Tuija Männistö

Perinatal outcome of children born to mothers with thyroid dysfunction or antibodies: a prospective population-based cohort study.

CONTEXT There are only a few large prospective studies involving evaluation of the effect of maternal thyroid dysfunction on offspring and observations are inconsistent. OBJECTIVE The objective of the study was to investigate the effects of thyroid dysfunction or antibody positivity on perinatal outcome. SETTING AND PARTICIPANTS The study included prospective population-based Northern Finland Birth Cohort 1986 including 9247 singleton pregnancies. First-trimester maternal serum samples were analyzed for thyroid hormones [TSH, free T(4) (fT4)] and antibodies [thyroid-peroxidase antibody (TPO-Ab) and thyroglobulin antibody (TG-Ab)]. Mothers were classified by their hormone and antibody status into percentile categories based on laboratory data and compared accordingly. MAIN OUTCOMES Outcomes were perinatal mortality, preterm delivery, absolute and gestational age-adjusted birth weight, and absolute and relative placental weight. RESULTS The offspring of TPO-Ab- and TG-Ab-positive mothers had higher perinatal mortality, which was not affected by thyroid hormone status. Unadjusted and adjusted (for maternal age and parity) risk for increased perinatal mortality was an odds ratio of 3.1 (95% confidence interval 1.4-7.1) and 3.2 (1.4-7.1) in TPO-Ab- and 2.6 (1.1-6.2) and 2.5 (1.1-5.9) in TG-Ab-positive mothers. TPO-Ab-positive mothers had more large-for-gestational age infants (2.4 vs. 0.8%, P = 0.017), as did mothers with low TSH and high fT4 concentrations vs. reference group (6.6 vs. 2.5%, P = 0.045). Significantly higher placental weights were observed among mothers with low TSH and high fT4 or high TSH and low fT4 levels as well as among TPO-Ab-positive mothers. CONCLUSIONS First-trimester antibody positivity is a risk factor for perinatal death but not thyroid hormone status as such. Thyroid dysfunction early in pregnancy seems to affect fetal and placental growth.

Elevated Blood Pressure in Pregnancy and Subsequent Chronic Disease Risk

Background— Preeclampsia, a new-onset hypertensive disorder of pregnancy, is associated with lifetime cardiovascular disease risk, but less is known about risk after other pregnancy-related hypertension. Methods and Results— The Northern Finland Birth Cohort 1966 included all expected births from 1 year (N=12 055 women). Blood pressure measurements and other prospective data were determined from prenatal care records and questionnaires for 10 314 women. Subsequent diagnoses were ascertained from Finnish registries (average follow-up, 39.4 years). Adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) estimate risks in hypertensive women compared with normotensive women. Hypertension during pregnancy was associated with increased risk of subsequent cardiovascular disease and arterial hypertension. Women with chronic hypertension and superimposed preeclampsia/eclampsia had high risk for future diseases. Gestational hypertension was associated with increased risk of ischemic heart disease (HR, 1.44 [95% CI, 1.24–1.68]), myocardial infarcts (HR, 1.75 [95% CI, 1.40–2.19]), myocardial infarct death (HR, 3.00 [95% CI, 1.98–4.55]), heart failure (HR, 1.78 [95% CI, 1.43–2.21]), ischemic stroke (HR, 1.59 [95% CI, 1.24–2.04]), kidney disease (HR, 1.91 [95% CI, 1.18–3.09]), and diabetes mellitus (HR, 1.52 [95% CI, 1.21–1.89]). Isolated systolic hypertension was associated with increased risk of myocardial infarct death (HR, 2.15 [95% CI, 1.35–3.41]), heart failure (HR, 1.43 [95% CI, 1.13–1.82]), and diabetes mellitus (HR, 1.42 [95% CI, 1.13–1.78]), whereas isolated diastolic hypertension was associated with increased risk of ischemic heart disease (HR, 1.26 [95% CI, 1.05–1.50]). Results were similar in nonsmoking women aged <35 years with normal weight and no diabetes mellitus during pregnancy. Conclusions— Elevated blood pressure during pregnancy, regardless of type and even without known risk factors, signals high risk of later cardiovascular disease, chronic kidney disease, and diabetes mellitus. Clinical monitoring, risk factor evaluation, and early intervention could benefit women with hypertension in pregnancy.

Thyroid dysfunction and autoantibodies during pregnancy as predictive factors of pregnancy complications and maternal morbidity in later life

CONTEXT Knowledge is scarce concerning the significance of thyroid dysfunction/antibodies during pregnancy in regard to pregnancy complications/later maternal morbidity. OBJECTIVE The aim of this study was to evaluate the association between maternal thyroid dysfunction/antibodies during pregnancy and pregnancy complications or later maternal hypertension, diabetes, and thyroid disease. DESIGN AND SETTING We studied a prospective population-based cohort, Northern Finland Birth Cohort 1986 (NFBC 1986), with follow-up of 20 yr. Medication and hospital discharge records were used to assess maternal morbidity to hypertension, diabetes, and thyroid diseases. PARTICIPANTS The study consisted of mothers of NFBC 1986 with early pregnancy serum samples for thyroid function and antibody analyses (n = 5805). Mothers were grouped and compared according to these test results. MAIN OUTCOME MEASURES We focused on preeclampsia and gestational diabetes during index pregnancy, later maternal hypertension, diabetes, and thyroid disease morbidity and total mortality. RESULTS Thyroid dysfunction and antibodies were not associated with pregnancy complications. Overt hypothyroidism was associated with subsequent maternal thyroid disease [hazard ratio (HR) (95% confidence interval), 17.7 (7.8-40.6)] and diabetes [6.0 (2.2-16.4)]. Subclinical hypothyroidism [3.3 (1.6-6.9)], TPO-Ab-positivity [4.2 (2.3-7.4)], and TG-Ab-positivity [3.3 (1.9-6.0)] were also associated with later thyroid disease. No association was found between thyroid dysfunction/antibodies and hypertension or overall mortality. CONCLUSIONS Thyroid dysfunction and antibodies during pregnancy seem to predict later thyroid disease. Overt hypothyroidism poses risk of diabetes.

Early Pregnancy Reference Intervals of Thyroid Hormone Concentrations in a Thyroid Antibody-Negative Pregnant Population

BACKGROUND Thyroid dysfunction and antibodies are increasingly recognized as risk factors during pregnancy. Thyroid function changes during pregnancy and there is a need for gestational age-specific reference intervals for thyroid hormones. The aim of this study was to calculate gestational age-specific thyrotropin (TSH), free thyroxine (fT4), and free triiodothyronine (fT3) reference intervals in an iodine-sufficient thyroid antibody-negative population. METHODS The study population consisted of a large, prospective population-based cohort, the Northern Finland Birth Cohort 1986 (singleton births, n = 9362), with extensive data throughout gestation. The subjects underwent serum sampling in early pregnancy. Samples were assayed for TSH, fT4, fT3, thyroid-peroxidase, and thyroglobulin antibodies (n = 5805). All mothers with thyroid antibodies or previous thyroid diseases were excluded when calculating gestational age-specific percentile categories for TSH, fT4, and fT3. Also, associations between body mass index (BMI) and thyroid hormones were established. RESULTS The upper reference limit for TSH was 2.5 multiples of median (2.7-3.5 mU/L, depending on gestational week). The lower reference limit was as low as 0.07 mU/L. Reference intervals for fT4 rose during early pregnancy and decreased thereafter, ranging between 11-22 pmol/L. Reference intervals for fT3 were uniform throughout gestation, ranging between 3.4 and 7.0 pmol/L. BMI was associated positively with early pregnancy TSH and fT3 concentrations and negatively with fT4 concentrations. CONCLUSIONS These gestational age-specific reference intervals for thyroid hormones provide a framework for clinical decision making. Overweight and obesity are increasing problems among fertile women and they are associated with possibility of thyroid dysfunction during pregnancy.

Thyroid Diseases and Adverse Pregnancy Outcomes in a Contemporary US Cohort

CONTEXT Thyroid diseases are inconsistently reported to increase risk for pregnancy complications. OBJECTIVE The objective of this study was to study pregnancy complications associated with common and uncommon thyroid diseases. DESIGN, SETTING, AND PARTICIPANTS We analyzed singleton pregnancies (N = 223 512) from a retrospective US cohort, the Consortium on Safe Labor (2002-2008). Thyroid diseases and outcomes were derived from electronic medical records. Multivariable logistic regression with generalized estimating equations estimated adjusted odds ratios (ORs) with 99% confidence intervals (99% CI). MAIN OUTCOME MEASURES Hypertensive diseases, diabetes, preterm birth, cesarean sections, inductions, and intensive care unit (ICU) admissions were analyzed. RESULTS Primary hypothyroidism was associated with increased odds of preeclampsia (OR = 1.47, 99% CI = 1.20-1.81), superimposed preeclampsia (OR = 2.25, 99% CI = 1.53-3.29), gestational diabetes (OR = 1.57, 99% CI = 1.33-1.86), preterm birth (OR = 1.34, 99% CI = 1.17-1.53), induction (OR = 1.15, 99% CI = 1.04-1.28), cesarean section (prelabor, OR = 1.31, 99% CI = 1.11-1.54; after spontaneous labor OR = 1.38, 99% CI = 1.14-1.66), and ICU admission (OR = 2.08, 99% CI = 1.04-4.15). Iatrogenic hypothyroidism was associated with increased odds of placental abruption (OR = 2.89, 99% CI = 1.14-7.36), breech presentation (OR = 2.09, 99% CI = 1.07-4.07), and cesarean section after spontaneous labor (OR = 2.05, 99% CI = 1.01-4.16). Hyperthyroidism was associated with increased odds of preeclampsia (OR = 1.78, 99% CI = 1.08-2.94), superimposed preeclampsia (OR = 3.64, 99% CI = 1.82-7.29), preterm birth (OR = 1.81, 99% CI = 1.32-2.49), induction (OR = 1.40, 99% CI = 1.06-1.86), and ICU admission (OR = 3.70, 99% CI = 1.16-11.80). CONCLUSIONS Thyroid diseases were associated with obstetrical, labor, and delivery complications. Although we lacked information on treatment during pregnancy, these nationwide data suggest either that there is a need for better thyroid disease management during pregnancy or that there may be an intrinsic aspect of thyroid disease that causes poor pregnancy outcomes.

Obstetric complications among US women with asthma.

OBJECTIVE We sought to characterize complications of pregnancy, labor, and delivery associated with maternal asthma in a contemporary US cohort. STUDY DESIGN We studied a retrospective cohort based on electronic medical record data from 223,512 singleton deliveries from 12 clinical centers across the United States from 2002 through 2008. RESULTS Women with asthma had higher odds of preeclampsia (adjusted odds ratio [aOR], 1.14; 95% confidence interval [CI], 1.06-1.22), superimposed preeclampsia (aOR, 1.34; 95% CI, 1.15-1.56), gestational diabetes (aOR, 1.11; 95% CI, 1.03-1.19), placental abruption (aOR, 1.22; 95% CI, 1.09-1.36), and placenta previa (aOR, 1.30; 95% CI, 1.08-1.56). Asthmatic women had a higher odds of preterm birth overall (aOR, 1.17; 95% CI, 1.12-1.23) and of medically indicated preterm delivery (aOR, 1.14; 95% CI, 1.01-1.29). Asthmatics were less likely to have spontaneous labor (aOR, 0.87; 95% CI, 0.84-0.90) and vaginal delivery (aOR, 0.84; 95% CI, 0.80-0.87). Risks were higher for breech presentation (aOR, 1.13; 95% CI, 1.05-1.22), hemorrhage (aOR, 1.09; 95% CI, 1.03-1.16), pulmonary embolism (aOR, 1.71; 95% CI, 1.05-2.79), and maternal intensive care unit admission (aOR, 1.34; 95% CI, 1.04-1.72). CONCLUSION Maternal asthma increased risk for nearly all outcomes studied in a general obstetric population.

Neonatal Outcomes and Birth Weight in Pregnancies Complicated by Maternal Thyroid Disease

Maternal hypothyroidism has previously been shown to increase risk for neonatal intensive care treatment, but otherwise the association between thyroid diseases and neonatal morbidity is understudied. The Consortium on Safe Labor, a retrospective cohort (2002-2008), included 223,512 singleton deliveries of which 0.2% had hyperthyroidism, 1.4% primary and 0.1% iatrogenic hypothyroidism, and 1.3% other/unspecified thyroid disease. Logistic regression with generalized estimating equations estimated adjusted odds ratios of adverse outcomes. Intensive care treatment was more common for neonates of women with thyroid disease. Hyperthyroidism and primary hypothyroidism were associated with sepsis, respiratory distress syndrome, transient tachypnea, and apnea. Iatrogenic hypothyroidism was associated with sepsis and neonatal anemia. Hyperthyroidism was also associated with rare outcomes (prevalence, <1%) including cardiomyopathy, retinopathy of prematurity, and neonatal thyroid diseases. Hyperthyroid non-Hispanic black women had higher odds of term infants that weighed <2,500 g, and hypothyroid non-Hispanic white women had higher odds of large-for-gestational-age infants. These analyses were stratified by race/ethnicity due to interaction. Associations were similar in analyses restricted to term infants. In conclusion, thyroid diseases were associated with increased neonatal morbidity. Although we lacked data on treatment during pregnancy, these nationwide data suggest a need for better thyroid disease management to reduce neonatal morbidity.

Preconception and early pregnancy air pollution exposures and risk of gestational diabetes mellitus

BACKGROUND Air pollution has been linked to gestational diabetes mellitus (GDM) but no studies have evaluated impact of preconception and early pregnancy air pollution exposures on GDM risk. METHODS Electronic medical records provided data on 219,952 singleton deliveries to mothers with (n=11,334) and without GDM (n=208,618). Average maternal exposures to particulate matter (PM) ≤ 2.5μm (PM2.5) and PM2.5 constituents, PM ≤ 10μm (PM10), nitrogen oxides (NOx), carbon monoxide, sulfur dioxide (SO2) and ozone (O3) were estimated for the 3-month preconception window, first trimester, and gestational weeks 1-24 based on modified Community Multiscale Air Quality models for delivery hospital referral regions. Binary regression models with robust standard errors estimated relative risks (RR) for GDM per interquartile range (IQR) increase in pollutant concentrations adjusted for study site, maternal age and race/ethnicity. RESULTS Preconception maternal exposure to NOX (RR=1.09, 95% CI: 1.04, 1.13) and SO2 (RR=1.05, 1.01, 1.09) were associated with increased risk of subsequent GDM and risk estimates remained elevated for first trimester exposure. Preconception O3 was associated with lower risk of subsequent GDM (RR=0.93, 0.90, 0.96) but risks increased later in pregnancy. CONCLUSION Maternal exposures to NOx and SO2 preconception and during the first few weeks of pregnancy were associated with increased GDM risk. O3 appeared to increase GDM risk in association with mid-pregnancy exposure but not in earlier time windows. These common exposures merit further investigation.

Increased levels of copeptin before clinical diagnosis of preelcampsia.

Copeptin, a surrogate biomarker of vasopressin, has been associated with renal function decline and may serve as a useful early biomarker for preeclampsia. We measured serum copeptin using samples collected longitudinally during pregnancy among unaffected controls (n=136) and cases of preeclampsia (n=169), gestational diabetes mellitus (n=92), gestational hypertension (n=101), and preterm birth (n=86) in the Calcium for Preeclampsia Prevention trial (1992–1995). Preeclampsia and gestational hypertension were defined as having a diastolic blood pressure ≥90 mm Hg on 2 occasions with and without proteinuria, respectively. The risk of pregnancy complications associated with copeptin was estimated by logistic regression adjusting for maternal age, race, body mass index, insurance status, marital status, current smoking, and clinical site. Baseline copeptin levels, at mean 16 weeks of gestation, were associated with increased preeclampsia risk (adjusted odds ratios and 95% confidence interval being 1.55 per log unit; 1.03–2.31) when compared with controls (P=0.03). The association was stronger among cases diagnosed before 37 weeks (1.86; 1.08–3.20) than those diagnosed later (1.45; 0.91–2.32). Copeptin levels rose with increasing gestational age in both cases and controls but remained significantly higher among those who were diagnosed with preeclampsia. Differences in levels of copeptin between cases and controls became more apparent closer to time of diagnosis. No significant associations were found for gestational hypertension without proteinuria, gestational diabetes mellitus, or preterm birth without preeclampsia. Copeptin levels are elevated in pregnant women before diagnosis of preeclampsia with elevation specific to this pregnancy complication rather than hypertension alone.

Controlled Direct Effects of Preeclampsia on Neonatal Health After Accounting for Mediation by Preterm Birth

Background: Preeclampsia is characterized by alterations in angiogenic factors that may increase neonatal morbidity independent of preterm birth. Methods: We estimated the controlled direct effect of preeclampsia on neonatal outcomes independent of preterm birth among 200,103 normotensive and 10,507 preeclamptic singleton pregnancies in the Consortium on Safe Labor (2002–2008). Marginal structural models with stabilized inverse probability weights accounted for potential confounders in the pathway from preeclampsia to preterm birth to neonatal outcomes, including mediator-outcome confounders related to preeclampsia status, such as cesarean delivery. Controlled direct effects of preeclampsia on perinatal mortality, small for gestational age (SGA), neonatal intensive care unit (NICU) admission, respiratory distress syndrome, transient tachypnea of the newborn, anemia, apnea, asphyxia, peri- or intraventricular hemorrhage, and cardiomyopathy were estimated for the hypothesized intervention of term delivery for all infants. Results: When delivery was set at ≥37 weeks, preeclampsia increased the odds of perinatal mortality (odds ratio = 2.2 [95% confidence interval = 1.1–4.5], SGA = (1.9 [1.8–2.1]), NICU admission (1.9 [1.7–2.1]), respiratory distress syndrome (2.8 [2.0–3.7], transient tachypnea of the newborn (1.6 [1.3–1.9]), apnea (2.2 [1.6–3.1]), asphyxia (2.7 [1.5–4.9]), and peri- or intraventricular hemorrhage (3.2 [1.4–7.7]). No direct effect of preeclampsia at term was observed for anemia or cardiomyopathy. Our results appear robust in the presence of moderate confounding, and restriction to severe preeclampsia yielded similar findings. Conclusion: Preeclampsia was directly associated with adverse neonatal outcomes beyond morbidity mediated by preterm birth. Although severe neonatal outcomes were less common at later gestational ages, marginal structural models suggested elevated neonatal risk due to preeclampsia even if it was possible to deliver all infants at term.