Danish Medical Birth Registry Research Articles

Association of Psychiatric and Neurologic Comorbidity With Mortality Among Persons With Autism Spectrum Disorder in a Danish Population.

Increased mortality has been reported among persons with autism spectrum disorder (ASD), especially among those who also have the comorbid condition of epilepsy or intellectual disability. The effects of psychiatric and neurologic comorbidity on mortality among persons with ASD have not been rigorously examined in large, population-based studies. To investigate the mortality patterns among persons with ASD overall and to assess the associations of comorbid mental, behavioral, and neurologic disorders with mortality among persons with ASD. Longitudinal cohort study of children born in Denmark during the period from 1980 to 2010 who were alive at 1.5 years of age and followed up through 2013. This population-based sample of children (N = 1,912,904) was identified via linkage between the Danish Civil Registration Service and the Danish Medical Birth Register using a unique 10-digit identifier assigned to all live births and new residents in Denmark. Children were followed up for diagnoses of ASD (International Classification of Diseases, Eighth Revision [ICD-8] codes 299.00, 299.01, 299.02, and 299.03 and ICD-10 codes F84.0, F84.1, F84.5, F84.8, and F84.9) and other mental/behavioral disorders (ICD-8 codes 290-315 and ICD-10 codes F00-F99) in the Danish Psychiatric Central Research Register and for diagnoses of neurologic disorders (ICD-8 codes 320-359 and ICD-10 codes G00-G99) in the Danish National Patient Register. Data analysis was performed in December 2014. Deaths and causes of death among cohort members were identified via the Danish Civil Registration Service and the Danish Cause of Death Register, respectively. Regressions analyses were performed using Cox regression. Of the 1,912,904 persons included in our study, 20,492 (1.1%) had ASD (15,901 [77.6%] were male). Of the 20,492 persons with ASD, 68 died (0.3%) (57 of 68 [83.8%] had comorbid mental/behavioral or neurologic disorders). The adjusted hazard ratio (aHR) for overall mortality was 2.0 (95% CI, 1.5-2.8) for ASD. The aHRs for ASD-associated mortality among cohort members who did not have neurologic (2.0 [95% CI, 1.4-3.0]) or other mental/behavioral disorders (1.7 [95% CI, 1.0-3.1]) were similar. The co-occurrence of ASD added no additional mortality risk for persons with neurologic (aHR, 0.7 [95% CI, 0.4-1.3]) or mental/behavioral disorders (aHR, 0.8 [95% CI, 0.5-1.2]) compared with persons with these disorders and no ASD. The mortality risk was 2-fold higher through young adulthood for persons with ASD than for persons without ASD, although mortality affected only 0.3% of persons with ASD. The mechanisms underlying ASD-associated mortality may be mediated through or shared with neurologic or mental/behavioral disorders, thereby providing insights into their potential neurobiological links. Health care professionals and family members should recognize the importance of these disorders with regard to the mortality risk for persons with ASD.

Can Intrapartum Cardiotocography Predict Uterine Rupture among Women with Prior Caesarean Delivery?: A Population Based Case-Control Study.

ObjectiveTo compare cardiotocographic abnormalities recorded during labour in women with prior caesarean delivery (CD) and complete uterine rupture with those recorded in controls with prior CD without uterine rupture.Study DesignWomen with complete uterine rupture during labour between 1997 and 2008 were identified in the Danish Medical Birth Registry (n = 181). Cases were validated by review of medical records and 53 cases with prior CD, trial of labour, available cardiotocogram (CTG) and complete uterine rupture were included and compared with 43 controls with prior CD, trial of labour and available CTG. The CTG tracings were assessed by 19 independent experts divided into groups of three different experts for each tracing. The assessors were blinded to group, outcome and clinical data. They analyzed occurrence of defined abnormalities and classified the traces as normal, suspicious, pathological or pre-terminal according to international guidelines (FIGO).ResultsA pathological CTG during the first stage of labour was present in 77% of cases and in 53% of the controls (OR 2.58 [CI: 0.96–6.94] P = 0.066). Fetal tachycardia was more frequent in cases with uterine rupture (OR 2.50 [CI: 1.0–6.26] P = 0.053). Significantly more cases showed more than 10 severe variable decelerations compared with controls (OR 22 [CI: 1.54–314.2] P = 0.022). Uterine tachysystole was not correlated with the presence of uterine rupture.ConclusionA pathological cardiotocogram should lead to particular attention on threatening uterine rupture but cannot be considered a strong predictor as it is common in all women with trial of labour after caesarean delivery.

Cesarean Section and Chronic Immune Disorders

A Seveisted, J Stokholm, K Bennelykke, H Bisgaard. Pediatrics. 2015;135(1):93–98 This study was designed to investigate the cesarean mode of delivery as a possible risk factor for the development of several chronic immune disorders. All full-term children born between January 1973 through January 1, 2012, were identified through the Danish Medical Birth Registry. Two and a half million children were born in the selected period (1973–2012), and after excluding preterm births, still-births, births to mothers born before 1952, and individuals with missing data, 1.9 million children were included in the analysis. The authors compared cesarean versus vaginal delivery and the incidence of selected immune-mediated diseases: asthma, systemic …

Validation of second trimester miscarriages and spontaneous deliveries.

ObjectiveTo validate the diagnosis of second trimester miscarriages/deliveries (16+0 weeks to 27+6 weeks of gestation) recorded as miscarriages in the Danish National Patient Registry or spontaneous deliveries in the Danish Medical Birth Registry, and asses the validity of risk factors, pregnancy complications, and cerclage by review of medical records.Materials and methodsIn a cohort of 2,358 women with a second trimester miscarriage/delivery in first pregnancy and a subsequent delivery during 1997–2012, we reviewed a representative sample of 682 medical records. We searched for clinically important information and calculated positive predictive values of the registry diagnoses stratified by type of registry, as well as sensitivity, specificity, positive predictive value, and kappa coefficients of risk factors, pregnancy complications, and cerclage.ResultsMiscarriage/spontaneous delivery in the second trimester was confirmed in 621/682 patients (91.1%). Pregnancy complications in second trimester miscarriages were underreported, resulting in low sensitivities and poor to moderate agreements between records and registries. There was a good agreement (kappa >0.6) between medical records and the registries regarding risk factors and cerclage. The diagnosis of cervical insufficiency had “moderate” kappa values for both miscarriages and deliveries (0.55 and 0.57).ConclusionSpontaneous second trimester deliveries and miscarriages recorded in the registers were confirmed by medical records in 91%, but register-based information on pregnancy complications need to be improved. We recommend that all pregnancies ending spontaneously beyond the first trimester are included in the national birth registry and described by appropriate variables.

Abstract 18284: Incidence of Epilepsy is Elevated in Children and Young Adults With Congenital Heart Defects Compared With the General Population: A Nationwide Cohort Study

Perioperative seizures related to surgery for congenital heart defects (CHD) are well described; however, few data exist on the long-term risk of epilepsy in patients with CHD. We aimed to estimate the incidence of epilepsy in children and young adults with CHD compared with the general population. Methods: Utilizing data from the Danish National Registry of Patients (DNRP) we identified all patients diagnosed with CHD before the age of 15 years between 1980 and 2010 who were born during the same period. The DNRP is a nationwide hospital discharge registry covering all Danish hospitals. Previously validated methodology using the DNRP was applied to measure the outcome, epilepsy, as well as presence of extra cardiac defects (ECD) and/or syndromes. We used the Danish Medical Birth Registry to identify preterm birth (gestational age<37 weeks). For each CHD subject, we identified 10 controls from the general population using the Danish Civil Registration System, matched by sex and birth year. A unique personal identifier assigned at birth and used in all Danish public registries enabled virtually complete follow up for migration, death, or epilepsy until January 1, 2013. We computed cumulative incidences and hazard ratios (HR) (split at 5 years of age to obtain proportional hazards) of time from CHD diagnosis (index date for controls) to epilepsy. Results: We identified 14,665 CHD subjects with a median age at diagnosis of 2 (IQR 19) months. By 15 years of age, the cumulative incidence of epilepsy was 4% among CHD subjects. The HR of epilepsy among CHD subjects compared with the control cohort was 3.7 (95% CI: 3.2-4.3) below 5 years of age, and 2.4 (95% CI: 2.1-2.7) from 5 to 33 years of age. In the older age group, HR for patients with severe CHD was 2.8 (95% CI: 2.3-3.5), and for mild and moderate CHD was 2.2 (95% CI: 1.8-2.6). After exclusion of all subjects with ECDs and/or syndromes and preterm birth, corresponding HRs were 2.2 (95% CI: 1.6-3.0) and 1.7 (95% CI: 1.3-2.2), respectively. Conclusion: The epilepsy risk was markedly increased in CHD subjects compared with the age and gender matched controls. These findings add evidence to support the importance of developing neuro-protective measures and potentially long-term epilepsy surveillance strategies in the CHD population.

Uterine rupture without previous caesarean delivery: a population-based cohort study

ObjectiveTo determine incidence and patient characteristics of women with uterine rupture during singleton births at term without a previous caesarean delivery. Study designPopulation based cohort study. Women with term singleton birth, no record of previous caesarean delivery and planned vaginal delivery (n=611,803) were identified in the Danish Medical Birth Registry (1997–2008). Medical records from women recorded with uterine rupture during labour were reviewed to ascertain events of complete uterine rupture. Relative Risk (RR) and adjusted Relative Risk Ratio (aRR) of complete uterine rupture with 95% confidence intervals (95% CI) were ascertained according to characteristics of the women and of the delivery. ResultsWe identified 20 cases with complete uterine rupture. The incidence of complete uterine rupture among women without previous caesarean delivery was about 3.3/100,000 deliveries. Multiparity (RR 8.99 (95% CI 1.86–43.29)), induction of labour (RR 3.26 (95% CI 1.24–8.57)), epidural analgesia (RR 10.78 (95% CI 4.25–27.39)), and augmentation by oxytocin (RR 9.50 (95% CI 3.15–28.63)) were associated with uterine rupture. Induction of labour was not significantly related to uterine rupture when adjusted for parity, epidural analgesia and augmentation by oxytocin. ConclusionAlthough uterine rupture is rare, its association with epidural analgesia and augmentation of labour with oxytocin in multipara should be considered. Thus, vigilance should be exercised when labour is obstructed and there is need for epidural analgesia and/or augmentation by oxytocin in multiparous women. Due to the rare occurrence of uterine rupture caution should be exerted when interpreting the findings of this study.

Gestational Age and Autism Spectrum Disorder: Trends in Risk Over Time.

Autism Spectrum Disorder (ASD) is a serious neurodevelopmental disorder. Several previous studies have identified preterm birth as a risk factor for ASD but none has studied whether the association between gestational age and ASD has changed over time. This is a Danish population-based follow-up study including live-born singletons born in Denmark between 1980 and 2009, identified in the Danish Medical Birth Registry, a study population of 1,775,397 children. We used a Cox regression model combined with spline to study the risk for ASD by gestational age across three decades of birth cohorts. We included 19,020 children diagnosed with ASD. Across all birth year cohorts, we found that the risk of being diagnosed with ASD increased with lower gestational age (P-value: <0.01). Across all gestational weeks, we found a statistically significant higher risk estimates in birth cohort 1980 to 1989, compared to birth cohorts 1990 to 1999 and 2000 to 2009, respectively. No statistically significant difference in risk estimates was observed between birth cohort 1990 to 1999 and 2000 to 2009. The observed time trend in risk of ASD after preterm birth may reflect: (1) a change in the risk profile of persons with ASD due to the broadening of ASD diagnostic criteria over time; or (2) improved neonatal care for low GA infants, which has reduced risk of adverse outcomes like ASD in preterm children.

Preconception venous thromboembolism and placenta‐mediated pregnancy complications

Placenta-mediated complications are leading causes of maternal and fetal morbidity and mortality. We hypothesized that a preconception history of venous thromboembolism (VTE) is associated with increased risk of placenta-mediated pregnancy complications. A nationwide population-based cohort study of all singleton pregnancies leading to delivery from 1997 to 2012 (n=964967). We obtained data on placenta-mediated pregnancy complications from the Danish Medical Birth Registry and data on VTE before pregnancy from the Danish National Patient Registry. We computed absolute risks, crude and adjusted risk differences (RDs) using a binomial regression model, and crude and adjusted risk ratios (RRs) from a modified Poisson regression model. Overall, 1419 women had a preconception history of VTE, while 578112 did not. Preeclampsia occurred in 4.2% of pregnancies in the VTE group and in 2.7% of pregnancies in a comparison cohort (adjusted RD=1.3%, 95% confidence interval (CI) 0.6-2.0%; adjusted RR=1.5, 95% CI 1.3-1.8). Stillbirth occurred in 0.7% of pregnancies in the VTE group and in 0.4% of pregnancies in the comparison cohort (adjusted RD=0.3%, 95% CI 0.02-0.6%; adjusted RR=1.8, 95% CI 1.1-3.0). Placental abruption occurred in 0.8% of pregnancies in the VTE group and in 0.5% of pregnancies in the comparison cohort (adjusted RD=0.3%, 95% CI -0.05-0.6%; adjusted RR=1.6, 95% CI 1.1-2.4). Small-for-gestational-age infants accounted for 10.9% of live births in the VTE group and 9.8% of live births in the comparison cohort (adjusted RD=0.6%, 95% CI -0.5-1.7%; adjusted RR=1.1, 95% CI 0.9-1.3). Women with a history of VTE were at increased risk of placenta-mediated complications.

Severe and Fatal Obstetric Injury Claims in Relation to Labor Unit Volume

Although obstetric severe adverse outcomes due to medical errors are not common, they can be devastating for families. High-volume labor units might be cost-effective, but smaller labor units may provide more personalized care and be located more closely to individuals in lower-density areas. This study examines obstetric injury claims and assesses any association between the delivery volume in Denmark and the incidences of approved severe and fatal obstetric injury claims. Data were collected from the Danish Patient Compensation Associations and the Danish Medical Birth Register, which includes information on all hospital and home births since 1973 in Denmark. Since 1995, approximately 37 obstetric claims have been approved each year. Even if the practitioner involved in a claim was not held legally responsible, patients may have claims approved and be compensated. Labor units were categorized in 5 groups of annual volume quantity range. Primary outcomes included submitted claims, approved claims, approved severe injury claims, approved fatal injury claims, and approved severe and fatal injury claims combined. Between 1995 and 2012, more than 1 million children were born, and more than 98% were delivered in hospital labor units; 1,151,734 births from 51 labor units were included in the study. During the 18-year study period, the median volume of labor units had an increase of 40 deliveries per year (P < 0.001). A total of 1872 claims, 672 of which were approved, were included in the study. Of the approved claims, 64 patients were severely injured, 4 died of injuries, and 91 died (84 children and 7 mothers). Overall, the incidence rate of approved claims was 5.8 per 10,000 births (95% confidence interval, 5.41–6.29 births). The 3 lowest-volume quintiles (<2802 deliveries per year) had 30% to 40% increased approval incidence rates compared with the fifth quintile (3800–6000 deliveries per year). The incidence rate of approved claims was inversely related to unit volume. These findings show that higher-volume labor units have a lower incidence rate of approved injury claims and lower rate of approved fatal injury claims than higher-volume labor units. Factors that may contribute to this is the smaller number of qualified specialists and lack of accessibility to specialties such as anesthesia or neonatology at smaller units. While these findings support the development of larger labor units from the consolidation of small units, it is also important to create obstetric safety initiatives tailored to unit volume.

Use of Antiepileptic Drugs During Pregnancy and Risk of Spontaneous Abortion and Stillbirth

Objective To determine whether use of antiepileptic drugs during pregnancy may increase the risk of spontaneous abortion or stillbirth. Design Population based cohort study. Setting Register based study in Denmark, 1997-2008. Participants 983 305 pregnancies identified in the Danish medical birth register and the Danish national hospital discharge register from 1 February 1997 to 31 December 2008 were linked to the Danish Register of Medicinal Product Statistics to obtain information on use of antiepileptic drugs. Main outcome measures Risk ratio of spontaneous abortion and stillbirth after use of antiepileptic drugs during pregnancy, estimated by using binomial regression adjusting for potential confounders of maternal age, cohabitation, income, education, history of severe mental disorder, and history of drug misuse. Results Antiepileptic drugs were used in a total of 4700 (0.5%) pregnancies. 16 out of 100 pregnant women using antiepileptics and 13 out of 100 pregnant women not using antiepileptics experienced a spontaneous abortion. After adjusting for potential confounders pregnant women using antiepileptics had a 13% higher risk of spontaneous abortions than pregnant women not using antiepileptics (adjusted risk ratio 1.13, 95% confidence interval 1.04 to 1.24). However, the risk of spontaneous abortion was not increased in women with an epilepsy diagnosis (0.98, 0.87 to 1.09), only in women without a diagnosis of epilepsy (1.30, 1.14 to 1.49). In an analysis including women with at least two pregnancies with discordant antiepileptic drug use (for example, use in the first pregnancy but not in the second), the adjusted hazard ratio for spontaneous abortion was 0.83 (0.69 to 1.00) for exposed pregnancies compared with unexposed pregnancies. Stillbirth was identified in 18 women who used antiepileptic drugs (unadjusted risk ratio 1.29, 0.80 to 2.10). Conclusion Among women with epilepsy and when analysing the risk in antiepileptic drug discordant pregnancies in the same woman, we found no overall association between the use of antiepileptic drugs during pregnancy and spontaneous abortions. Therefore unmeasured confounding may explain the slight increased risk for spontaneous abortion with any antiepileptic drug use (among women both with and without epilepsy). We found no association between antiepileptic drug use during pregnancy and stillbirth, but the statistical precision was low.

Risk of Fetal Death after Treatment with Antipsychotic Medications during Pregnancy.

BackgroundAntipsychotic medications are increasingly used during pregnancy. Nevertheless, fetal risks are still not fully studied. It is currently unclear whether the antipsychotic treatment might induce a higher risk of fetal death. We aimed to determine if use of antipsychotic medication during pregnancy is associated with an increased risk of spontaneous abortion or stillbirth.MethodsIn a historical cohort study, we identified all clinically recognized pregnancies registered in the nationwide Danish registries from 1997 to 2008 (N = 1,005,319). Exposure was defined as any prescription of antipsychotic medications redeemed by the pregnant women during the exposure window, and recorded in the Danish National Prescription Register. Outcome was defined as any spontaneous abortion or stillbirth recorded in the Danish National Hospital Register and the Danish Medical Birth Register respectively.ResultsWomen exposed to antipsychotic medications during pregnancy had a 34% higher risk of spontaneous abortion (adjusted relative risk = 1.34; 95% confidence interval = 1.22; 1.46) compared to unexposed women, but a similar risk compared to women exposed prior to (but not during) pregnancy (adjusted relative risk = 1.04; 95% confidence interval = 0.93; 1.17). The risk of spontaneous abortion was not increased in exposed pregnancies when compared to unexposed pregnancies in the same women (adjusted hazard ratio = 1.11; 95% CI = 0.94; 1.31). A twofold higher risk of stillbirth was found in women exposed to antipsychotic medications compared with unexposed women (relative risk = 2.27; 95% confidence interval = 1.45; 3.55) and compared with women exposed only prior to pregnancy (relative risk = 2.06; 95% confidence interval = 1.01; 4.19).ConclusionsThe increased risk of spontaneous abortion found in women treated with antipsychotic medications during pregnancy is most likely due to confounding factors. The risk of stillbirth was twofold higher in pregnancies exposed to antipsychotic medication during pregnancy. Treatment with antipsychotic medications during pregnancy requires careful consideration.

Pre-gravid oral contraceptive use in relation to birth weight: a prospective cohort study.

Few studies have evaluated the association between pregravid oral contraceptive (OC) use and birth weight, and findings have been conflicting. We conducted a prospective cohort study of 5921 pregnancy planners in Denmark to evaluate recency, duration, and type of OC used before conception in relation to infant birth weight. Participants completed online questionnaires and reported detailed information on contraceptive history and covariates at baseline. Participants completed bimonthly follow-up questionnaires to update their pregnancy status for up to 12months or until conception occurred. Birth weight data were ascertained from the Danish Medical Birth Registry for 4046 live births delivered by study participants between 2008 and 2010. We used multivariable linear and log-binomial regression analyses to control for confounding. Mean birth weight was higher among women who had used OCs within 0-1months (mean difference=97g, CI 26, 168) or 2-6months (mean difference=40g, CI -5, 85) before conception, compared with more than 12months before conception. Mean birth weight was lower among women who had used OCs for long durations (mean difference comparing ≥12 with <4years of OC use=-85g, CI -158, -11). Our findings indicate that pregravid OC use within 6months of conception may be associated with a small increase in birth weight, but that long duration of use may have the opposite effect. Results were stronger among male infants, among 2nd and 4th generation OC users, and among users of OCs with a higher estrogen dose.

Coffee Consumption During Pregnancy and Birth Weight: Does Smoking Modify the Association?

Background: A previous randomized trial demonstrated an association between coffee intake and birth weight in smokers only. This could be a chance finding or because smoking interferes with caffeine metabolism. This study assessed the association between coffee intake during pregnancy and birth weight and whether it was modified by the mothers' smoking habits. Methods: In the Danish National Birth Cohort, coffee intake and smoking during pregnancy were recorded prospectively in 89,539 pregnancies that ended with live born singletons. Information on birth weight was obtained from the Danish Medical Birth Register. For a total of 71,000 pregnancies, complete information was available on coffee intake and all covariates for the second trimester. Results: Second-trimester coffee intake was associated with reduced birth weight in a dose–response pattern for non-smokers and smokers (9 g/cup/day). Compared to non-coffee drinkers, intake of eight or more cups of coffee per day was associated with an adjusted birth weight difference of −65 g [95% confidence interval (CI) −92 to −39] for non-smokers and −79 g [95% CI −124 to −34] for women smoking more than 10 cigarettes per day. Women drinking eight or more cups of coffee per day had a higher risk of giving birth to a child small for gestational age (adjusted odds ratio=1.51 [95% CI 1.21–1.88]). These associations were found among both smokers and non-smokers. Conclusion: Coffee intake during pregnancy is associated with reduced birth weight in smokers as well as non-smokers, and may increase the risk of giving birth to small for gestational age children, but the association is small for intakes of coffee of less than eight cups per day.

Use of thyroid hormones in relation to pregnancy: a Danish nationwide cohort study.

To determine the rate of exposure of pregnant women to levothyroxine and to assess changes in these rates before, during and after pregnancy. Register-based cohort study. Danish nationwide registers. All women having a live birth in Denmark between 1 January 1997 and 31 December 2010 (n = 912 342). All pregnant women in the study period were identified from the Danish Medical Birth Register. Exposed women were identified from the Danish National Prescription Register, based on redemption of levothyroxine prescriptions before, during or after pregnancy. The rate of pregnant women redeeming levothyroxine prescriptions and maternal characteristics. We identified a fourfold increase in levothyroxine prescription redemption during the study period, from 0.34% in 1997 to 1.39% by 2010. A mean of 0.79% of our cohort received levothyroxine. Most of the women who were using levothyroxine before pregnancy continued the therapy during their pregnancy, but 9.4% stopped redeeming their prescriptions. Overall, 0.28% of our cohort received a levothyroxine prescription for the first time within 9 months after pregnancy. Fewer women than expected received levothyroxine treatment during pregnancy even though a fourfold increase was observed during the study period. Furthermore, one of 10 discontinued treatments during pregnancy. These findings all indicate that too few women are treated for hypothyroidism during pregnancy. Further research is needed to determine whether hypothyroid pregnant women are suboptimally treated and the possible consequences for the mother and fetus.

Medical augmentation of labor and the risk of ADHD in offspring: a population-based study.

Oxytocin for labor augmentation is widely used in obstetric care in Western countries. Two recent, smaller studies found opposing results regarding the association between prenatal exposure to oxytocin for labor augmentation and attention-deficit/hyperactivity disorder (ADHD). In Denmark, oxytocin is the medication used for nearly all medical augmentations of labor, and we examined the association between medical augmentation of labor and ADHD in a large cohort study based on national register data. All singletons born after spontaneous onset of labor in Denmark between 2000 and 2008 (N = 546 146) were included in the study. Data from the Danish Medical Birth Registry on medical augmentation of labor (yes/no) were used to identify exposed children. ADHD was defined based on the diagnostic codes of International Classification of Diseases, 10th Revision, for hyperkinetic disorder and information on dispensed ADHD medication. A multivariate proportional hazards regression model was used to test the association. Among 546 146 deliveries, 26% included medical augmentation of labor, and 0.9% of the children were identified as having ADHD (n = 4617). We found no association between augmentation of labor and ADHD in the offspring (hazard ratio: 1.05 [95% confidence interval: 0.98-1.13]). Our study does not support an association between medical augmentation of labor and ADHD in the child.

Prospective study of time to pregnancy and adverse birth outcomes

To investigate the association between time to pregnancy (TTP) and adverse birth outcomes. Prospective cohort study. Not applicable. A total of 3,521 singletons born to women aged 18-40 years at cohort entry. None. Selected birth outcomes, including preterm birth (PTB, <37 weeks' gestation), low birth weight (<2,500 g), small for gestational age, large for gestational age, and placental disorders, ascertained from the Danish Medical Birth Registry and Danish National Registry of Patients. Risk ratios (RRs) and 95% confidence intervals (CIs) were estimated using log-binomial regression, with adjustment for potential confounders and fertility treatment. Multivariable RRs for PTB in relation to TTP of 3-5, 6-11, and ≥12 vs. <3 cycles were 1.59 (95% CI 0.94-2.69), 0.85 (95% CI 0.48-1.50), and 1.57 (95% CI 0.93-2.65). The association was slightly stronger for spontaneous PTB (TTP ≥12 vs. <3 cycles: RR 1.69, 95% CI 0.84-3.42) than for medically indicated PTB (RR 1.39, 95% CI 0.62-3.12). Longer TTPs (≥12 cycles) were associated with increased risks of low birth weight (RR 1.80, 95% CI 0.97-3.35), cesarean delivery (RR 1.64, 95% CI 1.27-2.12), placental disorders (RR 2.21, 95% CI 1.07-4.56), ischemic placental disease (RR 1.56, 95% CI 0.99-2.44), pre-eclampsia (RR 1.45, 95% CI 0.79-2.65), and postpartum hemorrhage (RR 1.58, CI 1.14-2.19), and decreased risks of macrosomia (≥4,500 g; RR 0.63, 95% CI 0.35-1.13) and large for gestational age (RR 0.76, 95% CI 0.58-1.00). Longer TTP showed little association with small for gestational age. In a prospective cohort study of Danish pregnancy planners, delayed conception was a marker for adverse birth outcomes, after accounting for fertility treatment.

A prospective cohort study of a woman's own gestational age and her fecundability.

What is the magnitude of the association between a woman's gestational age at her own birth and her fecundability (cycle-specific probability of conception)? We found a 62% decrease in fecundability among women born <34 weeks of gestation relative to women born at 37-41 weeks of gestation, whereas there were few differences in fecundability among women born at later gestational ages. One study, using retrospectively collected data on time-to-pregnancy (TTP), and self-reported data on gestational age, found a prolonged TTP among women born <37 gestational weeks (preterm) and with a birthweight ≤1500 g. Other studies of women's gestational age at birth and subsequent fertility, based on data from national birth registries, have reported a reduced probability of giving birth among women born <32 weeks of gestation. We used data from a prospective cohort study of Danish pregnancy planners ('Snart-Gravid'), enrolled during 2007-2011 and followed until 2012. In all, 2814 women were enrolled in our study, of which 2569 had complete follow-up. Women eligible to participate were 18-40 years old at study entry, in a relationship with a male partner, and attempting to conceive. Participants completed a baseline questionnaire and up to six follow-up questionnaires until the report of pregnancy, discontinuation of pregnancy attempts, beginning of fertility treatment, loss to follow-up or end of study observation after 12 months. Among women born <34 gestational weeks, the cumulative probability of conception was 12, 28 and 48% within 3, 6 and 12 cycles, respectively. Among women born at 37-41 weeks of gestation, cumulative probability of conception was 47, 67 and 84% within 3, 6 and 12 cycles, respectively. Relative to women born at 37-41 weeks' gestation, women born <34 weeks had decreased fecundability (fecundability ratio (FR) 0.38, 95% confidence interval (CI): 0.17-0.82). Our data did not suggest reduced fecundability among women born at 34-36 weeks of gestation or at ≥42 weeks of gestation (FR 1.03, 95% CI: 0.80-1.34, and FR 1.13, 95% CI: 0.96-1.33, respectively). Data on gestational age, obtained from the Danish Medical Birth Registry, were more likely to be based on date of last menstrual period than early ultrasound examination, possibly leading to an overestimation of gestational age at birth. Such overestimation, however, would not explain the decrease in fecundability observed among women born <34 gestational weeks. Another limitation is that the proportion of women born before 34 weeks of gestation was low in our study population, which reduced the precision of the estimates. By using prospective data on TTP, our study elaborates on previous reports of impaired fertility among women born preterm, suggesting that women born <34 weeks of gestation have reduced fecundability. The study was supported by the National Institute of Child Health and Human Development (R21-050264), the Danish Medical Research Council (271-07-0338), and the Health Research Fund of Central Denmark Region (1-01-72-84-10). The authors have no competing interests to declare.

Ethnic Variation in Oral Cleft Occurrence in Denmark 1981–2002

Objective : To examine differences in oral cleft (OC) occurrence based on maternal only and parental country of origin in Denmark from 1981 to 2002. Methods : Data on all live births from the Danish Medical Birth Register from 1981 to 2002 were linked with the Danish Facial Cleft Database. Cleft cases were categorized into isolated and nonisolated cleft lip with or without palate (CL/P) and cleft palate only (CP). Birth prevalence was calculated as cases per 1,000 live born children by maternal country of origin, world region, and mixed parental groups. Results : We identified 3094 OC cases among 1,319,426 live births. Danish-born women had an OC birth prevalence of 2.38 with a 95% confidence interval (CI) (2.29-2.47) and foreign-born women a significant lower prevalence of 2.01 (CI, 1.77-2.27). This difference was explained by a lower isolated CL/P birth prevalence among foreign-born women of 0.97 (CI, 0.81-1.16) versus 1.35 (CI, 1.28-1.41). No significant differences were seen for the remaining subtypes. Parents with the same foreign country of origin had a lower overall OC (1.63; CI, 1.35-1.94) and isolated CL/P (0.76; CI, 0.57-0.99) birth prevalence than Danish-born parents. This was not the case for any of the mixed parental groups. Overall and subtype prevalence rates varied according to maternal categories of world region. Conclusion : In this study we found differences in OC occurrence among all live births in the Danish population based on maternal country of origin from 1981 to 2002. Danish-born women had higher OC and isolated CL/P birth prevalence compared with foreign-born women.

Birth outcomes after prenatal exposure to antiepileptic drugs--a population-based study.

We studied the potential impact of antiepileptic drugs (AEDs) on fetal growth and gestational age at birth. In the Danish Medical Birth Registry, we identified all pregnancies with birth outcomes from 1997 to 2008 and linked with data from the Danish National Prescription Register. We used binomial regression to study preterm birth (<37weeks), low birth weight (<2,500g), and small for gestational age (SGA), adjusted for potential confounding factors including maternal age, smoking, substance abuse, cohabitation, income, education, and parity. We identified 679,762 singletons, and 2,928 (0.4%) of these had been exposed to AEDs. Exposure to AEDs was associated with a risk of preterm birth (adjusted risk ratio (aRR) 1.32; 95% confidence interval [CI] 1.16-1.50) when compared to unexposed children. However, when stratifying on maternal epilepsy, there was no association between AED exposure and preterm birth in offspring of women with epilepsy (aRR 1.00; 95% CI 0.82-1.21), whereas there was a risk associated with AED exposure in offspring of women without epilepsy (aRR 1.56; 95% CI 1.27-1.92). AED exposure was associated with a risk of being born with low birth weight (aRR 1.40; 95% CI 1.22-1.60) both for children born of women with epilepsy (aRR 1.32; 95% CI 1.06-1.63) and children born of women without epilepsy (aRR 1.61; 95% CI 1.28-2.02). The risk of being born SGA associated with AED exposure (aRR 1.21; 95% CI 1.10-1.34) was found both in offspring of women with epilepsy (aRR 1.19; 95% CI 1.02-1.37) and without epilepsy (aRR 1.21; 95% CI 1.01-1.45). Prenatal AED exposure was associated with low birth weight and risk of being born SGA, but only with preterm birth among women without epilepsy.

Use of antiepileptic drugs during pregnancy and risk of spontaneous abortion and stillbirth: population based cohort study

Objective To determine whether use of antiepileptic drugs during pregnancy may increase the risk of spontaneous abortion or stillbirth. Design Population based cohort study. Setting Register based study in Denmark,...