Associations Between Overt and Subclinical Hypothyroidism in Pregnancy and Adverse Maternal and Neonatal Outcomes: A cohort study

TL;DR

This study found that hypothyroidism during pregnancy is linked to a higher risk of iron deficiency anemia at delivery but not to other major maternal or neonatal complications, likely due to effective treatment.

Contribution

The study provides new evidence on the specific association between hypothyroidism in pregnancy and iron deficiency anemia, while showing no significant links to other adverse outcomes.

Findings

Hypothyroidism during pregnancy was significantly associated with iron deficiency anemia at delivery.

No significant associations were found with gestational diabetes, hypertension, or pre-eclampsia.

Effective thyroxine therapy may explain the lack of increased risk for most adverse outcomes.

Abstract

This study aimed to determine associations between hypothyroidism during pregnancy and selected maternal and neonatal outcomes.

A retrospective, cohort study was conducted between January 2018 and December 2020 at the two main tertiary hospitals in Muscat, Oman. The study included 408 Omani pregnant women aged 18–45 years. Participants were divided into two groups: those diagnosed with overt or subclinical hypothyroidism (n = 201; exposed group) and those with normal thyroid function (n = 207; unexposed group), matched for relevant variables. Data were collected from electronic medical records to assess maternal and neonatal outcomes.

Most exposed women (94.5%) had overt hypothyroidism. No significant differences were observed between the two groups in gestational diabetes mellitus, gestational hypertension, or pre-eclampsia (P >0.05). Women with hypothyroidism had a significantly higher risk of iron deficiency anaemia at delivery (relative risk: 2.22, 95% confidence interval: 1.68–2.94; P = 0.05).

Hypothyroidism during pregnancy was not associated with an increased risk of most adverse maternal or neonatal outcomes in this cohort. This may be attributed to the effective management of hypothyroidism, as the majority of affected women were on thyroxine therapy, maintaining a clinically and biochemically euthyroid state throughout pregnancy.

Figures

Distribution of participants in the present study (N = 408).

Tables

Table 1.. Obstetric history of a sample of pregnant omani women with and without hypothyroidism (N = 408).

	Median (range)
Variable	Unexposed (euthyroid) group (n = 207)	Exposed (hypothyroid) group (n = 201)	P value
Number of pregnancies (gravidity)	4 (1–14)	4 (1–11)	0.072
Number of previous deliveries (parity)	3 (0–12)	2 (0–9)	0.153
Number of previous miscarriages*	0 (0–5)	0 (0–7)	0.079
Number of previous stillbirths†	0 (0–3)	0 (0–1)	0.172
Number of living children	3 (0–12)	2 (0–8)	0.254
Number of deceased children	0 (0–2)	0 (0–3)	0.370
Number of previous vaginal deliveries	2 (0–12)	2 (0–7)	0.041‡
Number of previous Caesarean section deliveries (elective/emergency)	0 (0–3)	0 (0–4)	0.033‡

Table 2.. Relative risk of selected maternal outcomes in a sample of pregnant omani women with and without hypothyroidism (N = 408).

	n (%)
Outcome	Unexposed (euthyroid) group (n = 207)	Exposed (hypothyroid) group (n = 201)	RR (95% CI)	P value
GDM	66 (31.9)	61 (30.3)	0.95 (0.71–1.26)	0.715
Gestational HTN	9 (4.3)	12 (6)	1.37 (0.59–3.19)	0.459
Pre-eclampsia/eclampsia	4 (1.9)	8 (4.0)	2.06 (0.63–6.73)	0.231
Miscarriage	3 (1.4)	5 (2.5)	1.71 (0.42–0.71)	0.455
Lower-segment Caesarean section	34 (16.4)	37 (18.4)	1.13 (0.74–1.73)	0.563
Iron deficiency anaemia (at delivery)	49 (23.7)	105 (52.2)	2.23 (1.69–2.94)	<0.001*}

Table 3.. Relative risk of selected neonatal outcomes in infants born to a sample of pregnant omani women with and without hypothyroidism (N = 408).

	n (%)
Outcome	Unexposed (euthyroid) group (n = 207)	Exposed (hypothyroid) group (n = 201)	RR (95% CI)	P value
Preterm delivery*	5 (2.4)	4 (2)	0.83 (0.23–3.06)	0.782
Low birth weight†	21 (10.1)	17 (8.5)	0.86 (0.46–1.55)	0.518
Macrosomia‡	4 (1.9)	2 (1)	0.52 (0.10–2.81)	0.448
Fetal death	3 (1.4)	0 (0)	0.15 (0.01–2.86)	0.206
Low APGAR score	4 (1.9)	6 (3)	1.56 (0.45–5.45)	0.485
Required resuscitation	4 (1.9)	5 (2.5)	1.30 (0.35–4.77)	0.691
SCBU/NICU admission	7 (3.4)	10 (5)	1.49 (0.58–3.73)	0.411
Abnormal cord TSH levels¶	2 (1)	0 (0)	0.21 (0.01–4.31)	0.310

Full text

1. Introduction

Thyroid disorders represent some of the most prevalent endocrine disorders worldwide; in women of reproductive age, thyroid disease is the second most common endocrine disorder after diabetes mellitus.^1^ Within this group of disorders, hypothyroidism emerges as the foremost thyroid-related disorder in pregnancy, affecting approximately 3–5% of all pregnant women.^23^ Maternal hypothyroidism is characterised by a decrease in thyroid hormone production and is divided into two primary types: overt or sub-clinical hypothyroidism.^1^ The former is diagnosed when there is a deficiency of thyroid hormones, denoted by low free thyroxine (FT4) levels and elevated thyroid-stimulating hormone (TSH) levels; conversely, the latter pertains to individuals who display no discernible symptoms, yet possess elevated TSH levels alongside normal FT4 levels.^145^ The global prevalence of sub-clinical hypothyroidism in pregnant women ranges from 2–3%, whereas overt hypothyroidism is less common (0.3–0.5%).^34^

During a typical pregnancy, the thyroid gland undergoes considerable strain as the hypermetabolic state prompts a notable 50% surge in thyroid hormone and iodine production and demand; failure to adequately acclimate to these changes can precipitate hypothyroidism.^6^ It is important to note that fetal thyroid function commences in approximately the 12^th^ week of gestation. Prior to this juncture, the fetus relies upon the transference of maternal thyroid hormones across the placenta for proper development. Maternal thyroid hormones, therefore play a crucial role in early pregnancy, facilitating neural proliferation and migration, while also contributing substantively to the development of the fetal brain.^67^

Routine hypothyroidism screening during pregnancy remains controversial. While the American College of Obstetricians and Gynaecologists (ACOG) discourages this practice, the American Thyroid Association (ATA) advocates for targeted screening in high-risk cases, such as patients with goiter, autoimmune diseases, or a familial history of autoimmune thyroid diseases, patients currently undertaking thyroid therapy, as well as those with a past history of neck radiation or who have previously given birth to an infant with thyroid disease.^89^ In accordance with the 2011 ATA guidelines, trimester-specific reference ranges for TSH values are 0.1–2.5 mIU/L in the first trimester, 0.2–3.0 mIU/L in the second trimester, and 0.3–3.5 mIU/L in the third trimester.^1011^

Various studies conducted worldwide have yielded diverse outcomes concerning the relationship between maternal hypothyroidism and a range of adverse fetal and maternal outcomes. In mothers, maternal hypothyroidism has been associated with an increased likelihood of Caesarean section delivery, placental complications, pre-eclampsia and gestational hypertension (HTN).^1213^ Furthermore, there is evidence to suggest that maternal hypothyroidism may increase the risk of miscarriage and stillbirth.^141516^ In turn, fetal complications associated with maternal hypothyroidism include prematurity, low birth weight, admission to the neonatal intensive care unit (NICU) and congenital hypothyroidism.^12141718^ Some studies have revealed associations with compromised fetal neuropsychological development, a heightened susceptibility to congenital malformations and increased perinatal mortality.^192021^

To date, only one study has been conducted in Oman investigating the implications of hypothyroidism during pregnancy on maternal and neonatal outcomes.^22^ Additionally, there is a lack of research originating from other countries in the Middle Eastern region, where population size and pregnancy rates differ considerably compared to Western populations.^18^ Therefore, the present study was warranted to further elucidate correlations between maternal hypothyroid status and specific maternal and neonatal outcomes. It was hypothesised that maternal hypothyroidism (overt or subclinical) would be associated with increased risk of adverse maternal and neonatal outcomes in a population of pregnant Omani women. Findings from this study could contribute to the development of antenatal recommendations tailored to Omani pregnant women with hypothyroidism.

2. Methods

2.1. Study design and population

A retrospective cohort study was conducted from January 2018 to December 2020 at the two main tertiary hospitals of Oman, the Royal Hospital and Sultan Qaboos University Hospital (SQUH). The exposed group consisted of pregnant Omani women who had been clinically diagnosed with hypothyroidism (either overt or subclinical) and were followed-up and gave birth at the designated study hospitals. To establish a comparison, a matched non-exposed group of pregnant Omani pregnant women with normal thyroid function was also recruited. Both groups were selected based on identical baseline characteristics and were subject to the same inclusion and exclusion criteria. The sole distinguishing feature between groups was thyroid function status (i.e., the presence or absence of hypothyroidism).

2.2. Inclusion and exclusion criteria

The target population consisted of Omani women aged 18 to 45 years with spontaneous singleton pregnancies. For participants in the exposed group, only women who had been clinically diagnosed with overt or subclinical hypothyroidism either during or prior to pregnancy were included. The diagnosis was confirmed through thyroid function tests, utilising trimester-specific TSH reference levels.^1011^ All women in the exposed group were currently taking medications to treat hypothyroidism, as indicated by their medical health records. However, it is important to note that the study incorporated both patients with well-controlled hypothyroidism and those with poorly controlled hypothyroidism.

Exclusion criteria were rigorously applied to all participants, regardless of group allocation. Women with pre-existing diseases directly affecting pregnancy outcomes were eliminated, such as hyperthyroidism, diabetes mellitus, HTN, uterine fibroids, polycystic ovarian syndrome, autoimmune diseases, hereditary blood disorders or malignancies. Furthermore, the study excluded women with pregnancies conceived through fertility treatments, those with multiple gestation (i.e., more than one fetus) and those lost to follow-up during the study period.

2.3. Sample size and recruitment

Using an online sample size calculator, the total sample size required for the study was calculated to be 398, evenly distributed with 199 participants in each of the two groups: the exposed (hypothyroid) group and the matched unexposed (euthyroid) group. This was determined based on the projected occurrence of complications, including preterm delivery, stillbirth, Caesarean section delivery and admission to the NICU or special care baby unit (SCBU). Based on a comprehensive literature review, the anticipated proportion of complications within the exposed group was deemed to be ~20% versus ~10% in the unexposed group. The ratio of participants in the exposed and unexposed groups was set at 1:1, with a confidence interval (CI) of 95% and selected power of 80%. Eligible participants were selected randomly, ensuring that the required sample size was achieved while maintaining a 1:1 ratio between exposed to unexposed participants.

2.4. Study outcomes

The primary objective of the study was to investigate the association between hypothyroidism during pregnancy and selected maternal and neonatal outcomes. Maternal outcomes encompassed a range of complications, including miscarriage, intrauterine fetal death (IUFD), gestational diabetes mellitus (GDM), gestational HTN, pre-eclampsia, preterm delivery and mode of delivery. Miscarriage was defined as the spontaneous loss of a pregnancy before the 20^th^ week of gestation, while IUFD was defined as the absence of life in utero thereafter. GDM was defined as any degree of glucose intolerance that emerged or was first recognized during pregnancy, with a positive 2-hour 75 g oral glucose tolerance test, either while fasting (≥5.1 mmol/L or ≥92 mg/dL) and/or two-hour postprandial (≥8.5 mmol/L or ≥153 mg/dL).^23^

Gestational HTN was identified by elevated blood pressure readings first noted after the 20^th^ week of gestation, in the absence of proteinuria or new signs of end-organ dysfunction. Pre-eclampsia was defined as gestational HTN accompanied by the onset of one or more of the following conditions: proteinuria (urine protein-to-creatinine ratio of ≥30 mg/mmol, albumin-to-creatinine ratio of ≥8 mg/mmol or ≥1 g/L [2+] on dipstick testing) or other maternal organ dysfunction such as renal insufficiency (creatinine level of ≥90 μmol/L), evidence of liver involvement (elevated alanine aminotransferase or aspartate aminotransferase levels of >40 IU/L, with or without right upper quadrant or epigastric abdominal pain), pulmonary oedema, altered mental status, blindness, stroke, clonus, severe headaches or persistent visual scotomata and haematological complications, including thrombocytopenia (platelet count of ≤150,000/μL), disseminated intravascular coagulation, or haemolysis. Iron deficiency anaemia at delivery was also evaluated (defined as a haemoglobin level of ≤11gm/dL).^23^

Studied neonatal outcomes included prematurity (defined as birth before the 37^th^ week of gestation), birth weight (with microsomia defined as <2.5 kg and macrosomia ≥4 kg), low APGAR scores (<7), admission to the NICU/SCBU, and abnormal fetal cord TSH levels (>25 mIU/L).^23^ In addition to these primary outcomes, the study also aimed to explore potential associations between hypothyroidism during pregnancy and various maternal sociodemographic variables as secondary outcomes, including age, parity and place of residence.

2.5. Data collection

The primary method of data collection involved accessing the patients' electronic health records. These records were obtained via the Al-Shifa software program (Ministry of Health, Muscat, Oman) used by the Royal Hospital and the TrackCare® system (InterSystems, Cambridge, MA, USA) used by SQUH. These software programs serve as a comprehensive platform for healthcare providers to record patient details, including sociodemographic information, current and previous pregnancy details, vital measurements at each visit, outcomes of postnatal follow-up visits (inclusive of pregnancy outcomes), medical procedures and the results of blood tests. Moreover, these systems link newborns to their respective mothers, thereby enabling the researchers to gather pertinent data regarding specific neonatal outcomes. To identify participants diagnosed with hypothyroidism, the health records system was used to retrieve individuals based on the relevant International Classification of Disease-10^th^ edition codes utilised by healthcare professionals to assign accurate clinical diagnoses to patients.

2.6. Statistical analysis

The data analysis was carried out utilising the Statistical Package for the Social Sciences (SPSS) software, Version 29 (IBM Corp., Armonk, NY, USA). Descriptive statistics (including percentages, medians, and ranges) were used to present various sociodemographic and clinical pregnancy characteristics of the participants, since they were categorical variables. To evaluate potential associations between hypothyroidism and adverse maternal and neonatal outcomes, crude odds ratios were calculated. These ratios facilitated comparisons between the exposed and unexposed groups. Statistical significance was determined using Pearson's Chi-squared (χ ^2^) test. A P value of ≤0.05 was considered statistically significant.

2.7. Ethical considerations

Ethical approval for this study was obtained from two authoritative bodies: the Research and Ethical Review and Approval Committee of the Directorate General of Planning and Studies, Ministry of Health, Muscat, Oman, as well as the Medical Research and Ethics Committee of the College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman. Patient consent was not deemed necessary for this study given that all personal identifiers were removed and the study data was fully anonymized.

3. Results

A total of 408 pregnant Omani women were included in the study, of which 178 women (43.6%) received care at the Royal Hospital, while the remaining 230 women (56.4%) were followed-up at SQUH. The exposed group consisted of 201 women (49.3%) with hypothyroidism while the unexposed group comprised 207 women (50.7%) with normal thyroid function. In the exposed group, 190 women (94.5%) had been diagnosed with overt hypothyroidism, while 11 women (5.5%) had subclinical hypothyroidism (TSH levels of ≥2.5 mIU/L) [Fig. 1]. Participants originated from various regions in Oman, including Muscat (n = 251, 61.5%), Al Batinah South (n = 83, 20.3%), Ad Dakhiliyah (n = 33, 8.1%) Al Batinah North (n = 26, 6.4%), Al Sharqiyah North (n = 10, 2.5%), Ad Dhahirah (n = 4, 1%) and Dhofar (n = 1, 0.2%). Within the unexposed group, the majority of participants were aged 41–45 years (n = 80, 38.6%); conversely, within the exposed group, most participants were aged 36–40 years (n = 67, 33.3%). This disparity in age distribution was statistically significant (P <0.001).

Distribution of participants in the present study (N = 408).

Significant differences between the unexposed and exposed groups were noted with regards to number of previous vaginal deliveries (median [range]: 2 [0–12] versus 2 [0–7]; P = 0.041) and number of previous Caesarean section deliveries (median [range]: 0 [0–3] versus 0 [0–4]; P = 0.033). No significant differences were observed with regards to other obstetric characteristics, including gravidity, parity, number of previous miscarriages, number of previous stillbirths, number of deceased children and number of living children. In addition, no significant differences were observed between the groups in terms of frequency of a previous history of GDM (17.6% versus 12.5%; P = 0.167), gestational HTN (2.9% versus 4.5%; P = 0.441) or pre-eclampsia (0.5% versus 1.5%; P = 0.367) [Table 1].

There were no statistically significant differences observed between the exposed and unexposed groups in terms of GDM, gestational HTN and pre-eclampsia/eclampsia. Similarly, with regards to pregnancy outcomes, no significant difference was found between the two study groups concerning risk of miscarriage or delivery by Caesarean section. However, compared to the unexposed group, pregnant women with hypothyroidism were twice as likely to experience iron deficiency anaemia at the time of delivery (relative risk [RR] = 2.23, 95% CI: 1.69–2.94; P <0.001) [Table 2].

Newborns born to mothers with hypothyroidism were less likely to be born prematurely (RR = 0.83, 95% CI: 0.23–3.06), be of low birth weight (RR = 0.86, 95% CI: 0.46–1.55), exhibit macrosomia (RR = 0.52, 95% CI: 0.010–2.81), or have abnormal cord TSH levels (RR = 0.21, 95% CI: 0.01–4.31) compared to those born to mothers with normal thyroid function. Conversely, these neonates exhibited a slightly elevated likelihood of having low APGAR scores at delivery (RR = 1.56, 95% CI: 0.45–5.45), requiring resuscitation (RR = 1.30, 95% CI: 0.35–4.77) and admission to the NICU/SCBU (RR = 1.49, 95% CI: 0.58–3.73). However, none of these associations reached the threshold for statistical significance [Table 3].

4. Discussion

In the present study, the vast majority of pregnant Omani women with hypothyroidism were found to suffer from overt rather than sub-clinical hypothyroidism (94.5% versus 5.5%). This finding is in direct contrast to international prevalence data, which typically shows that sub-clinical hypothyroidism is more common.^2^ The precise reasons for this discrepancy are unknown; however, thyroid function is believed to be subject to a range of influences, including nutritional iodine intake, environmental factors, dietary patterns, lifestyle habits and genetic disposition, which can vary across different populations.^24^

In particular, iodine deficiency is a potential risk factor for overt hypothyroidism, especially in pregnancy as a result of increased iodine requirements.^25^ Without sufficient iodine, the thyroid gland cannot produce adequate levels of thyroid hormones, leading to hypothyroidism. Previous research has shown that Omani women of reproductive age frequently suffer from a variety of micronutrient deficiencies, although iodine status was not specifically reported.^26^ However, as part of the World Health Organization's Regional Nutritional Strategy for 2020–2030, several Middle Eastern countries, including Oman, have initiated mandatory salt iodisation, a strategy found to have increased median urinary iodine concentration in schoolchildren.^2728^ Conversely, in individuals with autoimmune thyroid disorders such as Graves' disease or Hashimoto's thyroiditis, high iodine levels can exacerbate the autoimmune response and lead to hypothyroidism.^29^ Further research is therefore recommended to assess nutritional iodine intake and the presence of thyroid peroxidase and thyroglobulin antibodies in pregnant Omani women with hypothyroidism. At present, iodine status assessment and autoimmune marker testing are not routinely performed during pregnancy in Oman, as there is insufficient evidence to recommend their universal use; future studies are warranted to clarify their role in guiding screening and management strategies.

The guidelines of the ATA include age of >30 years as one of the risk factors for hypothyroidism in pregnancy.^11^ Notably, the present study identified a high prevalence of pregnant Omani women aged 36–40 years in the exposed group. A similar study from Turkey indicated a positive correlation between maternal age and elevated TSH levels in the third trimester of pregnancy.^30^ This suggests that age may play a role in the development of hypothyroidism, with women in their late thirties to early forties being at higher risk. The correlation between elevated TSH levels and maternal age further supports the idea that age is a factor in thyroid dysfunction in general.^31^ These findings highlight the importance of considering age as a potential risk factor and conducting further research to better understand the relationship between age and hypothyroidism.^32^

In the current study, no statistically significant differences in gravidity, parity, rates of past miscarriage and stillbirth, or mode of delivery were observed between euthyroid and hypothyroid participants. Interestingly, however, previous research has shown that women with hypothyroidism are more likely to report a history of delivery by lower-segment Caesarean section compared to euthyroid participants (P = 0.012).^33^ Similarly, Mahajan et al. reported that the rate of Caesarean section delivery was 1.38-times higher in pregnant Indian women with thyroid disorders compared to euthyroid subjects.^34^ This association was also supported by findings from a retrospective observational cohort study (2006-2016) in Malta (P = 0.043).^35^ This discrepancy in findings may be attributed to differences in the prevalence of uncontrolled hypothyroidism which can increase the incidence of fetal distress during labour, thereby necessitating Caesarean section delivery. Similarly, Mahajan et al. also noted that pregnant women with hypothyroidism in India had a significantly higher occurrence of miscarriage.^34^ Another cohort study targeting Asian-Indian population demonstrated that untreated hypothyroidism, whether subclinical or overt, at the time of conception was associated with a miscarriage rate of 31.4% compared to 4% in euthyroid subjects.^36^

Anaemia status was the only maternal factor found to be significantly different between the exposed and unexposed groups in the present study. In particular, pregnant Omani women diagnosed with hypothyroidism were found to have a two-fold increased risk of anaemia during delivery in comparison to pregnant women with normal thyroid function (P <0.001). A meta-analysis conducted in 2020 supported this finding, indicating that both treated and untreated hypothyroidism poses a risk for anaemia during the latter half of pregnancy.^37^ However, the biological basis for this association remains incompletely understood; proposed mechanisms include reduced erythropoietin production, impaired iron utilization, and concurrent autoimmune processes that may affect both thyroid and hematologic function.^38^ In pregnancy, physiological haemodilution and increased iron demand may exacerbate these effects, making women with thyroid dysfunction more vulnerable to clinically significant anaemia.^39^ Consequently, while anaemia emerged as a significant and plausible association, other clinically relevant outcomes may have been missed due to insufficient statistical power, highlighting the need for larger, prospective studies to fully elucidate the maternal and neonatal risks associated with overt and subclinical hypothyroidism in pregnancy.^40^

No significant differences were observed in neonatal outcomes between the two groups. This is consistent with results from a recent study (2020) in Saudi Arabia, which reported that rates of preterm delivery, abnormal birth weight, and low APGAR score were not significantly different between hypothyroid and euthyroid mothers, although NICU admission was significantly associated with maternal hypothyroidism.^18^ Although NICU admission was more frequent for infants born to mothers with hypothyroidism in the present study, this association did not reach statistical significance. An observational study from India also reported that low birth weight and NICU admission as significant fetal complications observed in maternal hypothyroidism.^33^ Furthermore, the Turkish study indicated that rates of neonatal complications were related to uncontrolled TSH levels, with TSH values of >2.5 mIU/L being associated with preterm delivery.^29^ This may explain why the rate of complications in the exposed group was not significant in the present study, given that the majority of patients had controlled TSH levels.

To ensure a healthy pregnancy, it is important to correct hypothyroidism prior to conception and initiate appropriate thyroxine replacement therapy promptly in early pregnancy, thereby allowing the patient to maintain an euthyroid state throughout pregnancy. Levothyroxine currently stands as the primary treatment modality for managing maternal hypothyroidism.^41^ In the present cohort, the majority of patients with hypothyroidism achieved euthyroid status during conception by using corrective doses of thyroxine, a factor that plausibly attenuated detectable association between thyroid dysfunction and adverse maternal and neonatal outcomes. This may explain the lack of significant differences observed in the incidence of GDM, gestational HTN, and pre-eclampsia between the two groups. Moreover, cases of overt and subclinical hypothyroidism were combined in the analysis as the exposed group due to the small number of cases with a subclinical disease status compared to those with an overt status. However, previous research has shown that Omani patients with hypothyroidism tend to show low-to-medium rates of adherence to levothyroxine treatment.^42^ Therefore, women with hypothyroidism wishing to conceive should be warned of the importance of medication compliance in order to maintain an euthyroid state. In addition, there is some evidence to suggest that levothyroxine dose may need to be increased during pregnancy for women with pre-existing treated hypothyroidism.^43^

The retrospective design limited verification of key treatment details, including adherence, dosing regimens, timely dose adjustments and achievement of trimester-specific TSH/FT4 targets, all of which influence outcomes in treated women. International and regional guidelines recommend rapid titration and pregnancy-appropriate TSH targets, with higher levothyroxine requirements early in gestation.^2344^ Missing granular treatment and monitoring data as well as inconsistent documentation of laboratory reference ranges despite national guidelines, may have led to misclassification and residual confounding. Thus, the findings reflect outcomes in a predominantly treated population rather than untreated overt or subclinical hypothyroidism in pregnancy. Future prospective studies with precise documentation are needed to clarify the true impact of thyroid dysfunction on pregnancy outcomes. Importantly, the forthcoming ATA 2025 guidelines, particularly regarding the management of subclinical hypothyroidism, are expected to influence clinical practice and outcomes and the present study provides valuable baseline data ahead of these anticipated changes.

Given these considerations, public health strategies should prioritise increasing awareness among women of reproductive age regarding the risks of uncontrolled hypothyroidism during pregnancy, emphasizing the need for preconception counselling and treatment optimisation. Screening programs in line with national Omani guidelines and international recommendations should be implemented to identify and manage thyroid dysfunction early, with particular focus on high-risk groups, to minimise adverse maternal and neonatal outcomes.

4.1. Study strengths and limitations

To the best of the authors' knowledge, this is the first retrospective cohort study that reports maternal and neonatal outcomes among pregnant women with hypothyroidism in Oman, conducted at the two main tertiary hospitals in Oman catering to patients from all regions of the country, thereby providing findings that may be considered nationally representative. Moreover, the results of this study lay the foundation for a more nuanced understanding of factors affecting maternal and neonatal outcomes in the context of hypothyroidism. However, the methodology used in this study may be subject to certain important limitations. In particular, because the study data were derived from patients' health records, there was a substantial proportion of missing information, including body mass index, nutritional status, socioeconomic status, treatment adherence, and indications for Caesarean sections. Moreover, there is a possibility of missed cases and potential misclassification due to coding errors or incorrect diagnosis entries. Although the sample size met the a priori calculated requirement, it may still be considered modest compared to larger international cohorts. This may limit the ability to detect less common outcomes and reduce the generalizability of findings beyond the national context. Autoimmune status of affected women was not consistently recorded in the electronic health records. It could therefore not be included in the present analysis, which may have limited the ability to assess its potential association with the study outcomes. Finally, it is essential to note that the results from this study only establish associations between variables; no definitive causal relationship can be drawn from any of the analyses described herein.

5. Conclusion

Thyroid disorders, considered one of the most prevalent endocrine disorders, are commonly observed in pregnancy. This study revealed no significant difference between a group of pregnant Omani women with hypothyroidism compared to a matched euthyroid group in terms of miscarriage rates, incidence of gestational DM, gestational HTN, pre-eclampsia, Caesarean section delivery and neonatal outcomes. However, women with hypothyroidism had a 2-fold increased risk of anaemia at the time of delivery, a factor which in itself could have a potential adverse impact on both maternal and fetal health. The results of the present study highlight the importance of early detection and optimal management of hypothyroidism at conception and throughout pregnancy, and support targeted antenatal monitoring, including anaemia screening and management, to reduce preventable complications.

Authors' Contribution

Rahma Al Kindi: Conceptualization, Methodology, Formal analysis, Writing - Original Draft preparation, Writing - Review & Editing, Supervision. Noof Al Ghamari: Conceptualization, Methodology, Investigation, Software, Formal analysis, Writing - Original Draft preparation. Amina Al Malki: Conceptualization, Methodology, Investigation, Software, Formal analysis, Writing - Original Draft preparation. Aida Al Ismaili: Conceptualization, Writing - Original Draft preparation, Supervision. Hana Al Sumri: Methodology, Formal analysis, Writing - Review & Editing, Supervision.

Acknowledgment

The authors wish to thank all of the women who participated in this study. They are also grateful to the staff at the Department of Obstetrics and Gynaecology at SQUH for their cooperation with the data collection procedures. A preprint version of this manuscript was posted online on 22nd February 2024 at https://doi.org/10.21203/rs.3.rs-3935815/v1.

Ethics Statement

Ethical approval for this study was obtained from two authoritative bodies: the Research and Ethical Review and Approval Committee of the Directorate General of Planning and Studies, Ministry of Health, Muscat, Oman (MoH/CSR/21/24931), as well as the Medical Research and Ethics Committee of the College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman (SQU-EC/588/2021). Patient consent was not deemed necessary for this study given that all personal identifiers were removed and the study data was fully anonymised.

Conflict of Interest

The authors declare no conflicts of interest.

Funding

No funding was received for this study.

Data Availability

Data is available upon reasonable request from the corresponding author.