Jørn Olsen

The Danish Medical Birth Register

The Danish Medical Birth Register was established in 1973. It is a key component of the Danish health information system. The register enables monitoring of the health of pregnant women and their offspring, it provides data for quality assessment of the perinatal care in Denmark, and it is used extensively for research. The register underwent major changes in construction and content in 1997, and new variables have been added during the last 20xa0years. The aim was to provide an updated description of the register focusing on structure, content, and coverage since 1997. The register includes data on all births in Denmark and comprises primarily of data from the Danish National Patient Registry supplemented with forms on home deliveries and stillbirths. It contains information on maternal age provided by the Civil Registration System. Information on pre-pregnancy body mass index and smoking in first trimester is collected in early pregnancy (first antenatal visit). The individual-level data can be linked to other Danish health registers such as the National Patient Registry and the Danish National Prescription Registry. The register informs several other registers/databases such as the Danish Twin Registry and the Danish Fetal Medicine Database. Aggregated data can be publicly accessed on the Danish Health Data Authority web page (www.esundhed.dk/sundhedsregistre/MFR). Researchers can obtain access to individual-level pseudo-anonymised data via servers at Statistics Denmark and the Danish Health Data Authority.

Attention deficit hyperactivity disorder and autism spectrum disorder in children born to mothers with thyroid dysfunction: a Danish nationwide cohort study

To examine the association between maternal hyper‐ and hypothyroidism and the risk of attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) in the child.

Menstrual cycle pattern and fertility: a prospective follow-up study of pregnancy and early embryonal loss in 295 couples who were planning their first pregnancy

OBJECTIVEnTo characterize how the menstrual cycle pattern relates to fertility regardless of potential biases caused by inappropriate coital timing during the menstrual cycle or early embryonal loss.nnnDESIGNnProspective follow-up study.nnnSETTINGnHealthy couples recruited throughout Denmark.nnnPATIENT(S)nTwo hundred ninety-five couples who were planning their first pregnancy were followed up from the discontinuation of birth control until a pregnancy was recognized within six menstrual cycles. Early embryonal losses were detected by changes in urinary hCG levels.nnnINTERVENTION(S)nNone.nnnMAIN OUTCOME MEASURE(S)nThe probability of pregnancy occurring within one menstrual cycle (fecundity).nnnRESULT(S)nIn women who had a cycle length that differed by >10 days from the usual cycle length, fecundity was approximately 25% that of women who had no variation (odds ratio 0.25, 95% confidence interval 0.09-0.68). When the combined effect of cycle variation and cycle length was assessed, cycle variation was a persistent strong predictor of fecundity.nnnCONCLUSION(S)nThe mechanisms of the present findings probably are female functional disturbances in ovulation, conception, implantation, or sustained pregnancy, linked with variable menstrual cycle length. Thus, identification of medical and environmental causes of abnormal menstrual cycle patterns may provide clues to the causes of infertility. Moreover, the menstrual cycle pattern also should be taken into consideration in the clinical decision-making process.

Augmentin treatment during pregnancy and the prevalence of congenital abnormalities: A population-based case-control teratologic study

OBJECTIVEnTo study the human teratogenic potential of augmentin (amoxicillin+clavulanic acid) treatment during pregnancy.nnnMATERIALS AND METHODSnPair analysis of cases with different congenital abnormalities and their matched controls in the population-based dataset of the Hungarian Case-Control Surveillance of Congenital Abnormalities, between 1991 and 1996.nnnRESULTSnThe case group included 6935 pregnant women who had offspring with congenital abnormalities, while the control group consisted of 10,238 pregnant women who had babies without any defects. The number (and rate) of pregnant women with augmentin treatment was 52 (0.75%) and 56 (0.55%) in the case and control groups, respectively (crude odds ratio (OR) with 95% confidence interval (CI) was 1.4, 0.9-2.0). The comparison of augmentin treatments during the second-third months of pregnancy (i.e. in the critical period for most major congenital abnormalities) in case-control pairs did not show a higher use of augmentin in any congenital abnormality group.nnnCONCLUSIONnAugmentin treatment of pregnant women in usual therapeutic doses is unlikely to increase the risk of congenital abnormalities in newborn infants. However, the number of cases and controls was limited, therefore, further multicenter-multinational studies are needed for the final risk assessment.

A population-based case-control teratologic study of oral erythromycin treatment during pregnancy.

The objective of the study was to evaluate the human teratogenic potential of oral erythromycin treatment during pregnancy in the population-based dataset of the Hungarian Case-Control Surveillance of Congenital Abnormalities, 1980-1996. Of 38,151 pregnant women who had newborn infants without any congenital abnormalities (population control group), 172 (0.5%) had received erythromycin, while of 22,865 pregnant women who had newborns or fetuses with congenital abnormalities, 113 (0.5%) had been treated with erythromycin (crude OR with 95% Cl = 1.1, 0.9-1.4). The case-control pair analysis did not indicate a teratogenic potential of erythromycin during the second through third months of gestation, i.e., in the critical period for most major congenital abnormalities. The frequency of maternal erythromycin treatments during the second-third months of pregnancy was also not higher in different congenital abnormality groups compared with the rate of the total control group as referent. Thus, treatment with oral erythromycin during pregnancy did not present detectable teratogenic risk to the fetus.

Severity of Birth Defects After Propylthiouracil Exposure in Early Pregnancy

BACKGROUNDnPropylthiouracil (PTU) used in the treatment of maternal hyperthyroidism in early pregnancy may be associated with a higher prevalence of birth defects in the face and neck region and in the urinary system but the severity of these complications remains to be elucidated.nnnMETHODSnReview of hospital-registered cases of birth defects in the face and neck region and in the urinary system after PTU exposure in early pregnancy. We obtained information on maternal redeemed prescription of PTU and child diagnosis of birth defect from nationwide registers for all children born in Denmark between 1996 and 2008 (n=817,093). The children were followed until December 31, 2010 (median age, 8.3 years) and the Cox proportional hazards model was used to estimate adjusted hazard ratio (HR) with 95% confidence interval (CI) for having a birth defect after PTU exposure versus nonexposed children (n=811,730).nnnRESULTSnFourteen cases of birth defects were identified in the face and neck region and in the urinary system after PTU exposure in early pregnancy; 11 children were exposed to PTU only (n=564), whereas 3 children were born to mothers who switched from methimazole (MMI)/carbimazole (CMZ) to PTU in early pregnancy (n=159). Among children exposed to PTU only, the adjusted HR for having a birth defect in the face and neck region was 4.92 (95% CI 2.04-11.86) and in the urinary system 2.73 (1.22-6.07). Looking into details of the 14 cases, 7 children were diagnosed with a birth defect in the face and neck region (preauricular and branchial sinus/fistula/cyst) and 7 children had a birth defect in the urinary system (single cyst of kidney and hydronephrosis). Surgical treatment was registered in 6 of the cases with a birth defect in the face and neck region and 3 of the cases with a birth defect in the urinary system. Two of the children with a birth defect in the urinary system also had other birth defects (genital organs).nnnCONCLUSIONSnWe report details on possible PTU-associated birth defects. They tend to be less severe than the defects observed after MMI/CMZ exposure. Yet, the majority of affected children had to undergo surgery.

Nitrofurantoin and congenital abnormalities.

OBJECTIVEnTo study human teratogenic potential of oral nitrofurantoin treatment during pregnancy.nnnMATERIALS AND METHODSnPair analysis of cases with congenital abnormalities and matched population controls in the population-based dataset of the Hungarian Case-Control Surveillance of Congenital Abnormalities, 1980-1996.nnnRESULTSnOf 38,151 pregnant women who had newborn infants without any congenital abnormalities (population control group), 774 (3.4%); of 22,865 case pregnant women who had newborns or fetuses with congenital abnormalities, 1079 (2.8%) and of 812 pregnant women who had newborns or fetuses with Downs syndrome (patient controls), 23 (2.8%) pregnant women were treated with nitrofurantoin. The above differences between population controls and cases may be connected with recall bias, because the case-control pair analysis did not indicate a teratogenic potential of nitrofurantoin use during the second and the third months of gestation, i.e. in the critical period for major congenital abnormalities.nnnCONCLUSIONnTreatment with nitrofurantoin during pregnancy does not present detectable teratogenic risk to the fetus.

Foetal programming by maternal thyroid disease

Foetal programming is an emerging concept that links a wide range of exposures during foetal life to later development of disease. Thyroid disorders are common in women of reproductive age, and careful management of pregnant women suffering from thyroid disease is important considering the crucial role of thyroid hormones during early brain development. It is possible that maternal thyroid dysfunction in pregnancy may lead to structural and/or functional changes during foetal brain development. Such an effect could later predispose the offspring to an increased risk of neurologic or psychiatric disease. We recently observed that children born to mothers with thyroid dysfunction had an increased risk of developing seizure disorders, autism spectrum disorders, attention‐deficit hyperactivity disorders and psychiatric disease in adolescence and young adulthood. In the review, we discuss the concept of potential foetal programming by maternal thyroid disease.

Dynamics and Predictors of Serum TSH and fT4 Reference Limits in Early Pregnancy: A Study Within the Danish National Birth Cohort

CONTEXTnThyroid hormones are important developmental factors and levels should be adequate both in the pregnant woman and in the fetus. However, there is no consensus on maternal thyroid test reference limits in early pregnancy.nnnOBJECTIVEnEstimation of week-to-week changes in and predictors of TSH and free T4 (fT4) reference limits in the first trimester of pregnancy.nnnDESIGNnMeasurement of TSH and fT4 in biobank sera collected in pregnancy weeks 5-19 from a random sample of the Danish National Birth Cohort that enrolled 101 032 pregnant in 1996-2002.nnnSETTINGnNational cohort of pregnant women.nnnPARTICIPANTSnHealthy participants (n = 6671) were identified and individual characteristics retrieved using interview data and data from Danish national health registers.nnnINTERVENTION(S)nNone.nnnMAIN OUTCOME MEASURE(S)nReference limits for TSH and fT4 in each first trimester pregnancy week and predictors of these reference limits.nnnRESULTSnTSH reference limits were very variable. Up to and including week 6, nonpregnancy reference limits could be used. In weeks 9-12, TSH upper reference limit was approximately 0.4 mU/L lower than the nonpregnancy upper limit. The TSH lower reference limit was approximately 0.1 mU/L. fT4 variations were reverse to those of TSH, but changes were small with approximately 4% higher reference limits during the weeks 9-12. TSH upper reference limit was lower in multiparous women and women with lower iodine intake but higher in obese women. fT4 was lower in smokers.nnnCONCLUSIONSnTSH reference limits differ widely in the first trimester of pregnancy. The use of a uniform set of reference limits is an inordinate simplification that will lead to frequent misclassification and possibly to incorrect choice of therapy.

Antithyroid Drug Side Effects in the Population and in Pregnancy

OBJECTIVEnMethimazole (MMI) and propylthiouracil (PTU) are both associated with birth defects and may also rarely be associated with agranulocytosis and liver failure. The frequency of these side effects when antithyroid drugs (ATDs) are used in the population in general or in pregnancy remains to be elucidated.nnnDESIGNnAll individuals registered as the parent of a live-born child in Denmark, 1973–2008, were identified (n = 2 299 952) and studied from 1995 through 2010 for the use of ATDs. Outcomes were agranulocytosis, liver failure, and birth defects in their offspring. To evaluate the frequency of these side effects associated with the use of ATDs in pregnancy, all live-born pregnancies (n = 830 680), 1996–2008, were identified in a subanalysis.nnnRESULTSnIn the population studied, 28 998 individuals redeemed prescriptions of ATDs (exposure in 2115 pregnancies), which was associated with 45 cases of agranulocytosis (one in pregnancy) and 10 cases of liver failure (one in pregnancy). This corresponded to 41 and 11 cases of agranulocytosis and liver failure per 5 million inhabitants during a 10-year period (agranulocytosis: 0.16% of ATDs exposed [MMI: 0.11% vs PTU: 0.27%, P = .02]; liver failure: 0.03% of ATDs exposed [MMI: 0.03% vs PTU: 0.05%, P = .4]). The majority (83%) developed the side effect within 3 months of ATD treatment and 25% during hyperthyroidism relapse. The use of ATDs in pregnancy was associated with birth defects in 3.4% of exposed children (44 cases per 5 million inhabitants per 10 y), and the frequency of birth defects after ATD exposure was 75 times higher than both maternal agranulocytosis and liver failure in pregnancy.nnnCONCLUSIONSnIn the Danish population in general, ATDs associated birth defects and agranulocytosis had similar frequencies and were more common than liver failure, whereas for the use of ATDs in pregnancy, birth defects were dominant. The burden of side effects to the use of ATDs can be reduced by restricting the use of ATDs in early pregnancy.