Thyroid disorder is common in women of reproductive age, and it is the most common endocrine disorders after diabetes in this age. Prevalence of thyroid disorders in pregnancy and its maternal and fetal complications in pregnant women vary greatly in different regions depending upon many factors. To date, there are few studies of thyroid function and pregnancy in Central India. The geographic location may be a factor in prevalence of thyroid disorder, because the amount of iodine in common salt and consumption of salt may vary from region to region. This study addresses issues related to abnormal thyroid function and feto-maternal outcomes in this setting.
Prevalence of thyroid disorder
The laboratory technique Enhanced Chemiluminiscence used in the study is “Vitros ECi” an orthoclinical diagnostics which is FDA approved. First trimester values are more important than 2nd and 3rd trimester. Because it has an immense role in preventing maternal complications later on, if SCH is diagnosed early, treatment with low doses of levo-thyroxin will prevent it. Debate on upper limit for defining 1st trimester reference value is addressed in the Guideline [7]. The Task Force advises; definition for reference range be as per results for that particular population and laboratory technique of that Institute. If internal or transferable pregnancy-specific TSH reference ranges are not available, an upper reference limit of ∼4.0 mU/L may be used. For most assays, this limit addresses a reduction in non-pregnant TSH upper reference limit of ∼0.5 mU/L.
As this study was conducted in 3rd trimester pregnant women, we do not report any outcomes for 1st or late 1st trimester.
As per older guideline, considering TSH cut off values for each trimester as, 1st trimester: 0.1–2.5mIU/L, 2nd trimester: 0.2–3.0mIU/L, 3rd trimester: 0.3 -3mIU/L is questionable [2]. Only modest reductions in upper limit of TSH in 1st trimester from a non-pregnant value was documented by studies published from India and Korea after 2011. Limited availability of trimester specific reference ranges is an important factor in dis-similarity in values in different geographical and demographic sites. The concept of 1st trimester value of 2.5 mU/L as cut off for SCH and hypothyroidism is contextual in studies from India and China published in 2011 [8] and 2014 [9]. In view of scarcity of recent reports from India we follow standard ATA 2017 guideline.
The observed prevalence of thyroid disorder in 3rd trimester of pregnancy in the present study is 11%, which is comparable to the prevalence observed in a study conducted by Weiwei Wang et al. (10.2%) [8] and Ajmani et al. (13.25%) [9]. Variations in different areas may be due to non-uniformity in the study setting or in laboratory techniques, personal human error, and differences in sample size. In India, the prevalence of hypothyroidism in pregnancy is much higher compared to that in Western countries. Iodine deficiency could be a contributing cause. The percentage of households consuming iodised salt in India, as per the Iodine Network Global score card 2010, is 51% [10]. Hashimoto’s thyroiditis is a cause of hypothyroidism in iodine-sufficient areas, such as North America and Western Europe.
In the present study, the prevalence of subclinical hypothyroidism, overt hypothyroidism, and subclinical hyperthyroidism in pregnancy is 5.6, 3.5, and 1.5%, respectively (Table 1). This is in agreement with the findings of some Indian studies in which the prevalence of subclinical hypothyroidism and overt hypothyroidism is 6.1 and 0.7% respectively [11]. Another Indian study in 2016 reports prevalence of SCH 8% in 3rd trimester [12]. In a recent review and meta-analysis, prevalence rates reported were 0.50, 3.47, and 2.05% for overt hypothyroidism, subclinical hypothyroidism and isolated hypothyroxinaemia respectively [6].
We report mean serum TSH levels in women with subclinical hypothyroidism, overt hypothyroidism, and subclinical hyperthyroidism being 8.02 ± 1.25mIU/ml, 11.92 ± 5.34mIU/ml, and 0.07 ± 0.03mIU/ml respectively. Mean serum fT3 levels among women with subclinical hypothyroidism, overt hypothyroidism, and subclinical hyperthyroidism were 2.92 ± 0.454 pg/ml.,1.58 ± 1.43 pg/ml and 4.1 ± 0.40 pg/ml respectively. Mean serum fT4 levels among subclinical hypothyroid, overt hypothyroidism, and subclinical hyperthyroid women were 1.09 ± 0.30 ng/dl, 0.36 ± 0.24 ng/dl and 1.2 ± 0.10 ng/dl, respectively while a report from India in 2016 quotes reference values for TSH, fT3 and fT4 as 0.47–5.78 (uIU/ml), 0.24–3.61(ng/100 ml) and 0.47–5.1 (ng/100 ml) in 3rd trimester [12].
A recent review suggests that stricter criteria of TSH values with a 2.5 cut-off may be considered too low. Many women would be unnecessarily diagnosed as having SCH and may be subjected to the therapeutic burden of LT4 treatment [13].
Risk factors
Thyroid dysfunction results in anovulatory cycles, luteal phase defect, high prolactin (PRL) levels, and sex hormone imbalances. All of these factors may result in infertility and irregular menstrual cycles, as documented by various authors [14]. In the present study, among women with hypothyroidism, 4.5% had a history of infertility treatment, compared to 3.8, and 4.0% women with hypothyroidism observed in other studies [15, 16]. We observed that, 22.7% of women with hypothyroidism had irregular menstrual rhythm.
Thyroid peroxidase (TPO) enzyme is responsible for the oxidation and organization of iodine, and for the formation of fT4 and fT3 hormones [17]. Thyroglobulin (TG) is a glycoprotein that acts as a substrate for synthesis and storage of thyroid hormones [18]. Autoimmune thyroid disorders present with antibodies to both resulting in hypothyroidism. Thyroid autoimmunity is associated with recurrent miscarriage likely to be due to generalized activation of the immune system and transplacental transfer of antibodies, causing fetal rejection [19, 20]. The presence of antibodies to thyroid peroxidase (TPO-Ab) or thyroglobulin in pregnancy is associated with significant increase in miscarriages, premature deliveries, gestational diabetes, postpartum thyroiditis and permanent hypothyroidism [21,22,23]. In the present study, miscarriage rate in women with hypothyroidism was 4.2%, which is similar to results of other studies, reporting rates of 5.6 and 5.0% [8, 15]. Hypothyroidism in pregnancy has immense relevance in clinical obstetric abnormalities.
First-degree relatives of patients with hypothyroidism due to Hashimoto’s thyroiditis have a nine-fold higher risk of developing this disease compared to the general population [24]. Family history of thyroid disorder was seen in 4.5% of women with hypothyroidism, which is comparable to the prevalence observed in other studies: 12.7% [8].
In this study, no statistically significant association was observed between thyroid dysfunction and clinical obstetrics and gynecological features, including miscarriage, menstrual irregularity, family history of thyroid disorder, and infertility (Table 2).
Association of Maternal and fetal outcome with thyroid disorder
Anemia
Iron deficiency causes impairment of the heme-dependent enzyme thyroid peroxidase, thereby limiting synthesis of thyroid hormones, which can lead to a reduction in circulating levels of tT3 and tT4. Iron repletion may reverse hypothyroidism [25]. In the present study, anemia was observed in 26.3% of women with hypothyroidism (p = 0.008) while other authors have observed occurrence of anemia in 4.2% of women with hypothyroidism [26]. In one study, prevalence of anemia in women with hypothyroidism was as high as 60% due to iron deficiency [27]. As per a report from North India anemia and hypothyroidism are very commonly associated [28]. It is likely that hypothyroidism may add to the severity of anemia. The results of this study support an important clinical picture of an association between anemia and hypothyroidism.
Pre-eclampsia
Hypothyroidism causes vascular smooth muscle contraction both in systemic and renal vessels, which leads to increased diastolic pressure, peripheral vascular resistance, and decreased tissue perfusion, which could be the pathophysiology of preeclampsia in hypothyroidism [29, 30]. Thyroid dysfunction can be associated with proteinuria, which is known to result in increased excretion of thyroxine and thyroid-binding globulins. Rare cases have been reported in which proteinuria is severe enough to result in losses of thyroid-binding globulins and thyroxine that cannot be compensated by the body [31,32,33]. In the present study, pre-eclampsia was observed in 15.8% of women (p = 0.041) with hypothyroidism. These results are comparable to those of other studies, in which preeclampsia was observed in 13.6% women with SCH and 14.7 in overt hypothyroidism [15, 34].
Cesarean section
Increased rate of cesarean delivery is another outcome, observed in 26.7% (p = 0.012) of women with hypothyroidism. Other authors have reported rates of cesarean delivery of 22.9% in women with hypothyroidism [34]. The reason for the increased risk of cesarean delivery may be due to the associated pregnancy complications, such as hypertensive disorders, gestational diabetes, and preterm birth. Whether otherwise uncomplicated hypothyroidism increases risk of cesarean section warrants further study [35,36,37]. Some authors reported, pre-eclampsia (p = < 0.001), preterm labor (p = 0.001) and abruption (p = 0.03) being significantly related to hypothyroidism [38].
Complications that were observed to have lower prevalence in women with hypothyroidism in this study were oligohydramnios (10.5%) and preterm labor (7.8%). These findings are similar to those of other reports [20, 27].
Fetal outcomes
Low birth weight is associated with hypothyroidism due to its association with preeclampsia. Reduced fetal thyroxine may cause disruption to the development of the pituitary-thyroid axis of the newborn, fetal pituitary growth hormone secretion, vascular responsiveness and maturation, and cardiovascular homeostasis in utero [39,40,41]. These factors are causative for the observation of reduced neonatal birth weight of offspring born to mothers with inadequately controlled hypothyroidism at initial presentation or at third trimester. In this study LBW was observed in 31.6% of women with hypothyroidism, as compared to 20% observed in another study [42].
NICU admission in thyroid dysfunction was 42.1%, which is similar to the rates of 46.6 and 42% [10, 42]. Low Apgar scores occurred in 21.1% of babies born to women with hypothyroidism, compared to 20% observed in another study [15].
We did not find Intrauterine death as a fetal complication of hypothyroidism, unlike the findings of one report [38]. In the present study, hypothyroidism was found to be significantly associated with LBW(p = 0.001) and NICU admission (p = 0.000) similar to study conducted by Gupta HP et al. [38].
Considering the results, we feel that estimation and diagnosis of thyroid parameters has high clinical relevance. However, there is an ongoing debate regarding cost-effectiveness of universal vs. targeted screening in pregnant women. Current recommendations suggest targeted TSH screening for women at high risk for thyroid disease before or during early pregnancy [7]. Recommendations also focus on TPOabs- positive and negative women. It states that risk of pregnancy loss is more in TPOabs- positives at 1st trimester cut off TSH 2.5 mU/L and more. In an RCT authors advice benefit of levothyroxine treatment around 9 weeks gestation [43]. They also document improvement in adverse pregnancy outcomes only in TPOabs-positive women with mild hypothyroidism (defined as a TSH > 2.5 mU/L) with thyroxin therapy. The Task Force advocates evaluation of TPOabs for asymptomatic women with higher TSH (2.5 mU/L) in first trimester. In this study we have not carried out TPOabs status of study subjects.
Based on our sample size (n = 198) the study is 80.7% powered for 8 independent variable comparison for the outcome, which is adequate.
Implications
Reporting observed values of TSH, T4 and T3 in 3rd trimester of pregnancy will add to available literature. High association of hypothyroidism and various feto-maternal adverse outcomes again supports argument for universal screening for thyroid function in pregnancy.
Limitations
Due to small sample size and variability in TSH estimation technique, we cannot authoritatively submit the values of TSH, T4, T3 in 3rd trimester of pregnancy.
