SUBCLINICAL HYPOTHYROIDISM IN PATIENTS WITH RECURRENT

EARLY MISCARRIAGE

Presented byMohamed Ashour Mohamed Elashram

(M.B., B.CH.) , Tanta Uuniversity, (2002)

Introduction

Recurrent miscarriage is classically defined as three or more consecutive pregnancy losses at 20 weeks or less or fetal weights less than 500 grams. Although the definition includes three or more miscarriages, many agree that evaluation should at least be considered following two consecutive losses. (Cunningham et al, 2010).

First trimester losses account for 75% of recurrent miscarriage and the remaining 25% occur in the second trimester .The causes of recurrent miscarriage may have genetic, immunologic, anatomical, infective, endocrine or environmental origin, but in many cases no cause is found. (Balen, 2008).

In early pregnancy, the maternal thyroid gland is challenged with an increased demand for thyroid hormone secretion, due mainly to three different factors: (1) the increase in thyroxine-binding globulin (TBG) due to the effect of estrogen in the liver, (2) the stimulatory effect of human chorionic gonadotropin (HCG) on the thyroid-stimulating hormone (TSH) receptor, (3) decreased supply of iodine available to the thyroid gland (Mestman, 2002).

Hypothyroidism complicates 0.3-0.7% of all pregnancies .Women with overt hypothyroidism are at an increased risk for complications such as early pregnancy failure, preeclampsia, placental abruption, low birth weight, and stillbirth. Also hypothyroidism that occurs during the first half of pregnancy is associated with a risk of a poor neurodevelopmental outcome. (Drews and Seremak-Mrozikiewicz, 2011).

The most common cause of hypothyroidism in pregnancy is Hashimoto's thyroiditis. (Pernoll, 2001).

The symptoms of hypothyroidism include excessive fatigue, dry skin, cold intolerance, constipation, anorexia, weight gain, depression, muscle weakness, constipation, menorrhagia or oligomenorrhoea and irritability. (Kumar and Clark’s, 2009)

Subclinical hypothyroidism (SCH) is biochemically diagnosed when there is a persistently high TSH level, while circulating free thyroid hormone levels are within range. Other terms for this condition are mild hypothyroidism, early thyroid failure, preclinical hypothyroidism, and decreased thyroid reserve. The prevalence of SCH is 3-8% which varies with population, age, sex, race, region and method of TSH measurement. (Raza and Mahmood, 2013)

Aim of the work

To asses the prevalence of subclinical hypothyroidism in a sample of Egyptian women suffering from recurrent early miscarriage.

Patients and methods

This case control study was conducted at Ain Shams University Maternity Hospital specialized clinic for recurrent miscarriage in the period between June 2011 and January 2014.

This study included 300 women divided into two equal groups:

A) Case group: consists of 150 women with recurrent early miscarriage.

B) Control group: consists of 150 women with at least one successful pregnancy and no history of miscarriage.

Inclusion criteria

1. Age: patients should be in the reproductive age group (17- 40 years.).

2. Suffering from at least 3 recurrent early miscarriages.

Exclusion criteria:

– Patients known to have overt thyroid dysfunction.

– All known causes of miscarriage either general or local causes.

– Any medications that may alter thyroid gland function.

All selected women for the study had giving an informed consent and were subjected to the following:

1. Full history taking, general, abdominal and pelvic examination with careful examination of the thyroid gland.

2. Screening for thyroid function by serum thyroid stimulating hormone level (serum TSH), freeT3 and freeT4 by enzyme linked immunosorbent Assay [ELISA].

Laboratory reference levels for TSH, free T4 and free T3 in the present study were 0.4-6 mIU/L, 0.65-1.97 ng/dl and 1.4-4.2 pg/ml respectively according to used kit's references (Burger and Patel, 1977), (Midgley, 2001) and (Wild, 2005) respectively.

Statistical methods

Statistical analysis was done on a personal computer using IBM© SPSS© Statistics version 21 (IBM© Corp., Armonk, NY, USA) and MedCalc© version 12.5 (MedCalc© Software bvba, Ostend, Belgium).

Data are expressed as mean ± SD (range) or number (%) of cases. Comparison of proportion and means between variables will be made by using x² test and paired t test, non parametric data will be analyzed using Mann-Whitney test.

Binary logistic regression was used to estimate odds ratio for repeated early miscarriage with subclinical hypothyroidism as a predictor adjusting for potential confounders.

All P values are two-tailed. P < 0.05 is considered as denoting statistical significance.

Results Table (6): Patients' personal and obstetric characteristics

Data are presented as mean (SD) or number (%).

NS= non significant

HS= highly significant

Table (11) shows the odds ratio of repeated early miscarriage for women with subclinical hypothyroidism as referenced to those without subclinical hypothyroidism. After adjustment for age and BMI with multivariable logistic regression, the adjusted odds ratio was 1.72 (95% CI, 0.65 to 4.54; p-value=0.271) denoting no statistically significant relationship between SCH and recurrent early miscarriage.

Table (12): Sensitivity and Specificity of TSH, FT3 and FT4 at different cutoff points in diagnosis of miscarriage

The previous table displays the sensitivity and specificity of TSH, FT3 and FT4 at different cutoff points:

For TSH ≥ 2.5 mIU/L showed the highest specificity (76.7%) with a corresponding sensitivity of (26.7%), while the highest sensitivity was at ≥ 2.85 mIU/L (66.0%).

For FT3 ≤ 2.35 pg/ml showed the highest specificity (66%) with a corresponding sensitivity of (44.7%), while the highest sensitivity was at ≤ 1.85 pg/ml (74.7%).

For FT4 ≤ 0.95 ng/dl showed the highest specificity (74.7%) with a corresponding sensitivity of (20.7%), while the highest sensitivity was at ≤ 0.65 ng/dl (63.3%).

p- Value of TSH ≥ 2.5 mIU/L = 0.506 (NS) to compare present study with other studies that minimized TSH cutoff level ≥ 2.5 mIU/L.

Conclusions

In the present study, no statistically significant differences were found between patients and controls regarding TSH levels. In addition, this study showed no statistically significant differences between patients and controls regarding fT4 and fT3 levels.

In the current research, subclinical hypothyroidism was found in 12 patients (8.0 %) in comparison to 7 cases (4.7 %) with no statistically significant differences between two groups.

The present study found no significant association between subclinical hypothyroidism and recurrent early pregnancy loss.

Recommendations

Further studies are required to determine the precise effects of SCH on obstetric outcome.

Measuring the thyroid function during pregnancy as there are many changes that occurs in the thyroid physiology during pregnancy and most of cases of SCH during pregnancy are transient and recover after pregnancy as pregnancy represent period of stress which may overlay poor thyroid state.

Antithyroid antibodies should be assessed with TSH, FT4 and FT3 as there is a strong association between recurrent pregnancy loss and antihyroid antibodies.

Full drug history should be taken especially combined oral contraceptive pills frequently used in cases of RPL which may alter thyroid function.

Physicians should screen women who are at risk for thyroid disease before they become pregnant; risk factors include personal or family history of thyroid disease, thyroid autoimmunity, type 1 diabetes, or other autoimmune disorders, including rheumatoid arthritis and systemic lupus erythematosus.

Physicians should counsel women about adequate iodine intake during pregnancy and lactation.

L-thyroxine is the treatment of choice of SCH. There is no evidence to support the use of liothyronine or combined L-thyroxine / liothyronine in the treatment of SCH.

In pregnancy, the upper limit of the normal range of TSH should be based on trimester-specific ranges for that laboratory. If trimester-specific ranges for TSH are not available in the laboratory, the following upper normal references are recommended: first trimester, 2.5 mIU/L, second trimester, 3.0 mIU/L and third trimester, 3.5 mIU/L.

Further studies are needed with different cutoff level of TSH, Ft4 and Ft3.