Risk Of Birth Defects Research Articles

Independent factors associated with birth defects during the whole of pregnancy in Shenyang City, China: a case-control study.

Birth defects, as a kind of diseases that seriously affect human life, have always attracted much attention. In the past, perinatal data have been studied for birth defects. This study analyzed the surveillance data of birth defects during the perinatal period and the whole of pregnancy, as well as the independent influencing factors, to help to minimize their risk of birth defects. A total of 23,649 fetuses delivered in the hospital from January 2017 to December 2020, were enrolled in this study. There were 485 cases of birth defects, including live births and stillbirths by detailed inclusion and exclusion criteria. Maternal and neonatal clinical data were collated to analyze the influencing factors associated with birth defects. Pregnancy complications and comorbidities were diagnosed according to the criteria of the Chinese Medical Association. Univariate and multivariate logistic regression models were used to investigate the association between independent variables and birth defect events. The incidence of birth defects during the whole of pregnancy was 175.46/10,000, while the incidence of perinatal birth defects was 96.22/10,000. The birth defect group had significantly higher maternal age, gravidity, parity, rate of preterm birth, cesarean section (CS) rate, scarred uterus, stillborn, and male newborns compared to the control group. Multivariate logistic regression model analysis showed that preterm birth [odds ratio (OR): 1.69, 95% confidence interval (CI): 1.01 to 2.86], CS (OR: 1.46, 95% CI: 1.08 to 1.98), scarred uterus (OR: 1.70, 95% CI: 1.01 to 2.85), and low birth weight (OR >4 compared to the other two classes) were significantly associated with birth defects during the whole of pregnancy (all P<0.05). The independent influencing factors associated with perinatal birth defects included CS (OR: 1.43, 95% CI: 1.05 to 1.93), gestational hypertension (OR: 1.70, 95%: 1.04 to 2.78), and low birth weight (OR >3.70 compared to the other two classes). The discovery and monitoring of known influencing factors associated with birth defects, such as, preterm birth, gestational hypertension, low birth weight, should be enhanced. For the controllable influencing factors, obstetrics providers should work with patients to minimize their risk of birth defects.

Congenital hypothyroidism: a case report of an Egyptian child with congenital heart disease, pelvic kidney and cavernous transformation of portal vein

BackgroundA case of thyroid hormone deficiency which presented at birth. Thyroid hormones are essential for brain development and normal cognitive function. Common symptoms of congenital hypothyroidism (CH) include constipation, decreased activity, increased sleep and feeding difficulty. Common signs include dry skin, macroglossia and umbilical hernia. If congenital hypothyroidism is left untreated after birth, it can lead to permanent intellectual disability and growth failure.Case presentation.Here, we report a 10.5-year-old female with the typical features of CH. She is the sixth in order of birth of consanguineous Egyptian parents. No family history of similar condition. Our patient had primary CH caused by thyroid agenesis. She had congenital heart disease, pelvic kidney, cavernous transformation of portal vein and parenchymatous liver disease.ConclusionsCongenital hypothyroidism is associated with an elevated risk of congenital anomalies. Clinical suspicion of symptoms and signs of congenital hypothyroidism are important for early diagnosis and prevention of serious problems that are related to congenital hypothyroidism.

Maternal cyclobenzaprine exposure and risk of birth defects in the National Birth Defects Prevention Study (1997-2011) and Birth Defects Study to Evaluate Pregnancy exposureS (2014-2018).

Cyclobenzaprine is a muscle relaxant indicated for acute pain. Little is known about cyclobenzaprine's safety during pregnancy. We explored the association between maternal cyclobenzaprine exposure and risk of birth defects among offspring. We combined data from two large, multi-site, population-based case-control studies in the United States. Cases were identified from birth defects registries across 10 states; controls were liveborn infants without birth defects randomly selected from the same catchment areas. Participants reported cyclobenzaprine use during the month before conception through the third month of pregnancy ("periconception") via computer-assisted telephone interview. We used logistic regression to assess associations between periconceptional cyclobenzaprine exposure and selected structural birth defects. We calculated crude odds ratios (OR) with corresponding 95% confidence intervals (CI). Our study included 33 615 cases and 13 110 controls. Overall, 51 case (0.15%) and 9 control (0.07%) participants reported periconceptional cyclobenzaprine use. We observed increased risk for all seven defects with ≥3 exposed cases: cleft palate (OR = 4.79, 95% CI 1.71-13.44), cleft lip (OR = 2.50, 95% CI 0.89-7.02), anorectal atresia/stenosis (OR = 6.91, 95% CI 1.67, 28.65), d-transposition of the great arteries (OR = 6.97, 95% CI 2.17-22.36), coarctation of the aorta (OR = 5.58, 95% CI 1.88-16.58), pulmonary valve stenosis (OR = 4.55, 95% CI 1.10-18.87), and secundum atrial septal defect (OR = 3.08, 95% CI 0.83-11.45). Even in our large sample, cyclobenzaprine use was rare. Our estimates are unadjusted and imprecise so should be interpreted cautiously. These hypothesis-generating results warrant confirmation and further research to explore possible mechanisms.

Frequent first-trimester pregnancy loss in rhesus macaques infected with African-lineage Zika virus.

In the 2016 Zika virus (ZIKV) pandemic, a previously unrecognized risk of birth defects surfaced in babies whose mothers were infected with Asian-lineage ZIKV during pregnancy. Less is known about the impacts of gestational African-lineage ZIKV infections. Given high human immunodeficiency virus (HIV) burdens in regions where African-lineage ZIKV circulates, we evaluated whether pregnant rhesus macaques infected with simian immunodeficiency virus (SIV) have a higher risk of African-lineage ZIKV-associated birth defects. Remarkably, in both SIV+ and SIV- animals, ZIKV infection early in the first trimester caused a high incidence (78%) of spontaneous pregnancy loss within 20 days. These findings suggest a significant risk for early pregnancy loss associated with African-lineage ZIKV infection and provide the first consistent ZIKV-associated phenotype in macaques for testing medical countermeasures.

Assessing the risk of adverse pregnancy outcomes and birth defects reporting in women exposed to ganciclovir or valganciclovir during pregnancy: a pharmacovigilance study.

Cytomegalovirus (CMV) is the leading cause of congenital infection worldwide. Reference anti-CMV treatment is valganciclovir/ganciclovir, which is contraindicated in pregnancy given questions about teratogenicity. We analysed reports from VigiBase, the world's largest safety database, and performed a disproportionality analysis of adverse pregnancy outcomes associated with (val)ganciclovir compared with any other drugs or with (val)aciclovir as comparators. Among 3 104 984 reports related to childbearing-age women or to pregnancy topics, 6186 were exposed to (val)ganciclovir or (val)aciclovir including 251 adverse pregnancy outcomes with (val)ganciclovir (n = 34) or (val)aciclovir (n = 217). We did not evidence any increased reporting of any adverse pregnancy outcome [miscarriage, stillbirth, small weight for gestational age, preterm birth (<37 weeks of gestation)] or birth defects with (val)ganciclovir compared with the use of (val)aciclovir during pregnancy. Four cases of oesophageal and anorectal atresia were identified with (val)ganciclovir, which may be related to concomitant drugs/medical conditions and require further analyses. These preliminary results require confirmation but suggest the possibility for trial evaluation of val(ganciclovir) in severe maternal or fetal CMV infections.

Associations between severe and notifiable respiratory infections during the first trimester of pregnancy and congenital anomalies at birth: a register-based cohort study

BackgroundEvidence regarding the association between acute respiratory infections during pregnancy and congenital anomalies in babies, is limited and conflicting. The aim of this study was to examine the association between acute respiratory infections during the first trimester of pregnancy and congenital anomalies in babies using record linkage.MethodsWe linked a perinatal register to hospitalisation and disease notifications in the Australian state of New South Wales (NSW) between 2001 to 2016. We quantified the risk of congenital anomalies, identified from the babies’ linked hospital record in relation to notifiable respiratory and other infections during pregnancy using generalized Estimating Equations (GEE) adjusted for maternal sociodemographic and other characteristics.ResultsOf 1,453,037 birth records identified from the perinatal register between 2001 and 2016, 11,710 (0.81%) mothers were hospitalised for acute respiratory infection, 2850 (0.20%) had influenza and 1011 (0.07%) had high risk infections (a record of cytomegalovirus, rubella, herpes simplex, herpes zoster, toxoplasmosis, syphilis, chickenpox (varicella) and zika) during the pregnancy. During the first trimester, acute respiratory infection, influenza and high-risk infections were reported by 1547 (0.11%), 399 (0.03%) and 129 (0.01%) mothers. There were 15,644 (1.08%) babies reported with major congenital anomalies, 2242 (0.15%) with cleft lip/ plate, 7770 (0.53%) with all major cardiovascular anomalies and 1746 (0.12%) with selected major cardiovascular anomalies. The rate of selected major cardiovascular anomalies was significantly higher if the mother had an acute respiratory infection during the first trimester of pregnancy (AOR 3.64, 95% CI 1.73 to 7.66). The rates of all major congenital anomalies and all major cardiovascular anomalies were also higher if the mother had an acute respiratory infection during the first trimester of pregnancy, however the difference was no statistically significant. Influenza during the first trimester was not associated with major congenital anomalies, selected major cardiovascular anomalies or all major cardiovascular anomalies in this study.ConclusionThis large population-based study found severe acute respiratory infection in first trimester of pregnancy was associated with a higher risk of selected major cardiovascular anomalies in babies. These findings support measures to prevent acute respiratory infections in pregnant women including through vaccination.

Prenatal exposure to tap water containing nitrate and the risk of small-for-gestational-age: A nationwide register-based study of Danish births, 1991–2015

BackgroundPrenatal nitrate exposure from household tap water has been associated with increased risk of fetal growth restriction, preterm birth, birth defects, and childhood cancer. We aim to examine the association between maternal consumption of drinking-water nitrate during pregnancy and small-for-gestational-age (SGA) in a nationwide study of Danish-born children, as only one prior study has examined this association. MethodsWe linked individual-level household estimates of nitrate in tap water and birth registry data to all live singleton Danish births during 1991–2015 from Danish-born parents where the mother resided in Denmark throughout the pregnancy. Exposure was both binned into four categories and modeled as an ln-transformed continuous variable. SGA was defined as the bottom 10% of births by birth weight per sex and gestational week. Multiple logistic regression models with generalized estimating equations were used to account for siblings born to the same mother while controlling for relevant confounders. ResultsIn the cohort of 1,078,892 births, the median pregnancy nitrate exposure was 1.9 mg/L nitrate. Compared to the reference group (≤2 mg/L), we found an increased risk of SGA in the second category (>2–5 mg/L) (OR = 1.04, 95% CI: 1.03–1.06) and third category (>5–25 mg/L) (OR = 1.02, 95% CI: 1.00–1.04) but not in the highest (>25 mg/L). There was strong (p = 0.002) evidence of an increase in SGA with nitrate in the model with continuous exposure (OR = 1.02, 95% CI: 1.01–1.04 per 10-fold increase in nitrate). Results were robust when restricting to households with nitrate levels at or below the current Danish and European Union regulatory drinking water standard (50 mg/L nitrate). ConclusionsOur findings suggest that exposure from nitrate in household tap water, even below current regulatory standards, may increase risk of SGA, raising concerns of whether current allowable nitrate levels in drinking water protect children from SGA.

Paternal methotrexate exposure affects sperm small RNA content and causes craniofacial defects in the offspring

Folate is an essential vitamin for vertebrate embryo development. Methotrexate (MTX) is a folate antagonist that is widely prescribed for autoimmune diseases, blood and solid organ malignancies, and dermatologic diseases. Although it is highly contraindicated for pregnant women, because it is associated with an increased risk of multiple birth defects, the effect of paternal MTX exposure on their offspring has been largely unexplored. Here, we found MTX treatment of adult medaka male fish (Oryzias latipes) causes cranial cartilage defects in their offspring. Small non-coding RNA (sncRNAs) sequencing in the sperm of MTX treated males identify differential expression of a subset of tRNAs, with higher abundance for specific 5′ tRNA halves. Sperm RNA methylation analysis on MTX treated males shows that m5C is the most abundant and differential modification found in RNAs ranging in size from 50 to 90 nucleotides, predominantly tRNAs, and that it correlates with greater testicular Dnmt2 methyltransferase expression. Injection of sperm small RNA fractions from MTX-treated males into normal fertilized eggs generated cranial cartilage defects in the offspring. Overall, our data suggest that paternal MTX exposure alters sperm sncRNAs expression and modifications that may contribute to developmental defects in their offspring.

Maternal dietary caffeine consumption and risk of birth defects in the National Birth Defects Prevention Study, 1997-2011.

Caffeine consumption is common during pregnancy, but published associations with birth defects are mixed. We updated estimates of associations between prepregnancy caffeine consumption and 48 specific birth defects from the National Birth Defects Prevention Study (NBDPS) for deliveries from 1997 to 2011. NBDPS was a large population-based case-control study conducted in 10 U.S. states. We categorized self-reported total dietary caffeine consumption (mg/day) from coffee, tea, soda, and chocolate as: <10, 10 to <100, 100 to <200, 200 to <300, and ≥ 300. We used logistic regression to estimate adjusted odds ratios (aORs [95% confidence intervals]). Analyses for defects with ≥5 exposed case children were adjusted for maternal race/ethnicity, age at delivery, body mass index, early pregnancy cigarette smoking and alcohol use, and study site. Our analysis included 30,285 case and 11,502 control children, with mothers of 52% and 54%, respectively, reporting consuming <100 mg caffeine, and 11% of mothers of both cases and controls reported consuming ≥300 mg per day. Low (10 to <100 mg/day) levels of prepregnancy caffeine consumption were associated with statistically significant increases in aORs (1.2-1.7) for 10 defects. Associations with high (≥300 mg/day) levels of caffeine were generally weaker, except for craniosynostosis and aortic stenosis (aORs=1.3 [1.1-1.6], 1.6 [1.1-2.3]). Given the large number of estimates generated, some of the statistically significant results may be due to chance and thus the weakly increased aORs should be interpreted cautiously. This study supports previous observations suggesting lack of evidence for meaningful associations between caffeine consumption and the studied birth defects.

Paternal preconception modifiable risk factors for adverse pregnancy and offspring outcomes: a review of contemporary evidence from observational studies

BackgroundThe preconception period represents transgenerational opportunities to optimize modifiable risk factors associated with both short and long-term adverse health outcomes for women, men, and children. As such, preconception care is recommended to couples during this time to enable them to optimise their health in preparation for pregnancy. Historically, preconception research predominately focuses on maternal modifiable risks and health behaviours associated with pregnancy and offspring outcomes; limited attention has been given to inform paternal preconception health risks and outcomes. This systematic review aims to advance paternal preconception research by synthesising the current evidence on modifiable paternal preconception health behaviours and risk factors to identify associations with pregnancy and/or offspring outcomes.MethodsMedline, Embase, Maternity and Infant care, CINAHL, PsycINFO, Scopus, and ISI Proceedings were searched on the 5th of January 2023, a date limit was set [2012–2023] in each database. A Google Scholar search was also conducted identifying all other relevant papers. Studies were included if they were observational, reporting associations of modifiable risk factors in the preconception period among males (e.g., identified as reproductive partners of pregnant women and/or fathers of offspring for which outcomes were reported) with adverse pregnancy and offspring outcomes. Study quality was assessed using the Newcastle–Ottawa Scale. Exposure and outcome heterogeneity precluded meta-analysis, and results were summarised in tables.ResultsThis review identified 56 cohort and nine case control studies. Studies reported on a range of risk factors and/or health behaviours including paternal body composition (n = 25), alcohol intake (n = 6), cannabis use (n = 5), physical activity (n = 2), smoking (n = 20), stress (n = 3) and nutrition (n = 13). Outcomes included fecundability, IVF/ISCI live birth, offspring weight, body composition/BMI, asthma, lung function, leukemia, preterm birth, and behavioural issues. Despite the limited number of studies and substantial heterogeneity in reporting, results of studies assessed as good quality showed that paternal smoking may increase the risk of birth defects and higher paternal BMI was associated with higher offspring birthweight.ConclusionThe current evidence demonstrates a role of paternal preconception health in influencing outcomes related to pregnancy success and offspring health. The evidence is however limited and heterogenous, and further high-quality research is needed to inform clinical preconception care guidelines to support men and couples to prepare for a health pregnancy and child.

A comparison of perinatal outcomes following fresh blastocyst or cleavage stage embryo transfer in singletons and twins and between singleton siblings.

Are perinatal outcomes following fresh blastocyst versus fresh cleavage stage embryo transfer (ET) different in singletons, twins, and between singleton siblings? Singleton babies conceived following fresh blastocyst, versus cleavage stage, ET are less likely to be small for gestational age (SGA) or to have a congenital anomaly (a result confirmed by comparing singleton siblings), while singletons born following fresh blastocyst ET were at a higher risk of being large for gestational age (LGA) than their sibling born following fresh cleavage stage ET. Blastocyst stage transfer is now the preferred strategy in most IVF units. Previous studies have suggested that babies conceived through blastocyst transfer are at increased risk of preterm birth and LGA. A national population-based retrospective cohort study was performed using linked Human Fertilisation and Embryology Authority (HFEA) data on 130 516 IVF and ICSI livebirths occurring from 103 062 women between 2000 and 2017. We included women who had at least one singleton livebirth resulting from IVF/ICSI fresh embryo treatment, using their own eggs and partner's sperm. A linked HFEA dataset was analysed using a multilevel framework, which accommodated repeated IVF cycles resulting in livebirths in the same woman. A population-averaged robust Poisson model was used for binary outcomes and a multinomial logistic regression model was used for categorical outcomes. Unadjusted and adjusted risk ratios (aRRs) (95% CI) were calculated. There were 130 516 livebirths in 103 062 women, including 86 630 singletons, 43 886 twin births, and 5384 pairs of singleton siblings. In comparison with fresh cleavage stage ET, fresh blastocyst stage transfer in singletons was associated with a lower risk of low birthweight (aRR = 0.92; 95% CI 0.86, 0.99), lower risk of being SGA (0.83; 0.78, 0.89), and lower risk of congenital anomaly (0.79; 0.71, 0.89). This analysis did not show an increase in risk associated with preterm birth (1.00; 0.94, 1.06), high birthweight (0.99; 0.93, 1.06), LGA (0.99; 0.93, 1.05), and the chance of healthy singleton baby (1.00; 1.00, 1.02). Twins resulting from fresh blastocyst stage ET were at slightly higher risk of preterm birth (1.05; 1.02, 1.10) compared with twins conceived following fresh cleavage stage ET. There was insufficient evidence for an association with the other perinatal outcomes. Singleton siblings born following fresh blastocyst stage ET were at a higher risk of being LGA (1.57; 1.01, 2.46) and at lower risk of having a congenital anomaly (0.52; 0.28, 0.97) compared to their singleton siblings born following cleavage stage ET. There was some evidence of excess risk of preterm birth (1.42; 0.97, 2.23) associated with blastocyst stage transfer. However, we could not confirm an association between blastocyst stage ET and low birthweight (1.35; 0.81, 2.27), high birthweight (1.19; 0.80, 1.77), and the chance of being a healthy baby (0.97; 0.86, 1.09). This was an observational study where we were unable to adjust for some key confounders, such as maternal smoking status and BMI, which may change from one pregnancy to another and are not recorded in the HFEA dataset. In the largest study of its kind, our analysis of singleton siblings, corrected for unmeasured, non-time varying maternal factors, confirms the previously reported association between blastocyst transfer and LGA babies, and shows a reduced risk of congenital anomaly following blastocyst transfer. Our sibling analysis did not confirm a decreased risk of low birthweight following blastocyst transfer. Overall, absolute risks are low and there is insufficient evidence to challenge the practice of extended culture of embryos. This project is financed by an NHS Grampian Endowment Research Grant, project number 17/052. One of the authors, S.B., was the Editor in Chief of HROpen until 31 December 2022 and would have been in that role when the paper was first submitted. As an invited speaker, S.B. has received travel expenses, accommodation and honoraria from Merck, Organon, and Ferring. A.M. has received travel expenses, accommodation, and honoraria from Merck Serono, Cook Medical, Pharmasure, Gedeon Richter, and Ferring. D.J.M. is currently a HROpen Associate Editor. N/A.

Increasing use of newer antiseizure medication during pregnancy: An observational study with special focus on lacosamide

IntroductionEpilepsy is a common neurological disease requiring long-term therapy also during pregnancy. Most studies on pregnancy outcomes in women with epilepsy are based on antiseizure medication (ASM) in monotherapy. However, about 20–30% of epilepsy patients require polytherapy and newer ASMs are an option, when seizure control is not achieved with first line ASMs. MethodsObservational study evaluating the use of newer ASMs with marketing authorization since 2005 reported to the Embryotox Center of Clinical Teratology and Drug Safety in Pregnancy between 2004 and 2019. In addition, course and outcome of lacosamide exposed pregnancies were analysed. ResultsOur study confirms the increasing use of newer ASMs also in pregnant women. This is especially true for lacosamide, eslicarbazepine and brivaracetam with rising numbers of exposed pregnancies soon after marketing authorization. Analysis of 55 prospectively and 10 retrospectively ascertained lacosamide exposed pregnancies does not indicate increased risks of major birth defects or spontaneous abortion. However, bradycardia observed in 3 neonates might be related to prenatal lacosamide exposure. ConclusionAvailable data do not support the assumption of lacosamide being a major teratogen. The increasing use of newer ASMs during pregnancy underscores the need for more studies to guide preconception counselling, especially for lacosamide, eslicarbazepine and brivaracetam.

The effect of the day 3 embryo cell number on the neonatal outcomes of day 5 single blastocyst transfer in frozen embryo transfer cycles

ObjectiveTo evaluate the influence of the day 3 embryo cell number on the neonatal outcomes of day 5 single blastocyst transfer in frozen embryo transfer (FET) cycles. MethodsThis retrospective study analysed a total of 2315 delivery cycles of day 5 single blastocyst transfer in FET cycles, including 489, 761 and 1103 live-born infants segregated according to a day 3 embryo cell number of <8, 8 and >8 cells, respectively. The neonatal outcomes of the three groups were compared. ResultsThe day 3 embryo cell number did not significantly affect the incidence of monozygotic twins. The sex ratio increased as the day 3 embryo cell number increased, but the difference was not statistically significant. There were no significant differences in the rates of preterm birth or low birth weight among the three groups. The rates of stillbirths and neonatal deaths were also not significantly different among the three groups. Moreover, the day 3 embryo cell number did not increase the risk of birth defects in newborns. ConclusionsThe day 3 embryo cell number did not significantly affect neonatal outcomes.

Trends in the incidence of major birth defects after assisted reproductive technologies in Lombardy Region, Northern Italy

PurposeThe incidence of birth defects is increased in children born after assisted reproductive technologies (ART). However, changes in ART over time could influence this incidence. To investigate this issue, we present the frequency and trends of birth defects in ART and natural pregnancies in Lombardy, Northern Italy, during the period 2014–2020.MethodsThis is a population-based study using automated system of healthcare utilization (HCU) databases. ART pregnancies included only those obtained with conventional IVF or ICSI. After identifying the total number of deliveries, the rate of newborns with birth defects was compared between natural and ART pregnancies. A logistic regression model was used to calculate the adjusted odd ratio (OR). Analyses were repeated for every calendar year.ResultsOverall, 508,421 deliveries were identified, of which 14,067 (2.8%) were achieved after IVF-ICSI. A decreasing trend in birth defects over time was highlighted. The adjusted OR dropped from 1.40 (95%CI: 1.03–1.91) in 2014 to 0.92 (95%CI: 0.69–1.22) in 2020. During the study period, a significant reduction in multiple pregnancy and in the ratio of ICSI to conventional IVF was also observed, explaining at least in part the positive trend observed for birth defects.ConclusionThe increased risk of birth defects in children born after IVF-ICSI is not steady over time. A decline of this risk emerged in our region. Policy changes in ART may explain this beneficial effect.

Birth prevalence of genital anomalies among males conceived by intracytoplasmic sperm injection cycles: A cross-sectional study.

Several studies have been conducted worldwide to evaluate the prevalence and relative risks of congenital anomalies associated with assisted reproductive technology cycles; however, there is limited data in Iran. To investigate male genital anomalies among live births from assisted reproductive technology. This cross-sectional study was conducted on children born after intracytoplasmic sperm injection (ICSI) at Royan Institute, Tehran, Iran from April 2013-December 2015. The prevalence of male genitalia disorders that included hypospadias, epispadias, cryptorchidism, micropenis, and vanishing testis were reported. The relationship between the cause of infertility and type of embryo transfer (fresh or frozen), gestational age at birth (term or preterm), and birth weight with these male genitalia anomalies were evaluated. In total, 4409 pregnant women were followed after their ICSI cycles to evaluate genitalia anomalies in their children. Out of 5608 live births, 2614 (46.61%) newborns were male, of which 14 cases (0.54%) had genital anomalies. The prevalence of various anomalies were cryptorchidism (0.34%), hypospadias (0.038%), micropenis (0.038%), vanishing testis (0.038%), and epispadias (0.077%). No relationship was found between the cause of infertility, type of embryo transfer (fresh or frozen), gestational age at birth (term or preterm), and male genital malformation (p = 0.33, p = 0.66, and p = 0.62, respectively). The prevalence of each male genital anomaly after the ICSI cycle was rare and less than 0.5%; however, no significant infertility-related factor was observed with these anomalies.

Discussion on Application Strategies of Genetic Counseling

In recent years, with the rapid development of the field of genetics, genetic counseling services have developed rapidly in obstetrics, reproductive genetics, pediatrics and other disciplines, and are also gradually developed in the medical process of other disciplines such as oncology and multidisciplinary consultation. Genetic counseling physicians can reduce the risk of recurrence of genetic diseases by judging the pathogenesis of genetic diseases, selecting appropriate genetic testing techniques, analyzing test results, diagnosing diseases, carrying out genetic counseling to assist the treatment of genetic diseases, and giving fertility guidance. Genetic counseling service is the genetic counseling physicians through appropriate genetic counseling strategies to genetic basic research and genetic laboratory testing technology into clinical transformation, reduces the risk of birth defects and genetic diseases recurrence,reduces the mental and economic burden of hereditary diseases on the patients themselves, their families and society. At the same time, with the opening-up of Chinese fertility policy, the increase of the proportion of older pregnant women and the increase of the risk of birth defects, as well as the implementation of the "Healthy China 2030" program, the demand for genetic counseling services has increased in many disciplines. This paper will discuss the practical application of the current genetic counseling service strategy in clinical medicine.

The Risks of Birth Defects and Childhood Cancer With Conception by Assisted Reproductive Technology

ABSTRACT As the proportion of births conceived with assisted reproductive technology (ART) continues to increase, a growing body of literature continues to examine the risks involved such as the higher risk of birth defects. Recently, several studies have suggested that ART-conceived children may have a greater risk of childhood cancer. This population-based cohort study aimed to evaluate the risk of childhood cancer as a function of birth defect status and method of conception. Data were obtained from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System, birth certificates (2004–2013), birth defect registries, and cancer registries in 4 states. The Society for Assisted Reproductive Technology Clinic Outcome Reporting System contains comprehensive information on ART procedures from 86% of all clinics and more than 92% of all ART cycles in the United States. Assisted reproductive technology cycles reported from January 2004 to December 2017 that resulted in live births were included in this study. For each ART-conceived delivery, the subsequent 10 deliveries were selected as the non-ART comparison group, and siblings of each ART birth were selected as the ART sibling group. The ART group was divided into 4 subgroups based on the combination of oocyte source (autologous or donor) and embryo state (fresh or thawed). A host of independent variables with established associations on birth defects, cancer, and/or ART were selected a priori for inclusion in statistical models. The total study population included 165,125 ART-conceived children, 31,524 non-ART siblings, 12,451 children born as a result of infertility treatment without ART (ovulation induction/intrauterine insemination [OI/IUI]), and 1,353,440 naturally conceived children. A total of 29,571 singleton children (2.0%) and 3753 twin children (3.5%) had a major birth defect. Compared with naturally conceived children, risks for defects were increased for all other groups for nonchromosomal (adjusted odds ratios [AORs] ranged from 1.20 to 1.24, except for donor-fresh), blastogenesis (AORs, 1.22–1.74), cardiovascular (AORs, 1.04–1.26), gastrointestinal (AORs, 1.28–2.01), musculoskeletal (AORs, 1.10–1.48), and genitourinary among male children (AORs, 1.15–1.40, except for donor-fresh). Orofacial defects were increased in the OI/IUI and autologous-fresh and autologous-thawed groups (AORs, 1.26–1.42). The risk of any cancer was increased among ART autologous-fresh and non-ART siblings (hazard ratios [HRs], 1.31 and 1.34, respectively). A total of 127 children had both birth defects and cancer, with 53 (42%) of these children having leukemia. A Cox proportional hazards regression model identified 2 components for the risk of cancer: method of conception and type and number of birth defects. The presence of chromosomal defects was strongly associated with cancer risk (HRs, 8.70 for all cancers and 21.90 for leukemia), and this was further increased in the presence of both chromosomal and nonchromosomal defects (HRs, 21.29 for all cancers, 64.83 for leukemia, and 4.71 for embryonal tumors). The results of this study demonstrate that compared with naturally conceived children a significantly increased risk of nonchromosomal birth defects was found among children conceived with infertility treatment and that the risk of cancer was increased by greater than 30% among non-ART siblings and ART children born from autologous-fresh cycles. Among both naturally conceived and ART-conceived children, the presence of birth defects was associated with a greater risk of cancer.

The Risk of Breakthrough Bleeding Justifies the Use of Combined Hormonal Contraception Over Progesterone-Only Pills While Breastfeeding.

Breakthrough bleeding is a side effect of progesterone-only pills (POPs) in 40% of women, and is reduced to 10% with combined hormonal contraceptives (CHCs). In addition, breakthrough bleeding is reduced if POP is supplemented with norethisterone. As breakthrough bleeding is responsible for a quarter of women stopping the pill, it is vital to realize that CHC is an alternative to POP-even during lactation. CHCs are considered safe during lactation, do not reduce milk production, nor impede infant development. Nevertheless, CHCs are often not prescribed for lactating mothers due to this misconception that they reduce milk production. Among Orthodox Jews, breakthrough bleeding frequently results in stopping POP, as Jewish religious law prohibits any physical contact of the mother with her partner during active bleeding, and for 7 days after bleeding. When such bleeding occurs, not choosing a CHC alternative, results in couples risking discontinuation of POP, and in conceiving within a year of the previous birth, with its increased risk of preterm labor and birth defects. To measure how physicians respond to the presumed dilemma of balancing the risk of breakthrough bleeding versus the concern of reduction of milk production, we conducted a preliminary online survey. Physicians were asked if they would prescribe CHC instead of POP to breastfeeding mothers, 3 months postpartum with breakthrough bleeding. Half of the physicians responded they would prescribe CHC, whereas close to half of the physicians responded that they would not. The main reasons given by the respondents for avoiding CHC was a concern regarding possible milk reduction. These results confirm a significant degree of a lack of updated pharmacological information regarding the options of oral contraceptive use for lactating mothers, particularly for those where breakthrough bleeding has major behavioral and religious consequences. Thus, we contend that the risk of breakthrough bleeding justifies the more routine use of CHC in lieu of POP in lactating mothers.

Adverse pregnancy outcomes of cancer survivors and infectious disease in their infants: The Japan Environment and Children's Study.

Birth cohort studies examining pregnancy and infant outcomes among adolescent and young adult (AYA) cancer survivors have been limited. The present study examined whether AYA cancer affects pregnancy outcomes of survivors and infectious diseases in their infants up to 1 year of age. Pregnant women were recruited for the Japan Environment and Children's Study, a nationwide, large-scale, prospective cohort study. The present study included 103,060 pregnant women and collected questionnaire-based data during the first and second/third trimester, and at 1 month, 6 months and 1 year after delivery. Adverse pregnancy outcomes and infectious diseases in infants up to 1 year of age were compared between AYA cancer survivors and pregnant women without a history of cancer using binominal logistic regression analyses and a multiple imputation method. Of 99,816 participants (3,244 were missing), 1,102 (1.1%) had a cancer history, including 812 participants (0.8%) with a history of cervical cancer. Among cervical cancer survivors, the adjusted (a)ORs were as follows: 3.25 (95% CI, 2.31-4.57; q=0.00) for a preterm birth <34 weeks' gestation; 2.82 (95% CI, 2.31-3.44; q=0.00) for a preterm birth <37 weeks' gestation; and 1.67 (95% CI, 1.36-2.06; q=0.00) for premature rupture of the membrane. Among the other cancer survivors, the aOR for caesarean section was 1.43 (95% CI, 1.10-1.87; q=0.0). Furthermore, lower respiratory tract inflammation in 1-year-old infants born by vaginal delivery increased significantly in cases with a history of cervical cancer (aOR, 1.77; 95% CI, 1.33-2.36; q=0.00). The present study identified the risk of lower respiratory tract inflammation in 1-year-old infants born by vaginal delivery in cervical cancer survivors for the first time. In addition, the frequency of caesarean section increased in all cancer survivors. No risk of congenital anomalies or other infections were found in the total group of cancer survivors.

320 Study design and interim recruitment into the post-authorization safety study to monitor pregnancy and infant outcomes following administration of dupilumab during planned or unexpected pregnancy in North America

Abstract Dupilumab is a recombinant human immunoglobulin G (IgG) 4 monoclonal antibody that inhibits interleukin-4 and interleukin 13 signallings. Dupilumab has been approved in the United States (US) and Canada for the treatment of moderate-to-severe atopic dermatitis (AD), moderate-to-severe asthma and chronic rhinosinusitis with nasal polyps, and additionally in the US for eosinophilic esophagitis and prurigo nodularis. Data on the safety of dupilumab exposure during pregnancy is limited. This is a North American-based registry study designed to monitor pregnancy and infant outcomes among women in the US and Canada exposed to dupilumab when used to treat moderate-to-severe AD and moderate-to-severe asthma. The primary data collected from this prospective post-marketing pregnancy registry will allow for a better understanding of any effects of dupilumab exposure on pregnancy and infant outcomes in a real-life clinical setting. Presented is an overview of the study design and interim recruitment into this pregnancy study. The study will assess the risks of major structural birth defects, spontaneous abortion, elective termination, stillbirth, preterm delivery, the pattern of three or more minor structural defects, small for gestational age, postnatal growth at approximately 1 year of age, and serious or opportunistic infections in the first year of life in pregnancies exposed to dupilumab compared to a disease-matched comparison (DC) group and a healthy comparison (HC) group. This OTIS research study is a North American, prospective cohort study comparing pregnancy outcomes in participants exposed to dupilumab for asthma and/or atopic dermatitis to a DC group with asthma and/or atopic dermatitis without dupilumab exposure, and to an HC group. Participants exposed to dupilumab during pregnancy who do not meet the eligibility criteria are enrolled into a ‘case series’ and these data may be used to further inform on the safety of dupilumab. Recruitment began in October 2018 and will continue through October 2023, with a goal of 500 participants in the cohort study (200 dupilumab-exposed, 200 DC and 100 HC). The study captures data on exposures, outcomes and covariates through maternal interviews and maternal and pediatric medical records, and a pediatric dysmorphology exam. Disease severity is measured by maternal questionnaires and patient-reported disease severity scales. Between 24 October 2018 and 1 November 2022, 354 participants were enrolled in the cohort study, 144 Dupilumab-exposed, 134 DC and 76 HC. An additional 28 participants were enrolled in the dupilumab case series group. The most common reason for enrollment into the case series was retrospective enrollment, followed by having an indication other than AD or asthma and having exposure prior to the last menstrual period. The publication of this data will help healthcare professionals and their patients make informed treatment decisions during pregnancy.