Is there an association of co-occurring hypospadias and congenital heart defects (CHD) with method of conception? There is a small excess risk for co-occurring hypospadias and CHD among boys conceived through in vitro fertilization (IVF) not fully explained by other risk factors. We previously reported a higher prevalence of major CHDs among boys born with hypospadias. Our previous analyses leveraged 3.7 million pregnancies recorded through birth defect registries in 11 US states but could not evaluate the role of IVF in the risks for these pregnancy outcomes. Simultaneously, in registry data linked to fertility parameters, we observed excess risk for hypospadias and CHD with conception by IVF. The rarity of co-occurring birth defects requires large sample sizes with key information on both IVF treatment parameters and maternal characteristics to differentiate their roles in birth defects. We conducted a population-based study of live births in four US states (Massachusetts, New York, North Carolina, and Texas) from 2004 to 2018 and linked to IVF cycles reported to the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS). Information on the treatment cycle included the use of autologous or donor oocytes, fresh or frozen embryos, male infertility diagnosis, and the use of ICSI. Non-IVF births were sampled 10:1 at the time of IVF births. For the purposes of evaluating isolated and co-occurring hypospadias and CHD, our study included 731 838 boys born over the study period. State birth defect registries reporting British Pediatric Association codes were used to identify major birth defects. We formed four outcome groups: (i) boys with CHD alone, (ii) boys with hypospadias alone, (iii) boys with both (hypospadias-CHD), and (iv) boys without birth defects (comparison group). We used unadjusted and adjusted logistic regression to associate IVF conception with each outcome group relative to the common comparison group. Adjustments in each outcome model included backward elimination for birth year, plurality, maternal race/ethnicity, age, education, diabetes, hypertension, and parity. We additionally calculated the prevalence of CHD and hypospadias by IVF treatment parameters. Among 731 838 boys, we identified 267 who had both hypospadias and a major CHD, 65 conceived through IVF and 202 controls. We observed strong unadjusted associations of IVF with hypospadias (OR 1.49, 95% CI 1.37-1.62), CHD (OR 1.64, 95% CI 1.49-1.81), and hypospadias-CHD (OR 2.63, 95% CI 1.39-4.69). The associations of IVF with isolated hypospadias and isolated CHD were attenuated, but not fully explained, after adjustment for key covariates (hypospadias adjusted OR 1.15, 95% CI 1.03-1.28; CHD adjusted OR 1.14, 95% CI 1.003-1.29). The adjusted association of IVF with hypospadias-CHD suggests a stronger association than for either defect alone (OR 2.16, 95% CI 1.17-3.99), and calculating the observed-expected multiplicative effect supports an excess risk for hypospadias-CHD co-occurrence among boys conceived through IVF (observed ratio 1.65 > expected ratio 1). Among boys with hypospadias, 4.4% (95% CI 4.0-4.8) of boys conceived without IVF also had a CHD, whereas 6.9% (95% CI 5.8-8.0) of boys conceived using IVF also had a CHD. We found that prevalence of CHD was highest among boys with the most severe form of hypospadias among those conceived with IVF (14.1% with CHD, 95% CI 5.5-22.6) or naturally conceived (10.8% with CHD, 95% CI 6.6-15.0). Calculating number needed to screen (NNS) suggests that incorporating information on hypospadias and method of conception could allow for targeted CHD screening opportunities (NNS range: 8-99). Description of fertility treatment parameters suggests the prevalence of hypospadias or CHD among boys conceived using frozen embryos (autologous or donor oocytes) is 2.8%, and is 2.7% among boys whose fathers were diagnosed with male infertility. For co-occurring hypospadias-CHD, the prevalence was highest among boys conceived using donor oocytes (both fresh or frozen embryos) and among boys whose fathers were diagnosed with male infertility, though the absolute risk remained low (0.09-0.12%). When further evaluating male infertility by the use of ICSI, we found that ICSI use increased the risk for isolated or co-occurring defects regardless of an underlying diagnosis of male infertility. Based on the rarity of co-occurring birth defects (0.08% prevalence of hypospadias-CHD among boys conceived using IVF), we were not able to fully evaluate IVF treatment parameters or subfertility for their role in the co-occurrence of hypospadias and CHD. However, we adjusted for maternal characteristics related to both birth defect risks and fertility. We further sought to characterize treatment parameters that warrant follow-up in future studies of health outcomes among children conceived using IVF. The use of IVF is associated with increased risk for co-occurrence of two of the most common birth defects in boys, hypospadias and CHD, but the absolute risk remains low. Additional investigations of combinations of birth defects, other childhood outcomes in relationship to method of conception, and mechanisms to explain these associations are warranted. This project was supported by grant R01 HD112081 from the National Institute of Child Health and Human Development, USA (Barbara Luke and Philip Lupo, Multiple Principal Investigators). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Child Health and Human Development, or the National Institutes of Health, nor any State Departments of Health which contributed data. M.L.E. declares stock/shares from their role as advisor to Swim Club, VSeat, Doveras, Legacy, Illumicell, Hannah, and HisTurn. E.W. is employed by Redshift Technologies, Inc., which is the data vendor for SART, and has received consulting fees from SART. The other authors declare no competing interests. N/A.
Birth defects constitute substantial contributor to neonatal mortality and morbidity particularly in low and middle income countries. In Bangladesh, limited screening and low awareness contribute to delayed diagnoses and inadequate care. This study aimed to delineate the patterns of birth defects and identify associated risk factors to provide baseline data in a tertiary care neonatal intensive care unit in Bangladesh to support future surveillance, inform policy development, and guide preventive strategies. This hospital based prospective observational study was conducted in the Department of Neonatology at Chittagong Medical College Hospital, Bangladesh, from August to December 2020. Neonates with birth defects were identified through detailed clinical examination and classified according to the International Classification of Diseases, 10th Revision, Clinical Modification. Relevant data were collected using a predesigned questionnaire. Data were analyzed in SPSS version 28. Logistic regression was done to identify perinatal risk factors. A p-value < 0.05 was considered statistically significant. Among 5,223 admitted neonates, 183 (3.5%) had birth defects. Musculoskeletal anomalies were most common (67 cases), followed by cleft lip/palate (30), circulatory (29), chromosomal (24), eye, ear, face and neck (23) anomalies. Among these neonates, 56 (30.6%) died, with a 1.59 fold higher mortality risk compared to those without defects (95% CI: 1.15-2.18; p = 0.005). Maternal hypertension (AOR: 3.92; 95% CI: 2.56-5.99; p < 0.001), diabetes mellitus (AOR: 4.15; 95% CI: 2.37-7.27; p < 0.001), polyhydramnios (AOR: 7.33; 95% CI: 2.63-20.41; p < 0.001), and oligohydramnios (AOR: 10.19; 95% CI: 3.68-28.23; p < 0.001) were strongly associated with birth defects. The study highlights the significant burden of birth defects and associated neonatal mortality. Musculoskeletal anomalies were the most frequently observed defects. Maternal hypertension and diabetes mellitus were identified as strong predictors, warranting targeted antenatal screening and timely intervention. Routine neonatal examination at community level as well as in hospital is recommended to facilitate early detection and proper referral of birth defects.
Effective repair of vaginal defects, including those associated with Mayer-Rokitansky-Küster-Hauser syndrome, requires biomaterials that combine tissue-mimetic softness, hydration, mechanical resilience, and therapeutic activity. Here, we report a 3D-printable multifunctional hydrogel scaffold enabled by tetrahydroxy diboron (THDB) chemistry for accelerated vaginal defect repair. THDB triggers rapid radical polymerization of 2-hydroxyethyl methacrylate under oxygen-rich conditions, forming a poly(2-hydroxyethyl methacrylate) network strengthened by hydrogen bonding and B─O coordination from multiple boron species. The incorporation of calcium ions (Ca2 +) and N,N'-methylenebisacrylamide further improves mechanical strength and water stability. The resulting hydrogel exhibits tensile strength above 1.0 MPa, compressive stress of ∼2.0 MPa at ∼70% strain, stable cyclic tensile and compressive performance, and long-term aqueous stability with a swelling ratio of ∼160% in phosphate-buffered saline after 30 days. In addition, sustained release of THDB and Ca2 + provides therapeutic bioactivity, including reactive oxygen species scavenging and activation of redox- and metabolism-related signaling pathways. In a standardized rat model of full-thickness vaginal defects, the hydrogel effectively promotes tissue repair, demonstrating its potential as a mechanically robust, swelling-resistant, and bioactive scaffold for vaginal tissue reconstruction.
Preventive dental care is recommended in children with congenital heart disease (CHD) to prevent infective endocarditis (IE). We examined average annual preventive dental care utilization and the association between preventive dental care and IE in children with CHD. We conducted a retrospective cohort study examining children (1-18-year-olds), covered by Georgia Medicaid, with at least one CHD-related ICD code and a healthcare encounter between 2008 and 2019. Preventive dental care encounters were based on Current Dental Terminology (CDT) codes (D1000-D1999). CHD native anatomy was captured based on ICD-9-and-10-CM codes. Log binomial regression estimated adjusted risk ratios (aRRs) and 95% confidence intervals (CIs) for IE risk, controlling for sex, race and ethnicity, birth year cohort, rurality, and Social Deprivation Index. Of 61,024 children with CHD, 65.64% (n = 40,058) had at least one annual preventive dental visit on average, of which 0.30% (n = 181) had IE. For subgroups with valve or shunt lesions, having at least one annual preventive dental care visit showed a significantly lower risk of IE (aRR = 0.32; 95% CI = 0.18, 0.58, and aRR = 0.17; 95% CI = 0.07, 0.38, respectively) compared to no dental visits. No association was found between preventive dental care and IE in those with severe CHD (aRR = 0.81; 95% CI = 0.51, 1.26). Although dental health is important for patients with CHD, and despite universal dental coverage, many children with CHD do not seek annual preventive dental care. Integrating dental health assessments into routine CHD management protocols is imperative not only to promote oral health but also to prevent IE.
Medication usage prior to conception and over the duration of pregnancy is common. Two frequent sources that record such medications are self-report and administrative databases. Our goal was to examine the pattern of agreement among medications reported in each source. We linked all interviewed subjects recruited for the Birth Defects Study To Evaluate Pregnancy exposureS (BD-STEPS) in California to their Medi-Cal insurance claims. BD-STEPS is a population-based case-control study including livebirths, stillbirths, and terminations with a major birth defect and livebirth controls without defects. Among 195 California BD-STEPS participants that completed a structured interview and linked to their Medi-Cal claims, we compared the agreement of self-reported medication use with that documented in insurance claims using the simple kappa statistic and 95% confidence intervals. Among the 195 subjects, accounting for both sources there were a total 128 medications recorded. Agreement between self-report and Medi-Cal claims based on the kappa statistic varied considerably; for example, we found that acetaminophen [k = 0.06 (-0.04, 0.15)], amoxicillin [k = 0.05 (-0.12, 0.21)], ibuprofen [k = 0.02 (-0.10, 0.14)], and ondansetron [k = 0.11 (-0.07, 0.28)] all had poor agreement. Five medications showed perfect agreement [k = 1.00 (1.00, 1.00)] including amlodipine, glyburide, methimazole, metoprolol, and mirtazapine. For some medications agreement varied by case and control status or time to recall, but estimates were often imprecise. Medication reporting during pregnancy that comes from administrative claims and self-report each have their distinct advantages and limitations. Understanding how and why certain medications will populate one but not the other is an important consideration. Data drawn from multiple sources have the ability to complement one another, perhaps more so than confirm.
Delayed childbearing is increasingly common worldwide, with more women conceiving at age ≥35 years. This demographic shift intersects with age-related fertility decline, affecting natural conception, assisted reproductive technology (ART) outcomes and perinatal health. We conducted a narrative review based on structured searches of PubMed, Embase and Web of Science (2015-2025), supplemented by landmark earlier studies. We included peer-reviewed original research, systematic reviews, meta-analyses and clinical guidelines. Findings were synthesised narratively. Social, economic and cultural factors drive pregnancy postponement, increasing demand for ART. Female reproductive ageing involves declining oocyte quantity and quality, mitochondrial dysfunction, and aneuploidy - reducing fecundability and live birth rates. Advanced maternal age (AMA) elevates risks of gestational diabetes, hypertensive disorders, preterm birth, foetal growth restriction, stillbirth and congenital anomalies. Advanced paternal age independently contributes to miscarriage, preterm birth and offspring neurodevelopmental risks via epigenetic alterations and de novo mutations. Donor oocytes partially offset embryonic decline, but uterine ageing persists, especially after 45 years. Social oocyte freezing offers age-dependent efficacy, with optimal cost-effectiveness when performed in the early 30s. The health challenges of delayed childbearing may stem from a fundamental mismatch between enabling societal structures and immutable biological timelines. Clinical practice should adopt proactive, age-stratified care that includes preconception education, timely ART, risk-adapted obstetric management and advocacy for supportive social policies. Many people are choosing to have children later in life. This reflects positive social changes – such as more education and career opportunities for women. However, it also creates challenges because female fertility naturally declines with age, especially after 35. This review explains how and why age affects fertility.In women, both the number and quality of eggs decrease over time. Problems with energy production in egg cells (mitochondria) and errors in chromosome division lead to higher miscarriage rates and lower success with fertility treatments. The womb (uterus) also ages, making it harder to maintain a healthy pregnancy. Older fathers may also contribute to pregnancy risks through changes in sperm DNA.Having a baby at an older age increases the chances of pregnancy complications, including diabetes, high blood pressure, preterm birth and stillbirth. While egg freezing and in vitro fertilisation can help, their success depends strongly on the age at which they are used.For doctors, this means providing clear information about fertility timelines, offering timely treatment and closely monitoring pregnancies in older mothers. For society, it means creating policies – like affordable childcare and parental leave – that help people have children at ages that are both personally right and biologically favourable.
The present study aims to contribute to the available experience on the systemic use of five different anthelmintics during pregnancy (albendazole, mebendazole, praziquantel, pyrantel and pyrvinium). Particular focus was placed on the occurrence of major birth defects and pregnancy loss following first-trimester exposure. As the assessed agents differ considerably in terms of their chemical structure and mechanism of action, they were analyzed separately. A total of 282 pregnancies with exposure to the study medication were recorded in the Embryotox database (January 1, 2000-February 28, 2023) and analyzed descriptively. Among 75 live-born infants with first-trimester exposure to mebendazole, five major malformations were reported, three of which were heart defects. Of the 21 live-born infants exposed to pyrantel in the first trimester, two were affected by aplasia cutis congenita of the scalp, one of whom was co-exposed to thiamazole. Among 47 live-born children with first-trimester pyrvinium exposure, one major birth defect was reported. No major malformations were observed among 4 and 10 live-born children exposed to praziquantel and albendazole, respectively. Given the limitations, the findings should be interpreted as descriptive observations and possible signals only. Further investigations with larger cohorts are required.
Pregnancy is a transformative period that profoundly affects couple relationships and interactions. While this phase may strengthen intimacy and mutual understanding between partners, it also introduces significant physiological, psychological, and social stressors that can challenge relationship satisfaction and overall well-being. The dynamics of couple relationships during pregnancy affect not only the partners' emotional and mental health but also pregnancy outcomes, family functioning, and postnatal adaptation. A growing body of research has examined various aspects of couple relationships during this period, yet a comprehensive synthesis of the key factors influencing these dynamics remains limited. This review synthesizes current research on couple relationships during pregnancy, focusing on factors such as emotional intimacy, communication patterns, role transitions, and male involvement. A literature search was conducted in PubMed, Web of Science, and CNKI databases for studies published from December 2003 to December 2023. A total of 71 articles were included in this review after screening. The article aims to review both facilitators and barriers to positive couple interactions, emphasizing the need for targeted interventions to foster healthy relationship dynamics. By identifying gaps in existing research and suggesting directions for future studies, this review offers valuable insights for healthcare professionals, policymakers, and researchers aiming to improve relationship quality and better support pregnant women and their partners.
Infant mortality from congenital cardiovascular defects (CCDs) is the leading cause of death among individuals with birth defects. A descriptive analysis of infant mortality due to CCDs in Wisconsin and the United States was performed using data from the Centers for Disease Control and Prevention's Wide-ranging ONline Database for Epidemiological Research (WONDER) from 1995 to 2022. Congenital cardiovascular defect-related infant mortality (CCDIM) declined during this period in the United States (P < .0001) and in Wisconsin (P = .024). In the United States, African American and American Indian or Alaska Native populations experienced higher rates than Asian or White populations. In Wisconsin, non-White populations experienced higher CCDIM rates than White populations. CCDIM in Wisconsin has declined over time. However, an excess of CCDIM in non-White populations persists compared with White populations. Because many risk factors for CCDIM are related to behavioral, environmental, and socioeconomic factors, these observed differences may represent opportunities for targeted prevention efforts.
Cleft lip with or without cleft palate (CL/P) is a prevalent congenital anomaly influenced by multifactorial genetic and environmental factors. This study investigated the prevalence, temporal trends, diversity, unclassified cases, and associated risk factors for isolated CL/P in a tertiary Iranian hospital setting over two decades. A retrospective analysis of 767 isolated CL/P cases from 620,000 live births at 15 Khordad Hospital (Tehran, Iran) from 2003 to 2023 was conducted. Data were extracted from anonymized medical records, focusing on demographic, perinatal, and clinical variables. Prevalence was calculated per 10,000 live births, with Cochran-Armitage trend tests for temporal patterns. Univariable and multivariable logistic regression assessed associations, adjusted for confounders (p < 0.05). Prevalence was 1.24 per 1000 live births (95% CI: 1.15-1.33), with male predominance (59.7%; ratio 1.59:1). A significant non-linear temporal pattern was observed (p = 0.045), with fluctuations peaking mid-2010s. Diversity included 48.4% combined CL/P, 71.6% unilateral (42.1% left), and 58.7% complete forms; 4.3% were unclassified "nasal-dominant variants." Multivariable models identified maternal smoking (11-20 cigarettes/day: aOR 1.52, 95% CI 1.30-1.78), obesity (extreme: aOR 1.37, 95% CI 1.23-1.53), pre-pregnancy diabetes (aOR 2.00, 95% CI 1.68-2.38), hypertension (aOR 1.20, 95% CI 1.05-1.37), previous preterm birth (aOR 1.44, 95% CI 1.30-1.60), and assisted reproductive technology (aOR 1.42, 95% CI 1.18-1.71) as risks; higher education (aOR 0.82, 95% CI 0.74-0.91) and maternal age 30-34 years (aOR 0.90, 95% CI 0.81-1.00) were protective (Nagelkerke R2 = 0.18). Isolated CL/P in Iran exhibits stable yet fluctuating trends, driven by modifiable maternal risks amenable to preconception interventions. Enhanced public health strategies targeting smoking and obesity could reduce incidence by 15%-25%, aligning with global goals for congenital anomaly prevention.
Maternal consumption of khat has been associated with adverse neonatal outcomes like preterm birth and low birth weight. These effects resemble those seen in neonatal hypothyroidism, suggesting that khat disrupts thyroid function in the fetus. There is, however, limited data on the microscopic alterations in the thyroid gland of offspring following maternal consumption of khat. We examined the same in rat offspring whose mothers were exposed to khat during pregnancy as the suitable animal model. Female rats were acquired and randomized into groups receiving khat extract (200 or 500 mg/kg) or distilled water. Maternal khat consumption was started 7 days before mating and continued throughout pregnancy. From the offspring born, 28 thyroid glands were harvested and processed for histological analysis with hematoxylin and eosin and Ki-67 staining. Data on the follicle density and diameter, follicular cell epithelia, follicular cell nuclear-cytoplasmic index, and expression of proliferation marker Ki-67 were collected. These were analyzed using SPSS and key findings presented in tables and photomicrographs. Compared to controls, khat-treated groups exhibited parenchymal disruption evidenced by a dose-dependent epithelial shift of follicular cells from columnar to cuboidal, reduced follicular diameter, reduced follicular density, and increased nuclear-cytoplasmic index. There was also suppressed proliferative activity evidenced by a reduction in cells expressing Ki-67. Infiltration of follicular cells into colloid was observed in treated groups. The observed parenchymal insult of the fetal thyroid gland following maternal exposure to khat could partially explain the adverse birth outcomes seen in the offspring.
Pregnancy complications such as miscarriage, preterm birth (PTB), and luteal phase defects (LPD) are significant reproductive health issues globally, with both physical and psychological implications. This review aims to examine the role of natural progesterone in pregnancy-related disorders, specifically threatened and recurrent miscarriage, PTB, and LPD. Additionally, it examines how natural progesterone's immune-modulating actions, including both direct and indirect involvement, contribute to maintaining pregnancy. This narrative review was conducted using PubMed, Google Scholar, and reference screening to identify English-language studies examining the role of natural progesterone in miscarriage, PTB, and LPD. Emphasis was placed on progesterone's immunomodulatory actions, including cytokine regulation and the activity of the progesterone-induced blocking factor (PIBF), and their relevance to pregnancy maintenance. Natural progesterone demonstrates clinical benefit in managing threatened miscarriage, recurrent pregnancy loss, preterm labor, and LPD. Evidence shows that it is well-tolerated with manageable side effects, reducing miscarriage rates, preventing PTB, and improving LPD outcomes through its effects on the maternal-fetal interface. This review also highlights progesterone's dual immunomodulatory action, direct cytokine regulation, and indirect influence via PIBF, which together contribute to improved pregnancy maintenance and outcomes. Natural progesterone supports pregnancy by preventing miscarriages, preterm labor, and LPD through its direct and indirect immunomodulatory mechanisms. Clinically, it is well-tolerated with no serious or unexpected adverse events. However, gaps remain in fully understanding its effectiveness, emphasizing the need for further research.
Anti-infective agents are widely used during pregnancy to prevent, treat, and mitigate the transmission of infections, and their utilisation has significantly increased over the past decade. However, concerns persist regarding their potential embryotoxicity, compounded by inconsistencies in safety data that complicate medication decision-making. This protocol details an umbrella review that aims to provide a comprehensive and methodologically sound synthesis of evidence from systematic reviews (SRs) on the adverse effects of prenatal anti-infective exposure on offspring. The review will incorporate a standardised, three-stage data extraction strategy and an R-based algorithm to efficiently identify and manage overlapping evidence. We will conduct a comprehensive search across six databases (PubMed, Embase, Scopus, Web of Science, Cochrane Library, and Epistemonikos) from inception to June 22, 2024. The search will cover three key concepts-pregnant women, anti-infective agents, and systematic reviews-without restrictions on controls or outcomes. We will include SRs, with or without meta-analyses, that evaluate the adverse effects of prenatal anti-infective exposure and report either neonatal outcomes (e.g. birth defects) or long-term offspring outcomes (e.g. neurodevelopmental disorders). To address overlapping evidence, a structured three-stage data extraction process, supported by an R-based algorithm, will be implemented, sequentially handling PICO definition extraction, overlapping evidence management, and quantitative data extraction. At least two independent reviewers will screen studies, extract data, and assess methodological quality and evidence strength using AMSTAR-2 and GRADE, respectively. Evidence synthesis will be conducted narratively, drawing on meta-analytic associations from direct comparative analyses and organising findings by anti-infective agents, indications, outcomes, effect estimates, certainty of evidence, and methodological quality. Anti-infectives with safety concerns will be summarised in tables and evidence maps. By adopting a standardised process that incorporates an automated algorithm for managing overlapping evidence, the planned umbrella review will provide a comprehensive synthesis of existing evidence on the adverse effects of anti-infective use during pregnancy. The findings are expected to inform clinical practice, guide policy decisions, and support infection management in pregnant patients. Furthermore, the review will identify key knowledge gaps, help prioritise future research, and ultimately contribute to improving maternal and offspring health outcomes. PROSPERO CRD42024577013.
Bronchopulmonary dysplasia (BPD), a leading respiratory complication in preterm infants, is strongly associated with hyperoxia-induced pulmonary vascular injury resulting from essential oxygen therapy. The precise pathological mechanisms linking hyperoxia to BPD, along with effective interventions, remain poorly understood. This review systematically analyzes existing literature to elucidate these mechanisms and evaluate potential therapies, thereby informing future research directions. A thorough search was conducted across electronic databases, including PubMed, Web of Science, and Embase. Literature up to August 2025 concerning hyperoxia and pulmonary vascular injury in both patients with BPD and animal models was reviewed. From 807 initial records, 359 remained after duplicate removal. Following eligibility screening, 55 articles were included for analysis. The vast majority were preclinical studies, with 32 focusing on disease mechanisms and 23 investigating potential treatments. Hyperoxia-induced pulmonary vascular injury in BPD is driven by a multifaceted network involving signaling pathways, epigenetic modifications, metabolic dysregulation, and phenotypic alterations, rather than a singular mechanism. Although emerging therapeutic strategies show promise and diversity, aligning with the complex etiology of BPD, the majority of interventions targeting pulmonary vascular injury remain at the preclinical stage. Advancing their clinical translation represents a key direction for future research. This review systematically synthesizes existing evidence, clarifies the central role of hyperoxia-induced pulmonary vascular injury in bronchopulmonary dysplasia, and further validates the vascular hypothesis. This review suggests that hyperoxia-induced pulmonary vascular injury is not attributable to a single cause, but a complex network of injury mechanisms, which is also consistent with the multifactorial pathogenesis of bronchopulmonary dysplasia. This review finds that the vast majority of current studies remain at the preclinical stage, and promising therapeutic strategies urgently need further clinical translation, which represents a key gap in this field. It points out the direction for future research. Graphical AbstractThe Injury-Mechanism-Intervention-Outcome Process of Hyperoxia-Induced Pulmonary Vascular Damage.
The association between Zika virus (ZIKV) infection in pregnant women and congenital defects is well-established. However, the consequences of infection with both ZIKV and Chikungunya virus (CHIKV) during pregnancy remain poorly understood. The aim for the present study was to estimate and compare the risk of adverse outcomes in infants born to mothers infected with ZIKV alone and those born to mothers infected with both ZIKV and CHIKV during pregnancy. A cohort study was conducted, following pregnant women with rash who were reported to the Strategic Health Surveillance Information Center of the State of Pernambuco between 2015 and 2017 and underwent laboratory testing for ZIKV and CHIKV. All participants resided within a 120-kilometer radius of the city of Recife, Pernambuco, Brazil. Newborns were monitored through standardized assessments conducted by specialists from the Microcephaly Epidemic Research Group. Adverse outcomes were compared between newborns prenatally exposed to ZIKV alone and those exposed to both ZIKV and CHIKV using descriptive statistics, as well as RRs. A total of 278 children (n = 198 exposed to ZIKV alone; n = 80 exposed to ZIKV and CHIKV) were included. No significant differences were observed between the groups in the offspring's risks of microcephaly, low birth weight, prematurity, small for gestational age, dysphagia, neurological, ophthalmological, audiological, or neuroimaging abnormalities. Although previous studies have revealed that each infection independently may be associated with adverse outcomes in newborns, the present study generally revealed no difference in the frequency or type of adverse effects in children born to mothers infected with both ZIKV and CHIKV compared with those exposed only to ZIKV during pregnancy.
Congenital anomalies (CA) are ranked as the 3rd and 4th leading cause of neonatal and under-5 mortality, respectively. Over 30% of infants born with a serious CA are found in sub-Saharan Africa. Yet there are few robust epidemiological data on the burden and distribution of CA and associated mortality, disability, and morbidity, which limits research and investment in clinical and public health interventions. The sub-Saharan African Congenital Anomalies Network (sSCAN) was established in 2021 to address the fragmented research, surveillance, and care programmes for children with CA in the region. The sSCAN established a community of practice with the long-term aim to promote the prevention and early diagnosis of CA and care for children and families, determining prevalence, promoting preventive interventions, and improving health outcomes by: (1) Sharing resources and multidisciplinary expertise; (2) Establishing a common response to public health questions; (3) Pooling and comparing data between countries; (4) Capacity building. The sSCAN includes 16 projects across 12 countries, in addition to other stakeholders in sub-Saharan Africa. Most projects are fully or jointly supported by donor partners with a specific disease/exposure focus: collaboration within Africa is uncommon. Lack of data harmonization, varied funding streams and related data access, and country- and institution-specific data-protection legislation limited regional data sharing. The sSCAN has hosted 15 webinars which are available with other resources on the website, and supported grant applications and publications. The sSCAN platform can provide opportunities to build capacity, share expertise, and optimize data use toward contextually-relevant solutions for CA in sub-Saharan Africa.
Pregnant women are at increased risk of severe illness from COVID-19, yet they were excluded from the initial clinical trials of COVID-19 vaccines, resulting in limited pregnancy-specific safety data. The COVID-19 Vaccines International Pregnancy Exposure Registry (C-VIPER) was established to prospectively collect safety and birth outcome data following COVID-19 vaccination during pregnancy. This article summarizes key operational, methodological, and scientific lessons from implementation of the registry. The C-VIPER was designed as an international, noninterventional, postmarketing cohort study using a web-based platform to enroll pregnant women exposed to COVID-19 vaccines and collect longitudinal maternal, pregnancy, birth, neonatal, and infant outcome data. Registry implementation, recruitment, retention, questionnaire design, comparator selection, data completeness, and evolving vaccination patterns were reviewed to identify lessons relevant to future pregnancy safety studies. Implementation during a global pandemic presented substantial challenges, including uncertainty regarding vaccine acceptance and study participation among pregnant women, widespread misinformation and vaccine hesitancy, evolving vaccination regimens, recruitment and long-term retention difficulties, and limitations in questionnaire design and data completeness. Despite these challenges, the C-VIPER demonstrated the feasibility of conducting a large-scale multinational, web-based pregnancy registry under emergency conditions and highlighted important methodological considerations for future postmarketing vaccine safety studies in pregnancy. The C-VIPER contributed to the broader evidence base evaluating COVID-19 vaccination during pregnancy and provided important lessons for the design and implementation of future pregnancy registries. Future studies should prioritize early planning, flexible protocol design, robust recruitment and retention strategies, careful comparator selection, and mechanisms to improve data completeness and quality. NCT04705116, EUPAS39096.
Primary ciliary dyskinesia (PCD) is a rare genetic disorder mainly characterized by impaired mucociliary clearance and chronic respiratory symptoms. From a consanguineous family, a male patient, although with respiratory complaints since birth, was diagnosed with PCD only in adulthood. Whole-exome sequencing disclosed a novel homozygous intronic single-nucleotide deletion, NM_001369.3(DNAH5):c.13723+4del, initially classified as of uncertain clinical significance. Digital highspeed videomicroscopy (HSVM) evidenced a null ciliary beating frequency; transmission electron microscopy showed absence of outer dynein arms (class-1); and immunofluorescence (IF) demonstrated markedly absent DNAH5 protein level in the apical cilia region with delocalization to the transition and basal-body regions. Bioinformatic analysis predicted altered splicing at the donor splice site of exon 78, whereas mRNA sequencing revealed two splicing defects: the mainly expressed transcript corresponding to exon 78 skipping and a minor transcript originated from a cryptic splice site in exon 78. The patient was infertile and showed severe oligoteratozoospermia. Sperm IF analysis revealed absence of DNAH5 from the flagellum with accumulation at the neck region. The family study confirmed homozygosity. The present results support a pathogenic role for the c.13723+4del variant and underscore the importance of integrating clinical, ultrastructural, DNA, mRNA and protein analyses to clarify and contribute to PCD diagnosis.
Our objective was to evaluate the occurrence of congenital anomalies in pregnant women who received at least one dose of COVID-19 vaccine from conception up to 11w and 6d in comparison to those vaccinated after 12 weeks of pregnancy or not vaccinated at all. This study is a Registry-Based Cohort Study carried out in the cities of Yasuj and Hormozgan, Iran. Participants involved divided into three groups for analysis: unvaccinated individuals, vaccinated during the teratogenic window (defined as women who received at least one dose of COVID-19 vaccine from conception up to 11w and 6d) and participants who received the vaccine after the first 12 weeks of pregnancy, (categorized as women vaccinated outside the organogenesis period). The primary outcome was congenital anomalies, which were identified as the presence of at least one birth defect detected prenatally through ultrasound. Overall, most congenital anomalies were rare and occurred at very low frequencies across groups. Atrioventricular septal defects (AVSD) were observed more frequently in women vaccinated within the teratogenic window compared with unvaccinated women (SMD = 0.22). Cleft palate also occurred slightly more frequently in this group (SMD = 0.13). For all other anomalies, effect sizes were small (SMD < 0.15) and no clinically meaningful differences were observed. This study provides preliminary descriptive evidence regarding the occurrence of congenital anomalies following COVID-19 vaccination during early pregnancy. Because of the low number of events and the exploratory nature of the analyses, no causal inference can be made.
Global Vhl knockout results in vascular defects and early lethality, limiting our knowledge of von Hippel-Lindau/HIF (hypoxia-inducible factor) signaling in coronary vessel formation and homeostasis. The hypoxia pathway has been implicated in cardiovascular diseases characterized by inflammation and vascular remodeling, such as atherosclerosis, but its involvement in Kawasaki disease (KD) remains unknown. Coronary artery dilation and vessel rupture are the most serious complications of KD. However, the molecular mechanisms underlying these cardiac events are not fully understood. We investigated the role of the von Hippel-Lindau/HIF pathway in cardiovascular pathology and its relevance to KD. We generated a novel mouse model with genetic hyperactivation of the hypoxia pathway in progenitors contributing to coronary vessels and cardiac fibroblasts. We characterized the model using echocardiography, magnetic resonance imaging, histology, and molecular profiling. In parallel, we examined cardiac tissues from patients with KD with fatal coronary aneurysms for evidence of HIF signaling and inflammation using immunohistochemistry. Mice with conditional deletion of Vhl in Wt1 (Wilms tumor 1)-expressing cells developed normally but exhibited cardiomegaly, vascular abnormalities, progressive coronary artery dilation, pericardial hemorrhage, and systemic inflammation shortly after birth. Histologic analysis revealed coronary arteritis, elastin breaks, vascular remodeling, smooth muscle cell loss, perivascular fibrosis, and frequent intracoronary thrombus formation. In addition, vascular calcification, severe cardiac inflammation, and interstitial hemorrhages were observed, culminating in sudden death between 15 and 20 weeks of age, likely due to vessel rupture. Cardiac transcriptomic profiling identified dysregulated expression of genes involved in extracellular matrix organization, epithelial-mesenchymal transition, angiogenesis, inflammation, coagulation, and calcification, indicating compromised vascular stability and increased remodeling in Vhl conditional knockout mice. Simultaneous deletion of Hif2a rescued both the cardiovascular abnormalities and transcriptomic profile observed in Vhl conditional knockout mice, implicating Hif2 (hypoxia-inducible factor 2) as a key mediator. Human KD cardiac samples showed expression of HIF2 in coronary lesions and surrounding inflammatory infiltrates, confirming hypoxia pathway activation in severe KD. Our findings establish HIF2 as a central driver of coronary inflammation, vascular remodeling, and thrombotic complications resembling those observed in severe KD. The Vhl/Wt1 conditional knockout mouse model recapitulates key cardiovascular features of KD and offers a valuable platform for mechanistic studies and therapeutic exploration.