Maternal verbal aggression in early infancy and child's internalizing symptoms: interaction by common oxytocin polymorphisms.

Genetic predisposition of social sensitivity might affect vulnerability to develop psychopathology after early life stress exposure. This study examined whether maternal verbally aggressive behavior in early infancy interacts with oxytocin polymorphisms in developing internalizing symptoms at ages 5-6 and 11-12. In the Amsterdam-Born-Children-and-their-Development (ABCD) study, a large observational, population-based birth cohort, maternal verbally aggressive behavior was assessed in the 13th postnatal week by a self-report questionnaire. Internalizing symptoms at age 5-6 were assessed by maternal report (N = 969) and internalizing symptoms at age 11-12 were assessed by self-report (N = 750). Data on oxytocin receptor polymorphisms rs53576 and rs2268498 and oxytocin polymorphisms rs2740210 and rs4813627 were collected. If the child was carrier of rs2740210 CA/AA polymorphism, exposure to maternal verbally aggressive behavior (10.6%) was positively associated with general anxiety at age 5-6 and emotional symptoms at age 11-12 (p for interaction = 0.011 and p = 0.015, respectively). If the child was carrier of rs4813627 GG (wild type), exposure to maternal verbally aggressive behavior was negatively associated with anxiety sensitivity and emotional symptoms at age 11-12 (p for interaction = 0.011 and p = 0.022, respectively). After exposure to maternal verbally aggressive behavior in early infancy, oxytocin polymorphisms may partly determine a child's vulnerability to internalizing symptoms.

Excessive infant crying doubles the risk of mood and behavioral problems at age 5: evidence for mediation by maternal characteristics.

The onset of behavioral problems starts in early life. This study examined whether excessive infant crying (maternal ratings) is a determinant of emotional and behavioral problems at age 5-6 years. In the Amsterdam Born Children and their Development (ABCD) study, a large prospective, observational, population-based multiethnic birth cohort, excessive infant crying (crying for three or more hours per 24 h day over the past week) during the 13th week after birth (range 11-25 weeks, SD 2 weeks), maternal burden of infant care and maternal aggressive behavior (either angry speaking, or physical aggression) was assessed using a questionnaire. Children's behavioral and emotional problems at the age of 5-6 were assessed by Goodman's Strengths and Difficulties Questionnaire (SDQ), by the subscale of generalized anxiety of the preschool anxiety scale (PAS), and by the Short Mood and Feelings Questionnaire (SMFQ). Inclusion criterion was singleton birth. Exclusion criteria were preterm born babies or congenital disorders. Among 3389 children, excessive infant crying (n = 102) was associated with a twofold increased risk of the overall problem behavior, conduct problems, hyperactivity, and mood problems at the age of 5-6 [ORs between 1.75 (95 % CI 1.09-2.81) and 2.12 (95 % CI 1.30-3.46)]. This association was mediated by maternal burden of infant care (change in odds' ratio 1-17 %) and maternal aggressive behavior (change in odds' ratio 4-10 %). There was no effect modification by the child's gender or maternal parity. Excessive infant crying was not associated with general anxiety problems. Excessive infant crying doubles the risk of behavioral, hyperactivity, and mood problems at the age of 5-6, as reported by their mother. Maternal burden of infant care partially mediates the association between excessive crying and behavioral and mood problems. Special care for mothers with a high burden of care for their excessive crying infant, notwithstanding their own good health, can be a feasible strategy for possible prevention of mood and behavioral problems in their children later in life.

Common oxytocin polymorphisms interact with maternal verbal aggression in early infancy impacting blood pressure at age 5-6: The ABCD study.

Early life stress has been shown to contribute to alterations in biobehavioral regulation. Genetic make-up, especially related to social sensitivity, might affect the child's vulnerability to these alterations. This study examined whether maternal verbally aggressive behavior in early infancy interacts with oxytocin polymorphisms in changing resting cardiovascular outcomes at age 5-6. In the Amsterdam-Born-Children-and-their-Development-(ABCD)-study, a large prospective, observational, population-based birth cohort, maternal verbally aggressive behavior was assessed in the 13th postnatal week (range 11-25 weeks, SD 2 weeks) by a questionnaire (maternal self-report). Indicators of resting cardiac autonomic nervous system activity (sympathetic drive by pre-ejection period, parasympathetic drive by respiratory sinus arrhythmia), heart rate, and blood pressure were measured at age 5-6 years. Data on oxytocin receptor gene polymorphisms rs53576, rs2268498 and oxytocin polymorphisms rs2740210, rs4813627, were collected (N = 966 included). If the child was carrier of the rs53576 GG variant, exposure to maternal verbally aggressive behavior (10.6%) was associated with increased systolic blood pressure at age 5-6 (B = 4.9 mmHg,95% CI[2.2;7.7]). If the child was carrier of the rs2268498 TT/TC variant, exposure to maternal verbally aggressive behavior was associated with increased systolic blood pressure at age 5-6 (B = 3.0 mmHg,95%CI[1.0:5.0]). No significant interactions of maternal verbally aggressive behavior with oxytocin gene polymorphisms on heart rate or cardiac autonomic nervous system activity were found. In conclusion, oxytocin receptor gene polymorphisms may partly determine a child's vulnerability to develop increased systolic blood pressure after being exposed to maternal verbally aggressive behavior in early infancy.

Effect of excessive infant crying on resting BP, HRV and cardiac autonomic control in childhood.

OBJECTIVE: Early life stress has been shown to influence the developing autonomic nervous system. Stressors in infancy may program the autonomic nervous system resting state set point, affecting cardiovascular function in later life. Excessive crying may be an indicator of increased stress arousal in infancy. We hypothesized that excessive infant crying is related to altered cardiac autonomic nervous system activity and increased blood pressure at age 5-6 years. METHODS: In the Amsterdam Born Children and their Development study, excessive crying, maternal burden of infant care and maternal aggressive behavior in the 13th week after birth (range 11-16 weeks) were reported using questionnaires. Blood pressure, heart rate, heart rate variability and indicators of cardiac autonomic nervous system activity (sympathetic drive by pre-ejection period, parasympathetic drive by respiratory sinus arrhythmia) were measured at age 5-6 years during rest. Inclusion criteria were singleton birth, term-born, and no reported congenital or cardiovascular problems (N = 2153 included). RESULTS: Excessive crying (2.8%) was not associated with resting heart rate, heart rate variability, pre-ejection period, respiratory sinus arrhythmia nor with blood pressure at age 5-6 years. CONCLUSIONS: Excessive infant crying as an indicator of increased stress arousal does not seem to be related to resting activity of the autonomic nervous system or blood pressure at age 5-6. Potential associations may become visible under stressed conditions.

A reduced IL2R (CD25) expression level in first and second degree female relatives of autoimmune thyroid disease patients. A sign of a poor capability to preserve tolerance?

There is room for immune markers other than TPO-Abs to identify an increased risk to develop autoimmune thyroid disease (AITD). Our aim was to test the hypothesis that activation of CD4+ T cells is such marker in relatives of AITD patients, who have an increased risk to develop AITD. We established a controlled study on 20 TPO-Ab positive and 20 TPO-Ab negative euthyroid female relatives. All these cases had at least one 1st or 2nd degree relative with a documented autoimmune hyper- or hypothyroidism in whom we studied the percentages of circulating subsets of activated (MHC class-II, CD25 (IL-2R), CD71 or CD69+) CD4+ T cells and the level of the soluble (s)-IL2R in serum. We found that euthyroid female relatives did not show an activation of their T cell system, but a reduced expression of CD25 on CD4+ T cells. The level of the shed IL2R in serum was also lower in comparison with levels found in healthy control females. A reduced T cell activity was found in both TPO-Ab positive and negative relatives. In conclusion, female relatives with at least one 1st or 2nd degree relative with an AITD show signs of a reduced expansion capability of their T cell pool. It is hypothesized that this reduced expansion capability may affect T cell tolerance mechanisms more than T effector mechanisms.

Natural history of the transition from euthyroidism to overt autoimmune hypo- or hyperthyroidism: a prospective study.

OBJECTIVE: To evaluate the progression in time from euthyroidism to overt autoimmune hypothyroidism or to overt autoimmune hyperthyroidism. SUBJECTS AND METHODS: The design is that of a nested case-control study within the prospective Amsterdam autoimmune thyroid disease (AITD) cohort study in which 790 healthy euthyroid women with at least one first or second degree relative with documented AITD were followed for 5 years. Thyroid function tests were assessed annually. Contrast between cases (overt hypothyroidism - TSH>5.7 mU/l and free thyroxine (FT(4))<9.3 pmol/l and overt hyperthyroidism - TSH<0.4 mU/l and FT(4)>20.1 pmol/l, also referred to as events) and controls (matched for age and duration of follow-up). RESULTS: At baseline, the 38 hypothyroid cases had already higher TSH and lower FT(4) concentrations than their 76 controls, and the difference between both the groups persisted 1 year before occurrence of the event. In contrast, neither TSH nor FT(4) values differed between the 13 hyperthyroid cases and their 26 controls at baseline or 1 year before the event. The prevalence of thyroid peroxidase-Ab was higher in both hypothyroid and hyperthyroid cases than in controls. At the time of event, hypothyroid cases were less common among current smokers (P=0.083) and more common in the postpartum period (P=0.006) than their controls, whereas hyperthyroid cases were pregnant more frequently (P=0.063). CONCLUSIONS: The data suggest that progression toward overt autoimmune hypothyroidism is a gradual process taking several years, but in contrast overt autoimmune hyperthyroidism develops faster in terms of months.

Prediction of progression to overt hypothyroidism or hyperthyroidism in female relatives of patients with autoimmune thyroid disease using the Thyroid Events Amsterdam (THEA) score.

BACKGROUND: Genetic and environmental factors are involved in the pathogenesis of autoimmune thyroid disease (AITD). Family members of patients with AITD are at increased risk for AITD, but not all will develop overt hypothyroidism or hyperthyroidism. Our goal was to develop a simple predictive score that has broad applicability and is easily calculated at presentation for progression to overt hypothyroidism or hyperthyroidism within 5 years in female relatives of patients with AITD. METHODS: We conducted a prospective observational cohort study of 790 healthy first- or second-degree female relatives of patients with documented Graves or Hashimoto disease in The Netherlands. Baseline assessment included measurement of serum thyrotropin (TSH), free thyroxine (FT(4)), and thyroid peroxidase (TPO) antibody levels as well as evaluation for the presence and levels of Yersinia enterocolitica antibodies. We also gathered data on family background, smoking habits, use of estrogen medication, pregnancy, and exposure to high levels of iodine. In follow-up, thyroid function was investigated annually for 5 years. As main outcome measures, termed events, we looked for overt hypothyroidism (TSH levels >5.7 mIU/L and FT(4) levels <0.72 ng/dL) or overt hyperthyroidism (TSH levels <0.4 mIU/L and FT(4) levels >1.56 ng/dL). RESULTS: The cumulative event rate was 7.5% over 5 years. The mean annual event rate was 1.5%. There were 38 hypothyroid and 13 hyperthyroid events. Independent risk factors for events were baseline findings for TSH and TPO antibodies in a level-dependent relationship (for TSH the risk already starts to increase at values >2.0 mIU/L) and family background (with the greatest risk attached to subjects having 2 relatives with Hashimoto disease). A numerical score, the Thyroid Events Amsterdam (THEA) score, was designed to predict events by weighting these 3 risk factors proportionately to their relative risks (maximum score, 21): low (0-7), medium (8-10), high (11-15), and very high (16-21). These THEA scores were associated with observed event rates of 2.7%, 14.6%, 27.1%, and 76.9%, respectively. CONCLUSIONS: An accurate simple predictive score was developed to estimate the 5-year risk of overt hypothyroidism or hyperthyroidism in female relatives of patients with AITD. However, in view of the small number of observed events, independent validation of the THEA score is called for.

Stress is not associated with thyroid peroxidase autoantibodies in euthyroid women.

OBJECTIVE: Multiple genes and environmental factors play a role in the etiology of autoimmune thyroid disease (AITD). In Graves' hyperthyroidism, stress is such an environmental factor, but whether it plays a role in Hashimoto's hypothyroidism is unknown. We used validated questionnaires to evaluate an association between TPO antibodies, an early marker for AITD, and self-reported stress. SUBJECTS AND METHODS: Recently Experienced Stressful Life Events, Daily Hassles, and mood (tendency to report positive and negative affects) were assessed in 759 euthyroid subjects. RESULTS: TPO antibodies were found in 183/759 (24%) of subjects. The TPO-Ab positive subjects were older (39.7+/-12 vs. 34.2+/-12 years; p<.001) than the TPO-Ab negative subjects, but the number of daily hassles (24+/-14 vs. 25+/-14; p=.24), the number of stressful life events (10+/-6 vs. 11+/-6; p=.09), and the scores on the affect scales (22.1+/-7.4 vs. 22.2+/-7.3; p=.89 for negative affect and 38.2+/-5.1 vs. 38.3+/-5.3; p=.91 for positive affect) were similar in TPO-Ab positive and TPO- Ab negative subjects. CONCLUSIONS: We found no association between recently experienced stressful life events, daily hassles or mood and the presence of TPO antibodies in these euthyroid women.

Risk factors for and prevalence of thyroid disorders in a cross-sectional study among healthy female relatives of patients with autoimmune thyroid disease.

OBJECTIVE: Autoimmune thyroid disease (AITD) is a common disorder especially in women, and both genetic and environmental factors are involved in its pathogenesis. We wanted to gain more insight into the contribution of various environmental factors. Therefore, we started a large prospective cohort study in subjects at risk of developing AITD, for example healthy female relatives of AITD patients. Here we report on their baseline characteristics. SUBJECTS: Only first- or second-degree female relatives of patients with documented AITD were included. MEASUREMENTS: Smoking habits, oestrogen use, pregnancy history and iodine exposure were assessed by questionnaires, and correlated to the thyroid function and antibody status. RESULTS: Of 803 subjects, 440 came from families with more than one patient with documented AITD. Of these families, 33% had documented cases of both Graves' disease and Hashimoto's thyroiditis. Although the subjects were in self-proclaimed good health, 3.6% were found to have hypothyroidism (overt disease in 1.3%) and 1.9% had hyperthyroidism (overt disease in 0.4%). These patients were older than the euthyroid subjects and were mostly positive for thyroid peroxidase (TPO) antibodies. Oestrogen use was associated with a lower rate of hyperthyroidism [relative risk (RR) 0.169; 95% confidence interval (CI) 0.06-0.52], whereas having been pregnant was associated with a higher relative risk for hyperthyroidism (RR 6.88; 95% CI 1.50-30.96). Of the 759 euthyroid subjects, 24% had TPO antibodies. Smoking and oestrogen use were negatively correlated with the presence of TPO antibodies. In the euthyroid subjects, TPO antibody titre correlated positively with TSH levels (r = 0.386; P < 0.001). CONCLUSIONS: The high prevalence of evidence for autoimmune thyroiditis at baseline supports the importance of genetic factors in its pathogenesis. The co-occurrence of Hashimoto's thyroiditis and Graves' disease within one family suggests a common genetic basis for these diseases. Oestrogen use is associated with a lower risk, and pregnancy with a higher risk for developing hyperthyroidism. The positive correlation between TPO antibody titres and TSH levels in euthyroid subjects suggests that TPO antibodies are indeed a marker of future thyroid failure.