Heather S. Lipkind

Maternal influenza vaccine and risks for preterm or small for gestational age birth.

OBJECTIVE To study the impact of influenza vaccine administered to pregnant women during all trimesters on the rates of preterm and small for gestational age (SGA) births, evaluating both increased and decreased risk. STUDY DESIGN This retrospective observational matched cohort study involved 7 Vaccine Safety Datalink sites across the US for the 2004-05 through 2008-09 influenza seasons. Cohort eligibility and outcomes were determined from administrative, claims, medical records, and birth data. In propensity score- and vaccine exposure time-matched analyses, ORs for preterm and SGA births were calculated. RESULTS Among 57 554 matched vaccinated and unvaccinated pregnant women, including 16 240 women in the first trimester, maternal vaccination was not associated with increased or decreased risk for preterm birth (OR for delivery at <37 weeks gestation, 0.97 [95% CI, 0.93-1.02]; for delivery at ≤32 weeks gestation, 0.98 [95% CI, 0.86-1.12]; and for delivery at ≤34 weeks gestation, 0.96 [95% CI, 0.88-1.04]) or SGA birth (OR for <5th percentile weight for gestational age, 1.02 [95% CI, 0.96-1.09], and for <10th percentile weight for gestational age, 1.00 [95% CI, 0.96-1.04]). Similarly, first trimester vaccination was not associated with increased or decreased risk for preterm or SGA birth. CONCLUSION Receipt of trivalent inactivated influenza vaccine during pregnancy was not associated with increased or decreased risk of preterm or SGA birth. These findings support the safety of vaccinating pregnant women against influenza during the first, second, and third trimesters, and suggest that a nonspecific protective effect of the influenza vaccine for these outcomes does not exist.

Maternal safety of trivalent inactivated influenza vaccine in pregnant women

OBJECTIVE: To estimate the risks for medically attended events occurring within 42 days of receiving trivalent inactivated influenza vaccine and to evaluate specific risks of first-trimester vaccination. METHODS: This retrospective observational cohort study compared rates of medically attended adverse events in trivalent inactivated influenza-vaccinated and unvaccinated pregnant women in the Vaccine Safety Datalink. Using a Poisson distribution and log link, we calculated maternal adjusted incident rate ratios for composite safety outcomes for the full cohort and the subset vaccinated during the first trimester. RESULTS: The cohort included 75,906 vaccinated (28.4% in the first trimester) and 147,992 unvaccinated women matched by age, site, and pregnancy start date. In the first 3 days after vaccination, trivalent inactivated influenza vaccine was not associated with increased risk of specified medically attended events, including allergic reactions, cellulitis, and seizures (full cohort adjusted incident rate ratio 1.12, 95% confidence interval [CI] 0.81–1.55; P=.48; first-trimester adjusted incident rate ratio .97, 95% CI 0.53–1.78; P=.93). In the first 42 days, no incident cases of Guillain-Barré syndrome, optic neuritis, transverse myelitis, or Bells palsy were identified. Trivalent inactivated influenza vaccine was not associated with thrombocytopenia (full cohort adjusted incident rate ratio 0.90, 95% CI 0.68--1.19; P=.45; first-trimester adjusted incident rate ratio 0.56, 95% CI 0.22–1.39; P=.21) or an acute neurologic event (full cohort adjusted incident rate ratio 0.92, 95% CI 0.54–1.6; P=.75; first-trimester adjusted incident rate ratio 1.05, 95% CI 0.46–2.38; P=.91). CONCLUSIONS: Receipt of trivalent inactivated influenza vaccine during pregnancy was not associated with increased risk of adverse events in the 42 days after vaccination, supporting its safety for the mother. LEVEL OF EVIDENCE: II

Inactivated influenza vaccine during pregnancy and risks for adverse obstetric events.

OBJECTIVE: To compare risks for adverse obstetric events between females who did and did not receive trivalent inactivated influenza vaccine during pregnancy. METHOD: This retrospective, observational cohort study was conducted at seven Vaccine Safety Datalink sites. Pregnancies were identified from administrative and claims data using a validated algorithm. Females vaccinated while pregnant from 2002 to 2009 were matched one-to-two with replacement to unvaccinated pregnant females. Using a generalized estimating equation method with a Poisson distribution and log link, we evaluated the association of trivalent inactivated influenza vaccine with 13 outcomes. Given our large sample size and multiple comparisons (19 contrasts), a cutoff for significance of P<.005 was selected a priori. RESULTS: Our cohort included 74,292 vaccinated females matched on age, site, and pregnancy start date with 144,597 unvaccinated females. We did not observe increased risks within 42 days of vaccination for hyperemesis, chronic hypertension, gestational hypertension, gestational diabetes, proteinuria, or urinary tract infection. Using a risk window from vaccination through pregnancy end, we did not observe increased risks after vaccination for proteinuria, urinary tract infection, gestational hypertension, preeclampsia or eclampsia, chorioamnionitis, puerperal infection, venous complications, pulmonary embolism, or peripartum cardiomyopathy. A reduced risk for gestational diabetes after vaccination was detected (adjusted hazard rate ratio 0.88, 95% confidence interval 0.83–0.93), likely as a result of healthy vaccine bias or earlier detection among vaccinees. CONCLUSION: In this large cohort, influenza vaccination during pregnancy was not associated with increased risks for medically attended adverse obstetric events. LEVEL OF EVIDENCE: II

Birth Outcomes Among Offspring of Women Exposed to the September 11, 2001, Terrorist Attacks

OBJECTIVE: To evaluate the effects of the September 11, 2001, World Trade Center attacks on birth outcomes. METHODS: Live singleton births between September 11, 2001, and October 31, 2002, to women enrolled in a World Trade Center Health Registry (the Registry, n=446) were compared with births to women residing more than 5 miles from the World Trade Center (n=49,616). Birth weight, gestational age, low birth weight, and preterm delivery were evaluated using linear and logistic regression. Births before September 11, 2001, were analyzed to assess possible seasonal biases of associations with pregnancy trimester on September 11. Associations of birth outcomes with September 11–related psychologic stress and physical exposures were assessed among births to women within the Registry (n=499). RESULTS: Birth weight and gestational age distributions were similar for births to women enrolled in the Registry and comparison births. Although mean gestational age and birth weight varied with trimester on September 11, a similar association was found among births in previous years, consistent with a seasonal effect not related to exposure. Registry-linked births to mothers with probable posttraumatic stress disorder (n=61) had a higher odds of low birth weight (adjusted odds ratio [OR] 2.49, 95% confidence interval [CI] 1.02–6.08) and preterm delivery (adjusted OR 2.48, 95% CI 1.05–5.84) compared with births to women without posttraumatic stress disorder. CONCLUSION: Women who lived, worked, or were near the World Trade Center on or soon after September 11 had pregnancy outcomes similar to women residing more than 5 miles away. However, among exposed women, probable posttraumatic stress disorder was associated with low birth weight and preterm delivery. LEVEL OF EVIDENCE: II

Maternal Tdap vaccination: Coverage and acute safety outcomes in the vaccine safety datalink, 2007-2013.

INTRODUCTION Since October 2012, the combined tetanus toxoid, reduced diphtheria toxoid, acellular pertussis vaccine (Tdap) has been recommended in the United States during every pregnancy. METHODS In this observational study from the Vaccine Safety Datalink, we describe receipt of Tdap during pregnancy among insured women with live births across seven health systems. Using a retrospective matched cohort, we evaluated risks for selected medically attended adverse events in pregnant women, occurring within 42 days of vaccination. Using a generalized estimating equation, we calculated adjusted incident rate ratios (AIRR). RESULTS Our vaccine coverage cohort included 438,487 live births between January 1, 2007 and November 15, 2013. Across the coverage cohort, 14% received Tdap during pregnancy. By 2013, Tdap was administered during pregnancy in 41.7% of live births, primarily in the 3rd trimester. Our vaccine safety cohort included 53,885 vaccinated and 109,253 matched unvaccinated pregnant women. There was no increased risk for a composite outcome of medically attended acute adverse events within 3 days of vaccination. Similarly, across the safety cohort, over a 42 day window, incident neurologic events, thrombotic events, and new onset proteinuria did not differ by maternal receipt of Tdap. Among women receiving Tdap at 20 weeks gestation or later, as compared to their matched controls, there was no increased risk for gestational diabetes or cardiac events while venous thromboembolic events and thrombocytopenia were diagnosed within 42 days of vaccination at slightly decreased rates. CONCLUSION Tdap coverage during pregnancy increased from 2007 through 2013, but was still below 50%. No acute maternal safety signals were detected in this large cohort.

Receipt of pertussis vaccine during pregnancy across 7 Vaccine Safety Datalink Sites

OBJECTIVE In response to widespread pertussis outbreaks and infant deaths, in 2010, the California Department of Health (CDPH) and in 2011 the Advisory Committee on Immunization Practices (ACIP) advised that the tetanus toxoid, reduced diphtheria toxoid and acellular pertussis (Tdap) vaccine be administered during pregnancy. The goals of this study were to describe Tdap coverage among pregnant women following these recommendations. METHODS In this observational cohort study, we utilized electronic medical record and claims data from seven Vaccine Safety Datalink sites to identify pregnancies and Tdap administrations. All Tdap doses were classified as pre-pregnancy, during pregnancy or post-pregnancy/postpartum. For pregnancies ending in a live birth, we evaluated factors associated with Tdap vaccination. RESULTS Among 289,141 live births at the California VSD sites, receipt of Tdap during pregnancy increased substantially in the years 2010, 2011, and 2012, when coverage was 15.9, 30.0 and 19.5%, respectively. Among 82,398 women with live births at the Oregon, Washington, Colorado, Wisconsin and Minnesota VSD sites, receipt of Tdap during pregnancy first increased in 2012, at 16.0%. Women receiving early prenatal care and other vaccine(s) during pregnancy had higher Tdap coverage. CONCLUSION We observed substantial increases in Tdap coverage during pregnancy following CDPH and ACIP recommendations.

Mode of delivery and neonatal outcomes in preterm, small-for-gestational-age newborns.

OBJECTIVE: To compare neonatal outcomes by method of delivery in preterm (34 weeks of gestation or prior), small-for-gestational-age (SGA) newborns in a large diverse cohort. METHODS: Birth data for 1995–2003 from New York City were linked to hospital discharge data. Data were limited to singleton, liveborn, vertex neonates delivered between 25 and 34 weeks of gestation. Births complicated by known congenital anomalies and birth weight less than 500 g were excluded. Small for gestational age was used as a surrogate for intrauterine growth restriction. Associations between method of delivery and neonatal morbidities were estimated using logistic regression. RESULTS: Two thousand eight hundred eighty-five SGA neonates meeting study criteria were identified; 42.1% were delivered vaginally, and 57.9% were delivered by cesarean. There was no significant difference in intraventricular hemorrhage, subdural hemorrhage, seizure, or sepsis between the cesarean delivery and vaginal delivery groups. Cesarean delivery compared with vaginal delivery was associated with increased odds of respiratory distress syndrome. The increased odds persisted after controlling for maternal age, parity, ethnicity, education, primary payer, prepregnancy weight, gestational age at delivery, diabetes, and hypertension. CONCLUSION: Cesarean delivery was not associated with improved neonatal outcomes in preterm SGA newborns and was associated with an increased risk of respiratory distress syndrome. LEVEL OF EVIDENCE: II

Mode of delivery in nulliparous women and neonatal intracranial injury.

OBJECTIVE: To compare neonatal neurologic complication rates of cesarean deliveries, forceps-assisted vaginal deliveries, and vacuum-assisted vaginal deliveries. METHODS: Data on singleton live births at 34 weeks or greater gestation born to nulliparous women from 1995 to 2003 in New York City were linked to hospital discharge data. Any diagnosis of neonatal subdural hemorrhage, intraventricular hemorrhage, seizures, scalp laceration or cephalohematoma, fracture, facial nerve palsy, brachial plexus injury, or 5-minute Apgar score of less than 7 was considered significant. Multivariable logistic regression was used to estimate associations between delivery mode and these neonatal morbidities. RESULTS: Forceps-assisted vaginal deliveries were associated with significantly fewer seizures and 5-minute Apgar scores less than 7 compared with vacuum-assisted vaginal deliveries and cesarean deliveries. Cesarean deliveries were linked to less subdural hemorrhages compared with forceps-assisted vaginal deliveries or vacuum-assisted vaginal deliveries. When seizure, intraventricular hemorrhage, and subdural hemorrhage were examined collectively to best predict neurologic outcome, forceps-assisted vaginal deliveries had an overall reduced risk compared with both vacuum-assisted vaginal deliveries (odds ratio [OR] 0.60, 95% confidence interval [CI] 0.40–0.90) and cesarean deliveries (OR 0.68, 95% CI 0.48–0.97). The number needed to treat to prevent one case of severe neurologic morbidity is 509 for forceps-assisted vaginal deliveries compared with vacuum-assisted vaginal deliveries and 559 for forceps-assisted vaginal deliveries compared with cesarean deliveries. CONCLUSION: Compared with vacuum-assisted vaginal delivery or cesarean delivery, a forceps-assisted vaginal delivery is associated with a reduced risk of adverse neonatal neurologic outcomes. LEVEL OF EVIDENCE: II

Disparities in cesarean delivery rates and associated adverse neonatal outcomes in New York City hospitals.

OBJECTIVE: To examine the primary cesarean delivery rates and associated neonatal outcomes by insurance status in public and private hospitals in New York City. METHODS: We accessed Vital statistics data on all births to women with Medicaid or private insurance from 1996 through 2003, compiling a total of 321,308 nulliparous women who delivered singleton neonates by either normal spontaneous vaginal delivery or primary cesarean delivery. Rates of primary cesarean delivery and adverse neonatal outcomes were examined by hospital type and insurance status while controlling for potential confounders. RESULTS: There were 51,682 and 269,626 women who delivered in public hospitals and private hospitals, respectively. The cesarean delivery rate of women with private insurance delivering in private hospitals was 30.4% compared with a cesarean rate of 21.2% in Medicaid patients delivering in public hospitals (adjusted odds ratio [OR] 1.57, 95% confidence interval [CI] 1.53–1.63). The percent of infants born to women with private insurance and Medicaid delivering in private hospitals with a 5-minute Apgar score less than 7 was 0.6% and 0.8% compared with 1.0% of infants delivering in the public hospital system (adjusted OR 0.59, 95% CI 0.51– 0.68 and adjusted OR 0.73, 95% CI 0.65– 0.82). The neonatal intensive care unit admission rate was also lower in neonates born in private hospitals at 6.7% and 8.5% compared with a 12.8% admission rate in public hospitals (adjusted OR 0.48, 95% CI 0.46–0.51 and adjusted OR 0.59, 95% CI 0.57– 0.62 after controlling for mode of delivery). CONCLUSION: Even when controlling for confounders, there was an association between primary cesarean delivery and insurance status regardless of hospital type. There was also a higher risk of adverse neonatal outcomes in the public hospitals regardless of mode of delivery. LEVEL OF EVIDENCE: III

Pregnancy-Induced Hypertension and Diabetes and the Risk of Cardiovascular Disease, Stroke, and Diabetes Hospitalization in the Year Following Delivery

Although pregnancy events predict the long-term risk of chronic disease, little is known about their short-term impact because of the rarity of clinical events. We examined hospital discharge diagnoses linked to birth certificate data in the year following delivery for 849,639 births during 1995-2004 in New York City, New York. Adjusted odds ratios characterized the relationship between pregnancy complications and subsequent hospitalization for cardiovascular disease, stroke, and diabetes. Gestational hypertension was related to heart failure (adjusted odds ratio = 2.6, 95% confidence interval: 1.5, 4.5). Preeclampsia was related to all of the outcomes considered except type 1 diabetes, with adjusted odds ratios ranging from 2.0 to 4.1. Gestational diabetes was strongly related to the risk of subsequent diabetes (for type 1 diabetes, adjusted odds ratio = 40.4, 95% confidence interval: 23.8, 68.5; for type 2 diabetes, adjusted odds ratio = 22.6, 95% confidence interval: 16.9, 30.4) but to no other outcomes. The relationship of pregnancy complications to future chronic disease is apparent as early as the year following delivery. Moreover, elucidating short-term clinical outcomes offers the potential for etiological insights into the relationship between pregnancy events and chronic disease over the life course.