Our study found maternal age, gestational age at antenatal visit, and history of miscarriages, as major maternal factors significantly affecting pregnancy outcomes in hypothyroid mothers, whereas the presence of gestational diabetes and hypothyroidism had a favourable effect.
There is sufficient evidence to support the effect of increasing maternal age on obstetric outcomes. In a study of 534 pregnant women, there was an independent association of risk of miscarriage among women older than 35 years of age (7.7%), although only 16 patients had increased TSH (30). Therefore, an older hypothyroid pregnant woman is at higher risk of adverse obstetric outcomes than a younger woman as also evident from our findings.
Data is scarce on the effect of the previous history of miscarriages as an independent factor for pregnancy loss or adverse pregnancy outcome in hypothyroid women. The subsequent pregnancy rate did not differ between the subclinical and euthyroid pregnant groups (55.4%, 31/56 vs 51.3%, 134/261, respectively) in a retrospective study, although the pregnancy loss rate (< 22 weeks of gestation) tended to be higher in the borderline-subclinical hypothyroid than the euthyroid group (29.0%, 9/31 vs 17.9%, 24/134; P = 0.16) (31). Similar results were reported in another study including those treated or untreated (32). However, there is plenty of data on the association of recurrent miscarriages and hypothyroidism (33). We need to analyse the findings in our study with prospective study designs in the future.
There is a significant association of hypothyroidism as a maternal factor affecting pregnancy outcomes in our study population. Several studies report an adverse effect on the fetal outcome due to the presence of thyroid disorders, especially hypothyroidism (21, 34). On the other hand, data also contradict this finding with studies describing no significant effect on pregnancy loss when compared with normal pregnant women (35, 36). Although, our study also did not support these findings, however, being diagnosed as hypothyroid was in fact, counter-protective. TSH levels remained in nearly euthyroid range in our population, as in most cases they were timely initiated on treatment. However, we do not have our trimester-specific ranges of TSH, therefore the clinical significance of these cut-offs is under the guidance of ATA. There was no difference in the outcomes of whether our women were diagnosed with hypothyroidism before or during pregnancy. There was also no difference in the outcomes of women whether they have overt or subclinical hypothyroidism in our population. The only exception was related to GDM, in women with subclinical hypothyroidism, as we have no GDM in overt hypothyroidism women. Carefully, analysing these findings further in large multicentre prospective trials is required to assess if this is because of our special obstetric care in such patients and other patient-based factors, or as they were timely started on levothyroxine treatment.
In a Chinese study, comparing the effects of different diagnostic criteria of subclinical hypothyroidism on pregnancy outcomes, the incidence of miscarriage, premature delivery, gestational hypertension and gestational diabetes mellitus (GDM) in the American Thyroid Association (ATA) based groups had statistically significant differences (p-value of < 0.05) when compared with the control group (2, 37). Two decades back, Gonzalez et al. showed that 26% of pregnant women with type 1 diabetes and 4% of healthy pregnant women had thyroid dysfunction. (38) Similarly, in another study by Ortega-Gonzalez et al, there were 50 healthy pregnant women, 50 GDM women and 50 pregnant women with type 2 diabetes, the thyroid peroxidase antibodies (TPO Ab) > 251 U/ml ( strongly positive) was found in 10% of healthy women, 10% of pregnant women with type 2 diabetes and 6% in women with GDM without statistically significant difference (39). One of the recent studies, however, described that the rate of thyroid dysfunction in GDM patients is similar to normal pregnant control women (40). The presence of these dual endocrinopathies is also analysed in pregnant women for several adverse pregnancy-related outcomes, with one of the studies reporting a significant rate of spontaneous first trimester abortions (9.3%) as compared to either comorbidity alone (41, 42). Interestingly, most studies are redundant to describe the independent association of these maternal factors with pregnancy loss. Moreover, studies are assessing the risk of developing GDM in hypothyroid pregnancies, rather than evaluating GDM as an independent factor affecting pregnancy outcomes in hypothyroid pregnant women, which is described in our study (43–45). Our data reported a significant protective effect of the presence of GDM in hypothyroid women (subclinical cases) with respect to pregnancy outcome. We assume this difference may be due to the presence of a separate health care system established for patients with GDM in our hospital, as we have a combined maternal diabetes clinic setup including multidisciplinary experts dealing with these groups of patients.
A limited amount of data is present on the timing of the first visit (the gestational age) at the healthcare centre by hypothyroid pregnant women. Jahan et al. however, did not find a statistically significant association between first-trimester pregnancy loss and high normal TSH level (Pearson Chi-square = 2.01, p = 0.1558) from Bangladesh (46). However, in our study, many patients were diagnosed with hypothyroidism before conception and were already on levothyroxine replacement. Although, majority of them did not have their preconception TSH levels measured (which is also our limitation due to retrospective study design), still those who presented early (second trimester) were more likely to have pregnancy loss compared to those who presented late (third trimester).
Our study had several limitations. Firstly, it was a retrospective study design due to which we could not compare all maternal characteristics between the study and control groups. Secondly, hypothyroidism and GDM as comorbidities providing favourable effect, need further analysis based on large randomized control trials, which in itself remains an ethical limitation in the obstetric population. However, this is the first study of its kind from Pakistan, and we had taken a good sample size for analysis and interpretation. Further, we recommend prospective cohort and case-control studies to assess risk factors for pregnancy loss catering to a large representative sample in our region.