BACKGROUND:Prenatal nicotine exposure (PNE) remains a significant public health concern due to persistent tobacco use, electronic nicotine delivery systems, and second-hand exposure during pregnancy. Epidemiological and experimental evidence has demonstrated that nicotine can readily cross the placenta, disrupt placental development, and interfere with tightly regulated processes of fetal organogenesis. These early perturbations are increasingly recognized as initiating a cascade of structural, functional, and molecular alterations that extend beyond gestation and influence health trajectories across the lifespan. However, existing studies are often compartmentalized by developmental stage, limiting mechanistic integration across prenatal, natal, postnatal, and later-life outcomes. METHODS:This review aims to (i) synthesize evidence from placental biology, developmental toxicology, neurobiology, and epigenetics to propose an integrated, life-course cascade model of PNE; (ii) delineate how nicotine-induced placental dysfunction and fetal hypoxia during prenatal development transition into structural, physiological, perinatal autonomic, and cardiorespiratory vulnerability, contributing to adverse birth outcomes and increased risk of sudden infant death syndrome; and (iii) examine how early disruption of nicotinic acetylcholine receptor mediated signaling alters neuronal differentiation, synaptic maturation, neuroimmune interactions, and stress-response pathways, leading to persistent cognitive, behavioral, and psychiatric susceptibility in postnatal life and adulthood. Emerging evidence for epigenetic reprogramming, sex-specific vulnerability, and intergenerational transmission, including paternal contributions, is also evaluated. RESULTS:Evidence synthesized across placental biology, developmental toxicology, neurobiology, and epigenetics supports a cascade in which nicotine-induced placental dysfunction and fetal hypoxia contribute to structural, physiological, perinatal autonomic, and cardiorespiratory vulnerability, adverse birth outcomes, and increased risk of sudden infant death syndrome. Early disruption of nicotinic acetylcholine receptor-mediated signaling is associated with alterations in neuronal differentiation, synaptic maturation, neuroimmune interactions, and stress-response pathways, contributing to persistent cognitive, behavioral, and psychiatric susceptibility in postnatal life and adulthood. Emerging evidence also supports roles for epigenetic reprogramming, sex-specific vulnerability, and intergenerational transmission, including paternal contributions. CONCLUSION:By integrating temporally distinct findings into a unified mechanistic framework, this review identifies critical developmental windows and molecular targets for intervention. Such an approach is essential for advancing preventive strategies, informing public health policy, and mitigating the long-term and transgenerational consequences of nicotine exposure.
OBJECTIVE:Congenital anomalies (CA) are health problems that can significantly affect individuals, families, health systems, and society. Our aim is to present the characteristics of CA observed in babies born at our institution between 2014 and 2023, including the Covid-19 pandemic period. MATERIALS AND METHODS:Retrospective data obtained from the delivery room records and hospital information system of Pamukkale University Hospital were analyzed. RESULTS:During the 10-year period covered by our study at our institution, 16,030 births occurred, and 941 (5.87%) newborns were diagnosed with CA. The most common anomalies were cardiovascular system (CVS) (42%), other congenital malformations (5%), musculoskeletal system (4%), and central nervous system (CNS) anomalies (7%). Two hundred twenty-nine newborns (24%) were found to have multiple congenital anomalies. The prevalence of CA was higher in 2020, 2021, and 2022 (during the COVID-19 pandemic) compared to other years. The mortality rate among newborns with CA was 21.25%. Of the CA babies who died, 37.5% had CVS, 30% had multiple anomalies, and 9% had CNS anomalies. The mortality rate due to congenital anomalies, based on the total number of births in our hospital, was 1.25%. CONCLUSION:We found that the mortality rate among newborns with CA was 21.25% and that the incidence of anomalies increased during the COVID-19 pandemic. Multidisciplinary efforts are required to provide parents with the necessary information during pregnancy and the prepregnancy planning period. It is crucial to examine the prevalence of CA during the Covid-19 pandemic period in other regional studies and to evaluate the impact of such epidemics on anomalies.
BACKGROUND:Congenital anomalies are common, costly, and potentially life-threatening. The impacts of structural determinants of health on risk for these conditions have scarcely been studied. We evaluated associations between residence in economically disadvantaged neighborhoods or Hispanic/Latino enclaves and congenital anomalies. METHODS:We performed a registry linkage study of 7.25 million births and 332,935 cases with anomalies in Texas, 1999-2018. We defined exposure groups using maternal residential address at delivery or termination and tract-level Yost socioeconomic index and Hispanic/Latino enclave index scores: high neighborhood socioeconomic status (nSES)-non-enclave (referent), high nSES-enclave, low nSES-non-enclave, and low nSES-enclave. We estimated adjusted birth prevalence ratios (aPRs) and 95% confidence intervals (CIs) for 146 congenital anomalies using Poisson regression. RESULTS:Maternal residence in a low nSES area was associated with increased prevalence of microcephaly, atrial septal defect, pulmonary artery and pulmonary valve anomalies, patent ductus arteriosus, anomalies of the great veins, polydactyly, and Down syndrome (PRs 1.06-1.96) but decreased prevalence of hypospadias, epispadias, and chordee (PRs 0.67-0.89). Maternal residence in an enclave was associated with increased prevalence of ventricular septal defect, pulmonary artery anomalies, female genital anomalies, and Down syndrome (PRs 1.09-1.96). Pyloric stenosis was associated with residence in a low nSES neighborhood (enclave: PR 1.09, CI 1.03-1.14; non-enclave: PR 1.12, CI 1.06-1.17) and inversely associated with residence in a high nSES enclave (PR 0.89, CI 0.80-0.98). CONCLUSIONS:Neighborhood socioeconomic and sociodemographic factors are associated with congenital anomalies, suggesting differences in risk factors or ascertainment in economically disadvantaged neighborhoods or Hispanic/Latino enclaves.
BACKGROUND:Childhood stunting (height-for-age z-score < -2 SD) remains a global developmental health burden. Traditional interventions centered on nutrition and infection have reached a bottleneck. Emerging evidence identifies chronic low-dose dietary environmental toxins as an independent, modifiable risk factor for early-life growth restriction. METHODS:This review synthesizes cohort studies, meta-analyses, and in vivo toxicological models published over the past decade to characterize exposures to mycotoxins, toxic heavy metals, and food-borne endocrine disruptors that are closely associated with stunting. RESULTS:Multi-layered mechanisms are elucidated, including environmental enteric dysfunction (EED), intestinal barrier disruption, persistent subclinical inflammation, GH-IGF-1 axis disturbance, gut microbiota dysbiosis, oxidative stress, and epigenetic alterations, which collectively impair linear growth. Critical surveillance gaps are identified, and integrated environment-nutrition-infection intervention strategies aligned with public health practice are proposed. CONCLUSIONS:Dietary environmental toxins cause irreversible developmental deficits by damaging intestinal function and disrupting endocrine regulation. Strengthening developmental toxicology-oriented monitoring and source control will support precise prevention of early childhood stunting within the critical first 1000-day window.
BACKGROUND:Major congenital anomalies (MCAs) are a leading cause of neonatal morbidity and mortality and frequently reflect underlying chromosomal, copy number, or single-gene defects. In neonates with multiple MCAs, early molecular diagnosis is critical but remains challenging due to phenotypic heterogeneity, overlapping developmental pathways, and limitations in selecting the most appropriate genetic test. METHODS:This prospective study included 146 neonates with congenital anomalies who were referred for genetic consultation from a tertiary neonatal intensive care unit between April 2022 and May 2025. A major congenital anomaly was defined as a structural abnormality present at birth with significant medical, functional, or cosmetic consequences, while multiple congenital anomalies were defined as two or more major anomalies involving different organ systems. Clinical features were systematically annotated using Human Phenotype Ontology terms and classified according to organ system and embryological origin. A tiered diagnostic strategy was applied, including conventional cytogenetic analysis, chromosomal microarray analysis (CMA), whole-exome sequencing (WES), and rapid-WES (rWES) in selected critically ill neonates. RESULTS:Cardiovascular anomalies were the most frequent (45.9%), and 88 of 146 neonates (60.3%) had two or more MCAs. Cytogenetic testing identified numerical chromosomal abnormalities in eight neonates. CMA detected pathogenic or likely pathogenic copy number variants in 6 of 65 tested cases (9.1%). In CMA-negative patients, WES achieved a diagnostic yield of 41.4%, identifying variants in genes involved in multisystem developmental pathways. Rapid WES established definitive molecular diagnoses in two of three critically ill neonates within 72 h, directly influencing clinical management. Embryological analysis revealed recurrent co-occurrence patterns, particularly cardiovascular-craniofacial and cardiovascular-genitourinary associations. CONCLUSION:A structured, tiered genomic approach enhances diagnostic yield in neonates with congenital anomalies. Integration of cytogenetics, CMA, and CNV-aware exome sequencing provides a pragmatic and clinically actionable framework for molecular diagnosis in NICU settings and supports developmentally informed interpretation of complex phenotypes.
BACKGROUND:The preterm birth rate among infants with trisomy 21 is more than twice the rate among the general population. Maternal hypertension and diabetes are established risk factors for preterm birth in the general population; however, their impact on pregnancies of infants with trisomy 21 is unknown. This study aimed to evaluate the association between maternal hypertensive disorders/diabetes and preterm birth among infants with trisomy 21. METHODS:We utilized data from the Texas Birth Defects Registry for deliveries between 1999 and 2018 (n = 9355). We conducted Poisson regression to estimate crude and adjusted risk ratios for preterm birth associated with any maternal hypertension and any diabetes, and their subtypes (pregestational, gestational). We also evaluated the risk associated with exposure to both (co-occurring) conditions compared to neither. Stratified analyses were conducted by racial/ethnic subgroups, preterm subtypes (< 32 weeks and 32-36 weeks), and presence/absence of congenital heart defects as part of secondary analyses. RESULTS:We found that maternal hypertension and diabetes were associated with 50% and 21% higher risk for preterm birth, respectively, while the presence of both conditions versus neither was associated with a 71% higher risk. The association with hypertension was much stronger for delivery at < 32 weeks aRR 2.60 (95% CI 1.83, 3.70) than for delivery at 32-36 weeks aRR 1.46 (95% CI 1.28, 1.66). CONCLUSIONS:Our findings shed light on the role of maternal hypertension and diabetes in preterm birth risk among infants with trisomy 21, particularly when both conditions co-occur and for extremely to very preterm birth.
BACKGROUND:Reproductive toxicity studies for industrial and agricultural chemicals require enumeration of ovarian follicles (OF). In recent years, the enumeration of corpora lutea (CL) in histological sections has also been requested. Both endpoints are now considered routine quantitative measures to assess female reproductive toxicity of (agro)chemicals and have also been used to support pharmaceutical drug development, when warranted. Procedural guidance for both endpoints from FDA, EPA, OECD, and other regional health authorities is generally limited. While most laboratories follow the generically stated procedures for including a statistically appropriate number of animals and ovarian section selection, methodologies vary significantly across the industry making cross-study data comparisons extremely challenging. In March 2023, the European Chemicals Agency (ECHA) published its report on its EOGRTS Review Project and noted the lack of information on laboratory proficiency and high variability as the main deficiencies in OF and CL count data which resulted in industry-wide discussions regarding the lack of published guidance and the need for updates to regulatory guidelines. In June 2025, OECD TG 443 was updated to include additional information regarding qualitative ovarian evaluation; however, no new information regarding laboratory proficiency or reduction of variability was included. METHODS:We discuss the biological relevance of these endpoints, the need for consistency across the industry, and technical and scientific considerations for quantitative ovarian assessments and present historical control data for these endpoints. RECOMMENDATIONS AND CONCLUSIONS:Based on the authors' collective experience and successful regulatory history, we put forth best practice recommendations for data collection and analysis with the goal to provide a frame of reference for industry laboratories.
INTRODUCTION:Children with birth defects often require complex medical care, contributing to increased healthcare costs. Understanding the economic burden of birth defects is important for resource planning, but recent Texas-specific data are lacking. METHODS:A retrospective data analysis was conducted using the Texas Hospital Inpatient Discharge Public Use Data File (PUDF) for all pediatric discharges (ages 0-17 years) documented between 2021 and 2023. We identified hospitalizations with birth defects based on the presence of an ICD-10 code (Q00-Q99) in any of the 26 diagnosis code fields. Median inflation-adjusted hospitalization charges were calculated for hospitalizations with and without birth defects and were then stratified by characteristics of interest. Median charges were compared using the Wilcoxon-rank sum test. Among hospitalizations of children with a birth defect in the principal diagnosis code field, charges were examined by birth defect phenotype. A sub-analysis assessed charges for hospitalizations that occurred primarily in the Intensive Care Unit (ICU). RESULTS:In Texas, 12.5% of all pediatric hospitalizations were for children with a birth defect. Aggregate total charges for these hospitalizations exceeded $26 billion and comprised 34.9% of all pediatric hospitalization charges. Hospitalizations for children with a birth defect had significantly higher median charges ($12,876 vs. $7,813) compared to hospitalizations for children without birth defects (p < 0.001). Higher charges were observed for hospitalizations among several subgroups (e.g., ICU hospitalizations). CONCLUSION:Inpatient hospitalization charges for children with birth defects had a disproportionately high impact on hospitalization charges in Texas.
BACKGROUND:Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used during pregnancy, yet information on their developmental safety during sensitive perinatal windows remains limited. This study evaluated the maternal and early developmental effects of paracetamol/acetaminophen, aspirin, and nimesulide administered at therapeutically relevant doses during late gestation and lactation. METHODS:Pregnant Wistar rats were treated daily by oral gavage with paracetamol/acetaminophen (APAP; 126 mg/kg/day), aspirin (ASA; 5.6 mg/kg/day), or nimesulide (NIM; 11 mg/kg/day) from gestational day 15 to postnatal day 22. Maternal clinical parameters, body weight, food and water intake, organ weights, hematological and biochemical markers, and maternal behavior were evaluated. In F1 offspring, early developmental indicators, anogenital distance, sexual maturation endpoints, reproductive organ weights, and hematological parameters were assessed. RESULTS:Exposure to the evaluated NSAIDs produced little evidence of overt maternal toxicity. Maternal body weight, food and water intake, gestational length, and most organ weights remained unchanged. Mild hematological and biochemical alterations were observed, particularly in NIM-treated dams. Maternal behavior was largely preserved, although APAP-treated dams showed reduced latency to initiate pup grooming. In offspring, anogenital distance and female reproductive maturation were unaffected. Male offspring exposed to APAP showed earlier testicular descent, whereas ASA exposure was associated with increased seminal vesicle weight. These findings were isolated and were not associated with a consistent pattern of reproductive alterations. CONCLUSION:Perinatal exposure to therapeutically relevant doses of paracetamol/acetaminophen, aspirin, and nimesulide produced little evidence of overt maternal or developmental toxicity during the evaluated period. Although a limited number of drug-specific findings were identified, they were isolated and did not indicate a consistent pattern of reproductive toxicity. These results contribute to the preclinical safety assessment of NSAID exposure during pregnancy and lactation and support further studies to determine the functional relevance of these early observations.
BACKGROUND:We assessed healthcare access and utilization among adults with congenital heart defects (ACHD) across racial and ethnic groups using a US population-based sample. METHODS:The cross-sectional CH STRONG was conducted from 2016 to 2019 among ACHD in Arkansas, Arizona, and Atlanta. Participants completed a self-administered questionnaire on their healthcare access, utilization, health status, comorbidities, and demographics. Differences in healthcare access and utilization among non-Hispanic White (NH-White), non-Hispanic Black (NH-Black), and Hispanic ACHD were assessed, and adjusted prevalence ratios (aPRs) and 95% confidence intervals (CI) reported. Health-related quality of life (HRQOL) was also compared with standardized norms for the general population from the Patient-Reported Outcomes Measurement Information System (PROMIS). Models were adjusted for age, sex, educational attainment, marital status, study site, and CHD severity. RESULTS:Of 1455 respondents, 76.7% were NH-White, 15.0% were NH-Black, and 8.9% were Hispanic. Compared to NH-White, NH-Black ACHD were less likely to have health insurance (aPR = 0.94; CI: 0.88-0.99) and more likely to report a prior gap in insurance coverage (aPR = 1.88; CI: 1.44-2.46). They were also less likely to have a usual place of care (aPR = 0.82; CI: 0.75-0.89) or any healthcare visits (aPR = 0.88; CI: 0.81-0.96) but more likely to have ≥ 1 emergency room visit (aPR = 1.66; CI: 1.38-2.00) and hospitalization (aPR = 1.96; CI: 1.40-2.74) in the past year. Hispanic ACHD were more likely than NH-White to report a prior gap in insurance coverage (aPR = 1.78; CI: 1.19-2.65). CH STRONG ACHD did not differ from the general population on global mental-health and physical-health scores. CONCLUSIONS:Racial and ethnic differences in healthcare access and utilization exist among a population-based group of ACHD. Strategies for improvement in access to quality care may help reduce differences.
INTRODUCTION:Little is known about routine testing practices and diagnosis of congenital cytomegalovirus (cCMV) infection in newborns admitted to neonatal intensive care units (NICUs) across the United States. We assessed demographics and clinical signs associated with cCMV testing and diagnosis in newborns admitted to US NICUs. METHODS:We analyzed Pediatrix Clinical Data Warehouse data, comprising 840,988 newborns admitted to 389 NICUs in 35 states during 2010-2020. We defined cCMV testing as culture or PCR performed on urine, saliva, blood, or cerebrospinal fluid collected within 21 days of life, and a positive result (except in saliva) as cCMV infection diagnosis. Logistic regression models examined associations between clinical signs and cCMV testing and diagnosis separately, adjusting for region, birth year, and prematurity. RESULTS:Among 10,033 (1.2%) newborns tested (67.7% by culture; 79.8% using urine), 559 (5.6%) were diagnosed with cCMV infection. During 2010-2020, among those tested, the proportion with ≤ 1 clinical sign increased from 12.9% to 32.0%. Hepatosplenomegaly, petechiae, microcephaly, hepatitis, thrombocytopenia, chorioretinitis, and intracranial calcifications were associated with increased odds of both cCMV testing and diagnosis, with varying specificity. CONCLUSIONS:Despite low CMV testing rates in the NICU, a shift toward testing newborns with fewer clinical signs occurred over time.
BACKGROUND:Massachusetts Department of Public Health (MDPH) disaggregated data on vaccine coverage for pregnant people by their specific racial and ethnic identities, finding lower coverage among several subpopulations, including Puerto Rican and Haitian pregnant people. Quantitative data could not explain contexts shaping vaccine decisions; thus, MDPH partnered with Tufts Interdisciplinary Evaluation Research (TIER) to conduct a community-led evaluation to understand COVID-19 vaccine perceptions and decision-making among Hispanic/Latina and Haitian residents pregnant when COVID-19 vaccine access became widespread. METHODS:The evaluation included a bilingual (English/Spanish) survey (n = 19) and in-depth interviews (n = 8) conducted in Haitian Creole. TIER trained two community members who identified as Latina (Puerto Rican) and Haitian in evaluation methods and mentored them to collect, analyze, and interpret data, and co-develop recommendations for improved community-level vaccine outreach. RESULTS:Two-thirds of participants across subpopulations (18/27) reported receipt of at least one COVID-19 vaccine dose. All but one Latina survey respondent received pregnancy-specific vaccine information. While 10 received information from medical providers, only three indicated that providers helped them make COVID-19 vaccine decisions. Most (n = 16) cited partners and family as helping them make vaccine decisions. In-depth interviews with Haitian participants revealed concerns about the COVID-19 vaccine including its safety in pregnancy, faith-based objections, harm to Black communities, workplace mandates, and misinformation. CONCLUSIONS:Coupling disaggregated data with community-led evaluation contextualized variations in vaccination during pregnancy. Strategies to support voluntary, informed vaccine decisions should emphasize provider communication, engage partners and families, and address concerns via trusted messengers. This replicable framework can support equitable outreach for vaccines recommended in pregnancy.
BACKGROUND:Early prediction of pregnancy syndromes such as preeclampsia, gestational diabetes mellitus (GDM), and preterm birth is critical for improving maternal and fetal outcomes. Traditional risk assessment tools rely primarily on structured clinical data and often fail to fully utilize the rich unstructured textual information contained in electronic health records (EHRs). OBJECTIVE:This study aimed to develop and evaluate an Adaptive Penguin-Improved Long Short-Term Memory (AP-ILSTM) model that integrates natural language processing (NLP) of clinical narratives with structured longitudinal data for predicting the risk of preeclampsia, GDM, and preterm birth. METHODS:This retrospective observational study used de-identified EHR data from 1248 consecutive pregnancies at a single regional hospital in China between April 2024 and April 2025. Structured clinical variables and unstructured free-text clinical notes were preprocessed using standard NLP techniques, including tokenization, TF-IDF weighting, and word embeddings. An Improved Long Short-Term Memory (ILSTM) network with dropout regularization was optimized using the Adaptive Penguin algorithm with Gaussian exploration. The dataset was stratified into training (70%), validation (15%), and independent test (15%) sets. Model performance was assessed using accuracy, sensitivity (recall), positive predictive value (precision), F1-score, specificity, negative predictive value, ROC-AUC, and mean absolute error, and compared against baseline machine learning models. RESULTS:On the independent test set (n = 188), the AP-ILSTM model achieved an accuracy of 98.85%, sensitivity of 98.69%, positive predictive value of 98.75%, F1-score of 98.72%, and ROC-AUC of 0.993, with a mean absolute error of 4.05. It outperformed all baseline classifiers (XGBoost, CatBoost, KNN) and regression models. Clinical narrative embeddings ranked as the second most important predictor after blood pressure trends. CONCLUSIONS:The AP-ILSTM model, by effectively combining structured data with NLP-derived features from clinical narratives and employing adaptive optimization, demonstrated superior performance for early multi-syndrome pregnancy risk prediction. This multimodal temporal approach shows strong potential to support clinical decision-making, although external validation and prospective implementation studies are required before clinical adoption.
Reliable interpretation of animal toxicology studies depends on the ability to reproduce and replicate experimental findings. Recent discussions of Virtual Control Groups (VCGs) in nonclinical toxicology have emphasized the importance of matching study variables when constructing control datasets. However, the biological implications of variability among studies have received limited explicit attention. In embryo-fetal developmental toxicity (EFDT) studies, numerous intrinsic and extrinsic variables can influence pregnancy outcomes, fetal development, and the interpretation of findings. Drawing on previous analyses of EFDT variability and recent discussions of VCG implementation, 69 potential sources of non-treatment variability were identified and organized into five general domains, including animals, pre-study practices, the microenvironment, the macroenvironment, and study design/procedures. These domains differ in the degree to which they can be controlled or standardized across laboratories. Some variables may have negligible effects under many conditions, whereas others, alone or in combination, may influence study outcomes. EFDT outcomes are therefore inherently context-dependent, reflecting the combined influence of treatment and study context. Under such conditions, strict replicability of control-group outcomes across studies becomes biologically improbable. Recognition of this inherent variability has implications for expectations of study concordance and for the construction of VCGs as well as often-used historical control data (HCD). The development of reliable VCGs is therefore most feasible within individual laboratories where major domains of variability can be more closely aligned.
INTRODUCTION: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. METHODS: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. RESULTS: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). CONCLUSIONS: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.
BACKGROUND:Hemifacial microsomia (HFM) is a congenital craniofacial malformation characterized by unilateral hypoplasia of structures derived from the first and second pharyngeal arches. Although the phenotype is well described, the underlying etiology remains incompletely understood. Disturbances in embryonic vascular development have long been proposed as a potential mechanism contributing to the characteristic unilateral craniofacial phenotype. METHODS:A systematic literature review was conducted following PRISMA guidelines. Searches were performed in PubMed, Embase, Web of Science, and CINAHL to identify studies investigating vascular mechanisms in hemifacial microsomia and related craniofacial microsomia phenotypes. Evidence from epidemiological, clinical, radiological, and genetic studies was synthesized narratively because of methodological heterogeneity. RESULTS:Of 450 screened records, eight studies met the inclusion criteria. Epidemiological studies identified associations between HFM and maternal factors potentially affecting embryonic perfusion, including vasoactive medication exposure, maternal diabetes, multiple gestations, and second-trimester vaginal bleeding. Population-based data further demonstrated an increased prevalence of single umbilical artery and growth restriction among affected infants. Clinical and radiological observations described regional vascular abnormalities, including carotid artery attenuation. One genetic association study suggested interactions between pathways involved in vascular development and neural crest cell biology. CONCLUSIONS:The available evidence is consistent with a possible contribution of disturbances in vascular development to the pathogenesis of hemifacial microsomia, particularly in unilateral presentations. However, current evidence remains indirect and heterogeneous. Vascular mechanisms may interact with genetic susceptibility and neural crest cell biology within a broader multifactorial developmental framework. Further studies integrating genomic analyses, developmental models, and detailed vascular imaging are needed to clarify the role of vascular mechanisms in craniofacial microsomia.
BACKGROUND: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. METHODS: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. RESULTS: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. CONCLUSIONS: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. TRIAL REGISTRATION:NCT04705116, EUPAS39096.
