Jacoba J. Bongers-Schokking

Maternal Thyroid Function during Early Pregnancy and Cognitive Functioning in Early Childhood: The Generation R Study

CONTEXT Thyroid hormones are essential for neurodevelopment from early pregnancy onward. Yet population-based data on the association between maternal thyroid function in early pregnancy and childrens cognitive development are sparse. OBJECTIVE Our objective was to study associations of maternal hypothyroxinemia and of early pregnancy maternal TSH and free T(4)(FT(4)) levels across the entire range with cognitive functioning in early childhood. DESIGN AND SETTING We conducted a population-based cohort in The Netherlands. PARTICIPANTS Participants included 3659 children and their mothers. MAIN MEASURES In pregnant women with normal TSH levels at 13 wk gestation (SD = 1.7), mild and severe maternal hypothyroxinemia were defined as FT(4) concentrations below the 10th and 5th percentile, respectively. Childrens expressive vocabulary at 18 months was reported by mothers using the MacArthur Communicative Development Inventory. At 30 months, mothers completed the Language Development Survey and the Parent Report of Childrens Abilities measuring verbal and nonverbal cognitive functioning. RESULTS Maternal TSH was not related to the cognitive outcomes. An increase in maternal FT(4) predicted a lower risk of expressive language delay at 30 months only. However, both mild and severe maternal hypothyroxinemia was associated with a higher risk of expressive language delay across all ages [odds ratio (OR) = 1.44; 95% confidence interval (CI) = 1.09-1.91; P = 0.010 and OR = 1.80; 95% CI = 1.24-2.61; P = 0.002, respectively]. Severe maternal hypothyroxinemia also predicted a higher risk of nonverbal cognitive delay (OR = 2.03; 95% CI = 1.22-3.39; P = 0.007). CONCLUSIONS Maternal hypothyroxinemia is a risk factor for cognitive delay in early childhood.

Hypothyroxinemia and TPO-Antibody Positivity Are Risk Factors for Premature Delivery: The Generation R Study

CONTEXT Premature delivery is an important risk factor for child mortality and psychiatric, metabolic, and cardiovascular disease later in life. In the majority of cases, the cause of prematurity cannot be identified. Currently, it remains controversial whether abnormal maternal thyroid function during pregnancy increases the risk of premature delivery. Therefore, we investigated the relation between maternal serum thyroid parameters and the risk of premature delivery in a large prospective population-based study. DESIGN Serum TSH, free T4 (FT4), T4, and TPO antibodies (TPOAbs) were determined during early pregnancy in 5971 pregnant women from the Generation R study. Data were available on maternal age, parity, smoking, socioeconomic status, ethnicity, maternal anthropometrics, and urinary iodine levels. RESULTS Of all women, 5.0% had a premature delivery (<37 weeks), 4.4% had a spontaneous premature delivery, and 1.4% had a very premature delivery (<34 weeks). High TSH levels and subclinical hypothyroidism were associated with premature delivery but not with spontaneous premature delivery. Maternal hypothyroxinemia was associated with a 2.5-fold increased risk of premature delivery, a 3.4-fold increased risk of spontaneous premature delivery, and a 3.6-fold increased risk of very premature delivery (all P < .01). TPOAb positivity was associated with a 1.7-fold increased risk of premature delivery (P = .01), a 2.1-fold increased risk of spontaneous premature delivery (P = .02), and a 2.5-fold increased risk of very premature delivery (P = .04). These effects remained similar after correction for TSH and FT4 levels. CONCLUSIONS Hypothyroxinemia and TPOAb positivity are associated with an increased risk of premature delivery. The increased risk in TPOAb-positive women seems to be independent of thyroid function.

Association of gestational maternal hypothyroxinemia and increased autism risk

Transient gestational hypothyroxinemia in rodents induces cortical neuronal migration brain lesions resembling those of autism. We investigated the association between maternal hypothyroxinemia (gestational weeks 6–18) and autistic symptoms in children.

Maternal Thyroid Hormone Parameters during Early Pregnancy and Birth Weight: The Generation R Study

CONTEXT Maternal hyperthyroidism during pregnancy is associated with an increased risk of low birth weight, predisposing to neonatal morbidity and mortality. However, the effects of variation in maternal serum thyroid parameters within the normal range on birth weight are largely unknown. OBJECTIVE The aim was to study the effects of early pregnancy maternal serum thyroid parameters within the normal range on birth weight, as well as the relation between umbilical cord thyroid parameters and birth weight. DESIGN, SETTING, AND PARTICIPANTS In early pregnancy, serum TSH, FT4 (free T(4)), and thyroid peroxidase antibody levels were determined in 4464 pregnant women. Cord serum TSH and FT4 levels were determined in 2724 newborns. Small size for gestational age at birth (SGA) was defined as a gestational age-adjusted birth weight below the 2.5th percentile. The associations between normal-range maternal and cord thyroid parameters, birth weight, and SGA were studied using regression analyses. RESULTS In mothers with normal-range FT4 and TSH levels, higher maternal FT4 levels were associated with lower birth weight [β = -15.4 (3.6) g/pmol · liter, mean (SE); P = 1.6 × 10(-5)], as well as with an increased risk of SGA newborns [odds ratio (95% confidence interval) = 1.09 (1.01-1.17); P = 0.03]. Birth weight was positively associated with both cord TSH [β = 4.1 (1.4) g/mU · liter; P = 0.007] and FT4 levels [β = 23.0 (3.2) g/pmol · liter; P = 9.2 × 10(-13)]. CONCLUSIONS We show that maternal high-normal FT4 levels in early pregnancy are associated with lower birth weight and an increased risk of SGA newborns. Additionally, birth weight is positively associated with cord TSH and FT4 levels. These data demonstrate that even mild variation in thyroid function within the normal range can have important fetal consequences.

Maternal Early Pregnancy and Newborn Thyroid Hormone Parameters: The Generation R Study

CONTEXT Abnormal maternal thyroid parameters are associated with adverse pregnancy outcomes, with consequences for both mother and child. Although various studies have studied maternal thyroid parameters during the first half of pregnancy, little is known about their relations with thyroid parameters of the child. OBJECTIVE The objective was to study maternal thyroid parameters during the first half of pregnancy as well as their relations with cord thyroid parameters. DESIGN, SETTING, AND PARTICIPANTS Serum TSH, free T(4) (FT4), T(4), and thyroid peroxidase antibody (TPOAb) levels were determined once between gestational wk 9 and 18 in 5393 pregnant women from the population-based Generation R study. Cord serum TSH and FT4 levels were determined in 3036 newborns. RESULTS Between gestational wk 9 and 18, the maternal TSH reference range (2.5th to 97.5th percentile) was 0.03-4.04 mU/liter. Gestational age was positively correlated with maternal TSH (r = 0.06, P = 6.3 × 10(-5)) and total T(4) (r = 0.21, P = 1.4 × 10(-44)) and negatively with FT4 (r = -0.27, P=7.3 × 10(-76)) and TPOAb-positivity (r=-0.04, P = 0.01). TPOAb positivity was associated with more subclinical (20.1 vs. 2.4%, P = 1.5 × 10(-39)) and overt hypothyroidism (3.3 vs. 0.1%, P = 1.4 × 10(-10)). Maternal and cord TSH were positively associated (β = 0.47 ± 0.15, P = 1.3 × 10(-5)) as well as maternal and cord FT4 (β = 0.11 ± 0.02, P = 4.5 × 10(-6)). CONCLUSIONS We confirm correlations of maternal thyroid parameters with gestational age during the first half of pregnancy and show a substantially increased risk of (subclinical) hypothyroidism in TPOAb-positive mothers. A substantial part of the mothers had a TSH level above 2.5 mU/liter, underlining the importance of using population-specific reference ranges. Maternal and cord thyroid parameters were positively correlated, the exact biological basis of which remains to be determined.

Maternal thyroid function during pregnancy and behavioral problems in the offspring: the generation R study.

Maternal thyroid function during pregnancy is implicated in the neurodevelopment of the offspring, yet little is known about the effect of maternal thyroid parameters on the behavior of children. We investigated the association of maternal thyroid function during the first half of pregnancy with parent-reported problem behavior of the offspring up to age of 3 y. In the Generation R study, a population-based cohort of 3736 children and their mothers, data on maternal thyroid function and childs behavior were examined. The degree of internalizing and externalizing problems in the children were assessed with the Child Behavior Checklist at ages 1½ and 3 y. Higher levels of maternal TSH during pregnancy predicted a higher externalizing scores in children at 1½ and 3 y (B = 0.22 per SD of TSH; 95% CI: 0.04, 0.40; B = 0.10 per SD for internalizing scores; 95% CI: −0.01, 0.21). Maternal free thyroxine (T4) and total T4 were not associated with internalizing or externalizing scores of children. The linear relationship with more externalizing scores was across the range of TSH; this implies that subtle impairments of maternal thyroid function may affect the child. The results suggest that thyroid function is crucial for fetal brain development, which determines problem behavior later in life.

Maternal thyroid autoimmunity during pregnancy and the risk of attention deficit/hyperactivity problems in children: The generation r study

BACKGROUND Maternal thyroid status and autoimmunity during pregnancy have been associated with impaired development of the offspring in animal and human studies. Our objective was to examine whether elevated titers of maternal thyroid peroxidase antibodies (TPOAbs) in early pregnancy increased the risk of cognitive impairment and problem behavior in preschool children. Second, we aimed at exploring to what extent any effect on child behavior was mediated by maternal thyroid parameters during pregnancy. METHODS In the Generation R Study, a population-based cohort of 3139 children and their mothers, we measured maternal thyroid parameters (thyrotropin [TSH], free Thyroxine, and TPOAbs) at 13.5±1.8 weeks of gestation. Childrens verbal and nonverbal cognitive functioning was measured at 2.5 years using the Language Development Survey and the Parent Report of Children Abilities. At 3 years, childrens behavior was assessed using the Child Behavior Checklist. RESULTS Elevated titers of TPOAbs during pregnancy did not predict the verbal and nonverbal cognitive functioning of the children. However, elevated titers of TPOAbs in mothers were associated with externalizing problems in children (odds ratio [OR]=1.64, 95% confidence interval [CI]: 1.17-2.29, p=0.004). In particular, children of TPOAb-positive mothers were at a higher risk of attention deficit/hyperactivity problems (OR=1.77, 95% CI: 1.15-2.72, p=0.01). To explore whether the effect of maternal TPOAbs on child problem behavior was mediated by maternal thyroid parameters, we added maternal TSH to the model. After correcting for TSH, the effect of TPOAbs on externalizing problems was attenuated slightly but remained significant (OR=1.56, 95% CI: 1.14, 2.14, p=0.005). CONCLUSIONS Our findings imply that the elevated titers of TPOAbs during pregnancy impact childrens risk of problem behavior, in particular, attention deficit/hyperactivity. The observed effect is only partially explained by maternal TSH levels. These findings may point to a specific mechanism of Attention Deficit/Hyperactivity Disorder in children. Nevertheless, we can only speculate about public health implication of the study, as there is no specific treatment for TPOAb-positive pregnant women with normal thyroid function. Further investigation is needed to explore whether TPOAb-positive pregnant women and their children can benefit from close monitoring and early detection of developmental delay in populations at risk.

Ethnic Differences in Maternal Thyroid Parameters during Pregnancy: The Generation R Study

CONTEXT Abnormal maternal thyroid function during pregnancy is associated with various complications. International guidelines advocate the use of population-based trimester-specific reference ranges for thyroid function tests. When unavailable, an upper TSH limit of 2.5 for the first trimester and 3.0 mU/L for the second and third trimesters is recommended. Although interindividual differences in thyroid function tests can partially be explained by ethnicity, data on the influence of ethnicity on TSH and free T4 reference ranges during pregnancy are sparse. DESIGN Serum TSH, free T4, T4, and TPO-antibody levels were determined during early pregnancy in 3944 women from the Generation R study, Rotterdam, The Netherlands. RESULTS The study population consisted of 2765 Dutch, 308 Moroccan, 421 Turkish, and 450 Surinamese women. Mean TSH levels were higher in Dutch and Turkish women than in Moroccan or Surinamese women (1.50-1.48 vs 1.29-1.33 mU/L; P < .01). Although no differences in free T4 were seen, T4 was lowest in Dutch women (142 vs 150-156 nmol/L; P < .01). Turkish women had the highest frequency of TPO-antibody positivity (9.3% vs 5.0-5.8%; P < .05) and of elevated TSH levels in the second trimester (11.0% vs 3.8-7.3%; P < .01). A comparison of disease prevalence between a population-based vs an ethnicity-specific reference range changed the diagnosis for 18% of women who were initially found to have abnormal thyroid function test results. CONCLUSIONS We show ethnic differences in serum TSH, T4, and TPO-antibody positivity and found significant diagnostic discrepancies depending on whether population or ethnicity-specific reference ranges were used to diagnose thyroid disease.

Low Urinary Iodine Excretion during Early Pregnancy Is Associated with Alterations in Executive Functioning in Children

The rare but deleterious effects of severe iodine deficiency during pregnancy on cognitive functioning of children are well known. Reports on possible associations between mild-to-moderate maternal iodine deficiency and child development, however, are scarce. In a population-based cohort we examined the association between maternal urinary iodine during early pregnancy and executive functioning in children at 4 y of age. In addition, we investigated the modification of this association by maternal diet and thyroid function. During pregnancy, we measured urinary iodine and thyroid hormone concentrations in 1156 women. In 692 of their children impairment of executive functioning was assessed by the Behavior Rating Inventory of Executive Function. Five hundred mothers of Dutch national origin completed an FFQ. Analyses were performed by using regression models. The children of mothers with low urinary iodine showed higher scores on the problem scales of inhibition [β = 0.05 (95% CI: 0.01, 0.10), P = 0.03] and working memory [β = 0.07 (95% CI: 0.02, 0.12), P = 0.003]. Although maternal dietary intake and thyroid hormone concentration did not significantly modify these associations, the associations between urinary iodine and problems of inhibition were attenuated after adjustment for maternal psychological symptoms. In addition, the consumption of bread [β = 0.61 (95% CI: 0.27, 0.95), P < 0.001] and eggs (β = 1.87 (95% CI: 0.13, 3.62), P = 0.04] was associated with higher urinary iodine. Thus, low maternal urinary iodine during pregnancy is associated with impaired executive functioning in children. Because these symptoms were subclinical and occurred at an early age, future studies are needed to show whether these children are more vulnerable to develop later clinical disorders.

Maternal Early-Pregnancy Thyroid Function Is Associated With Subsequent Hypertensive Disorders of Pregnancy: The Generation R Study

CONTEXT Hypertensive disorders during pregnancy are associated with a wide range of maternal and fetal complications, and only a few risk factors are known for the development of these disorders during pregnancy. Conflicting and limited data are available on the relationship between thyroid (dys)function and the risk of hypertensive disorders of pregnancy. OBJECTIVE The objective of the investigation was to study the associations between early-pregnancy thyroid dysfunction, thyroid function within the normal range, and the risk of hypertensive disorders. DESIGN, SETTING, AND PARTICIPANTS In early pregnancy, serum TSH, free T4 (FT4), and thyroperoxidase antibody (TPOAb) levels were determined in 5153 pregnant women. No interventions were done. The associations of thyroid function with the risk of hypertensive disorders were studied. MAIN OUTCOME MEASURES Mean blood pressures and hypertensive disorders, including pregnancy-induced hypertension (n = 209) and preeclampsia (n = 136), were measured. RESULTS Hyperthyroid mothers had a higher risk of hypertensive disorders [odds ratio (OR) 3.40 [95% confidence interval (CI) 1.46-7.91], P = .005], which was mainly due to an increased risk of pregnancy-induced hypertension [OR 4.18 (95% CI 1.57-11.1), P = .004]. Hypothyroidism and hypothyroxinemia were not associated with hypertensive disorders. Within the normal range, the high-normal FT4 levels were associated with an increased risk of hypertensive disorders [OR 1.62 (95% CI 1.06-2.47), P = .03], which was mainly due to an increased risk of preeclampsia [OR 2.06 (95% CI 1.04-4.08), P = .04]. The TPOAb status was not associated with hypertensive disorders. CONCLUSIONS We show that biochemical hyperthyroidism and also high-normal FT4 levels during early pregnancy are associated with an increased risk of hypertensive disorders. These data demonstrate that these associations are even seen for a mild variation in thyroid function within the normal range.