and creatinine of 0.71 mg/dL (0.5-0.8 mg/dL). Notably, her calcium level had been 19.2 mg/dL two weeks earlier during an episode of hyperemesis gravidarum. Hypercalcemia proved relatively resistant to treatment with intravenous hydration and subcutaneous calcitonin. Ultrasound of the neck failed to reveal a parathyroid adenoma. The patient then underwent surgical neck exploration, during which two parathyroid glands were removed, resulting in an intraoperative PTH drop from 440 to 340 pg/mL. Postoperative calcium levels remained elevated at 12.9 mg/dL, prompting the resumption of treatment. Oral sodium and potassium phosphate was added to bind dietary calcium. After an extensive multidisciplinary discussion, a 99mTc-sestamibi parathyroid scan with a lower dose of sestamibi and without CT was recommended. This revealed an ectopic parathyroid adenoma in the anterior mediastinum. Surgical removal of the ectopic parathyroid adenoma in the second trimester finally led to a significant intraoperative PTH drop from 315 to 28 pg/mL. The postoperative course was complicated by hypocalcemia and hypomagnesemia, requiring calcium, vitamin D, and magnesium supplements. These complications resolved over the following days. The patient remained normocalcemic for the remaining pregnancy and delivered a healthy male infant at 34 weeks. Conclusion: Hypercalcemia in pregnancy is associated with fetal and maternal complications, warranting adequate management and close follow-up. The use of 99mTc-sestamibi parathyroid scan is typically not recommended in pregnancy due to concern for fetal harm; however, there are a few studies showing no association with increased birth defects or adverse pregnancy outcomes at low radiotracer doses. Hence, a sestamibi parathyroid scan can be considered during pregnancy to localize an adenoma after a careful review of the benefits versus risks. Presentation: 6/2/2024

COVID-19 vaccination in first trimester: no increase in congenital abnormalities

COVID-19 vaccination in first trimester: no increase in congenital abnormalities

Pregnancy in times of war: What are the fallouts ? A review.

The beginning of the conflict in Ukraine has reminded Europeans the many and diverse consequences of armed conflicts. Indeed, the ever more sophisticated conflicts have led to the diffusion of numerous chemicals whose consequences spread even after the end of the war. We present through this paper a review of the consequences on pregnancies of the major conflicts that took place since the end of World War II. MEDLINE, Web of science, and Embase were screened for articles linking perinatal death or birth defects to wartime. A total of 50 papers treating of 8 countries and 4 major and medically documented conflicts were included in the final analysis. An increase in birth defects and perinatal death during and after the end of the conflicts was reported through all the conflicts analyzed. While more data are needed to conclude, maternal fetal medicine specialists ought to be wary when dealing with exposed populations.

O-306 Sperm DNA methylome changes in testicular cancer patients following chemotherapy treatment

Abstract Study question Does chemotherapy (CT) treatment for testicular cancer induce sperm methylome changes? Summary answer The analysis of 27 pre- and post-CT samples from testicular cancer survivors identified 65 differentially methylated regions. What is known already Research has shown that cancer treatment can cause DNA damage and aneuploidy in sperm, even years after the treatment. However, there is limited information available on the impact of CT on the sperm epigenome, and most of the information has been obtained from rodent models. Two recent studies, one involving one patient and the other involving three, have investigated this topic in humans. Both studies have suggested that cancer survivors may experience changes in sperm’s DNA methylation following oncological treatment. Study design, size, duration This is a multicenter prospective study. We included 27 patients [31.23 years (CI 95% 29.29-33.17)] diagnosed with testicular cancer who cryopreserved semen before CT (2009-2020). After receiving oncological treatment, these patients recovered their spermatogenesis. Patients who agreed to participate in this IRB-approved study, donated a second semen sample after their recovery, which was also frozen. Participants/materials, setting, methods Semen samples were thawed; sperm DNA was isolated and subsequently hybridized using the Human Infinitum DNA Methylation 850K EPIC BeadChip array platform (Illumina). A paired differential methylation analysis was performed between pre-CT and post-CT samples from the same patient, fitting a linear model of the methylated positions and regions. Minfi and DMRcate R packages were used to find differentially methylated positions (DMPs) and regions (DMRs). Subsequently, the functional impact of involved genes was evaluated. Main results and the role of chance DNA methylation data were available for the 54 sperm samples (27 collected before CT and 27 after CT treatment). Results were controlled by age and time elapsed between the cryopreservation of pre-CT and post-CT samples, which was 4.01 years (CI 95%: 3.42-5.64). After filtering for initial QC, the assessment was done on 445.000 CpGs per sample. The analysis revealed that a total of 228 CpG positions showed a tendency towards statistical significance. DMRcate identified 65 DMRs (40 hypomethylated and 25 hypermethylated) that reached a smoothed FDR p-value < 0.05 when compared post-CT samples to pre-CT within the same patient. We observed that 61 genes were located within DMRs, being TBC1D20, EN1, HOXB1 and SCNN1A the ones within the most significant DMRs (min-smoothed-FDR < 0.001). The functional enrichment analysis of putatively affected genes revealed that the biological processes more affected were: Regulation of macromolecule biosynthetic process, hormone receptor binding, signaling pathways regulating pluripotency of stem cells and pathways in cancer. Limitations, reasons for caution Epigenetics may be affected during cryopreservation and thawing. To ensure comparability, we also froze the samples after undergoing the CT process. Due to the high-throughput nature of the study and the limited access to samples, we only achieved marginal significance. Therefore, our results should be further validated. Wider implications of the findings This is the largest study suggesting distinct sperm DNA methylation signatures in testicular cancer survivors. Our findings emphasize the importance of counseling cancer patients in pretreatment sample collection and may explain the reported increase in birth defects after treatment. Trial registration number NOT APPLICABLE

P-776 School-age outcomes among IVF and ICSI -conceived children: a causal inference analysis using linked population-wide data

Abstract Study question What is the causal effect of method of oocyte insemination; standard in-vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI), on childhood development at school entry? Summary answer The developmental outcomes at school entry for children conceived by ICSI, without severe male factor infertility, are equivalent to those conceived via standard IVF. What is known already Over 12 million children have been conceived globally with the assistance of assisted reproductive technology (ART). Within ART, ICSI continues to increase as the most common mode of oocyte insemination, even when not clearly indicated (i.e. without male factor infertility). Large cohort studies have suggested that ART, and ICSI in particular, may be associated with an increase in congenital abnormalities, autism spectrum disorder, developmental delay and intellectual disability. However, the studies are heterogenous and the evidence conflicting. The association between the ICSI technique itself and long-term childhood development remains unclear. Study design, size, duration Causal inference methods were used to analyse observational data in a way that emulates a target randomised clinical trial. For example, patients where standard IVF was not an option, (e.g., due to severe male factor infertility), were excluded. The state-wide cohort included linked maternal and childhood administrative data from Victoria, Australia. To eliminate potential confounding associated with IVF, comparison was made with children conceived via standard IVF (rather than conception without assistance). Participants/materials, setting, methods The study included singleton infants conceived via ART and born between 2005-2013. The primary exposure was conception via ICSI, with those born following conventional IVF insemination as controls. The outcome examined was the Australian Early Development Census (AEDC), a broad assessment of development and well-being performed in Australian schools, every triennium, at school entry (age 4-6). We combined multiple imputation and inverse probability weighting with regression adjustment to estimate population average causal effects. Main results and the role of chance The final cohort included 4,035 IVF and ICSI conceived children across the two outcome cohorts. Linked records were available for 2,468 ICSI children and 1,567 IVF-conceived controls. Maternal characteristics between the two treatment cohorts were similar for age, parity, education, language background, and number of eggs collected during treatment cycle. The ICSI conceived children were generally from residential areas of lower socio-economic status and conception was more likely to involve donated gametes. The unadjusted rate of the primary outcome; AEDC-defined “developmental vulnerability”, was 10.83% among the IVF group and 10.14% among the ICSI group. Given the use of observational data, there were missing data and inherent differences in the covariate profile between exposure cohorts. Multiple imputation, bootstrapping and doubly robust inverse probability weighted regression adjustment modelling was utilised to allow a causal interpretation of results. There was no evidence of a causal effect of ICSI-conception on the risk of AEDC-defined developmental vulnerability at school entry compared with spontaneously conceived children; adjusted risk difference -0.8% (95% CI -2.7% to 1.1%) and adjusted risk ratio 0.92 (95% CI 0.76 to 1.12). The adjustment variable set was determined a priori via a modified Delphi procedure. Limitations, reasons for caution Children who did not attend school due to severe disability were excluded, leading to potential selection bias. Within our study cohort of 2,468 ICSI children, no increased risk of developmental vulnerability was identified. It is possible that unmeasured confounders could have led to bias in estimating the treatment effects. Wider implications of the findings This study, in contrast to previous evidence, suggests that empiric use of ICSI compared with conventional IVF insemination does not affect early childhood developmental outcomes. These findings provide important reassurance for current and prospective parents, and clinicians alike. Trial registration number not applicable

Antifungal medication use during pregnancy and the risk of selected major birth defects in the National Birth Defects Prevention Study, 1997-2011.

Recent studies suggest increased birth defect risk associated with maternal use of specific oral antifungals. We estimated associations between first-trimester antifungal use and selected non-cardiac birth defects using National Birth Defects Prevention Study (NBDPS) data. Participants with a pregnancy affected by a study-eligible birth defect ("cases") were ascertained from 10 birth defect surveillance programs; participants who delivered livebirths without a major birth defect ("controls") were randomly selected from birth records or hospital discharge lists. First-trimester antifungal use was self-reported via maternal interview. We estimated adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for birth defects with ≥5 exposed cases using logistic regression. We estimated crude ORs and exact 95% CIs for birth defects with 3-4 exposed cases. Additionally, we conducted a probabilistic bias analysis of exposure misclassification. Our analysis included 19 624 cases and 11 427 controls; 257 (1.3%) cases and 123 (1.1%) controls reported first-trimester antifungal use. Of those who reported antifungals, 62.6% of cases and 64.2% of controls reported topical antifungals; 10.1% of cases and 4.9% of controls reported oral antifungals. We observed the strongest associations for encephalocele and Dandy-Walker malformation and modestly elevated estimates for several other defects. Bias-adjusted estimates were similar to the main analysis. First-trimester antifungal use was positively associated with several birth defects in our analysis, although CIs were imprecise. Further study is warranted to investigate associations between antifungal use and birth defects, including potential bias due to confounding by indication.

Safety of early cumulus cell removal combined with early rescue ICSI in the prevention of fertilization failure

Research questionWhat are the clinical outcomes and safety implications of early cumulus cell removal after short-term insemination combined with early rescue intracytoplasmic sperm injection (ICSI) in preventing fertilization failure? DesignIn this retrospective study, a total of 14,360 cycles were divided into four groups based on insemination method and fertilization ability: conventional IVF group (n = 5519); early cumulus cell removal group (n = 4107); conventional ICSI group (n = 4215); and early rescue ICSI group (where failed or low fertilization was predicted, n = 519). Fertilization outcomes, pregnancy outcomes, neonatal outcomes and birth defects were analysed by comparing the early cumulus cell removal group with the conventional IVF group, and the early rescue ICSI group with the conventional ICSI group. ResultsThere were no significant differences in the outcomes of fertilization, pregnancy, neonates or birth defects between the conventional IVF group and the early cumulus cell removal group (P > 0.05). When compared with the conventional ICSI group, the early rescue ICSI group had similar rates of two pronuclei (2PN) at fertilization, clinical pregnancy, miscarriage, ectopic pregnancy, live birth, sex, mean gestational age, very low birthweight, macrosomia and birth defects (P > 0.05) but a higher polyploidy rate, lower high-quality embryo rate (both P < 0.001), lower twin pregnancy rate (P < 0.01), lower rate of low birthweight, and a higher rate of normal birthweight (both P = 0.024). ConclusionsEarly cumulus cell removal combined with early rescue ICSI led to good pregnancy and neonatal outcomes without an increase in birth defects. This approach could therefore be an effective and safe method for patients with fertilization failure in conventional IVF.

Sperm DNA methylome abnormalities occur both pre- and post-treatment in men with Hodgkin disease and testicular cancer

BackgroundCombination chemotherapy has contributed to increased survival from Hodgkin disease (HD) and testicular cancer (TC). However, questions concerning the quality of spermatozoa after treatment have arisen. While studies have shown evidence of DNA damage and aneuploidy in spermatozoa years following anticancer treatment, the sperm epigenome has received little attention. Our objectives here were to determine the impact of HD and TC, as well as their treatments, on sperm DNA methylation. Semen samples were collected from community controls (CC) and from men undergoing treatment for HD or TC, both before initiation of chemotherapy and at multiple times post-treatment. Sperm DNA methylation was assessed using genome-wide and locus-specific approaches.ResultsImprinted gene methylation was not affected in the sperm of HD or TC men, before or after treatment. Prior to treatment, using Illumina HumanMethylation450 BeadChip (450 K) arrays, a subset of 500 probes was able to distinguish sperm samples from TC, HD and CC subjects; differences between groups persisted post-treatment. Comparing altered sperm methylation between HD or TC patients versus CC men, twice as many sites were affected in TC versus HD men; for both groups, the most affected CpGs were hypomethylated. For TC patients, the promoter region of GDF2 contained the largest region of differential methylation. To assess alterations in DNA methylation over time/post-chemotherapy, serial samples from individual patients were compared. With restriction landmark genome scanning and 450 K array analyses, some patients who underwent chemotherapy showed increased alterations in DNA methylation, up to 2 to 3 years post-treatment, when compared to the CC cohort. Similarly, a higher-resolution human sperm-specific assay that includes assessment of environmentally sensitive regions, or “dynamic sites,” also demonstrated persistently altered sperm DNA methylation in cancer patients post-treatment and suggested preferential susceptibility of “dynamic” CpG sites.ConclusionsDistinct sperm DNA methylation signatures were present pre-treatment in men with HD and TC and may help explain increases in birth defects reported in recent clinical studies. Epigenetic defects in spermatozoa of some cancer survivors were evident even up to 2 years post-treatment. Abnormalities in the sperm epigenome both pre- and post-chemotherapy may contribute to detrimental effects on future reproductive health.

Effect of vinpocetine on embryonic heart rate in vitro

Vinpocetine is a readily available nutritional supplement claimed to improve memory and weight loss.However, it blocks the Ikr current essential for cardiac action potential repolarisation and Ikr inhibition can cause “torsade de pointes” arrhythmias and sudden death. Moreover, Ikr blockers have exhibited teratogenic effects in reproductive toxicology studies, leading to increased birth defects and embryonic mortality. The FDA advises against vinpocetine use in pregnant and prospective mothers based on animal studies showing dose-dependent fetal mortality in rats and rabbits, and cardiovascular malformations in surviving fetuses. However, the mechanisms responsible for vinpocetine's fetal toxicity remain unclear.The present study used rat embryo culture to evaluate vinpocetine and its major metabolite, apovincaminic acid, on embryonic heart rate, a possible causative factor behind its adverse effects. Both compounds induced embryonic bradycardia in a concentration-dependent manner, with vinpocetine proving more potent.The minimum vinpocentine concentration to induce bradycardia was 100 nM, a level unlikely to be reached in humans following typical doses. Embryonic arrhythmias were also observed at the highest concentrations.These results suggest that the FDA's cautionary statement may generate undue anxiety, although re-evaluation of teratogenicity risk associated with vinpocetine should be revisited if a link to cardiac arrhythmias in adults is established.

Pregnancy and infant outcomes by trimester of SARS-CoV-2 infection in pregnancy-SET-NET, 22 jurisdictions, January 25, 2020-December 31, 2020.

ObjectivesWe describe clinical characteristics, pregnancy, and infant outcomes in pregnant people with laboratory‐confirmed SARS‐CoV‐2 infection by trimester of infection.Study DesignWe analyzed data from the Surveillance for Emerging Threats to Mothers and Babies Network and included people with infection in 2020, with known timing of infection and pregnancy outcome. Outcomes are described by trimester of infection. Pregnancy outcomes included live birth and pregnancy loss (<20 weeks and ≥20 weeks gestation). Infant outcomes included preterm birth (<37 weeks gestation), small for gestational age, birth defects, and neonatal intensive care unit admission. Adjusted prevalence ratios (aPR) were calculated for pregnancy and selected infant outcomes by trimester of infection, controlling for demographics.ResultsOf 35,200 people included in this analysis, 50.8% of pregnant people had infection in the third trimester, 30.8% in the second, and 18.3% in the first. Third trimester infection was associated with a higher frequency of preterm birth compared to first or second trimester infection combined (17.8% vs. 11.8%; aPR 1.44 95% CI: 1.35–1.54). Prevalence of birth defects was 553.4/10,000 live births, with no difference by trimester of infection.ConclusionsThere were no signals for increased birth defects among infants in this population relative to national baseline estimates, regardless of timing of infection. However, the prevalence of preterm birth in people with SARS‐CoV‐2 infection in pregnancy in our analysis was higher relative to national baseline data (10.0–10.2%), particularly among people with third trimester infection. Consequences of COVID‐19 during pregnancy support recommended COVID‐19 prevention strategies, including vaccination.

ON ASSESSING THE MORBIDITY OF THE POPULATION ASSOCIATED WITH THE ATMOSPHERIC AIR QUALITY ON THE EXAMPLE OF A RUSSIAN CONSTITUENT ENTITY

According to the World Health Organization (WHO), 24% of the global burden of diseases and 23% of all deaths associate with environmental factors. The presence of chemical impurities in the air can have an adverse effect on the health of the population. A connection has been established between the increased content of chemical impurities in the air and the development of such pathologies as diseases of the respiratory system, circulatory system, the formation of malformations, etc. Many countries implement projects to improve air quality. For the purpose of targeted development of management decisions aimed at minimizing the adverse impact of atmospheric air on the health of the population, the study of the morbidity of the population associated with the impact of priority atmospheric air hazard factors is relevant. The research goal is to characterize the morbidity of the population associated with air quality (on the example of Krasnoyarsk Krai) to identify the priority factors of atmospheric air that form the greatest contribution to the associated morbidity. The qualitative characteristics of the atmosphere and the level of morbidity of the population in Krasnoyarsk Krai are estimated on the basis of official data of federal and industry statistics. The analysis of the primary morbidity of the population, designated by the WHO as an indication of the effect of environmental factors, has been carried out. The authors calculate the number of third-party cases of diseases associated with the quality of the atmosphere and determine the priority risk factors. High proportions of air samples that do not meet the standards for the content of heavy metals, benz(a)pyrene, xylenes (59% of samples) have been registered over the territory of Krasnoyarsk Krai. Since 2012, there has been an increase of 0.2%–6.4% in the indicators of primary morbidity, indicated by the WHO as an indicator of the effect of environmental factors and a significant increase in congenital anomalies (the growth rate is 93.2%). Up to 231 thousand third-party cases of diseases of the general population with diseases affecting the respiratory organs, circulatory system, hematopoietic organs, nervous system, eyes and their appendages determine the presence of aromatic hydrocarbons, nitrogen dioxide, hydroxybenzene (as well as its derivatives), benz(a)pyrene, nitrogen oxide, ammonia, dihydrosulfide and carbon disulfide, sulfur dioxide in the air in concentrations exceeding the standards. The most substantial number of diseases associated with air quality forms in the class of respiratory diseases (2020 – 587.4 cases per 100 thousand population, 64.5% of the total air-associated morbidity).

Nutrient Transporter Gene Expression in the Early Conceptus-Implications From Two Mouse Models of Diabetic Pregnancy.

Maternal diabetes in early pregnancy increases the risk for birth defects in the offspring, particularly heart, and neural tube defects. While elevated glucose levels are characteristic for diabetic pregnancies, these are also accompanied by hyperlipidemia, indicating altered nutrient availability. We therefore investigated whether changes in the expression of nutrient transporters at the conception site or in the early post-implantation embryo could account for increased birth defect incidence at later developmental stages. Focusing on glucose and fatty acid transporters, we measured their expression by RT-PCR in the spontaneously diabetic non-obese mouse strain NOD, and in pregnant FVB/N mouse strain dams with Streptozotocin-induced diabetes. Sites of expression in the deciduum, extra-embryonic, and embryonic tissues were determined by RNAscope in situ hybridization. While maternal diabetes had no apparent effects on levels or cellular profiles of expression, we detected striking cell-type specificity of particular nutrient transporters. For examples, Slc2a2/Glut2 expression was restricted to the endodermal cells of the visceral yolk sac, while Slc2a1/Glut1 expression was limited to the mesodermal compartment; Slc27a4/Fatp4 and Slc27a3/Fatp3 also exhibited reciprocally exclusive expression in the endodermal and mesodermal compartments of the yolk sac, respectively. These findings not only highlight the significance of nutrient transporters in the intrauterine environment, but also raise important implications for the etiology of birth defects in diabetic pregnancies, and for strategies aimed at reducing birth defects risk by nutrient supplementation.

No increase in birth defects after hydroxychloroquine during pregnancy

No increase in birth defects after hydroxychloroquine during pregnancy

P–784 Neonatal follow-up of babies born derived from mono-pronuclear zygotes

Abstract Study question Are the neonatal outcomes normal of babies derived from the transfer of blastocysts derived from mono-pronuclear(1PN) zygotes? Summary answer There was no effect on growth or increase in congenital anomalies up to 18-months in babies of 1PN-derived births. What is known already 1PN zygotes are observed in ART, albeit at a low rate. We have previously reported that 80.7% of 1PN zygotes derived from IVF or ICSI had a biparental chromosome using Live Cell imaging techniques, and some of these developed to the blastocyst stage (Tokoro et al. ASRM 2013). Furthermore, we have reported that these blastocysts can result in a viable pregnancy and healthy live birth (Tsuji et al. ASRM2020). However, there is some uncertainty about the developmental mechanism of 1PN zygotes, and there is no clear consensus on their clinical utility. Study design, size, duration This was a retrospective study which included 55 cases where there was a live birth after single embryo transfer of a blastocyst derived from 1PN zygote. The incidence of birth defects, birth weight was recorded as well as a physical development survey of 25 children who responded to the 18-months follow-up survey. The time period was 72 months (January 2013 to December 2018). Participants/materials, setting, methods Patients seeking fertility treatment at an established private IVF clinic. We compared the birth weight, birth after18-months height and weight of children born to 1PN zygotes with data from a control, 2PN group. Statistical significance was determined using the t-test (level of P &amp;lt; 0.05). Main results and the role of chance The incidence of birth defects in 1PN embryo-derived infants was 1.8% (1/55). The average birth weight of boys in the 1PN group was 3105.6+/–360.3g, which was not significantly different from 3041.0+/–443.3 g in the 2PN group. In girls, the average birth weight was 3085.7+/–454.9 g in the 1PN group, which was not significantly different from the 2PN group (2938.9+/–311.5 g). The average height at 18-months, was 81.6+/–2.5 cm vs 80.5+/–3.4 cm for boys; 79.0+/–1.8 cm vs 79.0+/–3.4 cm for girls in the 1PN and 2PN groups, respectively. The average body weights of the 1PN and 2PN groups were 11.1+/–1.1 kg vs 10.7+/–1.1 kg for boys; 9.7+/–0.9 kg vs 10.1+/–1.0 kg for girls, respectively. There was no significant difference in average height and weight up-to the 18-months follow-up survey. Limitations, reasons for caution The incidence of 1PN derived births is low and the study was limited to cases of single blastocyst embryo transfer. Wider implications of the findings: The incidence of congenital anomalies in Japan was around 1.7 to 2%, and the incidence was similar in the 1PN. There was no difference in the birth weight and 18-months follow-up survey of the 1PN compared with the 2PN. We have demonstrated that there is clinical utility of 1PN embryo. Trial registration number Not applicable

Periconceptional Folate Supplementation in Women after Bariatric Surgery—A Narrative Review

The prevalence of obesity is increasing globally, and along with it, there is a growing number of patients opting to undergo bariatric surgery to treat this condition. Whilst it has many advantages, bariatric surgery is known to induce micronutrient deficiency, with possible deleterious effects on overall health. This topic becomes even more relevant during pregnancy, where deficiencies can also affect the developing fetus, possibly being the cause of an increase in congenital anomalies. Most notably amongst these micronutrients is folate, or vitamin B9, which plays an essential role in development, gene expression and genomic stability. As insufficient levels of folate are associated with neural tube defects in the fetus, preventing and treating folate deficiencies during pregnancies after bariatric surgery is a relevant issue. Unfortunately, folate supplementation recommendations for bariatric patients who wish to become pregnant are not clear. In this narrative review, we discuss whether the recommendations for the general population are still valid for bariatric patients. Furthermore, we discuss the role of folate in the human body, folate status in both non-bariatric and bariatric patients, the various types of folate that are available for substitution and the risk associated with over-supplementation.

Macrolide use during pregnancy: no increase in congenital abnormalities

Macrolide use during pregnancy: no increase in congenital abnormalities

Apigenin as a Candidate Prenatal Treatment for Trisomy 21: Effects in Human Amniocytes and the Ts1Cje Mouse Model

Human fetuses with trisomy 21 (T21) have atypical brain development that is apparent sonographically in the second trimester. We hypothesize that by analyzing and integrating dysregulated gene expression and pathways common to humans with Down syndrome (DS) and mouse models we can discover novel targets for prenatal therapy. Here, we tested the safety and efficacy of apigenin, identified with this approach, in both human amniocytes from fetuses with T21 and in the Ts1Cje mouse model. Invitro, T21 cells cultured with apigenin had significantly reduced oxidative stress and improved antioxidant defense response. Invivo, apigenin treatment mixed with chow was administered prenatally to the dams and fed to the pups over their lifetimes. There was no significant increase in birth defects or pup deaths resulting from prenatal apigenin treatment. Apigenin significantly improved several developmental milestones and spatial olfactory memory in Ts1Cje neonates. In addition, we noted sex-specific effects on exploratory behavior and long-term hippocampal memory in adult mice, and males showed significantly more improvement than females. We demonstrated that the therapeutic effects of apigenin are pleiotropic, resulting in decreased oxidative stress, activation of pro-proliferative and pro-neurogenic genes (KI67, Nestin, Sox2, and PAX6), reduction of the pro-inflammatory cytokines INFG, IL1A, and IL12P70 through the inhibition of NFκB signaling, increase of the anti-inflammatory cytokines IL10 and IL12P40, and increased expression of the angiogenic and neurotrophic factors VEGFA and IL7. These studies provide proof of principle that apigenin has multiple therapeutic targets in preclinical models ofDS.

The Moral Imperative to Include Pregnant Women in Clinical Trials of Interventions for COVID-19

Although the number of clinical trials for patients with COVID-19 is increasing, many exclude pregnant women as participants or do not address pregnancy. This commentary discuss why pregnancy women should be included in clinical trials of interventions for COVID-19.

Zika virus infection differentially affects genome-wide transcription in neuronal cells and myeloid dendritic cells

Zika virus (ZIKV) is an emerging mosquito-borne flavivirus that has attracted global attention and international awareness. ZIKV infection exhibits mild symptoms including fever and pains; however, ZIKV has recently been shown to be related to increased birth defects, including microcephaly, in infants. In addition, ZIKV is related to the onset of neurological disorders, such as a type of paralysis similar to Guillain-Barré syndrome. However, the mechanisms through which ZIKV affect neuronal cells and myeloid dendritic cells and how ZIKV avoids host immunity are unclear. Accordingly, in this study, we analyzed RNA sequencing data from ZIKV-infected neuronal cells and myeloid dendritic cells by comparative network analyses using protein-protein interaction information. Comparative network analysis revealed major genes showing differential changes in the peripheral neurons, neural crest cells, and myeloid dendritic cells after ZIKV infection. The genes were related to DNA repair systems and prolactin signaling as well as the interferon signaling, neuroinflammation, and cell cycle pathways. These pathways were interconnected by the interaction of proteins in the pathway and significantly regulated by ZIKV infection in neuronal cells and myeloid dendritic cells. Our analysis showed that neuronal cell damage occurred through up-regulation of neuroinflammation and down-regulation of the DNA repair system, but not in myeloid dendritic cells. Interestingly, immune escape by ZIKV infection could be caused by downregulation of prolactin signaling including IRS2, PIK3C3, JAK3, STAT3, and IRF1 as well as mitochondria dysfunction and oxidative phosphorylation in myeloid dendritic cells. These findings provide insight into the mechanisms of ZIKV infection in the host and the association of ZIKV with neurological and immunological symptoms, which may facilitate the development of therapeutic agents and vaccines.

Long Term Risks to Neonatal Health from Exposure to War-9 Years Long Survey of Reproductive Health and Contamination by Weapon-Delivered Heavy Metals in Gaza, Palestine.

Introduction: High levels of environmental contaminants with long term effects and teratogenic and carcinogenic potential, such as heavy metals, were introduced by weaponry in war areas in the last decades. Poorer reproductive health and increases in non-communicable diseases were reported after wars and are the suspected long term effects of contamination by stable war remnants. Although potentially affecting millions of people, this is still an understudied issue of public health. Background: Gaza, Palestine since 2006 has been an object of repeated severe military attacks that left heavy metals remnants in the environment, in wound tissues and that were assumed by the population. Retrospective studies showed a progressive increase in birth defects since the 2006 attacks. In 2011 we started surveillance at birth alongside analysis of the heavy metals load carried by pregnant women and their babies. Methods: We used protocols for birth registration which also document the extent of exposures to attacks, war remnants and to other environmental risks that allow comparison of 3 data sets—2011, 2016 and 2018–2019 (4000–6000 women in each set). By ICP/MS analysis we determined the content of 23 metals in mothers’ hair. Appropriate statistical analysis was performed. Results: Comparison of data in birth registers showed a major increase in the prevalence in birth defects and preterm babies between 2011 and 2016, respectively from 1.1 to 1.8% and from 1.1 to 7.9%, values remaining stable in 2019. Negative outcomes at birth in 2016 up to 2019 were associated with exposure of the mothers to the attacks in 2014 and/or to hot spots of heavy metals contamination. Metal loads since the attacks in 2014 were consistently high until 2018–2019 for barium, arsenic, cobalt, cadmium, chrome, vanadium and uranium, pointing to these metals as potential inducers for the increased prevalence of negative health outcomes at birth since 2016. Conclusions: Bodily accumulation of metals following exposure whilst residing in attacked buildings predispose women to negative birth outcomes. We do not know if the metals act in synergy. Trial for mitigation of the documented negative effects of high metal load on reproductive health, and ensuing perinatal deaths, could now be done in Gaza, based on this documentary record. High load of heavy metals may explain recent increases in non-communicable diseases and cancers at all ages in Gaza. Modern war’s legacy of diseases and deaths extends in time to populations and demands monitoring.