Association of MTHFD1 gene polymorphisms and maternal smoking with risk of congenital heart disease: a hospital-based case-control study.

BACKGROUND: MTHFD1 gene may affect the embryonic development by elevated homocysteine levels, DNA synthesis and DNA methylation, but limited number of genetic variants of MTHFD1 gene was focused on the association with congenital heart disease (CHD). This study examined the role of MTHFD1 gene and maternal smoking on infant CHD risk, and investigated their interaction effects in Chinese populations. METHODS: A case-control study of 464 mothers of CHD infants and 504 mothers of health controls was performed. The exposures of interest were maternal tobacco exposure, single nucleotide polymorphisms (SNPs) of maternal MTHFD1 gene. The logistic regression model was used for accessing the strength of association. RESULTS: Mothers exposed to secondhand smoke during 3 months before pregnancy (adjusted odds ratio [aOR] = 1.56; 95% confidence interval [CI]: 1.13-2.15) and in the first trimester of pregnancy (aOR = 2.24; 95%CI: 1.57-3.20) were observed an increased risk of CHD. Our study also found that polymorphisms of maternal MTHFD1 gene at rs1950902 (AA vs. GG: aOR = 1.73, 95% CI: 1.01-2.97), rs2236222 (GG vs. AA: aOR = 2.38, 95% CI: 1.38-4.12), rs1256142 (GA vs.GG: aOR = 1.57, 95% CI: 1.01-2.45) and rs11849530 (GG vs. AA: aOR = 1.68, 95% CI: 1.02-2.77) were significantly associated with higher risk of CHD. However, we did not observe a significant association between maternal MTHFD1 rs2236225 and offspring CHD risk. Furthermore, we found the different degrees of interaction effects between polymorphisms of the MTHFD1 gene including rs1950902, rs2236222, rs1256142, rs11849530 and rs2236225, and maternal tobacco exposure. CONCLUSIONS: Maternal polymorphisms of MTHFD1 gene, maternal tobacco exposure and their interactions are significantly associated with the risk of CHD in offspring in Han Chinese populations. However, more studies in different ethnic populations with a larger sample and prospective designs are required to confirm our findings. TRIAL REGISTRATION: Registration number: ChiCTR1800016635 .

Brief report: Metabolic acidosis in newborn infants following maternal use of acetazolamide during pregnancy.

 The information regarding fetal effects of acetazolamide use during pregnancy and lactation is sparse. We report the clinical and pharmacodynamic characteristics of maternal acetazolamide use and the timing of its effects on acid-base balance in three cases who presented with metabolic acidosis in the newborn period. We found that the infants' clinical status soon after birth was inconsistently correlated with maternal drug dose and concentrations of medication in maternal serum. However, there was low transfer of the drug in breast milk and its use did not affect clinical symptomatology. We also present a review of literature on this subject to help consolidate our current knowledge on this topic.

Incidence of Neonatal Neutropenia and Leukopenia After In Utero Exposure to Chemotherapy for Maternal Cancer.

OBJECTIVE: The main purpose of this article was to report the incidence of neonatal neutropenia or leukopenia after chemotherapy exposure during pregnancy according to the time elapsed between treatment during pregnancy and birth. BACKGROUND: A single study reports 33% of infants exposed to chemotherapy within the last month of pregnancy are born with neutropenia, which can place the newborn at risk for nosocomial infections. On the basis of this report, chemotherapy is typically stopped by 34 weeks of pregnancy to avoid maternal or neonatal myelosuppression at delivery. Such a pause in treatment may affect maternal health. Determining the true incidence of neutropenia after chemotherapy in relation to the time of this lapse in treatment is important to support this practice. MATERIALS AND METHODS: Complete blood counts are collected for newborn whose mothers were treated for cancer during pregnancy and enrolled in the Cancer and Pregnancy Registry. Neutropenia was defined as absolute neutrophil count<1000 mm3 and leukopenia was defined as white blood cells <5000 cells/µL. Incidence of neutropenia was calculated according to the time elapsed from last chemotherapy treatment until birth. Fisher's exact test is used to determine if neutropenia or leukopenia is related to the time elapsed between chemotherapy during pregnancy and newborn birth. A Bayesian analysis evaluated the occurrence of neutropenia and leukopenia according to the number of days between the initiation of chemotherapy and birth. RESULTS: A total of 135 infants exposed to chemotherapy in utero with a complete blood count collected at birth were identified from the database. Only 7.3% and 2.9% of infants were born with neutropenia or leukopenia, respectively. The highest incidence of newborn neutropenia occurred in infants delivered 22 to 28 days after chemotherapy. CONCLUSIONS: The incidence of neutropenia peaks when chemotherapy is given 22 to 28 days before birth, while leukopenia is highest if delivery is <7 days from chemotherapy.

Antenatal exposure to nonsteroidal anti-inflammatory drugs and risk of neonatal hypertension.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are used as tocolytics, which are medications that suppress uterine contractions for preterm birth prevention. Their effect on cerebral/systemic vascular beds poses the question of whether antenatal NSAID exposure is associated with neonatal hypertension. We performed a retrospective case-control study in a tertiary neonatal intensive care unit, including 40 hypertension cases (hospitalized neonates ≥ 35 weeks with systolic BP > 100 mm Hg on three consecutive days) compared to 134 controls matched by gestational age at delivery, plurality, and delivery date. Cases and controls were compared by antenatal NSAID exposure, other common tocolytics, and maternal/neonatal characteristics and complications. Multivariable logistic regression was used to estimate the odds of hypertension among those with prenatal exposure to NSAIDs versus those without exposure. Newborns with hypertension had a lower gestational age at delivery and increased incidence of neonatal complications, including respiratory distress syndrome, bronchopulmonary dysplasia, surfactant administration, longer duration of ventilation, and history of umbilical artery catheterization. Days of indomethacin exposure were positively associated with greater odds of neonatal hypertension (OR 1.17 [1.00 to 1.38], P = 0.055), even after adjustment for other factors associated with neonatal hypertension. Newborns with hypertension were less likely to have been exposed to calcium channel blockers as a tocolytic. The results of our study suggest an association between prenatal exposure to nonsteroidal anti-inflammatory drugs and neonatal hypertension. Furthermore, our data suggest that prenatal calcium channel blocker exposure may protect against the development of neonatal hypertension. Future multicenter studies are needed to understand the risks of tocolytics and subsequent consequences in preterm infants.

Association Between Pregnancy and Perinatal Outcomes Among Women With Epilepsy.

Importance: To date, few attempts have been made to examine associations between exposure to maternal epilepsy with or without antiepileptic drug (AED) therapy and pregnancy and perinatal outcomes. Objectives: To investigate associations between epilepsy in pregnancy and risks of pregnancy and perinatal outcomes as well as whether use of AEDs influenced risks. Design, Setting, and Participants: A population-based cohort study was conducted on all singleton births at 22 or more completed gestational weeks in Sweden from 1997 through 2011; of these, 1 424 279 were included in the sample. Information on AED exposure was available in the subset of offspring from July 1, 2005, to December 31, 2011. Data analysis was performed from October 1, 2016, to February 15, 2017. Main Outcomes and Measures: Pregnancy, delivery, and perinatal outcomes. Multivariable Poisson log-linear regression was used to estimate adjusted risk ratios (aRRs) and 95% CIs, after adjusting for maternal age, country of origin, educational level, cohabitation with a partner, height, early pregnancy body mass index, smoking, year of delivery, maternal pregestational diabetes, hypertension, and psychiatric disorders. Results: Of the 1 429 652 births included in the sample, 5373 births were in 3586 women with epilepsy; mean (SD) age at first delivery of the epilepsy cohort was 30.54 (5.18) years. Compared with pregnancies of women without epilepsy, women with epilepsy were at increased risks of adverse pregnancy and delivery outcomes, including preeclampsia (aRR 1.24; 95% CI, 1.07-1.43), infection (aRR, 1.85; 95% CI, 1.43-2.29), placental abruption (aRR, 1.68; 95% CI, 1.18-2.38), induction (aRR, 1.31; 95% CI, 1.21-1.40), elective cesarean section (aRR, 1.58; 95% CI, 1.45-1.71), and emergency cesarean section (aRR, 1.09; 95% CI, 1.00-1.20). Infants of mothers with epilepsy were at increased risks of stillbirth (aRR, 1.55; 95% CI, 1.05-2.30), having both medically indicated (aRR, 1.24; 95% CI, 1.08-1.43) and spontaneous (aRR, 1.34; 95% CI, 1.20-1.53) preterm birth, being small for gestational age at birth (aRR, 1.25; 95% CI, 1.13-1.30), and having neonatal infections (aRR, 1.42; 95% CI, 1.17-1.73), any congenital malformation (aRR, 1.48; 95% CI, 1.35-1.62), major malformations (aRR, 1.61; 95% CI, 1.43-1.81), asphyxia-related complications (aRR, 1.75; 95% CI, 1.26-2.42), Apgar score of 4 to 6 at 5 minutes (aRR, 1.34; 95% CI, 1.03-1.76), Apgar score of 0 to 3 at 5 minutes (aRR, 2.42; 95% CI, 1.62-3.61), neonatal hypoglycemia (aRR, 1.53; 95% CI, 1.34-1.75), and respiratory distress syndrome (aRR, 1.48; 95% CI, 1.30-1.68) compared with infants of unaffected women. In women with epilepsy, using AEDs during pregnancy did not increase the risks of pregnancy and perinatal complications, except for a higher rate of induction of labor (aRR, 1.30; 95% CI, 1.10-1.55). Conclusions and Relevance: Epilepsy during pregnancy is associated with increased risks of adverse pregnancy and perinatal outcomes. However, AED use during pregnancy is generally not associated with adverse outcomes.

The impact of air pollution in the Southern Bohemia Region on fetuses and newborns.

Air pollution with increased concentrations of carcinogenic polycyclic aromatic hydrocarbons (c-PAHs, represented by benzo[a]pyrene, B[a]P) affect fetal development, reduce birth weights (LBW) of newborns, and increases intrauterine growth retardation (IUGR). The Southern Bohemia Region is believed to be one of the least air polluted regions in the Czech Republic. Monitoring air pollution in the city of Ceské Budejovice from 2011-2015, PM2.5 (particulate matter <2.5 µm) decreased from 20.3 ± 14.5 µg/m3 to 14.3 ± 8.6 µg/m3, but concentrations of B[a]P did not change between the years 2007-2015: 1.5 ± 0.6 ng/m3 vs. 1.4 ± 1.4 ng/m3. Higher B[a]P concentrations the winter induce genetic damage in newborns, increase frequency of micronuclei (chromosomal aberrations), deregulate genes for immunity in umbilical cord blood, and increase incidence of IUGR and LBW in newborns.

Aripiprazole combined with other psychotropic drugs in pregnancy: two case reports.

Maternal exposure to second generation antipsychotics during pregnancy has been associated with some negative effects for both mothers and infants. Aripiprazole is becoming more readily used, although data regarding its use in pregnancy are limited. Additionally there are limited data with regards to the impact of polypharmacy on pregnancy outcomes. Given the relative paucity of information related to aripiprazole use in pregnancy it is difficult to counsel women on potential risks or side effects. We present two cases that illustrate the use of aripiprazole as a part of a polypharmacy regimen in pregnancy and describe the pregnancy outcomes in an effort to help clinicians facing complex treatment decisions in pregnancy.

Psychiatric adverse effects of pediatric corticosteroid use.

Corticosteroids, highly effective drugs for myriad disease states, have considerable neuropsychiatric adverse effects that can manifest in cognitive disorders, behavioral changes, and frank psychiatric disease. Recent reviews have summarized these effects in adults, but a comprehensive review on corticosteroid effects in children has not been published since 2005. Here, we systematically review articles published since then that, we find, naturally divide into 3 main areas: (1) chronic effects of acute prenatal and neonatal exposure associated with prematurity and congenital conditions; (2) immediate behavioral effects of acute exposure via oncological protocols; and (3) acute behavioral effects of sporadic use in children and adolescents with other conditions. PsycInfo, MEDLINE, Embase, and Scopus were queried to identify articles reporting psychiatric adverse effects of corticosteroids in pediatric patients. Search terms included corticosteroids, adrenal cortex hormones, steroid psychosis, substance-induced psychoses, glucocorticoids, dexamethasone, hydrocortisone, prednisone, adverse effects, mood disorders, mental disorders, psychosis, psychotic, psychoses, side effect, chemically induced, emotions, affective symptoms, toxicity, behavior, behavioral symptoms, infant, child, adolescent, pediatric, paediatric, neonatal, children, teen, and teenager. Following guidelines for systematic reviews from the Potsdam Consultation on Meta-Analysis, we have found it difficult to draw specific conclusions that are more than general impressions owing to the quality of the available studies. We find a mixed picture with neonates exposed to dexamethasone, with some articles reporting eventual deficits in neuropsychiatric functioning and others reporting no effect. In pediatric patients with acute lymphoblastic leukemia, corticosteroid use appears to correlate with negative psychiatric and behavioral effects. In children treated with corticosteroids for noncancer conditions, adverse effects have been observed both during treatment and after cessation, although the data from article to article are not consistent enough to establish dose relationships. By and large, inhaled corticosteroids are considered safe and free of severe neuropsychiatric effects. Although both antipsychotic medications and benzodiazepines have been used to treat corticosteroid-induced mania and psychosis, no unified management strategy has emerged. Large-scale standardized investigations are needed to clarify the psychiatric effect of corticosteroids on children in all these conditions. Meanwhile, there is general agreement that patients as well as caregivers should be warned of the potential for behavioral adverse effects when patients receive these drugs.

The effects of long-term exposure to disease-modifying drugs during pregnancy in multiple sclerosis.

BACKGROUND AND OBJECTIVE: Women with multiple sclerosis (MS) who intend to get pregnant are often advised to discontinue disease modifying therapy (DMT) prior to conception. This recommendation is not based on medical evidence and may interfere with disease control by immunomodulatory drugs. The present study was designed to help discuss the effect of DMT for MS on pregnancy and on disease course. PATIENTS AND METHODS: Retrospective data from 152 pregnancies of 132 women with MS were collected by the physician in charge of the case. All data were entered into a specific file for qualitative and quantitative statistical analysis. RESULTS: From the total group of patients, 89 pregnancies occurred without any exposure to MS drugs, while 61 pregnancies occurred with at least eight weeks of exposure to MS immunomodulatory drugs. The rate of obstetric and neonatal complications was similar in both groups, except for the newborn weight and height which was smaller for mothers receiving medications. Mothers' post-delivery relapse rate and EDSS scores in the follow-up period were significantly higher in the absence of treatment. CONCLUSION: It is possible that, with further such supportive data, international guidelines on MS treatment in young women who intend to get pregnant may need to be revised.

Neonatal complications after maternal concomitant use of SSRI and other central nervous system active drugs during the second or third trimester of pregnancy.

Drugs acting on the central nervous system (CNS) and given to a pregnant woman during the latter part of pregnancy may affect neonatal morbidity of the infant. Little is known on the combined effects of different categories of such drugs. The redeeming of prescriptions for CNS-active drugs during the second or third trimester of pregnancy was studied by linkage between a register of prescribed drugs and the Swedish Medical Birth Register for the deliveries during 2006-2008 (n = 15,045 live-born infants). Neonatal morbidity was defined as the presence of neonatal diagnoses of respiratory problems, hypoglycemia, convulsions, or other CNS pathologic abnormalities including intraventricular hemorrhage, or low 5-minute Apgar score. The risk of such neonatal morbidity after maternal use of selective serotonin reuptake inhibitors (SSRIs) with or without other CNS-active drugs were evaluated as odds ratios or risk ratios, comparing with unexposed infants or infants only exposed to SSRI drugs. An increased risk for neonatal morbidity was seen for most studied groups of CNS-active drugs when used alone. Benzodiazepines seemed to have a stronger effect than other sedatives/hypnotics. The combination of SSRIs with 1 or more other CNS-active drug groups increased the risk for neonatal morbidity. This was seen for all types of sedatives/hypnotics, which may suggest a confounding by indication. Polypharmacy with CNS-active drugs during the later part of the pregnancy seems to increase the occurrence of neonatal morbidity but difference in nature or strength of underlying psychiatric pathology may confound the findings.

Treatment of breast cancer during pregnancy: an observational study.

BACKGROUND: Little is known about the treatment of breast cancer during pregnancy. We aimed to determine whether treatment for breast cancer during pregnancy is safe for both mother and child. METHODS: We recruited patients from seven European countries with a primary diagnosis of breast cancer during pregnancy; data were collected retrospectively if the patient was diagnosed before April, 2003 (when the registry began), or prospectively thereafter, irrespective of the outcome of pregnancy and the type and timing of treatment. The primary endpoint was fetal health for up to 4 weeks after delivery. The registry is ongoing. The study is registered with ClinicalTrials.gov, number NCT00196833. FINDINGS: From April, 2003, to December, 2011, 447 patients were registered, 413 of whom had early breast cancer. Median age was 33 years (range 22-51). At the time of diagnosis, median gestational age was 24 weeks (range 5-40). 197 (48%) of 413 women received chemotherapy during pregnancy with a median of four cycles (range one to eight). 178 received an anthracycline, 15 received cyclophosphamide, methotrexate, and fluorouracil, and 14 received a taxane. Birthweight was affected by chemotherapy exposure after adjustment for gestational age (p=0·018), but not by number of chemotherapy cycles (p=0·71). No statistical difference between the two groups was observed for premature deliveries before the 37th week of gestation. 40 (10%) of 386 infants had side-effects, malformations, or new-born complications; these events were more common in infants born before the 37th week of gestation than they were in infants born in the 37th week or later (31 [16%] of 191 infants vs nine [5%] of 195 infants; p=0·0002). In infants for whom maternal treatment was known, adverse events were more common in those who received chemotherapy in utero compared with those who were not exposed (31 [15%] of 203 vs seven [4%] of 170 infants; p=0·00045). Two infants died; both were exposed to chemotherapy and delivered prematurely, but both deaths were thought not to be related to treatment. Median disease-free survival for women with early breast cancer was 70·6 months (95% CI 62·1-105·5) in women starting chemotherapy during pregnancy and 94·4 months (lower 95% CI 64·4; upper 95% CI not yet reached) in women starting chemotherapy after delivery (unadjusted hazard ratio 1·13 [95% CI 0·76-1·69]; p=0·539). INTERPRETATION: Although our data show that infants exposed to chemotherapy in utero had a lower birthweight at gestational age than did those who were unexposed, and had more complications, these differences were not clinically significant and, since none of the infants was exposed to chemotherapy in the first trimester, were most likely related to premature delivery. Delay of cancer treatment did not significantly affect disease-free survival for mothers with early breast cancer. Because preterm birth was strongly associated with adverse events, a full-term delivery seems to be of paramount importance. FUNDING: BANSS Foundation, Biedenkopf, Germany and the Belgian Cancer Plan, Ministry of Health, Belgium.

Prenatal hazardous substance use and adverse birth outcomes.

OBJECTIVE: Assess the relative effects of a variety of illicit and licit drugs on risk for adverse birth outcomes. METHODS: We used data from two large prospective investigations, and a novel analytic method, recursive partitioning class analysis to identify risk factors associated with preterm birth and delivering a small for gestational age infant. RESULTS: Compared to cocaine and opiate non-users, cocaine users were 3.53 times as likely (95% CI: 1.65-7.56; p = 0.001) and opiate users 2.86 times as likely (95% CI: 1.11-7.36; p = 0.03) to deliver preterm. The odds of delivering a small for gestational age infant for women who smoked more than two cigarettes daily was 3.74, (95% CI: 2.47-5.65; p<0.0001) compared to women who smoked two or less cigarettes daily and had one previous child. Similarly, less educated, nulliparous women who smoked two or fewer cigarettes daily were 4.12 times as likely (95% CI: 2.04-8.34; p < 0.0001) to have a small for gestational age infant. CONCLUSIONS: Among our covariates, prenatal cocaine and opiate use are the predominant risk factors for preterm birth; while tobacco use was the primary risk factor predicting small for gestational age at delivery. Multi-substance use did not substantially increase risk of adverse birth outcomes over these risk factors.

Transient ventricular hypocinesia after in utero anthracyclines exposure: a case-report and review of the literature.

Due to the low occurrence of cancer during pregnancy, limited data are available about outcome of infants exposed to chemotherapy in utero. We report the case of a newborn who developed transient ventricular hypocinesia and late-onset infection after in utero exposure to four epirubicin cycles for pregnancy-associated breast cancer. Moreover, we provide an overview of literature on neonatal outcome after anthracyclines-based chemotherapy regimen during pregnancy. Existing data support use of anthracyclines, as few cases of fetal cardiac toxicity were reported and most of short-term complications were transient. Need for prospective collection of data and longer follow-up is highly recognized.

Tabaquismo durante el embarazo / Smoking during pregnancy

El tabaquismo durante el embarazo ha sido relacionado a muchas patologías obstétricas y neonatales, como desprendimiento de placenta, placenta previa, embarazo ectópico, aborto, parto prematuro, síndrome de distress respiratorio del recién nacido, bajo peso de nacimiento, muerte súbita, síndromes neurocognitivos, entre otros. En relación a la patología respiratoria el tabaquismo durante el embarazo produce alteraciones en la función de la vía aérea, traducido por flujos espiratorios disminuidos, sibilancias recurrentes y asma bronquial, hiperreactividad bronquial, mayor frecuencia de hospitalizaciones e infecciones respiratorias bajas. Finalmente es fundamental aplicar medidas tendientes a evitar el tabaquismo en las mujeres embarazadas y en el producto de la concepción.

[Morbidity in newborns exposed to organophosphorus pesticides].

INTRODUCTION: Insecticides are toxins by which we destroy harmful insects. The most frequent insecticides which are used today are organophosphorus pesticides. This group of compounds make substances whose activity mechanism is based on the inhibition of acetylcholinesterase in nerve synapsis, thus producing holynergic syndrome, resulting from the accumulation of acetylcholine which developed due to the absence of decomposition under the influence of cholinesterase. In the clinical picture of acute toxication by cholinesterase inhibitors there is a clear difference between muscarinic and nicotine effects. The basic aim of the study was to establish the effects of organophosphorus pesticides present in blood and breast milk of mothers on newborns morbidity. MATERIAL AND METHODS: The study group consisted of 18 newborns whose mothers had isolated organophosphorus pesticides in their blood and breast-milk on the third day after delivery, and the control group consisted of 84 newborns whose mothers did not have isolated organophosphorus pesticides in their blood and breastmilk. RESULTS: Morbidity is three times greater, often in combination with some disorders of the central nervous system, and the relative risk for its appearance is eight time greater in newborns exposed to organophosphorus pesticides. DISCUSSION: Disorders that appear in newborns exposed to pesticides are mutagenic, cancerogenic and neurotoxic and some agenses could disturb the immune system which is reflected in morbidity increase, primarly of the central nervous system. CONCLUSION: The presence of organophosphorus pesticides in blood and breast milk has negative effects on newborns. In addition to acetylcholinesterase inhibition, organophosphorus pesticides react by means of other mechanisms as well.

Granulocyte colony stimulating factor in neonatal alloimmune neutropenia: a possible association with induced thrombocytopenia.

Neonatal alloimmune neutropenia (NAIN) is a rare cause of congenital neutropenia seen in <1% of births. Significant morbidity, usually infections, may result from this disease. The pathophysiology of NAIN, mediated by maternal antibodies crossing the placenta to destroy fetal cells expressing paternal antigens, is similar to that of neonatal alloimmune thrombocytopenia, as well as Rh/ABO hemolytic disease of the newborn. The use of high-dose granulocyte colony stimulating factor in patients with NAIN may cause a reversible thrombocytopenia in some patients.

Pregnancy and infant outcomes in the clinical trials of a human papillomavirus type 6/11/16/18 vaccine: a combined analysis of five randomized controlled trials.

OBJECTIVE: To present a combined analysis of the pregnancy outcomes for women aged up to 45 years enrolled in five phase III clinical studies of the prophylactic quadrivalent human papillomavirus 6/11/16/18 vaccine. METHODS: Twenty thousand five hundred fifty-one women aged 15-45 years received quadrivalent HPV vaccine or placebo at day 1 and months 2 and 6. Urine pregnancy tests were performed immediately before each injection; participants testing positive were not vaccinated. Women who became pregnant after enrollment were discontinued from further vaccination until resolution of pregnancy. All pregnancies were followed for outcomes. RESULTS: During the studies, 1,796 vaccine and 1,824 placebo recipients became pregnant, resulting in 2,008 and 2,029 pregnancies with known outcomes. No significant differences were noted overall for the proportions of pregnancies resulting in live birth, fetal loss, or spontaneous abortion. A total of 40 neonates born to vaccinated women and 30 neonates born to women given placebo had one or more congenital anomalies (P=.20). The anomalies were diverse and consistent with those most commonly observed in the general population. The vaccine was well tolerated among women who became pregnant. CONCLUSION: Administration of quadrivalent human papillomavirus vaccine to women who became pregnant during the phase III clinical trials did not appear to negatively affect pregnancy outcomes. The vaccine is a U.S. Food and Drug Administration pregnancy category B medication (animal studies revealed no evidence of fetal harm, but there are no adequate and well-controlled studies in pregnant women); however, vaccination is not recommended during pregnancy. Postlicensure surveillance is ongoing. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00092521, NCT00092534, NCT00092495, NCT00092547 and NCT00090220. LEVEL OF EVIDENCE: II.