| Abstract |
Introduction: Early-life environmental events have long-term impact on human health and development. Thyroid hormones are well-established epigenetic factors that regulate the genetic expression of multiple genes and drive fetal growth and development. The fetal thyroid gland becomes metabolically active after the 10th gestational week and the fetal hypothalamus-pituitary-thyroid axis matures after the 18th gestational week, consequently the fetus is exclusively dependent on maternal thyroid hormones’ supply until mid-gestation and remains partially dependent until birth. In most pregnant women multiple physiological changes occur and facilitate the increased demand of thyroid hormones’ production, however, thyroid dysfunction is a common hormonal abnormality among women of the reproductive age and consequently it consists of a usual clinical problem in pregnancy that affects the availability of thyroid hormones for the fetus. There is robust evidence that maternal clinical thyroid dysfunction during pregnancy has detrimental effects on offspring development and in recent decades observational studies have suggested that even mild thyroid dysfunction may lead to suboptimal offspring developmental outcomes. In this thesis, we aim to explore the link between maternal thyroid functioning in early pregnancy and offspring development and provide evidence that will contribute to informed public health policies regarding the unresolved relevant dispute on the necessity of universal maternal thyroid screening and the appropriate management of mild maternal thyroid dysfunction in pregnancy.
The specific objectives of this thesis are:
To identify patterns of early-life sociodemographic and environmental factors and explore their association with child cognitive, motor, and behavioral development in preschool age.
To explore the association of the concentration levels of maternal thyroid hormones, maternal mild thyroid dysfunction (subclinical hypothyroidism, hypothyroxinemia), and maternal thyroid autoimmunity with offspring cognitive and motor development from infancy to early childhood.
To explore the association of the concentration levels of maternal thyroid hormones, maternal mild thyroid dysfunction (subclinical hypothyroidism, hypothyroxinemia), and maternal thyroid autoimmunity with offspring behavioral and emotional development in preschool age and childhood.
To explore the association of the concentration levels of maternal thyroid hormones, maternal mild thyroid dysfunction (subclinical hypothyroidism, hypothyroxinemia), and maternal thyroid autoimmunity with offspring obesity and cardiometabolic health in preschool age and childhood. Methods: This thesis uses data from the “Rhea” birth cohort, which is a prospective mother-child cohort that was established in 2007 in Crete, Greece. Pregnant women were recruited in the study at the time of the first ultrasound examination, around the 12th gestational week, from two public and two private prenatal clinics in Heraklion, during a twelve-month period, from 02/2007 until 02/2008. Trained midwives described in detail the study to pregnant women, obtained written informed consent, measured height, weight, and blood pressure, collected urine and blood samples, and completed a thorough questionnaire concerning participants’ diet, sociodemographic and lifestyle characteristics, and exposure to various environmental agents. Mother-child pairs were invited to participate in child follow-up assessments when the children were 18 months, 4 years, and 6 years of age.
Maternal blood samples were collected at the first prenatal visit (mean gestational age 14.1 weeks, SD 3.6 weeks). Serum samples were collected in 10 ml vacutainer tubes, were centrifuged and stored in aliquots at -80° C until assayed. Maternal thyroid functioning was assessed by quantitative analysis of serum thyroid stimulating hormone (TSH), free thyroxine (fT4), antibodies to thyroid peroxidase (TPO-Abs), and antibodies to thyroglobulin (Tg-Abs), by Immulite 2000 immunoassay system (Siemens Healthcare Diagnostics, Los Angeles, CA). For TSH, the inter- and intra-assay variability were < 5.3 and < 6.4 respectively, for levels of 0.32 - 39 mIU/mL. For fT4, the inter- and intra-assay variability were < 7.8% and < 7.1% respectively, for levels of 0.51 - 4.82 ng/dL or 6.56 - 62.03 pmol/L. For antibodies to thyroglobulin (Tg-Abs), the inter- and intra-assay variability were < 4.9% and < 5.8% and for antibodies to thyroid peroxidase (TPO-Abs) < 7.4% and 7.2%, respectively. Population-based, and trimester-specific reference intervals, were used in the analyses, according to the relevant guidelines for thyroid dysfunction screening and management in pregnancy. The normal reference ranges for the 1st trimester were for TSH: 0.05 - 2.53 μIU/mL and for fT4: 0.95 - 1.53 ng/dL, and for the 2nd trimester for TSH: 0.18 - 2.73 μIU/mL and for fT4: 0.87 - 1.45 ng/dL. Categorical entities of mild thyroid dysfunction were also used in the analyses of present thesis. Subclinical hypothyroidism was defined as TSH above the upper limit of the trimester-specific reference interval but below 10 mIU/mL and fT4 within the normal range and hypothyroxinemia was defined as TSH within the normal trimester-specific reference range and fT4 below the 5th percentile. Maternal thyroid antibodies were considered elevated if TPO-Abs were equal or greater than 35 IU/mL, and if Tg-Abs were greater than 40 IU/mL, according to the limits proposed by the manufacturer.
The assessment of offspring’s cognitive and motor development was conducted at 18 months using the 3rd edition of Bayley Scales of Infant and Toddler Development (Bayley-III), which assess infant and toddler development across five domains: cognitive, receptive communication, expressive communication, gross motor ability, and fine motor ability. Cognitive and motor development assessment at 4 years was conducted using the McCarthy Scales of Children’s Abilities (MSCA), which evaluate children’s development across five domains: verbal, perceptual, quantitative, memory, and motor and offers a composite index of general cognitive development. Cognitive and motor development assessment at 6 years of age was conducted using the Raven’s Colored Progressive Matrices (RCPM), which assess non-verbal general intelligence, the Finger Tapping Test (FTT), which assess motor speed, and the Trail Making Test part A & part B (TMT-Part A & TMT-Part B), which assess visual search, speed of processing, mental flexibility, and executive functions. Behavioral and emotional development were assessed through the parent-report questionnaires. At 4 years of age the Attention Deficit Hyperactivity Disorder Test (ADHDT) and the Strengths and Difficulties Questionnaire (SDQ) were completed by participants’ parents. The ADHDT is based on ADHD criteria of DSM-IV and provides 4 indexes, corresponding to 3 subscales (hyperactivity, inattention, impulsivity) and a total ADHD difficulties index. The SDQ is a brief screening questionnaire designed to assess behavioral strengths and difficulties in children and evaluates emotional symptoms, conduct problems, hyperactivity and inattention, peer-relationship problems, and prosocial behaviour. SDQ provides two additional composite indexes of internalizing and externalizing problems. Behavioral and emotional problems at 6 years of age were assessed through Child Behaviour Checklist – Parent Report Form (CBCL) and the Conner’s Parent Rating Scale, Revised, Short Form (CPRS-R: S). The CBCL includes 6 scales that correspond to different diagnostic categories of the DSM-IV: affective problems, anxiety problems, somatic problems, attention deficit/hyperactivity problems, oppositional defiant problems, and conduct problems, and two composite indexes of internalizing and externalizing problems. The CPRS-R: S assess oppositional problems, cognitive problems/inattention, and hyperactivity, and provides an index of total ADHD symptoms. Information on birthweight and birth-length/height was obtained from medical records. Anthropometry at the follow up examinations at 4 and 6 years of age was conducted by trained research assistants according to standard protocols. The anthropometric measures included weight, height, waist circumference, skinfold thickness, and bioelectric impedance analysis. Systolic and diastolic blood pressure were also measured. At the end of the clinical assessment blood samples were collected to assess the children’s lipid profile.
Descriptive analyses on the characteristics of the population, and the distribution of the exposures, and the outcomes were conducted. Generalized additive models were used to assess the linearity of the associations of interest. Principal component analysis was used to identify patterns of early-life sociodemographic and environmental factors. Group-based trajectory modelling was used to construct trajectories of longitudinal non-verbal cognitive development from infancy to early childhood. Multiple linear and logistic regression models were used to explore the associations of interest, accordingly.
Results: The results of the current thesis support that:
1. Higher parental social status, preschool attendance and less TV watching, nonsmoking during pregnancy and breastfeeding, and parental involvement in child life are protective factors of child cognitive and behavioral development at 4 years of age. Increased child birth order is associated with decreased verbal ability at 4 years of age. Increased child birth order is associated with decreased ADHD-related symptoms at 4 years of age. Offspring's size at birth is not associated with any measure of child cognitive and behavioral development at 4 years of age.
2. Maternal hypothyroxinemia during gestation is related with decreased offspring verbal and motor ability scores in preschool age and childhood. Exposure to maternal thyroid autoimmunity is associated with decreased child perceptual performance and motor ability scores. Maternal thyroid autoimmunity in pregnancy increases the risk for adverse child non-verbal cognitive development from infancy to childhood.
3. Maternal subclinical hypothyroidism in early pregnancy is associated with behavioral and emotional difficulties in early childhood. Maternal thyroid autoimmunity further reinforces the association of subclinical hypothyroidism with child behavioral and emotional difficulties in early childhood. Elevated maternal thyroid antibodies in euthyroid pregnant women are associated with adverse behavioral outcomes. No association between maternal hypothyroxinemia and child behavioral development is observed. No sex-related differences are identified in the association of mild maternal thyroid dysfunction with child behavioral and emotional development.
4. Maternal subclinical hypothyroidism is associated with increased offspring BMI and total fat mass at 4 years of age. Maternal hypothyroxinemia is associated with increased waist circumference at 4 years of age. Maternal thyroid mild dysfunction is not associated with any other offspring measure of cardiometabolic health at 4 and 6 years of age (lipid profile, blood pressure).
Conclusions: In conclusion, the present thesis showed that patterns of early-life sociodemographic and environmental factors are strongly associated with child neuropsychological development, proposing an innovative method to select target groups and aims of preventive programmes and extended previous knowledge regarding the role of mild maternal thyroid dysfunction on offspring development, providing evidence for public health policies regarding thyroid management in pregnancy. More specifically, the results support that maternal hypothyroxinemia is linked with offspring suboptimal cognitive and motordevelopment, maternal subclinical hypothyroidism is associated with increased offspring behavioral and emotional problems, and thyroid autoimmunity is associated with adverse offspring cognitive, motor and behavioral outcomes. In addition, the repeated assessment of child cognitive development from infancy to childhood has been used to construct trajectories of non-verbal cognitive development; the consequent analyses support that maternal thyroid autoimmunity in euthyroid women increases the risk for adverse non-verbal cognitive development longitudinally, from infancy to early childhood. In addition, maternal thyroid autoimmunity is found to reinforce the observed relationships between maternal subclinical hypothyroidism and offspring behavioral and emotional problems, indicating that maternal thyroid autoimmunity may pose an additional risk for subclinically hypothyroid pregnant women. Future studies with multiple measurements of maternal thyroid hormones during pregnancy are essential to clarify whether elevated thyroid antibodies impact independently on offspring development or through their effect on thyroid hormones’ concentration levels. Our results also indicate that maternal thyroid hormones may be implicated in offspring physical development and body composition, however further studies are needed to replicate the specific results, since the relevant associations are evident in 4 years but are not observed in 6 years of age.
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