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«Thyroid autoimmunity and obstetric outcomes in women with recurrent miscarriage – A case control study Short title: Thyroid autoimmunity and ...»

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Page 1 of 18 Endocrine Connections Publish Ahead of Print, published on April 2, 2013 as doi:10.1530/EC-13-0012

Thyroid autoimmunity and obstetric outcomes in women with recurrent

miscarriage – A case control study

Short title: Thyroid autoimmunity and recurrent miscarriage

Kusum Lata* M.D.,

Pinaki Dutta** M.D., D.M.,

Subbiah Sridhar**M.D., D.M.,

Minakshi Rohilla* M.D.,

Anand Srinivasan*** M.D,

GRV Prashad* M.D.,

Viral N Shah** M.D., D.M.,

Anil Bhansali** M.D., D.M.

Author’s affiliation Departments of Obstetrics and Gynecology*, Endocrinology**, Pharmacology***, Post Graduate Institute of Medical Education and Research (PGIMER) - Chandigarh, India.

Corresponding Author:

Dr. Anil Bhansali Professor and Head Department of Endocrinology Post Graduate Institute of Medical Education and Research, Chandigarh, India.

Copyright 2013 by Society for Endocrinology and European Society of Endocrinology.

Page 2 of 18 Email: anilbhansaliendocrine@rediffmail.com Telephone number: 91-172-2756583 Fax: 91-172-2744401, 2745078 Key words: recurrent miscarriage, thyroid peroxidase, hypothyroidism, preterm birth No of words in


– 251 Word Count – 2590 No of Tables – 2 Page 3 of 18 Objectives: Thyroid antibody positivity during pregnancy has been associated with adverse outcomes including miscarriage and preterm delivery. The aim of the study is to evaluate the obstetric outcome in pregnant women with recurrent miscarriage and their response to L- thyroxine therapy.

Study design and methods: All pregnant and non pregnant women between 21 – 35 years of age with history of two or more consecutive miscarriages were included in the study. A third group comprised of 100 pregnant women without past history of miscarriage were also taken as healthy controls. Thyroid autoimmunity, prevalence of subclinical hypothyroidism, maternal and foetal complications were analyzed in all the groups with appropriate statistical methods.

Results: The mean age of the patients included in the study was 27.0 ± 3.1 years. Out of 100 pregnant patients with previous recurrent miscarriage, thyroid autoimmunity (thyroid peroxidise antibody; TPOAb+ 34U/ml) was found in 31% of the cases. The incidence of subclinical hypothyroidism was higher in TPOAb+ group than in TPOAb- group (52% vs 16%; p=0.0002). There was no difference in the prevalence of miscarriage or obstetric outcomes between recurrent miscarriage and healthy pregnant women group irrespective of

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Conclusions: The prevalence of thyroid autoimmunity was higher in pregnant women with history of recurrent abortion as compared to healthy pregnant control population. Following levothyroxine treatment, there was no difference in prevalence of miscarriage between hypothyroid and euthyroid individuals in TPOAb+ positive women. All euthyroid women with thyroid autoimmunity should be treated with levothyroxine to achieve a favourable

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Miscarriage is spontaneous loss of the conceptus before 20 weeks of gestation.

Potential amount of possible miscarriage before pregnancy is recognised is about 30%. In clinically recognised pregnancy it is 10-15% before eighth week and 3% between 8-28th week. Recurrent miscarriage, defined as loss of 2 or more consecutive pregnancies (ASRM Practice committee Report, 2008), occurs in approximately 1-2 % of couples attempting to bear children1-4.

Several disorders are known to contribute recurrent miscarriage including chromosomal anomalies, anticardiolipin antibodies, endocrine disorders like poorly controlled diabetes mellitus, hyperprolactinemia and thyroid diseases, and pelvic anatomic abnormalities5. Recurrent miscarriage can be classified as either primary or secondary.

Primary aborters are women who have lost all their pregnancies, whereas secondary aborters have at least one live born infant, before the abortions.

Autoimmune thyroid disease (AITD) is by far the most frequent cause of hypothyroidism in women of reproductive age. The prevalence of hypothyroidism in the general population of reproductive age is approximately 2-3%6,7. Overt hypothyroidism is commonly associated with infertility, since thyroid hormones have direct effect on granulosa cells, luteal cells and oocytes maturation8. Women in euthyroid state but with thyroid autoimmunity are twice likely to experience spontaneous miscarriages9, as it probably represents a generalized activation of immune system, or there is an increased risk of progression to subclinical hypothyroidism or probably due to transplacental transfer of thyroid receptor blocking antibodies 10,11. Hence there is a need for screening subclinical hypothyroidism and thyroid autoimmunity in pregnancy especially in women with history of miscarriages.

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autoimmunity remains controversial. Some investigators recommend the use of empirical thyroxine therapy in women with thyroid peroxidise antibody positive (TPOAb+), even though there was no evidence of hypothyroidism12. A few studies showed that empirical thyroxine therapy in patients with TPOAb+ did not improve the obstetrical outcome13.

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history of two or more consecutive miscarriages were included in the study. A third group comprised of 100 pregnant women without past history of miscarriage were also taken as healthy controls. Among 100 pregnant women with recurrent miscarriages, 85% were recruited in the first trimester and remaining (15%) in the second trimester. 67% of patients had primary recurrent abortion while rests had secondary recurrent abortion. This case control study was conducted between June 2010 and December 2011 in Departments of Obstetrics & Gynaecology and Endocrinology, Postgraduate Institute of Medical Education & Research, Chandigarh, India. It was a prospective study for pregnant women with recurrent abortions; and cross sectional for non pregnant women with past history of recurrent abortions. The study was approved by Institute’s ethics committee. All patients provided

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incompetence or any other uterine pathology were excluded. All patients underwent a comprehensive medical evaluation including a detailed history and a thorough physical examination.

Hormonal Profile: 3ml of venous blood was collected in EDTA vacutainers at the initial visit. Each blood sample was analysed for thyroid stimulating hormone (TSH), free T3 (FT3), free T4 (FT4), and anti-thyroid peroxidise (Anti-TPO) by electro-chemiluminiscence immunoassay (ELECSYS-2010, Roche-Hitachi diagnostics, Mannheim, Germany). The reference range for the above hormones are (TSH), RR - 0.27 to 4.2 ulU/ml (inter-assay CV,

2.5 to 3.2 %; intra-assay CV, 0.5 to 1.5%), FT3, RR – 1.7 to 4.2 ng/ml, (inter-assay CV, 1.4 to 3.2% ; intra-assay CV, 0.5 to 2.0%), FT4, RR – 0.7 to 1.8 ng/ml, (inter-assay CV, 1.0 to 2.5%; intra-assay CV, 1.0 to 2.5%), and Anti-TPO, RR – less than 34 IU/ml.

All patients with TPOAb+ were treated with L-thyroxine 25 g and titrated according to TSH at the time of recruitment in the study. The patients who were having sub clinical hypothyroidism were treated as deemed necessary. All patients were followed up in antenatal out-patient department (OPD) every 4 weekly till 28 weeks. Ultrasonography (USG) was done at 8 weeks to all pregnant women for confirmation of viability and repeat scan was done around 18 weeks of gestation to find out any foetal anomalies. After 28 weeks they were followed up fortnightly till 37 weeks. All patients were monitored for development of any sign or symptoms of preeclampsia, intrauterine growth retardation (IUGR) and preterm labour. USG for fetal growth and biophysical profile (BPP) was done as per clinical findings. After 37 weeks they were followed up weekly and were delivered according to the obstetric indications. Details of the mode of delivery and any intrapartum or postpartum complications were noted. After delivery, the birth weight, gestational age and APGAR score at 1 and 5 minutes and the presence of congenital malformations were noted.

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complications (gestational hypertension, pre eclampsia and eclampsia), gestational diabetes mellitus, intrahepatic cholestasis of pregnancy, preterm labour, IUGR, postdatism, preterm premature rupture of membranes (PTPROM) and postpartum hemorrhage. Neonatal outcomes were measured in the form of prematurity (delivery between 20-37 weeks),

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abortions were also recruited and investigated for causes of recurrent abortions. Blood sample for thyroid function tests was taken at first visit and treated according to the results. A third group comprising of 100 pregnant women without any past history of abortion were taken as healthy controls. Table 1 compares the baseline characteristics, thyroid hormone profile and maternal, foetal outcome between the pregnant patients of miscarriage group and the healthy

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median with interquartile range was used. The normality was assessed by KolmogorovSmirnov and Anderson-Darling test. Unpaired t test was used for normal data and Mann

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fisher exact tests were used. Multivariate analysis was carried out to determine the effect of T3, T4, TSH and AntiTPO on percentage of live birth per individual. The covariates included for multivariate analysis were age, weight, T3, T4, TSH, AntiTPO titre, period of gestation and haemoglobin level of the patients. P value of 0.05 was considered significant. All the

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odds ratio of having TPOAb+ was higher (2.05) in miscarriage group compared to the healthy group.

Out of 100 pregnant patients with previous recurrent miscarriage, thyroid autoimmunity (Anti-TPO 34U/ml) was found in 31% (p = 0.031) and subclinical hypothyroidism was observed in 27% (p = 0.74) of the cases. The incidence of subclinical hypothyroidism was higher in TPOAb+ group than in TPOAb- group (52% vs 16%;

p=0.0002). TPOAb titre was significantly higher in hypothyroid group than in the euthyroid with recurrent pregnancy loss (81.7 ± 132.7 vs 31.9 ± 68.7 IU/ml, p = 0.016).In the healthy control group, which comprised of pregnant women without history of abortion the prevalence of subclinical hypothyroidism was 24% and TPO positivity was 18% (P=0.70) There was no difference in the prevalence of miscarriage between hypothyroid and euthroid individuals in anti TPO positive women (P=0.23). On linear regression in euthyroid (after exclusion of hypothyroid) women with anti TPO positivity the percentage of live birth was found to correlate with level of TPO antibody(r=0.17, P=0.01). Similarly on multivariate linear regression, the percentage of live birth was found to correlate with the level of free T4 (R=0.17, p=0.001). Comparison of TPOAb+ and TPOAb- pregnant women with recurrent miscarriage are shown in table 2. The modes of delivery between the two groups were comparable (p = 0.7). Among the 4 aborters in the recurrent miscarriage group, two were in TPOAb+ group and remaining were in TPOAb- group with no statistically significant difference (p = 0.39). Intrahepatic cholestasis was more common in TPOAb+ group (p = 0.04). The odds ratio of having miscarriage was increased (5.62) when TPOAb+ with elevated TSH when compared with normal values.

Page 9 of 18 Twenty five non-pregnant women with recurrent miscarriage were also analyzed for their

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pregnant women with history of recurrent abortion as compared to healthy pregnant control population. Even though the TSH value was higher in TPOAb+ group than in TPOAb- group, the prevalence of subclinical hypothyroidism was comparable between the two groups. There was no absolute difference in the prevalence of miscarriage between subclinical hypothyroid and euthyroid pregnant women irrespective of TPO status. However, the odds of having miscarriage in TPOAb+ group increases with rising TSH level as compared to normal TSH level. A similar phenomenon was observed with decreasing free T4 levels. There was no difference in any of the parameters between pregnant women with recurrent miscarriages compared to nonpregnant women with history of recurrent abortion.

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pregnant women with recurrent abortion) while it was significantly lower in the healthy group 18% (31% vs 18%, p = 0.03). The population prevalence described in the literature is 10-15%14,15. The odds ratio of having TPOAb+ was higher (2.05) in miscarriage group, indicated that strong association between them. In a meta-analysis by Prummel MF et al16 showed that TPOAb+ was associated with two fold increased risk of miscarriage as shown similar in our study. In both the groups, the outcome of current pregnancy was not influenced

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of all cases with either isolated TPOAb positivity or with elevated TSH during the course of pregnancy.

Similar results were also found by Negro et al12, in which the miscarriage rate in TPOAb+ positive group supplemented with thyroxine was comparable to healthy controls (3.5% vs 2.4%). However, these patients had no previous history of recurrent miscarriages unlike our study population. None of our patients had isolated hypothyroxinemia. However, the odds of having the miscarriage were increased with decreasing free T4 values. As expected the mean TSH in the TPOAb+ group was higher 3.1+ 1.9 as compared to those with TPOAb- 2.0+ 1.0 (P.001). The possible explanation of high TSH in TPOAb+ group is due to reduced functional thyroid reserve associated with chronic autoimmune thyroiditis17,18.

In the present study, the prevalence of subclinical hypothyroidism was 24% and 27% in healthy pregnant women without miscarriage and pregnant women with history of recurrent miscarriage respectively (P=0.74). It was relatively higher than the reported prevalence of 10-16% in literature14,15. Such a high prevalence could be due to selection bias, lack of iodine status of our patients, different assay methods and various cut off level of TSH used to define subclinical hypothyroid in previous studies.

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