subclinical hypothyroidism in patients with recurrent early miscarriage (1)

Subcl inical Hypothyroidism in Patients with Recurrent

Early Miscarriage

Presented by

Mohamed Ashour Mohamed Elashram)M.B., B.CH.) , Tanta Uuniversity, )2002)

Under Supervision of

Prof. Dr. Hatem Saad ShalabyProfessor of Obstetrics and Gynaecology

Faculty of Medicine, Ain Shams University

Dr. Hosam Mohamed HemedaLecturer of Obstetrics and Gynaecology

Faculty of Medicine, Ain Shams University

Faculty of MedicineAin Shams University

2014

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).

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)

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)

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 methodsStatistical 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 (1): Patients' personal and obstetric characteristics

Data are presented as mean (SD) or number (%).NS= non significantHS= 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)

Table (2): Comparison of TSH level in cases and controls


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

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)



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)



Table (5): Prevalence of subclinical hypothyroidism in cases and controls


Cases (n=150) p-value

Subclinical hypothyroidism 7 (4.7%) 12 (8.0%) 0.236 (NS)

• Data are presented as number (%).


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.

Table (7): Sensitivity and Specificity of TSH, FT3 and FT4 at different cutoff points in diagnosis of miscarriage

Parameter Sensitivity SpecificityTSH•2.5•2.85•2.95•3.05•3.15

0.267

0.6600.6070.5870.560

0.7670.3600.4470.4470.507

AUC (95% CI) 0.530 (0.465 – 0.596)FT3

• 1.85• 1.95• 2.05• 2.15• 2.25• 2.35

0.7470.6930.6530.5670.5070.447

0.3070.4000.4330.5470.593

0.660AUC (95% CI) 0.562 (0.497 – 0.627)FT4

• 0.65• 0.75• 0.85• 0.95

0.6330.4930.3330.207

0.2730.4400.613

0.747AUC (95% CI) 0.445 (0.380 – 0.510)

P= 0.506

0.660

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

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.

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.

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.

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.

Further studies are needed with different cutoff level

of TSH, Ft4 and Ft3.