Subclinical hypothyroidism in patients with recurrent early miscarriage

1. SUBCLINICAL HYPOTHYROIDISM IN
PATIENTS WITH RECURRENT EARLY
MISCARRIAGE
Presented by
Mohamed Ashour Mohamed Elashram
)M.B., B.CH.) , Tanta Uuniversity, )2002)

2. 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).

3. 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).

4. 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)

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

6. 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.

7. Inclusion criteria
1. Age: patients should be in the reproductive
age group (17- 40 years.).
2. Suffering from at least 3 recurrent early
miscarriages.

8. 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.

9. 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.

10. 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.

11. Results
 Table (6): Patients' personal and obstetric characteristics
 Data are
presented as
mean (SD) or
number (%).
 NS= non
significant
 HS= highly
significant

14. 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.

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

16. 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.

17. 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.

18. 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.

19.  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.

20.  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.