Multivitamin intake and the risk of congenital heart defects: A cohort study.

OBJECTIVE: Congenital heart disease (CHD) is the most common type of congenital birth defect, but little is known about possible modifiable behavioral risk factors. The study aimed to assess whether intake of periconceptional or postconceptional multivitamin was associated with a decreased risk of CHD in the offspring. STUDY DESIGN: The study population comprised 15,567 women from the Copenhagen Pregnancy Cohort with complete data on multivitamin intake before and during pregnancy, who gave birth to live-born singletons from October 2012 to October 2016. Main outcome measure was CHD defined according to the International Classification of Diseases (ICD), 10th revision. Cases of CHD were classified into five subgroups based on the clinical phenotype: 1) Conotruncal defects, 2) Left ventricular outflow tract obstruction, 3) Right ventricular outflow tract obstruction, 4) Septal defects, and 5) Other CHD. Multivariate logistic regression analyses were performed with adjustment for maternal age, chronic disease, assisted reproductive technology, smoking status, and alcohol consumption. RESULTS: Of the 15,567 included women, 31.9 % reported a daily multivitamin intake in the periconceptional period, 53.7 % in the postconceptional period, and 14.4 % women did not report a daily multivitamin intake. The prevalence of CHD in the population was 0.7 % (n = 112). Periconceptional and postconceptional multivitamin intake was not associated with risk of overall CHD in offspring: Adjusted OR was 0.64 (95 % CI 0.36-1.13) and 0.77 (95 % CI 0.47-1.30), respectively. CONCLUSION: The current large cohort study did not show a preventive effect of multivitamin intake in the periconceptional or postconceptional period on the risk of CHD in the offspring.

Mode of delivery and adverse short- and long-term outcomes in vertex-presenting very preterm born infants: a European population-based prospective cohort study.

OBJECTIVES: To compare mortality, morbidity and neurodevelopment by mode of delivery (MOD) for very preterm births with low prelabour risk of caesarean section (CS). METHODS: The study was a population-based prospective cohort study in 19 regions in 11 European countries. Multivariable mixed effects models and weighted propensity score models were used to estimate adjusted odds ratios (aOR) by observed MOD and the unit's policy regarding MOD. Population: Singleton vertex-presenting live births at 24 + 0 to 31 + 6 weeks of gestation without serious congenital anomalies, preeclampsia, HELLP or eclampsia, antenatal detection of growth restriction and prelabour CS for fetal or maternal indications. RESULTS: Main outcome measures: A composite of in-hospital mortality and intraventricular haemorrhage (grade III/IV) or periventricular leukomalacia. Secondary outcomes were components of the primary outcome, 5 min Apgar score <7 and moderate to severe neurodevelopmental impairment at two years of corrected age. The rate of CS was 29.6% but varied greatly between countries (8.0-52.6%). MOD was not associated with the primary outcome (aOR for CS 0.99; 95% confidence interval [CI] 0.65-1.50) when comparing units with a systematic policy of CS or no policy of MOD to units with a policy of vaginal delivery (aOR 0.88; 95% CI 0.59-1.32). No association was observed for two-year neurodevelopment impairment for CS (aOR 1.15; 95% CI 0.66-2.01) or unit policies (aOR 1.04; 95% CI 0.63-1.70). CONCLUSIONS: Among singleton vertex-presenting live births without medical complications requiring a CS at 24 + 0 to 31 + 6 weeks of gestation, CS was not associated with improved neonatal or long-term outcomes.

[Magnesium sulphate treatment decreases the risk of cerebral palsy after preterm birth].

Children born preterm have an increased risk of severe morbidity, e.g. cerebral palsy (CP), compared to children born at term. CP cannot be treated, which is why a prophylactic approach is essential, as argued in this review. Six randomised controlled trials (RCTs) have provided data on MgSO4 treatment as CP neuroprotection in preterm birth, including a new RCT from Denmark. Recently, an updated meta-analysis with trial sequential analysis detected a significant neuroprotective effect of MgSO4 treatment in preterm birth. There is now sufficient evidence, that MgSO4 treatment should be used as neuroprotection in preterm birth.

Multivitamin intake does not affect the risk of preterm and very preterm birth.

INTRODUCTION: The aim of this study was to assess the association between multivitamin intake during pregnancy and the risk of preterm birth and very preterm birth. METHODS: The study population comprised 15,629 women from the Copenhagen Pregnancy Cohort with data on pregnancy multivitamin intake during their first trimester who gave birth to singletons from October 2012 to October 2016. Data on pregnancy multivitamin intake were linked to the Medical Birth Registry to identify the birth outcome. The main outcome measures were preterm birth before 37 weeks of gestation and very preterm birth before 32 weeks of gestation. RESULTS: Among the included women, 85.6% had taken daily pregnancy multivitamins during their first trimester. We found no evidence that pregnancy multivitamin intake during the first trimester was associated with a decreased risk of preterm birth (adjusted odds ratio (OR) = 1.01; 95% confidence interval (CI): 0.77-1.33) or very preterm birth (adjusted OR = 1.06; 95% CI: 0.63-1.77). Stratification for BMI into lesser-than 25 kg/m2 and ≥ 25 kg/m2 did not alter these findings. CONCLUSIONS: Pregnancy multivitamin intake during the first trimester was not associated with a decreased risk of preterm birth or very preterm birth among women in a high-income population. FUNDING: none. TRIAL REGISTRATION: not relevant.

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.

Multivitamin use and risk of preeclampsia in a high-income population: A cohort study.

OBJECTIVE: The objective of this study was to examine the association between multivitamin use in the periconceptional period and the risk of preeclampsia. STUDY DESIGN: The association was investigated in a prospective cohort study. 15,154 deliveries in women followed at a large university hospital in Denmark were included between 16 September 2012 and 31 October 2016. Pregnant women were sent a questionnaire containing items related to socio-demographic-, lifestyle- and health factors. The responses on multivitamin use were merged with the preeclampsia diagnosis from the Danish Medical Birth Registry. We used multiple logistic regression analyses to assess the association and to adjust for potential confounders. MAIN OUTCOME MEASURES: The outcome of interest, preeclampsia, included the preeclampsia subtypes eclampsia and HELLP (Haemolysis, Elevated Liver enzymes, and Low Platelets) syndrome. RESULTS: In total 12,954 women (85%) reported multivitamin use. A diagnosis of preeclampsia was found in 397 women (2.6%). We found a similar risk of preeclampsia in multivitamin user and non-users, adjusted odds ratio (AOR) for periconceptional multivitamin use = 0.97 (95% CI: 0.70 to 1.36) and AOR for early pregnancy multivitamin use = 0.97 (95% CI: 0.71 to 1.32). Subgroup analyses stratified on body mass index showed that among women with overweight, both periconceptional and early pregnancy multivitamin use were associated with a statistically significant lower risk of preeclampsia (AOR = 0.49, 95% CI: 0.24 to 0.99 and AOR = 0.35, 95% CI: 0.18 to 0.69, respectively). CONCLUSION: Periconceptional- and early pregnancy multivitamin use was found to be associated with a similar risk of preeclampsia compared to non-users.

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.

Association of Short Antenatal Corticosteroid Administration-to-Birth Intervals With Survival and Morbidity Among Very Preterm Infants: Results From the EPICE Cohort.

Importance: Administration-to-birth intervals of antenatal corticosteroids (ANS) vary. The significance of this variation is unclear. Specifically, to our knowledge, the shortest effective administration-to-birth interval is unknown. Objective: To explore the associations between ANS administration-to-birth interval and survival and morbidity among very preterm infants. Design, Setting, and Participants: The Effective Perinatal Intensive Care in Europe (EPICE) study, a population-based prospective cohort study, gathered data from 19 regions in 11 European countries in 2011 and 2012 on 4594 singleton infants with gestational ages between 24 and 31 weeks, without severe anomalies and unexposed to repeated courses of ANS. Data were analyzed November 2016. Exposure: Time from first injection of ANS to delivery in hours and days. Main Outcomes and Measures: Three outcomes were studied: in-hospital mortality; a composite of mortality or severe neonatal morbidity, defined as an intraventricular hemorrhage grade of 3 or greater, cystic periventricular leukomalacia, surgical necrotizing enterocolitis, or stage 3 or greater retinopathy of prematurity; and severe neonatal brain injury, defined as an intraventricular hemorrhage grade of 3 or greater or cystic periventricular leukomalacia. Results: Of the 4594 infants included in the cohort, 2496 infants (54.3%) were boys, and the mean (SD) gestational age was 28.5 (2.2) weeks and mean (SD) birth weight was 1213 (400) g. Mortality for the 662 infants (14.4%) unexposed to ANS was 20.6% (136 of 661). Administration of ANS was associated with an immediate and rapid decline in mortality, reaching a plateau with more than 50% risk reduction after an administration-to-birth interval of 18 to 36 hours. A similar pattern for timing was seen for the composite mortality or morbidity outcome, whereas a significant risk reduction of severe neonatal brain injury was associated with longer administration-to-birth intervals (greater than 48 hours). For all outcomes, the risk reduction associated with ANS was transient, with increasing mortality and risk for severe neonatal brain injury associated with administration-to-birth intervals exceeding 1 week. Under the assumption of a causal relationship between timing of ANS and mortality, a simulation of ANS administered 3 hours before delivery to infants who did not receive ANS showed that their estimated decline in mortality would be 26%. Conclusions and Relevance: Antenatal corticosteroids may be effective even if given only hours before delivery. Therefore, the infants of pregnant women at risk of imminent preterm delivery may benefit from its use.

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.

Use of evidence based practices to improve survival without severe morbidity for very preterm infants: results from the EPICE population based cohort.

OBJECTIVES:  To evaluate the implementation of four high evidence practices for the care of very preterm infants to assess their use and impact in routine clinical practice and whether they constitute a driver for reducing mortality and neonatal morbidity. DESIGN:  Prospective multinational population based observational study. SETTING:  19 regions from 11 European countries covering 850 000 annual births participating in the EPICE (Effective Perinatal Intensive Care in Europe for very preterm births) project. PARTICIPANTS:  7336 infants born between 24+0 and 31+6 weeks' gestation in 2011/12 without serious congenital anomalies and surviving to neonatal admission. MAIN OUTCOME MEASURES:  Combined use of four evidence based practices for infants born before 28 weeks' gestation using an "all or none" approach: delivery in a maternity unit with appropriate level of neonatal care; administration of antenatal corticosteroids; prevention of hypothermia (temperature on admission to neonatal unit ≥36°C); surfactant used within two hours of birth or early nasal continuous positive airway pressure. Infant outcomes were in-hospital mortality, severe neonatal morbidity at discharge, and a composite measure of death or severe morbidity, or both. We modelled associations using risk ratios, with propensity score weighting to account for potential confounding bias. Analyses were adjusted for clustering within delivery hospital. RESULTS:  Only 58.3% (n=4275) of infants received all evidence based practices for which they were eligible. Infants with low gestational age, growth restriction, low Apgar scores, and who were born on the day of maternal admission to hospital were less likely to receive evidence based care. After adjustment, evidence based care was associated with lower in-hospital mortality (risk ratio 0.72, 95% confidence interval 0.60 to 0.87) and in-hospital mortality or severe morbidity, or both (0.82, 0.73 to 0.92), corresponding to an estimated 18% decrease in all deaths without an increase in severe morbidity if these interventions had been provided to all infants. CONCLUSIONS:  More comprehensive use of evidence based practices in perinatal medicine could result in considerable gains for very preterm infants, in terms of increased survival without severe morbidity.

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.

Persistence and reappearance of high-risk human papillomavirus after conization.

OBJECTIVE: Women with early cervical cancer or intraepithelial neoplasia grades 2 and 3 (CIN2+) are treated by conization; however, they still have a higher risk for subsequent CIN2+ than the general female population. Persistence of high-risk (HR) human papillomavirus (HPV) is a key factor in the development of CIN2+. We investigated persistence and reappearance of type-specific HR HPV infection after conization and evaluated possible co-factors. METHODS: During 2002-2006, cervical swabs from 604 women were collected before conization, at 4-6 months and at 8-12 months after conization. HPV was detected by HC2 and genotyped by LiPAv2. Information on co-factors was collected through a questionnaire. Associations were assessed by multivariate logistic regression analysis. RESULTS: HR HPV persistence rate was 9.5%. The α5/6 species were more likely to persist than α9 species (OR, 2.28; 95% CI, 1.11-4.70). For single infections, a doubling in viral load at enrolment increased the risk for persistence by 36% (95% CI, 1.13-1.63). In addition, margin status was associated with risk of persistence. Smoking, oral contraceptive use and severity of the cervical lesion did not significantly affect persistence. Among the HPV infections that had cleared, 2.2% reappeared. CONCLUSION: Our study indicates that viral load is important in predicting HPV persistence. The α5/6 species were most likely to persist. However, most of these HPV types have a lower carcinogenic potential than the α7/α9 species and may be by-standers. Further studies are needed to assess whether pre-conization viral load can also predict subsequent CIN2+.

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.

[Severe vitamin D deficiency in children born in Denmark of dark-skinned women]. / Svær D-vitamin-mangel hos børn født i Danmark af kvinder med mørk hud.

Rickets due to malnutrition is rare in Denmark. The Danish Board of Health recommend that: pregnant women are treated with a daily dose of vitamin D daily (10 micrograms); emigrants with coloured skin have their vitamin D level assessed during pregnancy; all children receive a daily dose of vitamin D (10 micrograms) until two years old. Despite of these recommendations two cases of severe nutritional rickets among children of emigrants were discovered upon hospital admission. The symptoms were heterogeneous: delayed walking skills and convulsions. We conclude that nutritional rickets is a tricky diagnosis, but is preventable.