This study aimed to assess the prevalence of subclinical hypothyroidism in Egyptian women with recurrent early miscarriage. The study included 150 women with recurrent early miscarriage and 150 controls. The results found no significant differences in TSH, FT3 or FT4 levels between the two groups. Subclinical hypothyroidism was found in 8% of women with recurrent miscarriage and 4.7% of controls, with no significant association between subclinical hypothyroidism and recurrent early pregnancy loss. The study recommends further research on the effects of subclinical hypothyroidism on pregnancy outcomes.

1. Subclinical Hypothyroidism
in Patients with Recurrent
Early Miscarriage
Presented by
Mohamed Ashour Mohamed Elashram
)M.B., B.CH.) , Tanta Uuniversity, )2002)

2. Under Supervision of
Prof. Dr. Hatem Saad Shalaby
Professor of Obstetrics and Gynaecology
Faculty of Medicine, Ain Shams University
Dr. Hosam Mohamed Hemeda
Lecturer of Obstetrics and Gynaecology
Faculty of Medicine, Ain Shams University
Faculty of Medicine
Ain Shams University
2014

3. Introduction

4. 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).

5. 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).

6. 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).

7. 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).

8. 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)

9. 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)

10. Aim of the work

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

12. Patients
and
methods

13. 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.

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

15. 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.

16. 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].

17. 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.

18. 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

19. 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.

20. Results

21.  Table (1): Patients' personal and obstetric characteristics
Data are presented as mean (SD) or number (%).
NS= non significant
HS= highly significant
Variable
Controls
(n=150)
Cases
(n=150)
p-value
Age (years) 27.5 ± 4.7 26.7 ± 4.7 0.177 (NS)
BMI (kg/m2
) 22.1 ± 1.7 22.3 ± 1.9 0.335 (NS)
Parity: N (%) <0.001 (HS)
• Nulliparous 0 (0.0)
150 (100.0)
• P1-2 136 (90.7) 0 (0.0)
• P3+ 14 (9.3) 0 (0.0)
Previous abortions: N (%) <0.001 (HS)
• None 145 (96.7) 0 (0.0)
• 1-2 Times 5 (3.3) 0 (0.0)
• 3-5 Times 0 (0.0) 130 (86.7)
• 6+ Times 0 (0.0) 20 (13.3)

22. Table (2): Comparison of TSH level in cases and controls
Variable
Controls
(n=150)
Cases
(n=150)
p-
value
TSH (mIU/ml) 3.43 (1.62) 3.82 (2.39) 0.102 (NS)
• Data are presented as mean (SD).
• NS= non significant

23. Table (3): Comparison of fT4 level in cases and controls
Variable Controls (n=150) Cases (n=150) p-value
fT4 (ng/dl) 0.84 (0.36) 0.76 (0.25) 0.096 (NS)
• Data are presented as mean (SD).
• NS= non significant

24. Table (4): Comparison of fT3 level in cases and controls
Variable Controls (n=150) Cases (n=150) p-value
FT3 (pg/ml) 2.11 (0.88) 2.30 (10.91) 0.063 (NS)
• Data are presented as mean (SD).
• NS= non significant

25. Table (5): Prevalence of subclinical hypothyroidism in
cases and controls
Variable
Controls
(n=150)
Cases
(n=150)
p-value
Subclinical hypothyroidism 7 (4.7%) 12 (8.0%) 0.236 (NS)
• Data are presented as number (%).
• NS= non significant

26. Table (6): Adjusted odds ratio for repeated early miscarriage
Factor Odds ratio* 95% CI p-value
Subclinical hypothyroidism 1.72 0.65 to 4.54 0.271 (NS)
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.

27. Table (7): Sensitivity and Specificity of TSH, FT3 and
FT4 at different cutoff points in diagnosis of miscarriage
Parameter Sensitivity Specificity
TSH
•2.5
•2.85
•2.95
•3.05
•3.15
0.267
0.660
0.607
0.587
0.560
0.767
0.360
0.447
0.447
0.507
AUC (95% CI) 0.530 (0.465 – 0.596)
FT3
• 1.85
• 1.95
• 2.05
• 2.15
• 2.25
• 2.35
0.747
0.693
0.653
0.567
0.507
0.447
0.307
0.400
0.433
0.547
0.593
0.660
AUC (95% CI) 0.562 (0.497 – 0.627)
FT4
• 0.65
• 0.75
• 0.85
• 0.95
0.633
0.493
0.333
0.207
0.273
0.440
0.613
0.747
AUC (95% CI) 0.445 (0.380 – 0.510)
P= 0.506
0.660

28. 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%).

29.  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.

30. Conclusions

31.  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.

32.  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.

33. Recommendations

34.  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.
 Further studies are required to determine the precise
effects of SCH on obstetric outcome.

35.  Full drug history should be taken especially combined
oral contraceptive pills frequently used in cases of RPL
which may alter thyroid function.
 Antithyroid antibodies should be assessed with TSH,
FT4 and FT3 as there is a strong association between
recurrent pregnancy loss and antihyroid antibodies.

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

37.  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.
 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.

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