Second-trimester fetal head circumference in more than 350 000 pregnancies: Outcome and suggestion for sex-dependent cutoffs for small heads.

OBJECTIVE: To explore the relationship between small fetal second-trimester head circumference (HC) and pregnancy outcome and identify a cutoff point for offering genetic testing. METHOD: Data from second-trimester scans in Denmark were linked to national registers. Fetuses with anomalies diagnosed before this scan were excluded. Fetuses were grouped according to HC z-score. RESULTS: We included 352 515 singleton fetuses. The mean HC was significantly larger among males than among females with z-scores averaging 0.52 more in males. Small HC was associated with chromosomal anomaly, malformations of the CNS and heart, miscarriage/perinatal death, termination, preterm delivery, and intrauterine growth restriction (test for trend: P < .001 for all outcomes). Fetuses in the group with z-score less than -3 had the highest incidence of adverse outcome, irrespective of fetal sex. In the groups with z-scores between -3 and -2.5, and between -2.5 and -2, risk of adverse outcome was lower for females than males for all outcome categories. CONCLUSION: Small HC in second trimester is a prognostic marker for adverse outcome. The smaller the HC, the higher the risk of adverse outcome. We suggest an HC cutoff point of -2 SD for males and -2.5 SD for females for offering genetic testing.

Early BCG-Denmark and Neonatal Mortality Among Infants Weighing <2500 g: A Randomized Controlled Trial.

Background: BCG vaccine may reduce overall mortality by increasing resistance to nontuberculosis infections. In 2 randomized trials in Guinea-Bissau of early BCG-Denmark (Statens Serum Institut) given to low-weight (LW) neonates (<2500 g at inclusion) to reduce infant mortality rates, we observed a very beneficial effect in the neonatal period. We therefore conducted the present trial to test whether early BCG-Denmark reduces neonatal mortality by 45%. We also conducted a meta-analysis of the 3 BCG-Denmark trials. Methods: In 2008-2013, we randomized LW neonates to "early BCG-Denmark" (intervention group; n = 2083) or "control" (local policy for LW and no BCG-Denmark; n = 2089) at discharge from the maternity ward or at first contact with the health center. The infants were randomized (1:1) without blinding in blocks of 24. Data was analyzed in Cox hazards models providing mortality rate ratios (MRRs). We had prespecified an analysis censoring follow-up at oral poliovirus vaccine campaigns. Results: Early administration of BCG-Denmark was associated with a nonsignificant reduction in neonatal mortality rate (MRR, 0.70; 95% confidence interval [CI], .47-1.04) and a 34% reduction (0.66; .44-1.00) when censoring for oral poliovirus vaccine campaigns. There was no reduction in mortality rate for noninfectious diseases, but a 43% reduction in infectious disease mortality rate (MRR, 0.57; 95% CI, .35-.93). A meta-analysis of 3 BCG trials showed that early BCG-Denmark reduced mortality by 38% (MRR, 0.62; 95% CI, .46-.83) within the neonatal period and 16% (0.84; .71-1.00) by age 12 months. Conclusion: Early administration of BCG-Denmark in LW infants is associated with major reductions in mortality rate. It is important that all LW infants receive early BCG in areas with high neonatal mortality rates. Clinical Trials Registration: NCT00625482.

The Effect of Oral Polio Vaccine at Birth on Infant Mortality: A Randomized Trial.

BACKGROUND: Routine vaccines may have nonspecific effects on mortality. An observational study found that OPV given at birth (OPV0) was associated with increased male infant mortality. We investigated the effect of OPV0 on infant mortality in a randomized trial in Guinea-Bissau. METHODS: A total of 7012 healthy normal-birth-weight neonates were randomized to BCG only (intervention group) or OPV0 with BCG (usual practice). All children were to receive OPV with pentavalent vaccine (diphtheria, tetanus, pertussis, Haemophilus influenzae type b, and hepatitis B) at 6, 10, and 14 weeks of age. Seven national OPV campaigns were also conducted during the trial period. Children were followed to age 12 months. We used Cox regression to calculate hazard ratios (HRs) for mortality. RESULTS: The trial contradicted the original hypothesis about OPV0 increasing male infant mortality. Within 12 months, 73 children in the BCG + OPV group and 87 children in the BCG-only group died, all from infectious diseases. Comparing BCG + OPV0 vs BCG only, the HR was 0.83 (95% confidence interval [CI], .61-1.13): 0.72 (95% CI, .47-1.10) in boys and 0.97 (95% CI, .61-1.54) in girls. For children enrolled within the first 2 days of life, the HR for BCG + OPV0 vs BCG only was 0.58 (95% CI, .38-.90). From enrollment until the time of OPV campaigns, the HR was 0.68 (95% CI, .45-1.00), the beneficial effect being separately significant for males (0.55 [95% CI, .32-.95]). CONCLUSIONS: This is the only randomized trial of the effect of OPV0 on mortality. OPV0 may be associated with nonspecific protection against infectious disease mortality, particularly when given early in life. There are reasons to monitor mortality when OPV is being phased out. CLINICAL TRIALS REGISTRATION: NCT00710983.

Factors associated with thymic size at birth among low and normal birth-weight infants.

OBJECTIVE: To study the effect of gestational and perinatal exposures on thymic size in 366 normal birth weight and 426 low birth weight (LBW) neonates in Guinea-Bissau in West Africa. STUDY DESIGN: In a cross-sectional study, thymic size was measured at birth by the use of ultrasound. Information on possible determinants was collected from pregnancy cards, hospital records, and interviews with the mother. We used the log-transformed thymic index and thymus/weight index as outcome measures. Data were analyzed with adjusted linear regression models providing geometric mean ratios (GMRs) with 95% CI. RESULTS: Determinants of thymic size among normal birth weight infants were pathologic amniotic fluid (adjusted GMR for thymic index: 0.84 [0.74-0.96]) and male sex (GMR: 1.13 [1.06-1.22]). Among LBW infants, birth season (1.11 [1.01-1.22]), maternal body temperature (0.89 [0.79-0.98]), antibiotic treatment at the time of labor (0.84 [0.70-1.00]), number of pregnancy consultations (1.03 [1.00-1.05]), maternal age (0.91 [0.84-0.98]), Apgar score (1.06 [1.03-1.10]), and infant convulsions (0.44 [0.29-0.65]) were all independent determinants of thymic index but not all were determinants of thymus/weight index. Pathologic amniotic fluid and cesarean delivery were associated with thymus/weight index among LBW infants (0.85 [0.75-0.95] and 0.80 [0.67-0.96]) but were only borderline significant for thymic index. CONCLUSION: Exposures mainly related to stress and infections were associated with a smaller thymus, mainly in LBW infants.

Neonatal vitamin A supplementation associated with a cluster of deaths and poor early growth in a randomised trial among low-birth-weight boys of vitamin A versus oral polio vaccine at birth.

BACKGROUND: The effect of oral polio vaccine administered already at birth (OPV0) on child survival was not examined before being recommended in 1985. Observational data suggested that OPV0 was harmful for boys, and trials have shown that neonatal vitamin A supplementation (NVAS) at birth may be beneficial for boys. We set out to test this research question in a randomised trial. METHODS: The trial was carried out at the Bandim Health Project, Guinea-Bissau. We planned to enrol 900 low-birth weight (LBW) boys in a randomised trial to investigate whether NVAS instead of OPV0 could lower infant mortality for LBW boys. At birth, the children were randomised to OPV (usual treatment) or VAS (intervention treatment) and followed for 6 months for growth and 12 months for survival. Hazard Ratios (HR) for mortality were calculated using Cox regression. We compared the individual anthropometry measurements to the 2006 WHO growth reference. We compared differences in z-scores by linear regression. Relative risks (RR) of being stunted or underweight were calculated in Poisson regression models with robust standard errors. RESULTS: In the rainy season we detected a cluster of deaths in the VAS group and the trial was halted immediately with 232 boys enrolled. The VAS group had significantly higher mortality than the OPV0 group in the rainy season (HR: 9.91 (1.23 - 80)). All deaths had had contact with the neonatal nursery; of seven VAS boys enrolled during one week in September, six died within two months of age, whereas only one died among the six boys receiving OPV (p = 0.05). Growth (weight and arm-circumference) in the VAS group was significantly worse until age 3 months. CONCLUSION: VAS at birth instead of OPV was not beneficial for the LBW boys in this study. With the premature closure of the trial it was not possible to answer the research question. However, the results of this study call for extra caution when testing the effect of NVAS in the future. TRIAL REGISTRATION: http://www.clinicaltrials.gov NCT00625482. Registered 18 February 2008.

A prospective study of twinning and perinatal mortality in urban Guinea-Bissau.

BACKGROUND: Despite twinning being common in Africa, few prospective twin studies have been conducted. We studied twinning rate, perinatal mortality and the clinical characteristics of newborn twins in urban Guinea-Bissau. METHODS: The study was conducted at the Bandim Health Project (BHP), a health and demographic surveillance site in Bissau, the capital of Guinea-Bissau. The cohort included all newborn twins delivered at the National Hospital Simão Mendes and in the BHP study area during the period September 2009 to August 2011 as well as singleton controls from the BHP study area. Data regarding obstetric history and pregnancy were collected at the hospital. Live children were examined clinically. For a subset of twin pairs zygosity was established by using genetic markers. RESULTS: Out of the 5262 births from mothers included in the BHP study area, 94 were twin births, i.e. a community twinning rate of 18/1000. The monozygotic rate was 3.4/1000. Perinatal mortality among twins vs. singletons was 218/1000 vs. 80/1000 (RR = 2.71, 95% CI: 1.93-3.80). Among the 13783 hospital births 388 were twin births (28/1000). The hospital perinatal twin mortality was 237/1000.Birth weight < 2000g (RR = 4.24, CI: 2.39-7.51) and caesarean section (RR = 1.78, CI: 1.06-2.99) were significant risk factors for perinatal twin mortality. Male sex (RR = 1.38, CI: 0.97-1.96), unawareness of twin pregnancy (RR = 1.64, CI: 0.97-2.78) and high blood pressure during pregnancy (RR = 1.77, CI: 0.88-3.57) were borderline non-significant. Sixty-five percent (245/375) of the mothers who delivered at the hospital were unaware of their twin pregnancy. CONCLUSIONS: Twins had a very high perinatal mortality, three-fold higher than singletons. A birth weight < 2000g was the strongest risk factor for perinatal death, and unrecognized twin pregnancy was common. Urgent interventions are needed to lower perinatal twin mortality in Guinea-Bissau.

Randomized trial of BCG vaccination at birth to low-birth-weight children: beneficial nonspecific effects in the neonatal period?

BACKGROUND: Observational studies have suggested that BCG may have nonspecific beneficial effects on survival. Low-birth-weight (LBW) children are not given BCG at birth in Guinea-Bissau; we conducted a randomized trial of BCG at birth (early BCG) vs delayed BCG. METHODS: In the period 2004-2008 we recruited 2320 LBW children in Bissau. The children were visited at home at 2, 6, and 12 months of age. With a pretrial infant mortality of 250 per 1000, we hypothesized a 25% reduction in infant mortality for LBW children. RESULTS: Infant mortality was only 101 per 1000 during the trial. In the primary analysis, infant mortality was reduced insignificantly by 17% (mortality rate ratio [MRR] = .83 [.63-1.08]). In secondary analyses, early BCG vaccine was safe with an MRR of .49 (.21-1.15) after 3 days and .55 (.34-.89) after 4 weeks. The reduction in neonatal mortality was mainly due to fewer cases of neonatal sepsis, respiratory infection, and fever. The impact of early BCG on infant mortality was marked for children weighing <1.5 kg (MRR = .43 [.21-.85]) who had lower coverage for diphtheria-tetanus-pertussis vaccinations. CONCLUSIONS: Though early BCG did not reduce infant mortality significantly, it may have a beneficial effect in the neonatal period. This could be important for public health because BCG is often delayed in low-income countries.

Correction: Stillbirths in urban Guinea-Bissau: A hospital- and community-based study.

[This corrects the article DOI: 10.1371/journal.pone.0197680.].

Stillbirths in urban Guinea-Bissau: A hospital- and community-based study.

BACKGROUND: Stillbirth rates remain high in many low-income settings, with fresh (intrapartum) stillbirths accounting for a large part due to limited obstetrical care. We aimed to determine the stillbirth rate and identify potentially modifiable factors associated with stillbirth in urban Guinea-Bissau. METHODS: The study was carried out by the Bandim Health Project (BHP), a Health and Demographic Surveillance System site in the capital Bissau. We assessed stillbirth rates in a hospital cohort consisting of all deliveries at the maternity ward at the National Hospital Simão Mendes (HNSM), and in a community cohort, which only included women from the BHP area. Stillbirth was classified as fresh (FSB) if fetal movements were reported on the day of delivery. RESULTS: From October 1 2007 to April 15 2013, a total of 38164 deliveries were registered at HNSM, among them 3762 stillbirths (99/1000 births). Excluding deliveries referred to the hospital from outside the capital (9.6%), the HNSM stillbirth rate was 2786/34490 births (81/1000). During the same period, 15462 deliveries were recorded in the community cohort. Of these, 768 were stillbirths (50/1000). Of 11769 hospital deliveries among women from Bissau with data on fetal movement, 866 (74/1000) were stillbirths, and 609 (70.3%) of these were FSB, i.e. potentially preventable. The hospital FSB rate was highest in the evening from 4 pm to midnight (P = 0.04). In the community cohort, antenatal care (ANC) attendance correlated strongly with stillbirth reduction; the stillbirth rate was 71/1000 if the mother attended no ANC consultations vs. 36/1000 if she attended ≥7 consultations (P<0.001). CONCLUSION: In Bissau, the stillbirth rate is alarmingly high. The majority of stillbirths are preventable FSB. Improving obstetrical training, labour management (including sufficient intrapartum monitoring and timely intervention) and hospital infrastructure is urgently required. This should be combined with proper community strategies and additional focus on antenatal care.

National Immunization Campaigns with Oral Polio Vaccine Reduce All-Cause Mortality: A Natural Experiment within Seven Randomized Trials.

BACKGROUND: A recent WHO review concluded that live BCG and measles vaccine (MV) may have beneficial non-specific effects (NSEs) reducing mortality from non-targeted diseases. NSEs of oral polio vaccine (OPV) were not examined. If OPV vaccination campaigns reduce the mortality rate, it would suggest beneficial NSEs. SETTING: Between 2002 and 2014, Guinea-Bissau had 15 general OPV campaigns and other campaigns with OPV plus vitamin A supplementation (VAS), VAS-only, MV, and H1N1 vaccine. In this period, we conducted seven randomized controlled trials (RCTs) with mortality as main outcome. METHODS: Within these RCTs, we assessed whether the mortality rate was lower after-campaign than before-campaign. We used Cox models with age as underlying time and further adjusted for low birth-weight, season and time trend in mortality. We calculated the adjusted mortality rate ratio (MRR) for after-campaign vs before-campaign. RESULTS: The mortality rate was lower after OPV-only campaigns than before, the MRR being 0.81 (95% CI = 0.68-0.95). With each additional dose of campaign-OPV the mortality rate declined further (MRR = 0.87 (95% CI: 0.79-0.96) per dose) (test for trend, p = 0.005). No other type of campaign had similar beneficial effects. Depending on initial age and with follow-up to 3 years of age, the number needed to treat with campaign-OPV-only to save one life was between 68 and 230 children. CONCLUSION: Bissau had no case of polio infection so the results suggest that campaign-OPV has beneficial NSEs. Discontinuation of OPV-campaigns in low-income countries may affect general child mortality levels negatively.

Contrasting female-male mortality ratios after routine vaccinations with pentavalent vaccine versus measles and yellow fever vaccine. A cohort study from urban Guinea-Bissau.

BACKGROUND: In addition to protection against the target diseases, vaccines may have non-specific effects (NSEs). Measles vaccine (MV) has beneficial NSEs, providing protection against non-measles deaths, most so for girls. By contrast, though protecting against diphtheria, tetanus and pertussis, DTP vaccine is associated with increased female mortality relative to male mortality. In 2008, Guinea-Bissau replaced DTP with the DTP-containing pentavalent vaccine (Penta; DTP-H. influenza type B-Hepatitis B) at 6, 10 and 14weeks and yellow fever vaccine (YF) was to be given with MV. We investigated possible sex-differential mortality rates following Penta and MV+YF vaccination. METHODS: Bandim Health Project (BHP) registers vaccines given by the three government health centres in the study area and vital status through demographic surveillance. We assessed the association between sex and mortality by vaccination status in Cox proportional hazards models with age as underlying timescale. Follow-up was censored at a subsequent vaccination contact or after 6months of follow-up. RESULTS: Between September 2008 and April 2011, we registered 23,448 vaccination contacts for children aged 42-365days; 17,313 were for Penta and 3028 for MV (2907 co-administered with YF). During follow-up 112 children died. The female/male mortality rate ratio was 1.73 (1.11-2.70) following Penta and 0.38 (0.12-1.19) after MV (p=0.02 for same effect). Adjusting for maternal education or weight-for-age at the time of vaccination did not change the estimates. CONCLUSION: Penta appears to have the same negative effects on mortality as those seen for DTP. Assessing post-vaccination mortality for boys and girls is necessary to improve the vaccination programme.

The immunological effects of oral polio vaccine provided with BCG vaccine at birth: a randomised trial.

BACKGROUND: Vaccines may have non-specific effects. An observational study from Guinea-Bissau suggested that oral polio vaccine at birth (OPV0) provided with Bacillus Calmette-Guérin (BCG) vaccine was associated with down-regulation of the immune response to BCG vaccine 6 weeks later. Based on the previous finding, we wanted to test our a priori hypothesis that OPV would dampen the immune response to BCG, and secondarily to test immune responses to other antigens. METHODS: The study was conducted at the Bandim Health Project in Guinea-Bissau in 2009-2010. Infants were randomised to OPV0+BCG versus BCG alone at birth, and subsequently randomised to have a blood sample taken at 2, 4 or 6 weeks post-randomisation. Excreted levels of cytokines (IL-2, IL-5, IL-10, TNF-α and IFN-γ) were measured from whole blood in vitro stimulations with a panel of recall vaccine antigens (BCG, PPD, OPV), mitogen (PHA) or innate agonists (LPS, Pam3cys, PolyI:C). Additionally, we measured the local reaction to BCG, white blood cell distribution, C-reactive protein (CRP) and retinol-binding protein (RBP). Cytokine production was analysed as the prevalence ratios of responders above the median. RESULTS: Blood samples from 430 infants (209 OPV0+BCG; 221 BCG alone) were analysed. There were no strong differences in effects 2, 4 and 6 weeks post-randomisation and subsequent analyses were performed on the pooled data. As hypothesised, receiving OPV0+BCG versus BCG alone was associated with significantly lower prevalence of IFN-γ responses to PPD (prevalence ratio (PR): 0.84 (0.72-0.98)) and reduced IL-5 to PPD (PR: 0.78 (0.64-0.96)). No effects were observed for CPR, RBP, white blood cell distribution, or BCG scar prevalence. CONCLUSION: The results corroborate that OPV attenuates the immune response to co-administered BCG at birth.

Does oral polio vaccine at birth affect the size of the thymus? Observations within a randomized trial.

BACKGROUND: There is increasing evidence that vaccines have an effect on general mortality which goes beyond specific disease protection. Oral polio vaccine (OPV) is widely used in low-income countries, but in observational studies in Guinea-Bissau we observed that not receiving OPV at birth was associated with reduced overall male infant mortality and enhanced immune response to BCG vaccine. We therefore initiated a randomized trial to test the overall effect of OPV at birth (OPV0). OBJECTIVE: A small thymic gland is a predictor of mortality in high-mortality settings. Within the trial we aimed to test whether no-OPV0 was associated with increased thymic size. METHODS: In 511 normal birth weight infants who were randomized to receive or not receive OPV0, thymic index and thymus/weight index were measured before randomization and after 2 weeks (N=49), 4 weeks (N=308) or 6 weeks (N=27). The association between OPV0 and the log transformed thymic size indicators were analyzed in ANCOVA models with thymic size at follow-up as the outcome and adjusting for thymic size at enrollment and age at follow-up. Estimates were reported as geometric mean ratios (GMR) with 95% confidence intervals, comparing no-OPV0 to OPV0. RESULTS: No-OPV0 was not associated with thymic index after 2 weeks (GMR: 1.14 (0.99-1.30)), after 4 weeks (GMR: 0.98 (0.93-1.05)) or after 6 weeks (GMR: 1.00 (0.81-1.23)). However, no-OPV0 was associated with increased thymus/weight index after 2 weeks (GMR: 1.22 (1.06-1.40)), but the effect was not seen after 4 weeks (GMR: 0.97 (0.92-1.03)) and 6 weeks (GMR: 0.99 (0.82-1.19)). There were no strong sex-differences. DISCUSSION: Overall there was no effect on thymic size of OPV0 when administered with BCG. The results could indicate that if an effect occurs, it is only within the first weeks after vaccination.

No effect of oral polio vaccine administered at birth on mortality and immune response to BCG. A natural experiment.

BACKGROUND: WHO recommends oral polio vaccine at birth (OPV0) in polio endemic countries. During a period without OPV in Guinea-Bissau in 2004, we observed that not receiving OPV0 was associated with significantly decreased mortality in boys and better immune response to BCG vaccination. In 2007, whilst conducting a trial of BCG and vitamin A supplementation (VAS) at birth to low birthweight (LBW) children, OPV was again lacking for a short period. We used this natural experiment to test the previous observations. METHODS: In the trial LBW infants were randomised to early or delayed BCG and VAS or placebo at birth. We noted whether the children received OPV0 or not. We compared children who received No OPV0 with those who received OPV0 in the 2 months before and the 2 months after the period without OPV. Mortality was compared in Cox regression models providing adjusted hazard ratios (aHR); the immune response to BCG was assessed in Poisson models providing adjusted prevalence ratios (aPR). RESULTS: Ninety-nine children received No OPV0 and were compared with 243 children who received OPV0. No OPV0 was associated with insignificantly higher mortality during the first year of life, the aHR being 1.83 (95% CI: 0.93-3.61). The effect was similar in boys and girls. Overall, there was no significant association between No OPV0 and having a positive PPD response (aPR=1.33 (0.64-2.78)) or a scar (aPR=1.02 (0.93-1.11)) after BCG vaccination, though No OPV0 boys were more likely to develop a scar (aPR: 1.10 (1.01-1.20)). CONCLUSIONS: The findings did not support our previous observation that not receiving OPV0 was associated with reduced mortality in boys. The findings weakly supported that OPV0 leads to a dampened response to simultaneously administered BCG vaccine in boys.

Early diphtheria-tetanus-pertussis vaccination associated with higher female mortality and no difference in male mortality in a cohort of low birthweight children: an observational study within a randomised trial.

BACKGROUND: Studies from low-income countries have suggested that diphtheria-tetanus-pertussis (DTP) vaccine provided after Bacille Calmette-Guerin (BCG) vaccination may have a negative effect on female survival. The authors examined the effect of DTP in a cohort of low birthweight (LBW) infants. METHODS: 2320 LBW newborns were visited at 2, 6 and 12 months of age to assess nutritional and vaccination status. The authors examined survival until the 6-month visit for children who were DTP vaccinated and DTP unvaccinated at the 2-month visit. RESULTS: Two-thirds of the children had received DTP at 2 months and 50 deaths occurred between the 2-month and 6-month visits. DTP vaccinated children had a better anthropometric status for all indices than DTP unvaccinated children. Small mid-upper arm circumference (MUAC) was the strongest predictor of mortality. The death rate ratio (DRR) for DTP vaccinated versus DTP unvaccinated children differed significantly for girls (DRR 2.45; 95% CI 0.93 to 6.45) and boys (DRR 0.53; 95% CI 0.23 to 1.20) (p=0.018, homogeneity test). Adjusting for MUAC, the overall effect for DTP vaccinated children was 2.62 (95% CI 1.34 to 5.09); DRR was 5.68 (95% CI 1.83 to 17.7) for girls and 1.29 (95% CI 0.56 to 2.97) for boys (p=0.023, homogeneity test). While anthropometric indices were a strong predictor of mortality among boys, there was little or no association for girls. CONCLUSION: Surprisingly, even though the children with the best nutritional status were vaccinated early, early DTP vaccination was associated with increased mortality for girls.

Selective serotonin reuptake inhibitor exposure in utero and pregnancy outcomes.

OBJECTIVE: To investigate the effect of intrauterine selective serotonin reuptake inhibitor (SSRI) exposure on pregnancy outcomes. DESIGN: Prospective cohort study. SETTING: Department of Obstetrics, Aarhus University Hospital, Aarhus, Denmark. PARTICIPANTS: Pregnant women receiving prenatal care in our hospital from 1989 to 2006. MAIN EXPOSURE: Maternal SSRI use during pregnancy. OUTCOME MEASURES: Gestational age, birth weight, head circumference, 5-minute Apgar score, and admission to the neonatal intensive care unit. RESULTS: Three hundred twenty-nine pregnant women reported treatment with SSRIs, 4902 were not treated with SSRIs but had a history of psychiatric illness, and 51 770 reported no history of psychiatric illness. Gestational age was 5 days (95% confidence interval [CI], -6 to -3) shorter and the odds ratio (OR) for preterm birth was 2.0 (95% CI, 1.3-3.2) in the women exposed to SSRIs compared with women with no history of psychiatric illness. In utero-exposed newborns had increased risk of admission to the neonatal intensive care unit (OR, 2.4; 95% CI, 1.7-3.4) and of 5-minute Apgar scores of less than 8 (OR, 4.4; 95% CI, 2.6-7.6) compared with those not exposed. Head circumference and birth weight did not differ between infants in the exposed and unexposed groups. The results were similar when compared with infants of women with a psychiatric history. CONCLUSIONS: Exposure to SSRIs during pregnancy was associated with an increased risk of preterm delivery, a low 5-minute Apgar score, and neonatal intensive care unit admission, which was not explained by lower Apgar scores or gestational age. The study justifies increased awareness to the possible effects of intrauterine exposure to antidepressants.