Chun Sen Wu

Birth Defects After Early Pregnancy Use of Antithyroid Drugs: A Danish Nationwide Study

INTRODUCTION Hyperthyroidism in pregnant women should be adequately treated to prevent maternal and fetal complications, but teratogenic effects of antithyroid drug (ATD) treatment have been described. Evidence is still lacking in regard to the safety and choice of ATD in early pregnancy. OBJECTIVE Our objective was to determine to which degree the use of methimazole (MMI)/carbimazole (CMZ) and propylthiouracil (PTU) in early pregnancy is associated with an increased prevalence of birth defects. METHODS This Danish nationwide register-based cohort study included 817 093 children live-born from 1996 to 2008. Exposure groups were assigned according to maternal ATD use in early pregnancy: PTU (n = 564); MMI/CMZ (n = 1097); MMI/CMZ and PTU (shifted in early pregnancy [n = 159]); no ATD (ATD use, but not in pregnancy [n = 3543]); and nonexposed (never ATD use [n = 811 730]). Multivariate logistic regression was used to estimate adjusted odds ratio (OR) with 95% confidence interval (95% CI) for diagnosis of a birth defect before 2 years of age in exposed versus nonexposed children. RESULTS The prevalence of birth defects was high in children exposed to ATD in early pregnancy (PTU, 8.0%; MMI/CMZ, 9.1%; MMI/CMZ and PTU, 10.1%; no ATD, 5.4%; nonexposed, 5.7%; P < .001). Both maternal use of MMI/CMZ (adjusted OR = 1.66 [95% CI 1.35-2.04]) and PTU (1.41 [1.03-1.92]) and maternal shift between MMI/CMZ and PTU in early pregnancy (1.82 [1.08-3.07]) were associated with an increased OR of birth defects. MMI/CMZ and PTU were associated with urinary system malformation, and PTU with malformations in the face and neck region. Choanal atresia, esophageal atresia, omphalocele, omphalomesenteric duct anomalies, and aplasia cutis were common in MMI/CMZ-exposed children (combined, adjusted OR = 21.8 [13.4-35.4]). CONCLUSIONS Both MMI/CMZ and PTU were associated with birth defects, but the spectrum of malformations differed. More studies are needed to corroborate results in regard to early pregnancy shift from MMI/CMZ to PTU. New ATD with fewer side effects should be developed.

Early or Recurrent Preterm Birth and Maternal Cardiovascular Disease Risk

PURPOSE Preterm birth (PTB) has been associated with a later increased risk of maternal cardiovascular disease (CVD). We hypothesized a more pronounced relation between early or recurrent PTB and maternal CVD risk. METHODS We related PTB severity (earlier gestational age at delivery) and recurrence (>/=2) among women with births from 1973-1983 in Denmark (n = 427,765) to maternal CVD morbidity or mortality (1977-2006). Birth data were linked to CVD hospitalizations and deaths identified in national registers and data were analyzed using Cox proportional hazards models. RESULTS Women with a prior PTB had excess CVD after adjustment for age, parity, and education (hazard ratio [HR] = 1.36 [95% confidence interval (CI): 1.31, 1.41]). This was only modestly attenuated when women with preeclampsia or small for gestational age births were excluded, and the relationship was stronger for CVD mortality (HR = 1.98 [1.73, 2.26]). Recurrent PTB was associated with higher CVD morbidity compared to women with one PTB, particularly for ischemic events (HR = 1.78 [1.40, 2.27] vs. 1.22 [1.09, 1.36]). Risk was similarly elevated among women with early, moderate, and late PTB. Sensitivity analysis suggested that confounding by smoking only partly explained these associations. CONCLUSIONS Women with PTB, especially recurrent PTB, were at increased risk for CVD, suggesting common causes of these conditions.

Low Birth Weight in Children Born to Mothers with Hyperthyroidism and High Birth Weight in Hypothyroidism, whereas Preterm Birth Is Common in Both Conditions: A Danish National Hospital Register Study

Objectives: Maternal hyper- and hypothyroidism have been associated with increased risk of adverse pregnancy outcomes, but studies have led to inconsistent results. We aimed to identify children born to mothers with a hospital-recorded diagnosis of thyroid dysfunction in Denmark and to study the association with gestational age at delivery and birth weight of the child. Study Design: Population-based cohort study using Danish nationwide registers. All singleton live births in Denmark between January 1, 1978 and December 31, 2006 were identified and stratified by maternal diagnosis of hyper- or hypothyroidism registered in the Danish National Hospital Register before January 1, 2007. Results: Maternal first-time diagnosis of thyroid dysfunction before, during or after pregnancy was registered in 32,809 (2.0%) of the singleton live births (n = 1,638,338). Maternal diagnosis of hyperthyroidism (adjusted OR 1.22, 95% CI 1.15-1.30) and hypothyroidism (adjusted OR 1.17, 95% CI 1.08-1.27) were associated with increased risk of preterm birth. Moreover, birth weight in children born to mothers with a diagnosis of hyperthyroidism was lower (adjusted difference -51 g, 95% CI -58 to -43 g) and higher in relation to maternal hypothyroidism (adjusted difference 20 g, 95% CI 10-30 g). Hyperthyroidism was associated with small-for-gestational-age (adjusted OR 1.15, 95% CI 1.10-1.20) and hypothyroidism with large-for-gestational-age children (adjusted OR 1.24, 95% CI 1.17-1.31). Conclusions: Based on Danish nationwide registers, both maternal hyper- and hypothyroidism were associated with increased risk of preterm birth. Actual birth weight of the child and birth weight for gestational age were low if the mother had a diagnosis of hyperthyroidism and high if the diagnosis was hypothyroidism.

Severity of Birth Defects After Propylthiouracil Exposure in Early Pregnancy

BACKGROUND Propylthiouracil (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. METHODS Review 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). RESULTS Fourteen 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). CONCLUSIONS We 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.

An international contrast of rates of placental abruption: An age-period-cohort analysis

Background Although rare, placental abruption is implicated in disproportionately high rates of perinatal morbidity and mortality. Understanding geographic and temporal variations may provide insights into possible amenable factors of abruption. We examined abruption frequencies by maternal age, delivery year, and maternal birth cohorts over three decades across seven countries. Methods Women that delivered in the US (n = 863,879; 1979–10), Canada (4 provinces, n = 5,407,463; 1982–11), Sweden (n = 3,266,742; 1978–10), Denmark (n = 1,773,895; 1978–08), Norway (n = 1,780,271, 1978–09), Finland (n = 1,411,867; 1987–10), and Spain (n = 6,151,508; 1999–12) were analyzed. Abruption diagnosis was based on ICD coding. Rates were modeled using Poisson regression within the framework of an age-period-cohort analysis, and multi-level models to examine the contribution of smoking in four countries. Results Abruption rates varied across the seven countries (3–10 per 1000), Maternal age showed a consistent J-shaped pattern with increased rates at the extremes of the age distribution. In comparison to births in 2000, births after 2000 in European countries had lower abruption rates; in the US there was an increase in rate up to 2000 and a plateau thereafter. No birth cohort effects were evident. Changes in smoking prevalence partially explained the period effect in the US (P = 0.01) and Sweden (P<0.01). Conclusions There is a strong maternal age effect on abruption. While the abruption rate has plateaued since 2000 in the US, all other countries show declining rates. These findings suggest considerable variation in abruption frequencies across countries; differences in the distribution of risk factors, especially smoking, may help guide policy to reduce abruption rates.

Long-Term Health Outcomes in Children Born to Mothers with Diabetes: A Population-Based Cohort Study

Background To examine whether prenatal exposure to parental type 1 diabetes, type 2 diabetes, or gestational diabetes is associated with an increased risk of malignant neoplasm or diseases of the circulatory system in the offspring. Methods/Principal Findings We conducted a population-based cohort study of 1,781,576 singletons born in Denmark from 1977 to 2008. Children were followed for up to 30 years from the day of birth until the onset of the outcomes under study, death, emigration, or December 31, 2009, whichever came first. We used Cox proportional hazards model to estimate hazard ratios (HR) with 95% confidence intervals (95% CI) for the outcomes under study while adjusting for potential confounders. An increased risk of malignant neoplasm was found in children prenatally exposed to maternal type 2 diabetes (HR = 2.2, 95%CI: 1.5–3.2). An increased risk of diseases of the circulatory system was found in children exposed to maternal type 1 diabetes (HR = 2.2, 95%CI: 1.6–3.0), type 2 diabetes (HR = 1.4, 95%CI: 1.1–1.7), and gestational diabetes (HR = 1.3, 95%CI: 1.1–1.6), but results were attenuated after excluding children with congenital malformations. An increased risk of diseases of the circulatory system was also found in children exposed to paternal type 2 diabetes (HR = 1.5, 95%CI: 1.1–2.2) and the elevated risk remained after excluding children with congenital malformations. Conclusions This study suggests that susceptibility to malignant neoplasm is modified partly by fetal programming. Diseases of the circulatory system may be modified by genetic factors, other time-stable family factors, or fetal programming.

Association of CRP genetic variants with blood concentrations of C-reactive protein and colorectal cancer risk.

High blood concentrations of C‐reactive protein (CRP) have been associated with elevated risk of colorectal cancer in several prospective studies including the European Prospective Investigation into Cancer and Nutrition (EPIC), but it is unknown whether these observations reflect a causal relationship. We aimed to investigate whether CRP genetic variants associated with lifelong higher CRP concentrations translate into higher colorectal cancer risk. We conducted a prospective nested case–control study within EPIC including 727 cases diagnosed between 1992 and 2003 and 727 matched controls selected according to an incidence‐density sampling protocol. Baseline CRP concentrations were measured in plasma samples by a high sensitivity assay. Tagging single nucleotide polymorphisms (SNPs) in the CRP gene (rs1205, rs1800947, rs1130864, rs2808630, rs3093077) were identified via HapMap. The causal effect of CRP on colorectal cancer risk was examined in a Mendelian Randomization approach utilizing multiple CRP genetic variants as instrumental variables. The SNPs rs1205, rs1800947, rs1130864 and rs3093077 were significantly associated with CRP concentrations and were incorporated in a CRP allele score which was associated with 13% higher CRP concentrations per allele count (95% confidence interval 8–19%). Using the CRP‐score as instrumental variable, genetically twofold higher CRP concentrations were associated with higher risk of colorectal cancer (odds ratio 1.74, 95% confidence interval 1.06–2.85). Similar observations were made using alternative definitions of instrumental variables. Our findings give support to the hypothesis that elevated circulating CRP may play a direct role in the etiology of colorectal cancer.

Bayesian methods for meta-analysis of causal relationships estimated using genetic instrumental variables.

Genetic markers can be used as instrumental variables, in an analogous way to randomization in a clinical trial, to estimate the causal relationship between a phenotype and an outcome variable. Our purpose is to extend the existing methods for such Mendelian randomization studies to the context of multiple genetic markers measured in multiple studies, based on the analysis of individual participant data. First, for a single genetic marker in one study, we show that the usual ratio of coefficients approach can be reformulated as a regression with heterogeneous error in the explanatory variable. This can be implemented using a Bayesian approach, which is next extended to include multiple genetic markers. We then propose a hierarchical model for undertaking a meta-analysis of multiple studies, in which it is not necessary that the same genetic markers are measured in each study. This provides an overall estimate of the causal relationship between the phenotype and the outcome, and an assessment of its heterogeneity across studies. As an example, we estimate the causal relationship of blood concentrations of C-reactive protein on fibrinogen levels using data from 11 studies. These methods provide a flexible framework for efficient estimation of causal relationships derived from multiple studies. Issues discussed include weak instrument bias, analysis of binary outcome data such as disease risk, missing genetic data, and the use of haplotypes.

Spontaneous Abortion, Stillbirth and Hyperthyroidism: A Danish Population-Based Study

Objectives: Pregnancy loss in women suffering from hyperthyroidism has been described in case reports, but the risk of pregnancy loss caused by maternal hyperthyroidism in a population is unknown. We aimed to evaluate the association between maternal hyperthyroidism and pregnancy loss in a population-based cohort study. Study Design: All pregnancies in Denmark from 1997 to 2008 leading to hospital visits (n = 1,062,862) were identified in nationwide registers together with information on maternal hyperthyroidism for up to 2 years after the pregnancy [hospital diagnosis/prescription of antithyroid drug (ATD)]. The Cox proportional hazards model was used to estimate adjusted hazard ratio (aHR) with 95% confidence interval (CI) for spontaneous abortion (gestational age <22 weeks) and stillbirth (≥22 weeks), reference: no maternal thyroid dysfunction. Results: When maternal hyperthyroidism was diagnosed before/during the pregnancy (n = 5,229), spontaneous abortion occurred more often both in women treated before the pregnancy alone [aHR 1.28 (95% CI 1.18-1.40)] and in women treated with ATD in early pregnancy [1.18 (1.07-1.31)]. When maternal hyperthyroidism was diagnosed and treated for the first time in the 2-year period after the pregnancy (n = 2,361), there was a high risk that the pregnancy under study had terminated with a stillbirth [2.12 (1.30-3.47)]. Conclusions: Both early (spontaneous abortion) and late (stillbirth) pregnancy loss were more common in women suffering from hyperthyroidism. Inadequately treated hyperthyroidism in early pregnancy may have been involved in spontaneous abortion, and undetected high maternal thyroid hormone levels present in late pregnancy may have attributed to an increased risk of stillbirth.

Fetal Growth and Preterm Birth in Children Exposed to Maternal or Paternal Rheumatoid Arthritis: A Nationwide Cohort Study

To assess indicators of fetal growth and risk of preterm birth in children of parents with rheumatoid arthritis (RA).