Structural Birth Defects Research Articles

Low FT4 Concentrations around the Start of Recombinant Human Growth Hormone Treatment: Predictor of Congenital Structural Hypothalamic-Pituitary Abnormalities?

Background: Growth hormone (GH) treatment may unmask central hypothyroidism (CeH). This was first observed in children with GH deficiency (GHD), later also in adults with GHD due to acquired “organic” pituitary disease. We hypothesized that newly diagnosed CeH in children after starting GH treatment for nonacquired, apparent isolated GHD points to congenital “organic” pituitary disease. Methods: Nationwide, retrospective cohort study including all children with nonacquired GHD between 2001 and 2011 in The Netherlands. The prevalence of CeH, hypothalamic-pituitary (HP) abnormalities, and neonatal congenital hypothyroidism screening results were evaluated. Results: Twenty-three (6.3%) of 367 children with apparent isolated GHD were prescribed LT4 for presumed CeH within 2 years after starting GH treatment. Similarly to children already diagnosed with multiple pituitary hormone deficiency, 75% of these 23 had structural HP abnormalities. In children not prescribed LT4, low pre- or post-GH treatment FT4 concentrations were also associated with structural HP abnormalities. Neonatal screening results of only 4 of the 23 children could be retrieved. Conclusion: In children with nonacquired, apparent isolated GHD, a diagnosis of CeH after, or a low FT4 concentration around the start of GH treatment, is associated with congenital structural HP abnormalities, i.e., “organic” pituitary disease. Neonatal values could not be judged reliably.

Novel Molecular and Phenotypic Insights into Congenital Lung Malformations.

Disruption of normal pulmonary development is a leading cause of morbidity and mortality in infants. Congenital lung malformations are a unique model to study the molecular pathogenesis of isolated structural birth defects, as they are often surgically resected. To provide insight into the molecular pathogenesis of congenital lung malformations through analysis of cell-type and gene expression changes in these lesions. Clinical data, and lung tissue for DNA, RNA, and histology, were obtained from 58 infants undergoing surgical resection of a congenital lung lesion. Transcriptome-wide gene expression analysis was performed on paired affected and unaffected samples from a subset of infants (n = 14). A three-dimensional organoid culture model was used to assess isolated congenital lung malformation epithelium (n = 3). Congenital lung lesions express higher levels of airway epithelial related genes, and dysregulated expression of genes related to the Ras and PI3K-AKT-mTOR (phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin) signaling pathways. Immunofluorescence confirmed differentiated airway epithelial cell types throughout all major subtypes of congenital lung lesions, and three-dimensional cell culture demonstrated a cell-autonomous defect in the epithelium of these lesions. This study provides the first comprehensive analysis of the congenital lung malformation transcriptome and suggests that disruptions in Ras or PI3K-AKT-mTOR signaling may contribute to the pathology through an epithelial cell-autonomous defect.

Reproductive suppression, birth defects, and periviable birth.

We argue that reproductive suppression has clinical implications beyond its contribution to the burden of spontaneous abortion. We theorize that the incidence of births before the 28th week of gestation, which contribute disproportionately to infant morbidity and mortality, varies over time in part due to reproductive suppression in the form of selection in utero. We further theorize that the prevalence of structural birth defects among survivors to birth from conception cohorts gauges selection in utero. We based these theories on literature positing that natural selection conserved mechanisms that spontaneously abort “risky” pregnancies including those otherwise likely to yield infants with structural birth defects or small‐for‐gestational age males. We test our theory using high‐quality birth defect surveillance data. We identify 479,885 male infants exposed to strong selection defined as membership in conception cohorts ranked in the lowest quartile of odds of a birth defect among live‐born females. We estimate the risk of periviable birth among these infants as a function of selective pressure as well as of mother's race/ethnicity and age. We find that male infants from exposed conception cohorts exhibited 10% lower odds of periviable birth than males from other conception cohorts. Our findings support the argument that selection in utero has implications beyond its contribution to the burden of spontaneous abortion.

ZIC1 Function in Normal Cerebellar Development and Human Developmental Pathology.

Zic genes are strongly expressed in the cerebellum. This feature leads to their initial identification and their name "zic," as the abbreviation of "zinc finger protein of the cerebellum." Zic gene function in cerebellar development has been investigated mainly in mice. However, association of heterozygous loss of ZIC1 and ZIC4 with Dandy-Walker malformation, a structural birth defect of the human cerebellum, highlights the clinical relevance of these studies. Two proposed mechanisms for Zic-mediated cerebellar developmental control have been documented: regulation of neuronal progenitor proliferation-differentiation and the patterning of the cerebellar primordium. Clinical studies have also revealed that ZIC1 gain of function mutations contribute to coronal craniosynostosis, a rare skull malformation. The molecular pathways contributing to these phenotypes are not fully explored; however, embryonic interactions with sonic hedgehog signaling, retinoic acid signaling, and TGFβ signaling have been described during mouse cerebellar development. Further, Zic1/2 target a multitude of genes associated with cerebellar granule cell maturation during postnatal mouse cerebellar development.

Recent Advances and Trends in Pediatric Cardiac Imaging.

Cardiac imaging is central to today's pediatric cardiology practice not only to diagnose structural congenital defects and delineate cardiac and extracardiac anatomy but also for determining the hemodynamic impact of the structural defects and acquired pediatric diseases. Not so long ago, clinicians had to heavily rely on angiography as the main cardiac imaging modality to visualize the heart. Particularly, the development of echocardiography in the 1970s and 1980s together with the development of magnetic resonance imaging (MRI) and computed tomography (CT) resulted in a non-invasive diagnostic revolution with diagnostic catheterization becoming obsolete apart for very specific indications. The continuous improvements in non-invasive imaging modalities allow an unprecedented level of understanding of cardiac morphology and function. Over the last few years, the specific roles of the three imaging modalities and their complementary roles in diagnosis and treatment have become well established resulting in a multimodality approach to specific congenital lesions. Recently, multimodality guidelines were published for postoperative tetralogy of Fallot and patients with transposition of the great arteries (Cohen et al. J Am Soc Echocardiogr. 2016;29(7):571-621, Valente et al. J Am Soc Echocardiogr. 2014;27(2):111-41). In this paper, we aim to highlight some of the most significant advances and highlight some emerging trends in pediatric cardiac imaging.

Analysis of cystic hygroma diagnosed in the prenatal period: 5-years’ experience at a tertiary hospital in Southeastern Turkey

Purpose Our aim was to evaluate the association of cystic hygroma (CH) with fetal malformations and also to investigate the outcome of fetuses with CH diagnosed in the prenatal period. Methods We divided the CH patients into two main groups as isolated CH or CH associated with the congenital structural abnormality (CSA) by measuring the thickness of CH and showing other fetal abnormalities. Pregnancy outcomes were recorded as spontaneous abortion, elective termination, intrauterine death, live birth, postnatal death, and lost to follow-up. Results There were 74 cases of fetal CH including 19 in CSA-CH group and 55 in isolated-CH group diagnosed between 11 and 21 weeks’ gestation. Karyotype analysis of these 28 patients revealed 18 (64.2%) normal karyotypes. Pregnancy outcomes included 54 elective terminations, five postnatal deaths, one spontaneous abortion, six live births, four intrauterine deaths, and four patients were lost to follow-up. Conclusion In the presence of any CSA concurrent with CH, prognosis may be considered as poor and any additional help of fetal karyotyping is questionable. But fetal karyotyping may be advocated in counseling patients with isolated CH, in which a better prognosis and resolvement of CH may be expected in case of a normal karyotype.

Genetic epidemiology of neural tube defects.

It has been estimated that 60-70% of neural tube defects (NTDs) have a genetic component, but few causative genes have been identified. The lack of information on genes associated with non-syndromic NTDs in humans is especially notable as the "genomic revolution" has led to new tools (e.g., genome-wide genotyping arrays, next-generation sequencing) that are helping to elucidate the full spectrum of genetic variation (from common to rare) contributing to complex traits, including structural birth defects. However, the application of modern genomic approaches to the study of NTDs has lagged behind that of some other common structural birth defects. This may be due to the difficulty of assembling large study cohorts for anencephaly or spina bifida. The purpose of this review is to outline the evolution of genetic studies of NTDs, from studies of familial aggregation to candidate gene and genome-wide association studies, through whole-exome and whole-genome sequencing. Strategies for addressing gaps in NTD genetic research are also explored.

Echocardiography allows for analysis of pulmonary arterial flow in mice with congenital diaphragmatic hernia

BackgroundCongenital diaphragmatic hernia (CDH) is a structural birth defect associated with pulmonary hypoplasia and pulmonary arterial hypertension (PAH). We hypothesize that echocardiography provides a method to assess real-time right ventricle (RV) function, remodeling, and pulmonary artery (PA) flow. Materials and methodsSlit3 wild-type (WT) (n = 6) and knockout (KO) (n = 5) mice were analyzed at 2-3 months of age. Mice were anesthetized using isoflurane. Echocardiography was performed to analyze left and right ventricular wall thickness, internal diameter (ID), and function. Color Doppler was used to analyze flow in the PA and across the tricuspid valve. ResultsThere was significant RV dilation in the KO mice versus WT, with an average RVID of 1.99 mm versus 1.26 mm, respectively (P = 0.007). Flow in the PA of KO mice was altered compared to WT, with elevated PA velocity time indices, 30.68 mm versus 22.13 mm (P = 0.012), elevated PA peak velocities, 952.61 mm/s versus 628.73 mm/s (P = 0.003), and decreased pulmonary acceleration times, 8.94 ms versus 16.18 ms (P = 0.002), respectively. Pulmonary vascular resistance, calculated by measuring tricuspid regurgitation peak velocity and right ventricular outflow tract velocity time index, was increased in KO versus WT mice, 17.61 mm2/s versus 8.91 mm2/s (P = 0.003), respectively. ConclusionsSlit3 KO mice with CDH show evidence of PAH and resultant RV dilation. Using direct cardiac puncture, elevated RV systolic pressures have been demonstrated in KO mice as evidence of PAH. Echocardiography allows direct analysis of the PA and real-time RV function without sacrifice of the mouse. This mode of evaluation allows longitudinal study in mice with PAH and CDH.

NIH Funds Pediatric Data Resource Center.

Children's Hospital of Philadelphia will lead a collaborative effort-funded with $14.8 million from the NIH-to pool genomic and phenotypic data from tens of thousands of patients to study the causes of pediatric cancer and structural birth defects.

Practice Bulletin No. 187 Summary: Neural Tube Defects.

Neural tube defects (NTDs) are congenital structural abnormalities of the central nervous system and vertebral column. Neural tube defects may occur as an isolated malformation, in combination with other malformations, as part of a genetic syndrome, or as a result of teratogenic exposure (1). Neural tube defects are the second-most-common major congenital anomaly (2) after cardiac malformations, and their prevalence varies by geographic region, race, and environmental factors (3). Outcomes and disabilities depend on level and extent of lesion; for instance, anencephaly is incompatible with life but most infants with spina bifida will survive after surgical repair (4). Importantly, and in contrast to many other congenital abnormalities, primary prevention of NTDs is possible with folic acid. In addition, prenatal screening and diagnosis are widely available, and fetal surgery has improved outcomes for some newborns. The purpose of this document is to provide information about NTDs and make management recommendations for the pregnancy complicated by a fetal NTD.

Practice Bulletin No. 187: Neural Tube Defects.

Neural tube defects (NTDs) are congenital structural abnormalities of the central nervous system and vertebral column. Neural tube defects may occur as an isolated malformation, in combination with other malformations, as part of a genetic syndrome, or as a result of teratogenic exposure (1). Neural tube defects are the second-most-common major congenital anomaly (2) after cardiac malformations, and their prevalence varies by geographic region, race, and environmental factors (3). Outcomes and disabilities depend on level and extent of lesion; for instance, anencephaly is incompatible with life but most infants with spina bifida will survive after surgical repair (4). Importantly, and in contrast to many other congenital abnormalities, primary prevention of NTDs is possible with folic acid. In addition, prenatal screening and diagnosis are widely available, and fetal surgery has improved outcomes for some newborns. The purpose of this document is to provide information about NTDs and make management recommendations for the pregnancy complicated by a fetal NTD.

Association between severe nausea and vomiting in early pregnancy and the risk of neural tube defects in Northern China.

This study assessed the association between severe NVP and the risk of NTD in offspring compared with a population and a malformed control group. We also assessed whether folic acid supplements modified this association. A case-control study was conducted with subjects enrolled from June 19, 2002, to November 18, 2014, from a population-based birth defects surveillance system that monitors major external structural birth defects through active case ascertainment in Shanxi Province, China. The main comparison was between women with NTD-affected offspring who experienced NVP in early pregnancy versus those who did not. A multivariable logistic regression model was used to examine the associations between severe NVP and the risk of NTD while adjusting for potential confounding factors. The risk was estimated by calculating the odds ratio (OR) and 95% confidence intervals (CIs). The adjusted OR (AOR) of severe NVP for NTDs was 3.25 (95%CI 2.56, 4.12) compared with the population control, and 1.65 (95%CI 1.00, 2.72) compared with the malformed controls. When stratified by intake of folic acid supplements, the AOR for severe NVP was 3.40 (95%CI 2.61, 4.42) in the non-intake of folic acid supplements stratum and 2.51 (95%CI 1.42, 4.43) in the intake of folic acid supplements stratum. We conclude that severe NVP is associated with NTDs, and that severe NVP may be a consequence, rather than a cause, of NTDs.

Maternal report of fever from cold or flu during early pregnancy and the risk for noncardiac birth defects, National Birth Defects Prevention Study, 1997-2011.

As maternal fever affects approximately 6-8% of early pregnancies, it is important to expand upon previous observations of an association between maternal fever and birth defects. We analyzed data from the National Birth Defects Prevention Study, a multistate, case-control study of major structural birth defects. Telephone interviews were completed by mothers of cases (n = 17,162) and controls (n = 10,127). Using multivariable logistic regression, we assessed the association between maternal self-report of cold or flu with fever and cold or flu without fever during early pregnancy and 30 categories of non-cardiac birth defects. Maternal report of cold or flu with fever was significantly associated with 8 birth defects (anencephaly, spina bifida, encephalocele, cleft lip with or without cleft palate, colonic atresia/stenosis, bilateral renal agenesis/hypoplasia, limb reduction defects, and gastroschisis) with elevated adjusted odds ratios ranging from 1.2 to 3.7. Maternal report of cold or flu without fever was not associated with any of the birth defects studied. This study adds to the evidence that maternal fever during early pregnancy is associated with an increased risk for selected birth defects. Elevated associations were limited to mothers who reported a fever, suggesting that it is fever that contributes to the excess risk rather than illnesses associated with it. However, fever may also serve as a marker for more severe infections.

Population-based birth defects data in the United States, 2010-2014: A focus on gastrointestinal defects.

Gastrointestinal defects are a phenotypically and etiologically diverse group of malformations. Despite their combined prevalence and clinical impact, little is known about the epidemiology of these birth defects. Therefore, the objective of the 2017 National Birth Defects Prevention Network (NBDPN) data brief was to better describe the occurrence of gastrointestinal defects. As part of the 2017 NBDPN annual report, 28 state programs provided additional data on gastrointestinal defects for the period 2010-2014. Counts and prevalence estimates (per 10,000 live births) were calculated overall and by demographic characteristics for (1) biliary atresia; (2) esophageal atresia/tracheoesophageal fistula; (3) rectal and large intestinal atresia/stenosis; and (4) small intestinal atresia/stenosis. Additionally, we explored the frequency of these malformations co-occurring with other structural birth defects. Pooling data from all participating registries, the prevalence estimates were: 0.7 per 10,000 live births for biliary atresia (713 cases); 2.3 per 10,000 live births for esophageal atresia/tracheoesophageal fistula (2,472 cases); 4.2 per 10,000 live births for rectal and large intestinal atresia/stenosis (4,334 cases); and 3.4 per 10,000 live births for small intestinal atresia/stenosis (3,388 cases). Findings related to co-occurring birth defects were especially notable for esophageal atresia/tracheoesophageal fistula, rectal and large intestinal atresia/stenosis, and small intestinal atresia/stenosis, where the median percentage of non-isolated cases was 53.9%, 45.5%, and 50.6%, respectively. These population-based prevalence estimates confirm some previous studies, and provide a foundation for future epidemiologic studies of gastrointestinal defects. Exploring the genetic and environmental determinants of these malformations may yield new clues into their etiologies.

A cross sectional study on the prevalence of structural congenital anomalies among neonates delivered in a tertiary care hospital, Chennai from January 2016 to February 2017

Background: Congenital anomalies are important contributors to infant and childhood deaths, chronic illness and disability. The pattern and type of anomaly varies regionally. The planning and the implementation of public health programs for congenital anomalies are dependent on the prevalence data. Adequate data is unavailable in our country. The objective of this study was to study the prevalence of congenital anomalies and the factors influencing them, in Government RSRM lying in hospital, Chennai from January 2016 to February 2017.Methods: This is a cross-sectional study conducted in Government RSRM lying-in hospital, a tertiary care neonatal unit, from January 2016 to February 2017. The case records of neonates delivered during the study period were studied to identify those with congenital anomalies. The factors possibly influencing congenital anomalies were studied.Results: The number of case records analyzed was 11242, out of which 157 neonates were reported to have structural congenital anomalies; the prevalence was 1.4%. Congenital heart disease formed the majority, 46.5% (73/157) of congenital anomalies identified. The most common extra-cardiac congenital anomalies noted were cleft lip/cleft palate (15/157) 9.6%, followed by single umbilical artery which was noted in 5.7% (9/157). Down’s syndrome was seen in 3.8% (6/157) and neural tube defects in 3.2% (5/157) of the babies with congenital anomalies.Conclusions: The prevalence of commonly occurring congenital anomalies in the study hospital was comparable to the prevalence in other similar studies in India. The prevalence of neural tube defects was lower in our area compared to other countries whereas, that of acyanotic heart diseases were higher than in other studies.

Tdap Vaccination Coverage During Pregnancy - Selected Sites, United States, 2006-2015.

Tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine is recommended during the third trimester of each pregnancy to provide protection to newborns, who are at risk for pertussis-related morbidity and mortality (1). As part of its case-control surveillance study of medications and birth defects, the Birth Defects Study of the Slone Epidemiology Center at Boston University (the Birth Defects Study) has recorded data on vaccinations received during pregnancy since 2006. Among 5,606 mothers of infants without structural birth defects in this population (control group), <1% had received Tdap vaccine before 2009. By 2012, the percentage of mothers of infants in the control group (control infants) who had received Tdap increased to approximately 9%, and then in 2013 and continuing through 2015, increased markedly, to 28% and 54%, respectively. As the prevalence of maternal Tdap vaccination increased, so did the proportion of pregnant women who received Tdap in the third trimester, as recommended (94%-100% from 2010 to 2015). The vast majority of Tdap vaccinations (96%) were received in a traditional health care setting (e.g., the office of the woman's obstetrician or primary care physician or her prenatal clinic). Increasing vaccination coverage during pregnancy could help reduce the impact of pertussis on infant morbidity and mortality.

The avian embryo as a model for fetal alcohol spectrum disorder.

Prenatal alcohol exposure (PAE) remains a leading preventable cause of structural birth defects and permanent neurodevelopmental disability. The chicken (Gallus gallus domesticus) is a powerful embryological research model, and was possibly the first in which the teratogenicity of alcohol was demonstrated. Pharmacologically relevant exposure to alcohol in the range of 20-70 mmol/L (20-80 mg/egg) disrupt the growth of chicken embryos, morphogenesis, and behavior, and the resulting phenotypes strongly parallel those of mammalian models. The avian embryo's direct accessibility has enabled novel insights into the teratogenic mechanisms of alcohol. These include the contribution of IGF1 signaling to growth suppression, the altered flow dynamics that reshape valvuloseptal morphogenesis and mediate its cardiac teratogenicity, and the suppression of Wnt and Shh signals thereby disrupting the migration, expansion, and survival of the neural crest, and underlie its characteristic craniofacial deficits. The genetic diversity within commercial avian strains has enabled the identification of unique loci, such as ribosome biogenesis, that modify vulnerability to alcohol. This venerable research model is equally relevant for the future, as the application of technological advances including CRISPR, optogenetics, and biophotonics to the embryo's ready accessibility creates a unique model in which investigators can manipulate and monitor the embryo in real-time to investigate the effect of alcohol on cell fate.

Birth Defects at the Outpatient Department of the Philippine General Hospital from 2000-2010

Introduction. Birth defects or congenital anomalies are a major global concern. An estimated 7.9 million children are born worldwide each year. Birth defects are among the top ten leading causes of infant deaths in the Philippines for more than six decades. The objectives of this study were to: 1) determine the frequency of birth defects among patients seen at the Outpatient Department (OPD) of the Philippine General Hospital (PGH) from 2000 to 2010; 2) describe the birth defects by organ systems and presentation (isolated, part of a recognizable syndrome, chromosomal syndrome or multimalformed case); 3) present the distribution of patients by geographic origin; 4) describe the birth defects according to age group and organ system; and 5) compare the data from this study to the previously published report among admitted patients at PGH in the same time period. Methods. Medical records of new patients seen at the PGH OPD from 2000 to 2010 were reviewed. Medical records that included written diagnosis of any of the following International Classification of Diseases (ICD) -10 codes (Q 00 – Q 99, P 35.0, P 83.5, K40, H49.0, H50.0, H50.1, H53.0, H54.42, H54.7, and H55.01) were considered birth defect cases. Results. Out of the 804,410 new patients at the PGH OPD from 2000 to 2010, 12,827 patients (1.59%) had a diagnosis of at least one major structural birth defect. The most common birth defects were cardiovascular, digestive, genital organ and nervous system anomalies. The top 5 anomalies in this report were: congenital malformations of cardiac septa, other congenital malformations not elsewhere classified, cleft palate with cleft lip, congenital hydrocoele, and congenital hydrocephalus. The highest percentage of birth defects were from the &lt; 1 age group (40.3%), followed by the 1 to 4 age group (29%) and the 5 to 9 age group (14.6%). NCR, Region IV-A and Region III had the highest percentages of patients with birth defects, 51.4%, 26.03% and 10.97%, respectively. Conclusion. This study revealed a prevalence of birth defects among PGH OPD patients of 1.59%. The most common birth defects were possibly surgically correctable reflecting the nature of PGH as a referral center. Majority of patients affected were in the under-5 population. The study reflects the importance of a birth defects surveillance to develop policies on strategies that will reduce the burden of morbidity and mortality secondary to preventable birth defects like congenital rubella syndrome that can be aborted by a successful immunization program. The birth defects surveillance will generate data that will support strengthening the regional hospitals with a better complement of specialists and capability for both medical and surgical management of the patients.

P.419 - Cataracts, cognitive impairment, and congenital myasthenic syndrome with myopathic features caused by mutation in GMPPB gene

Mutations in guanosine diphosphate mannose (GDP-mannose) pyrophosphorylase B (GMPPB) can result in muscular dystrophy variants with hypoglycosylated alfa-dystroglycan. The firsts patients described with defects in this gene showed a broad phenotypic spectrum ranging from congenital muscle weakness, eye and brain structural abnormalities and intellectual delay to adult-onset limb-girdle muscular dystrophies without mental retardation. More recently, a relationship between defects in this gene has been associated to congenital myasthenic syndromes (CMS). Here we describe three sibling, two boys and one girl, from consanguineous Egyptian family aged 17, 12 and 6 y/o, respectively, with congenital myasthenic syndrome (CMS) due to AR mutation in GMPPB gene. All 3 patients showed a homogeneous clinical picture characterized by hypotonia since the first months of life, congenital cataract, axial and proximal muscle weakness, fatigability and intellectual disability. Complementary studies showed: increased CPK, cerebral MRI with a mild increase in cerebellar foliation. EMG with a myopathic pattern and decremented pathological response of 24% was observed just in the oldest patient.Muscular biopsy showed dystrophic pattern and reduction of the expression of alpha-Dystroglycan. Therapeutic testing with anticholinesterase drugs showed and dramatic improvement in the functional test, increasing the distance in 6MWT up to 10 times in the younger patient (30 to 370mts). Genetic studied showed homozygous mutation GMPPB: c.553C>T, p.Arg185Cys. Clinical recognition of GMPPB-associated to congenital myasthenic syndrome may be complicated by the presence of myopathic features. Clinicians should keep in mind this treatable disorder since there is a dramatic response to antocholinesterase drugs even in advanced stages of the disease. Cataracts and cognitive involvement have been described in other Egyptian patients with the same mutation, suggesting a genotype-phenotype correlation.

Maternal and Infant Outcomes After Human Papillomavirus Vaccination in the Periconceptional Period or During Pregnancy.

To evaluate whether quadrivalent human papillomavirus vaccine (4vHPV) administered during the periconceptional period or during pregnancy was associated with increased risks for adverse obstetric events, adverse birth outcomes, or selected major structural birth defects. We conducted a retrospective, observational cohort study using administrative and health care data from the Vaccine Safety Datalink. Insured women 13-27 years old with singleton pregnancies and a live birth from January 1, 2007, through September 1, 2013, who received 4vHPV during the periconceptional period (2 weeks before to 2 weeks after their last menstrual period), during pregnancy, or during both periods combined were compared with women who had a live birth during the same time period and received 4vHPV 4-18 months before their last menstrual period. We examined risks of gestational diabetes, hypertensive disorders of pregnancy, chorioamnionitis, preterm birth, small-for-gestational-age birth, and selected major structural birth defects in offspring. We estimated relative risks associated with receipt of 4vHPV during the periconceptional period, during pregnancy, and both exposure periods combined using a generalized linear model with Poisson distribution including a propensity score that included relevant maternal demographic and pregnancy characteristics. Of 92,579 potentially eligible pregnant women, 720 received 4vHPV during the periconceptional period, 638 received 4vHPV during pregnancy, and 8,196 received 4vHPV during the comparison period. Administration of 4vHPV during pregnancy was not associated with increased risk of adverse obstetric events, birth outcomes. Preterm birth occurred in 7.9% of pregnancies with vaccine exposures during pregnancy compared with 7.6% of pregnancies with vaccination in the comparison period (adjusted relative risk 0.97, 95% CI 0.72-1.3). Major structural birth defects were diagnosed in 2.0% of pregnancies with vaccine exposure during pregnancy compared with 1.8% of pregnancies with vaccine exposure during the comparison period (adjusted prevalence ratio 1.0, 95% CI 0.52-1.9). Results were similar for 4vHPV exposure during the periconceptional period. Quadrivalent HPV vaccine inadvertently administered in pregnancy or during the periconceptional period was not associated with adverse pregnancy or birth outcomes.