Abstract
Thyroid insufficiency in early pregnancy includes a series of disorders that may affect maternal pregnancy outcomes and the offspring's mental development, and the knowledge in this area has been expanding rapidly in the recent years. Shan Zhongyan (2) screened 4800 pregnant women in the first half of pregnancy using gestation-specific reference intervals for thyroid parameters in China and found that the prevalences of overt hypothyroidism, subclinical hypothyroidism, hypothyroxinemia, and thyroid peroxidase antibody (TPOAb) positivity were 0.6%, 5.27%, 2.15%, and 8.6%, respectively. The results were consistent with those from studies in the United States and Europe.
In their prospective study, Yu Xiaohui and colleagues (3) observed the effect of intervention with levothyroxine (LT4) treatment for subclinical hypothyroidism in early pregnancy on the neuropsychological development of the offspring. In this study, 23 patients with subclinical hypothyroidism (normal free thyroxine [FT4] and negative TPOAb) received LT4 before the 8th gestational week. Another 53 patients with subclinical hypothyroidism without LT4 intervention served as positive controls, and 54 normal women served as negative controls. The results indicated that the mental development index (MDI) and the psychomotor developmental index (PDI) of the children born from pregnant women with subclinical hypothyroidism were 5.94 points and 6.29 points lower than those of the children of negative controls, respectively (p<0.01), and LT4 treatment for subclinical hypothyroidism during early pregnancy could promote MDI and PDI of the children to the levels similar to those of negative controls. The authors also found that the MDI and PDI of the children born to the women with isolated positive TPOAb only (but normal thyrotropin [TSH] and FT4) were 3.58 and 4.22 points lower than those of the negative controls, respectively (p=0.035 and p=0.038). Li Yuanbin (4), a member of the same group, and colleagues had drawn the same conclusion from a retrospective study. In that study, using frozen sera from 1268 women during 16–20 weeks of gestation, they screened out 18 cases of isolated subclinical hypothyroidism (normal FT4 and negative TPOAb), 19 cases of isolated hypothyroxinemia (normal TSH and negative TPOAb), 34 cases of isolated positive TPOAb (normal TSH and FT4), and 142 normal controls. Intellectual and motor development score evaluations were performed in the women's children at 25–30 months of age. The results showed that the MDI of children of women with isolated subclinical hypothyroidism, hypothyroxinemia, and positive TPOAb was 9.98, 7.57, and 9.03 points lower than in the control group, respectively; and the PDI was 9.23, 5.52, and 8.25 points lower, respectively. These investigations indicated that the three kinds of isolated thyroid disorders were all harmful to the mental development of the fetuses.
The policy of “one child per couple” has been implemented for 32 years in China, and much attention has been paid to the quality of the birth population. In China, thyroid diseases in early pregnancy aroused attention first from endocrinologists, and then rapidly from gynecologists, obstetricians, and health workers of eugenics. The Chinese Journal of Endocrinology and Metabolism sponsored by the Chinese Society of Endocrinology published two special issues regarding thyroid diseases during pregnancy in 2008 and in 2010, respectively. Thyroid disease has also been one of the hot topics at the annual meetings of endocrinology in China for five consecutive years. Guideline for Management of Thyroid Diseases in China (published in 2007) included content on pregnancy and thyroid diseases (5). The guideline has been used as one of the National Continuing Medical Education Programs spread nation wide. More than 9000 doctors (mainly endocrinologists) from nearly all over the country received the training. During the “Thyroid Week” held by the International Thyroid Federation, over 150 cities in China were engaged in spreading knowledge about thyroid disorders during pregnancy, using mass media, publications, and educational courses. As a result, a large number of pregnant women and women planning pregnancy came to the hospitals to have thyroid parameters tested and to look for guidance and appropriate management.
Facing the problem regarding the intellectual quality of 15% of population born in China, endocrinologists, gynecologists and obstetricians, and workers in maternal and child health care have received considerable pressure because of the uncertainty in diagnostic criteria and management for thyroid disease during pregnancy. For instance, in the diagnosis of subclinical hypothyroidism during pregnancy, The Clinical Practice Guideline for management of thyroid dysfunction during pregnancy and postpartum issued by The Endocrine Society recommended that a cutoff value of 2.5 mIU/L for TSH should be used to diagnose subclinical hypothyroidism in the first trimester (6). Although Panesar et al. (7) reported the normal upper limit for TSH in the first trimester was 2.3 mIU/L in Hong Kong, another two articles from the Chinese mainland reported the upper limit was 3.93 mIU/L (DPC corporation) (8) and 4.51 mIU/L (Bayer Corporation) in the first trimester (9), respectively. Xue Haibo et al. (10) analyzed the relationship between the levels of TSH in pregnant women and their children's intelligence. The results indicated the children of pregnant women with TSH ≥3.93 mIU/L had lower MDI and PDI. However, those of women with TSH 2.5 mIU/L to <3.93 mIU/L had similar MDI and PDI to those of controls. These results suggested that the elevation of TSH in pregnant women was associated with damage to their children's intelligence. The cutoff value of TSH in pregnant women should be the upper limit of gestation-specific reference interval rather than 2.5 mIU/L (10). Furthermore, physicians have reached agreement that it is impractical to establish gestation-specific reference intervals for TSH and thyroid hormones in their own hospitals. So a universal diagnostic criterion for thyroid diseases during pregnancy is desirable.
Health care of pregnant women is provided by centers for maternal and child health care and departments of obstetrics of hospitals in China. So it is necessary to cooperate with doctors from the centers and hospitals for the screening and management of thyroid disease during pregnancy. In 2010, the Chinese Society of Endocrinology and Chinese Thyroid Association established cooperation with Chinese Society of Obstetrics and Gynecology and Chinese Society of Perinatal Medicine. We are planning to fulfill three tasks. The first is to start a multicenter clinical trial to look for the answers for the problems regarding the diagnosis and indications for intervention of thyroid diseases during pregnancy. The second is to develop The Clinical Guidelines for the Diagnosis and Management of Thyroid Disease during Pregnancy in China for doctors of endocrinology, obstetrics and gynecology, and maternal and child health care nationwide. The third is to promote legislation regarding thyroid diseases during pregnancy and integrate it into the Health Care Routine During Pregnancy in China promulgated by the Ministry of Health of China (11).
Clinical trial
A clinical trial entitled Subclinical Hypothyroid and Iodine Deficiency in Early Pregnancy and Women Planning for Pregnancy: Screening and Intervention (SHEP study) will be launched soon in China. The SHEP study will include women with iodine deficiency, subclinical hypothyroidism, and positive TPOAb. A total of 21,500 women will be screened and 4800 women will be followed. The expected duration of the study is 4 years, and it will include doctors and nurses from the fields of endocrinology, obstetrics and gynecology, pediatrics, maternal and child health care, and nutrition in 26 hospitals. One of the features of this study is that it will screen and treat women who are planning pregnancy, which will achieve the primary prevention for the thyroid hormone–related defects in fetal brain development. We have finished a survey (n=15,008) regarding the relationship between thyroid diseases and iodine nutrition in 10 cities in China recently. The results of the survey showed that the prevalence of overt hypothyroidism, subclinical hypothyroidism, and positive TPOAb in childbearing women (n=4438) was 0.77%, 5.32%, and 12.96%, respectively (12).
Developing guidelines
The Chinese Thyroid Association and the Chinese Perinatal Medicine Association have been cooperating to develop The Clinical Guidelines for the Diagnosis and Management of Thyroid Disease During Pregnancy. This guideline will be separate from the Clinical Guidelines for the Diagnosis and Management of Thyroid Disease in China and will be published independently, to reflect the specificity and importance of thyroid diseases during pregnancy. This Guideline will refer to contents of guidelines (6,13), those of The Endocrine Society and the American Thyroid Association. It will reflect not only the latest developments in this area but also the recent findings by Chinese scholars. It will be based on the Chinese conditions and meet the clinical needs of doctors from obstetrics and gynecology, maternal and child health care, and endocrinology. This Guideline is expected to be completed early next year when it will be distributed countrywide by National Continuing Medical Education Programs.
Legislation for screening and treating thyroid disease during pregnancy
According to the Standards of Health Care During Pregnancy in China promulgated by the Ministry of Health in 2011, pregnant women in China will receive examinations at least five times during their pregnancy, including once in the first trimester, twice in the second trimester, and twice in the third trimester. Acquired immune deficiency syndrome (AIDS), syphilis, hepatitis B, diabetes mellitus, anemia, and Down's syndrome are among the disorders to be screened for. Newborns will be screened for phenylketonuria, congenital hypothyroidism, and hearing disability. After the SHEP study is finished, the results will be reported to Ministry of Health as evidence-based medical data. We hope that the projects of screening and treating for thyroid diseases during pregnancy will be included in Standards of Health Care During Pregnancy in China.
In short, the study of thyroid diseases during pregnancy in China is at a standardized and universal stage. We are looking forward to cooperating with the international academic community to establish reasonable and feasible routines for screening and treating thyroid disease during pregnancy.