Multivitamin use and adverse birth outcomes in high-income countries: a systematic review and meta-analysis.

BACKGROUND: In high-income countries, a healthy diet is widely accessible. However, a change toward a poor-quality diet with a low nutritional value in high-income countries has led to an inadequate vitamin intake during pregnancy. OBJECTIVE: We conducted a systematic review and meta-analysis to evaluate the association between multivitamin use among women in high-income countries and the risk of adverse birth outcomes (preterm birth [primary outcome], low birthweight, small for gestational age, stillbirth, neonatal death, perinatal mortality, and congenital anomalies without further specification). STUDY DESIGN: We searched electronic databases (MEDLINE, Embase, Cochrane, Scopus, and CINAHL) from inception to June 17, 2016, using synonyms of pregnancy, study/trial type, and multivitamins. Eligible studies were all studies in high-income countries investigating the association between multivitamin use (3 or more vitamins or minerals in tablets or capsules) and adverse birth outcomes. We evaluated randomized, controlled trials using the Cochrane Collaboration tool. Observational studies were evaluated using the Newcastle-Ottawa Scale. Meta-analyses were applied on raw data for outcomes with data for at least 2 studies and were conducted using RevMan (version 5.3). Outcomes were pooled using the random-effect model. The quality of evidence was assessed using the Grades of Research, Assessment, Development and Evaluation approach. RESULTS: We identified 35 eligible studies including 98,926 women. None of the studies compared the use of folic acid and iron vs the use of multivitamins. The use of multivitamin did not change the risk of the primary outcome, preterm birth (relative risk, 0.84 [95% confidence interval, 0.69-1.03]). However, the risk of small for gestational age (relative risk, 0.77 [95% confidence interval, 0.63-0.93]), neural tube defects (relative risk, 0.67 [95% confidence interval, 0.52-0.87]), cardiovascular defects (relative risk, 0.83 [95% confidence interval, 0.70-0.98]), urine tract defects (relative risk, 0.60 [95% confidence interval, 0.46-0.78]), and limb deficiencies (relative risk, 0.68 [95% confidence interval, 0.52-0.89]) was decreased. Of the 35 identified studies, only 4 were randomized, controlled trials. The degree of clinical evidence according to the Grades of Research, Assessment, Development, and Evaluation system was low or very low for all outcomes except for recurrence of neural tube defects in which a moderate degree of clinical evidence was found. CONCLUSION: Routine multivitamin use in high-income countries can be recommended but with caution because of the low quality of evidence. Randomized, controlled trials or well-performed, large prospective cohort studies are needed.

Long-term follow-up of the risk for cervical intraepithelial neoplasia grade 2 or worse in HPV-negative women after conization.

Little research has been conducted on the long-term value of human papillomavirus (HPV) testing after conization. We investigated whether cytology adds to the value of a negative HPV test for long-term prediction of cervical intraepithelial neoplasia grade 2 or worse (CIN2+). In addition, we compared risk of CIN2+ following a negative HPV test in women after conization with that in women from the general population. During 2002-2005, 667 women treated for CIN2+ were tested for HPV and cytology 46 months after conization. Only HPV-negative women were included. Women participating in routine screening were age-matched with post-conization HPV-negative women, leaving 13,230 and 477 women, respectively, for analysis. By linkage to the Pathology Data Bank, we identified all cases of CIN2+ by December 2013. The 3-, 5-, 8- and 10-year risks for CIN2+ were 0.7, 0.9, 2.8 and 5.7% after a negative HPV test and 0.5, 0.8, 2.9 and 6.1% in HPV and cytology-negative women. HPV-negative women in the general population had similar 3-year and 5-year risks of 0.4 and 1.0%; thereafter, they had lower risks of 1.9% at 8 years and 2.7% at 10 years. Our results indicate that HPV testing may be used as a test of cure after conization. In the first 5 years after testing, the risk for CIN2+ of women who were HPV-negative at 34 months after conization was similar to that of HPV-negative women in the general population. After 67 years, however, women who have undergone conization may be at higher risk for CIN2+.

Role of human papillomavirus testing and cytology in follow-up after conization.

OBJECTIVE: Adequate follow-up of women who have undergone conization for high-grade cervical lesions is crucial in cervical cancer screening programs. We evaluated the performance of testing for high-risk human papillomavirus (HPV) types, cytology alone, and combined testing in predicting cervical intraepithelial neoplasia grade 2 or worse (CIN2+) after conization. DESIGN: Prospective cohort study. SETTING: Denmark. POPULATION: 667 women attending for conization. METHODS: Cervical specimens were collected during 2002-2006 at first visit after conization for cytological examination and Hybrid Capture 2 detection of high-risk HPV. The women were passively followed until 2 years after first follow-up visit by linkage to the nationwide Pathology Data Bank. RESULTS: At first visit after conization (median time, 3.4 months), 20.4% were HPV-positive and 17.2% had atypical squamous intraepithelial lesions or more severe cytology (ASCUS+). The 2-year incidence of CIN2+ after conization was 3.6%. Sensitivity for detection of CIN2+ after conization was 81.0% [95% confidence interval (CI) 58.1-94.6] for positive cytology (ASCUS+ threshold) and 95.2% (95% CI 76.2-99.9) for HPV testing and for combined testing. Specificity of ASCUS+ cytology (85.2%; 95% CI 82.0-88.0) was higher than that of HPV testing (82.4%; 95% CI 79.0-85.4) and markedly higher than that of combined testing (73.2%; 95% CI 69.3-76.8). The margin status had no significant added value. CONCLUSIONS: Testing for high-risk HPV three to four months after conization is more sensitive than ASCUS+ cytology for identifying women at risk for relapse of CIN2+ within 2 years. Further studies are needed to evaluate whether HPV testing could be a stand-alone test in follow up after conization.

Conclusive meta-analyses on antenatal magnesium may be inconclusive! Are we underestimating the risk of random error?

Results from meta-analyses significantly influence clinical practice. Both simulation and empirical studies have demonstrated that the risk of random error (i.e. spurious chance findings) in meta-analyses is much higher than previously anticipated. Hence, authors and users of systematic reviews and meta-analyses have a responsibility to carefully consider the risk of random errors to avoid misleading conclusions. Trial sequential analysis is a useful meta-analytic method for gauging the risk of random error in meta-analysis and the amount of additional evidence required to reach firm conclusions about the investigated intervention effect(s). We outline the rationale for conducting trial sequential analysis including some examples of the meta-analysis on antenatal magnesium for women at risk of preterm birth.

Unit policies regarding tocolysis after preterm premature rupture of membranes: association with latency, neonatal and 2-year outcomes (EPICE cohort).

After preterm premature rupture of membranes (PPROM), antibiotics and antenatal steroids are effective evidence-based interventions, but the use of tocolysis is controversial. We investigated whether a unit policy of tocolysis use after PPROM is associated with prolonged gestation and improved outcomes for very preterm infants in units that systematically use these other evidence-based treatments. From the prospective, observational, population-based EPICE cohort study (all very preterm births in 19 regions from 11 European countries, 2011-2012), we included 607 women with a singleton pregnancy and PPROM at 24-29 weeks' gestation, of whom 101, 195 and 311 were respectively managed in 17, 32 and 45 units with no-use, restricted and liberal tocolysis policies for PPROM. The association between unit policies and outcomes (early-onset sepsis, survival at discharge, survival at discharge without severe morbidity and survival at two years without gross motor impairment) was investigated using three-level random-intercept logistic regression models, showing no differences in neonatal or two-year outcomes by unit policy. Moreover, there was no association between unit policies and prolongation of gestation in a multilevel survival analysis. Compared to a unit policy of no-use of tocolysis after PPROM, a liberal or restricted policy is not associated with improved obstetric, neonatal or two-year outcomes.

Mode of delivery and mortality and morbidity for very preterm singleton infants in a breech position: A European cohort study.

OBJECTIVE: Caesarean section (CS) may reduce mortality and morbidity for very preterm breech infants, but evidence is inconclusive. We evaluated neonatal outcomes for singleton breech infants by mode of delivery in a European cohort. STUDY DESIGN: Data come from the EPICE population-based cohort of very preterm births in 19 regions in 11 European countries (7770 live births). The study population was singleton spontaneous-onset breech births at 24-31 weeks gestational age (GA) without antenatal medical complications requiring caesarean delivery (N = 572). Mixed-effects regression models adjusting for maternal and pregnancy covariates and propensity score matching was used to examine the effect of (1) CS and (2) a unit policy of systematic CS for breech presentation by GA. The primary outcome was a composite of in-hospital mortality, intraventricular haemorrhage grades III & IV or cystic periventricular leukomalacia. Secondary outcomes were each component separately, five minute Apgar score below seven and mortality within six hours of delivery. RESULTS: 64.4% of infants were delivered by CS with a range across regions from 41% to 100%; these infants had higher GA and were more likely to be small for gestational age, receive antenatal steroids, and have mothers who were hospitalised for more than one day before delivery compared to those delivered vaginally. CS was associated with lower risks of all outcomes in mixed-effects adjusted models (odds ratio (OR) for the composite outcome: 0.50, 95% confidence interval (CI): 0.30-0.81), but not in propensity score matched models (OR: 0.72, 95% CI: 0.41; 1.29). A systematic CS policy was associated with lower mortality and morbidity in unadjusted, but not adjusted models (OR for composite outcome: 0.76, 95% CI: 0.44; 1.28). 35% of births 24-25 weeks were delivered by CS and protective effects were consistently stronger, but not statistically significant. CONCLUSIONS: Point estimates indicated protective effects of caesarean delivery for very preterm breech infants in conventional statistical models. However, analyses using propensity scores and based on unit policies did not confirm statistically significant associations. Prospective large-scale studies are needed to establish best practice and could be implemented in European regions where vaginal delivery remains an option.