Assessing the outcome of management of thyroid dysfunction in pregnancy with second aliated hospital of Chongqing Medical University guideline.

Pregnancy comes with hormonal changes which, when not properly managed, could lead to complications. Thyroid hormone is one of the hormones that are affected during pregnancy, and it plays a signicant role in pregnancy, from conception to delivery. In a bid to identify intended pregnant women and pregnant women with thyroid dysfunction, the Endocrinology Branch of Chinese Medical Association and Perinatal medicine branch of Chinese Medical Association set guidelines for diagnosis and treatment of thyroid diseases in pregnancy and postpartum women. The guideline recommends screening for all women who desire getting pregnant soon and pregnant women, which Second Aliated Hospital of Chongqing Medical University is implementing. This study was carried out to Identify the common thyroid disease found among pregnant women in Chongqing, evaluate the effectiveness of the management guideline toward improving pregnancy outcome among women diagnosed with thyroid disease during their pregestational and gestational period, and ascertain the need for additional measures to be taken towards thyroid disease management during pregnancy in certain areas with unfavourable outcome. Our ndings showed an association between maternal age and abortion among pregnant women diagnosed with subclinical hypothyroidism, P-0.018(OR 1.459, 95%CI 1.067–1.997) and signicant difference in pregnant women who developed intrauterine growth restriction after being diagnosed with hypothyroidism in the second trimester, P-0.048(OR-0.152, 95%CI 0.024–0.981). There was also a signicant difference in gravida, P-0.032(OR 1.368, 95%CI 1.028 1.821) and normal delivery mode, P-0.010(OR 2.521, 95%CI 1.246-5.100). The study shows a promising result as less complication is observed. However, more attention is needed toward managing subclinical hypothyroidism in pregnancy to curb abortion/miscarriage incidence. Hypothyroidism in second trimester could lead to intrauterine growth restriction. Multigravida increases the risk of complication among pregnant women with thyroid dysfunction.


Introduction
Several investigations report that at least 2 to 3% of healthy, non-pregnant women of childbearing age have an elevated serum thyroid-stimulating hormone (TSH). The prevalence may be higher in areas of iodine insu ciency [1]. Thyroid disorders are the second most common endocrine disorders found in pregnancy.
Overt hypothyroidism is estimated to occur in 0.3-0.5% of pregnancies. Subclinical hypothyroidism appears to occur in 2-3%, and hyperthyroidism is present in 0.1-0.4% [2]. The study on thyroid hormone and its role during pregnancy and childbearing has been a major concern today. Limited research and evidence in this vital area have prompt lots of research in this eld in recent times. These thyroid disorders include clinical hypothyroidism, Subclinical hypothyroidism, hypothyroxinemia, hyperthyroidism, thyroiditis, and other thyroid dysfunction.
The primary cause of Hypothyroidism or subclinical hypothyroidism (SCH) in developing countries is iodine de ciency, while in developed countries it is caused by chronic autoimmune thyroiditis (CAT). Thyroid autoantibodies are detected in about 50% of pregnant women with subclinical hypothyroidism and more than 80% with overt hypothyroidism [3]. Hence, both developed and developing nations are in one way or the other at risk of developing thyroid disease or experiencing thyroid dysfunction. Increased and decreased thyroid hormone levels result from various factors like autoimmune condition, tumour, infection, metabolic disorder, in ammation, and low feedback mechanism. It could also be due to physiological hormonal changes that occur during pregnancy. CAT is the leading cause of hypothyroidism during pregnancy [4]. Normal pregnancy is accompanied by a physiologic rise in thyroid hormone synthesis, facilitated by an increase in thyroid size by 10% in iodide su cient areas and 20 to 40% in iodide de cient regions [1]. During pregnancy, the thyroid hormone needed to maintain the mother and foetus's metabolic activities depends mostly upon the mother's thyroid hormone release, especially in the rst trimester, and gradually reduces as the pregnancy advances due to thyroid hormone production by the foetus [5]. This gradual reduction in demand on the maternal thyroid hormone speci cally T4 is due to the fetus's ability to produce its thyroid hormone by the eleventh week of gestation, as demanded by the body [6].
However, it is a fact that the thyroid hormone plays a signi cant role in placenta formation. Hence, it can determine the outcome of pregnancy on both the mother and foetus. Similarity has been found between hyperthyroidism and hypothyroidism complications during prenatal, natal, and postnatal phases between the mother and baby. Among these similar complications found on the maternal side are; preterm delivery, preeclampsia, miscarriage, placenta abruption, and cardiac dysfunction [7]. While on the foetal/neonatal side are prematurity, low birth weight, congenital anomalies, and stillbirth [7]. These unpleasant outcomes have made thyroid hormone management a thing of importance to improve maternal and foetal wellbeing during pregnancy. Failure to manage these conditions will likely amount to complications, and undesirable outcomes, as seen in Parizad et al. [8] where preterm birth incidence was higher among mothers with clinical hypothyroidism, subclinical hypothyroidism, and hypothyroxinemia during pregnancy compared to euthyroid mothers, with a p-value of 0.005, 0.013, and 0.020, respectively.
Despite the signi cant impact of thyroid hormone abnormality in pregnancy, it is still a thing of deliberation on whether to conduct a routine screening test for all pregnant women or not. The following may be the reason for this indecisive approach towards this critical health condition that needs a proactive and intense management policy. Firstly, insu cient statistical evidence of the true prevalence of this condition worldwide, as studies carried out in India and some middle-east nations have shown that subclinical hypothyroidism has a prevalence rate of 13.13% [9], against the western world with a prevalence rate of 3% [10]. Secondly, the cost of screening may have been perceived as a burden to the patients or the government in countries offering free health care to her masses. Thirdly, to date, there is no standard or uniform upper and lower limit (value) for the diagnosis of hypo and hyperthyroidism. Various nations, provinces, states, districts, and even hospitals have their range of value for diagnosing this condition, hence making it more challenging to initiate screening since some studies have shown a signi cant discrepancy in thyroid hormone value during pregnancy across races.
Considering the in uence of race and its physiologic variation, it becomes a thing of great importance to identify what works for speci c population, community, nation, and race, rather than emulating that which works for others. Two studies from China and one study from India, for example, demonstrated a signi cantly higher TSH reference range for each trimester; in particular, the study by Li et al. [11], showed that the Chinese population displays 0.12-5.08mU/l as rst-trimester reference range; as a consequence, using the suggested 0.1-2.5mU/l as reference range means that about 28% of the pregnant women in China would suffer from hypothyroidism, versus 4% when using an ethnically speci c reference range [10].
Due to the variation in thyroid hormone value across geographical location, one of the recommendations in 2017 American Thyroid Association (ATA) guideline in management of thyroid disease during pregnancy is that pregnancy-speci c population-based reference intervals should be determined locally. However, if the TSH trimester-speci c reference ranges are not available in the laboratory, the following reference range upper limits are recommended: First trimester 0.1-2.5mU/l; second trimester, 0.2-3.0mU/I; third trimester, 0.3-3.5mU/l [12]. A recent guideline recommends that, when available, the population and trimester-speci c reference ranges for serum TSH during pregnancy should be de ned by a provider's institute or laboratory and should represent the speci c population for whom care is provided. If those are not available, an upper reference limit of near 4.0mU/L may be used [1,12]. Most endocrinologists were convinced about an evident association between mild thyroid impairment and adverse outcomes in pregnancy, thus using a TSH value of 2.5mU/L as the threshold for diagnosing hypothyroidism and starting levothyroxine in pregnant women [13].
In China, the issue of standard cut-off in upper and lower value of thyroid hormone in pregnant women is not different. These values vary in various hospitals, depending on the gestational age. This reference range variation could be identi ed in Table 1 and 2 below, between Chongqing and Nanjing hospital reference range.  Diseases in Pregnancy and postpartum [15], reference range should be generated and set by various region/health institution/community as recommended below: 1. To diagnose thyroid dysfunction during pregnancy, there is need to establish a method to ascertain speci c reference range at each gestational period (early, middle and late) for serum thyroid function index (TSH, FT4, TT4).
2. The method used must be that which is recommended by National Academia of Clinical Biochemistry (NACB) to develop a reference range by choosing areas with adequate iodine, single births, no previous   thyroid disease, and thyroid gland disease. For pregnant women with negative body antibodies and no goitre, the reference range is 2.5 ~ 97.5 percentile.
Because various health care institutions have different methods and means of testing thyroid function, it is more challenging to have a harmonised reference range. The variation in the test reagents and kits was addressed by providing a pregnancy-speci c TSH and Free thyroxine(FT4) trimester reference range used in hospitals that use the same kit [16][17][18][19][20][21], as seen in Table 3. and group of people. Hence, there is a need to establish a management guideline that meets the target population's aims and goals.
In China, this management guideline was set by the endocrinology branch of the Chinese Medical Association and Perinatal medicine branch of the Chinese Medical Association to meet the expected management goals. The guideline for the management of patients in this category is shown in Table 4. In principle, no operation should be taken to treat hyperthyroidism during pregnancy. If necessary, the best time for thyroidectomy is in the second trimester of pregnancy. For pregnant women whose maternal hyperthyroidism can not be controlled or stored in high titer TRAb (3 times higher than the upper limit of the reference range) in the second half of pregnancy, fetal heart rate should be monitored from the second trimester, and fetal thyroid volume, growth and development, amniotic uid volume and so on should be examined by ultrasound. The thyroid function of newborns with high-risk factors of hyperthyroidism should be closely monitored.  times, the doctors fail to identify these patients due to limited medical and family history. As well, these patients might present without any clinical signs and symptoms that will suggest possible thyroid screening.
These missed women with thyroid dysfunction could be due to similarity in their clinical presentation of thyroid dysfunction and pregnancy physiology, such as constipation, weight gain and fatigue. According to research conducted in the Middle East, 27% of pregnant women with thyroid disease were undiagnosed by the doctors. This is also shown in the study conducted by Vaidya et al. [22] which demonstrated that focusing screening on only suspected high-risk pregnant women will lead to failure to identify and diagnose about 30% of hypothyroid and 69% of hyperthyroid women. Similarly, in China, research conducted [10,23] shows that A case-nding strategy for screening thyroid function in the high-risk group would miss about 81.6% of pregnant women with hypothyroidism and 80.4% pregnant women with hyperthyroidism.
Thyroid screening is recommended for every pregnant woman in China, because they recognised the potential danger this condition posse to pregnancy outcome, and saw the need to be proactive toward preventing such from occurring. However, no published study evaluates the outcome of this policy towards the overall wellbeing and outcome of pregnancies. This study's pregnancy outcome was divided into two, complications and non-complication, from conception to delivery. The complications examined are gestational hypertension, preeclampsia/eclampsia, abortion/miscarriage, preterm delivery, stillbirth, and intrauterine growth restriction. Other variables like gestational age, parity, gravida, age, and delivery mode were also included, as seen in Fig. 1. Women with incomplete data and inadequate follow-up during pregnancy for proper history were excluded in this study's analysis and result.
In this study, the rst trimester (T1) starts from the 1st week to 13th week + 6 days, 2nd trimester (T2) starts from 14th week to 27th week + 6 days, and the 3rd trimester (T3) starts from 28th week to 42nd week. The reference range used in the diagnosis of thyroid dysfunction in this study is trimester dependent and was adopted by Second A liated Hospital of Chongqing Medical University, and are as follow; TSH (µIU/ml) 0.35- weeks' gestation. Stillbirth was de ned as a pregnancy loss after 20 weeks' gestation. Preterm birth was a birth between 20 + 0 weeks and 36 + 6 weeks. Preeclampsia (PE) is de ned as systolic blood pressure at ≥ 140 mm Hg or diastolic blood pressure at ≥ 90 mm Hg on at least two occasions measured 4 hours apart in previously normotensive woman and is accompanied by one or more of the following new-onset conditions at or after 20 weeks gestation: proteinuria; evidence of other maternal organ dysfunction; uteroplacental dysfunction [24]. Gestational hypertension is de ned as a systolic blood pressure 140 mmHg or more or diastolic blood pressure of 90mmHg or more, or both, on two occasions at least 4 hours apart after 20 weeks of gestation, in a woman with previously normal blood pressure [25]. The most widely used de nition of IUGR is a foetus whose estimated weight is below the 10th percentile for its gestational age and whose abdominal circumference is below the 2.5th percentile. IUGR was de ned by a birth weight below the 10th percentile Participants were grouped according to the time they were diagnosed and managed, group 0 are those with history of thyroid dysfunction (G0), group 1 are those diagnose and managed at rst trimester (G1), group 2 are those diagnosed and managed at second trimester (G2), group 3 are those diagnosed and managed at third trimester (G3).
The following set of patients were not included in this study; Non-pregnant women with thyroid dysfunction, post gestational thyroid dysfunction, pregnant foreigners(non-Chinese) diagnosed with pregestational or gestational thyroid dysfunction using the hospital's facility, and patients who were diagnosed with thyroid dysfunction without a complete medical record up to delivery.
Statistical analysis, using SPSS package, was performed to compare outcome using the multiple logistic regression and binary logistic regression. The con dence interval (CI) at 95% was calculated. Level of signi cance was set at p-value < 0.05. All analyses were adjusted for potential confounders such as maternal age.

Result
A total of 10,108 pregnant women were screened, of which 774(7.66%) patients were diagnosed with thyroid dysfunction during their prenatal care from 2016-2018. Of the total number of diagnosed pregnant women, 448(4.43%) were diagnosed with subclinical hypothyroidism, 259(2.56%) were diagnosed with hypothyroidism, 36(0.36%) were diagnosed with hyperthyroidism, and 26(0.26%) were diagnosed with other thyroid diseases. Of the 774 women, only 724 have a complete history from prenatal to postpartum and were considered for the analysis, excluding 50 women with incomplete data. Women with complete data, diagnosed and managed for subclinical hypothyroidism, hypothyroidism, hyperthyroidism, and other thyroid dysfunction are 420, 246, 32, and 26, respectively. See Fig. 2 below. 79(10.9%) among these women diagnosed and managed for various thyroid dysfunction developed complication, 41(5.63%), 30(4.12%), 4(0.55%), and 4(0.55%) for subclinical hypothyroidism, hypothyroidism, hyperthyroidism, and other thyroid dysfunction respectively.
Out of 724 analysed cases, 189(26.1%) women have an existing history of thyroid dysfunction, 276 (38.1%) women were diagnosed at their rst trimester, 164(22.7%) women were diagnosed at their second trimester, and 95(13.1%) women were diagnosed at their third trimester. Among these women the following developed complication at the course of pregnancy; 21(11.1%) women with an existing history of thyroid dysfunction, 33(12%) women among those diagnosed at their rst trimester, 13(7.9%) women among those diagnosed at their second trimester, and 12(12.6%) women among those diagnosed at their third trimester. The descriptive analysis of the age distribution shows that the means age and standard deviation is 30.03 ± 4.413, with their age ranging from 18 to 47. The mean (95% CI) gestational age at delivery of all women enrolled in this study was 38.7 (38.5-38.9) weeks.
To ascertain the outcome of the management approach employed for pregnant women with a history of thyroid dysfunction or diagnosed with thyroid dysfunction after conception, we analysed the data using respectively. Also, there was no signi cant difference in maternal age, parity, and gestational age of the foetus at delivery. However, there was a signi cant difference in gravida, P-0.032(OR 1.368, 95%CI 1.028 1.821) and normal delivery mode, P-0.010(OR 2.521, 95%CI 1.246-5.100). As shown in Table 5. To examine the relationship of each complication among all the four groups with age, for subclinical Hypothyroidism and Hypothyroidism alone, we analysed this using a binary logistic regression. The result shows a signi cant difference in maternal age for abortion/miscarriage among patients diagnosed with subclinical hypothyroidism P-0.018(OR 1.459, 95%CI 1.067-1.997) and a signi cant difference in G2 for intrauterine growth restriction among women diagnosed with Hypothyroidism, P-0.048(OR-0.152, 95%CI 0.024-0.981) as shown in Table 6.  [29]. Hypothyroid women were 259(2.6%) which appears to be higher than the typical pregnancy prevalence value of 0.3%-0.5% [2,27] and as well higher than the prevalence rate of 1.0% [30]. Despite high cut-off values set by the Second A liated Hospital of Chongqing Medical University for diagnosis of hypothyroidism, the number of pregnant women with hypothyroidism appeared to be higher than what was obtained in other studies. This increase could be due to an increased Assisted Reproduction Technique application which has increased the incidence of multiply pregnancy, a risk factor to hypothyroidism [31]. Hyperthyroidism among pregnant women in this study is, 36(0.4%), which is in line with 0.1-0.4% [2]. Due to uncommon and infrequent occurrence of other thyroid dysfunction like subclinical hyperthyroidism, hypothyroxinemia, TPOA, and other thyroid dysfunction, which could lead to insigni cant and inadequate sample size, hence they were grouped together with a total of 26(0.3%).
Various authors have suggested the time of diagnosis and management of thyroid dysfunction to be a contributing factor toward the pregnancy outcome as some believe that early diagnosis and management improves the outcome of the pregnancy on both the mother and baby [27], this might be true when it comes to thyroid dysfunction and its effect on Intelligent Quotient (IQ) [32,33], but it is not within the scope of this study. The time of diagnosis and initiation of appropriate management following the hospital guideline was noted, and the patients were divided into four groups. We analysed the relationship between thyroid dysfunction in all the four groups with pregnancy outcome, and there was no signi cant difference in all the groups as it relates to thyroid dysfunction and pregnancy outcome. This shows that pregnancy outcomes for women who developed thyroid dysfunction at any pregnancy stage are favourable when immediately identi ed and managed accordingly.
To ascertain the relationship between modes of delivery for thyroid dysfunction women in all the groups, we observed a signi cant difference in normal vagina delivery. The signi cance of normal vagina delivery could be a re ection of minimal complication. However, more than 60% of caesarean sections (CS) performed in the hospital this study was conducted are elective c-section; hence, it cannot be said to measure the e cacy of the management outcome. Gravida is seen as a possible risk factor for complication among pregnant women with thyroid dysfunction, as shown in this study. For every increase in pregnancy (gravida), there is 0.368 risk of developing complication during pregnancy. Most studies do not show the relationship between gravida and pregnancy outcome among women managed for thyroid dysfunction during pregnancy. This unidenti ed in uence of gravida could be the reason why there is no special consideration among multigravida women, grand-multigravida, multiparous, and grand-multiparous in the management guideline. Primigravida and multigravida are risk factors to certain unfavourable pregnancy outcome like preeclampsia, dystocia [34,35], and abnormal foetal presentation, uterine atony, postpartum haemorrhage, placenta previa, and amniotic uid embolism [36], respectively, and should be considered while managing pregnant women diagnosed with thyroid dysfunction.
Individual analysis of each complication for women diagnosed and managed of subclinical Hypothyroidism and Hypothyroidism at various gestational ages (G0, G1, G2, G3) with maternal age showed a positive association between maternal age and abortion/miscarriage among women diagnosed and managed for subclinical hypothyroidism. Increase in maternal age by 1year increases the risk of abortion/miscarriage by 0.459 among women diagnosed and managed in-line with the guideline for subclinical hypothyroidism. The guideline does not recommend intervention with Levothyroxine (LT4) for pregnant women diagnosed with subclinical hypothyroidism, whose TSH > 2.5mu/L and higher than the lower limit of the speci c reference range (or 0.1 mu/L). When TPOAb is positive, TSH is monitored. When TPOAb is negative, there is no need to monitor TSH (Recommendation D) [37,38]. Despite efforts made to manage pregnant women diagnosed with subclinical hypothyroidism with optimum seriousness by deciding the therapeutic drugs, therapeutic targets and monitoring frequency of pregnant women with SCH to be the same as those of pregnant women with hypothyroidism, these lapses which perhaps explain the reason for the signi cant difference in abortion/miscarriage for aged women could be as a result of the recommendation that allows the therapeutic dose of LT4 to be less than that of clinical hypothyroidism during pregnancy. Depending on the degree of TSH elevation, different doses of LT4 may be given to initiate treatment (Recommendation A) [37,38]. This degree of freedom to choose, when to and how to, might sabotage the goals and objectives of SCH management in pregnancy. The mean age of 30.03 of women in this study indicates a drift towards advancing maternal age pregnancy in society and should be considered while drawing policy for thyroid dysfunction management. The signi cance of this outcome shows there is need for improvement in the management approach to curb the incidence of abortion/miscarriage among pregnant women with subclinical hypothyroidism as they advance in age.
Also, there appears to be a relationship between hypothyroidism and intrauterine growth restriction (IUGR) among women diagnosed and managed in their second trimester (G2). Our result shows for every increase in gestational age by one week, the chances of developing intrauterine growth restriction during second trimester increases by 0.848. This complication could be attributed to delayed antenatal care, as most pregnant women commence antenatal in their second trimester. It is expected that the effect of pregnancy on thyroid function will be minimal in the second trimester due to decrease in demand by the foetal system as the foetal thyroid gland develops and synthesise thyroid hormone need by the body (6).
Limitations in this study include insu cient sample size for each thyroid dysfunction, which leads to the combination of thyroiditis, thyrotoxicosis, and other thyroid dysfunction. We do not compare the outcome of management of these women with a control group. This study is not a multicentre study, hence the reason for sampling bias.
As a population-level retrospective analysis, our study can provide evidence of association only, not of causation. Over 50 women were excluded from the study due to incomplete follow-up records and could be considered a considerable sample size capable of in uencing the outcome of the study.

Conclusion
The screening of thyroid dysfunction among pregnant women and intending pregnant women has led to early identi cation of pregnant women in need of close monitoring and thyroid dysfunction management. The overall pregnancy outcome of women diagnosed and managed for thyroid dysfunction in line with the guideline for diagnosis and treatment of thyroid diseases in pregnancy and postpartum which is set by Endocrinology branch of Chinese Medical Association and Perinatal medicine branch of Chinese Medical Association shows a promising result as less complication is observed. However, more attention is needed to properly manage subclinical hypothyroidism in pregnancy, hence curbing the incidence of abortion/miscarriage. Hypothyroidism in second trimester could lead to intrauterine growth restriction when not adequately managed. Multigravida could increase the risk of complication among pregnant women with thyroid dysfunction.

Declarations
Funding: There was no funding from any institution or organisation for this study.
Con ict of interest/competing interest: The authors declare that they have no con ict of interest.
Availability of data and material Parameters needed for the study