Association between thyroid dysfunction and perinatal outcomes in women with gestational hypertension: a retrospective study

Preeclampsia is a major public health problem due to its frequency as well as its related maternal and perinatal morbidity and mortality, with a prevalence of 4.6% among pregnant women worldwide [1]. It is not only associated with adverse pregnant outcomes, but also contribute to higher risk of cardiovascular diseases, renal failure, type 2 diabetes mellitus, hypothyroidism and cognitive defects in future [2]. Furthermore, children born from preeclamptic pregnancies are more prone to hypertension, insulin resistance and diabetes mellitus, neurological complications, stroke, and mental disorders in their later lives [2].

Thyroid dysfunction is common among pregnant women. According to previous reports, the prevalence of clinical overt hyperthyroidism or subclinical hyperthyroidism is about 0.1–0.4% during pregnancy. The prevalence of hypothyroidism is about 2.5%, with clinical hypothyroidism accounting for 0.2–0.3%, and subclinical hypothyroidism for 2–3% [3, 4], while hypothyroxinemia for 1–2% [5]. According to domestic reports in China, the prevalence of gestational clinical hypothyroidism is approximately 0.5–0.6%, with subclinical hypothyroidism 2–3%, and hypothyroxinemia 1.6%. The prevalence of subclinical hypothyroidism is the highest.

Hypothyroidism is known to be one of the causes of hypertension [6]. Both untreated subclinical hypothyroidism and overt hypothyroidism are associated with multiple adverse outcomes in the mother and fetus [3, 7‐23]. Women with treated hypothyroid diseases are not at higher risk than healthy pregnant women for adverse neonatal outcomes, but may also be at increased risk for preeclampsia [24]. However, Casey et al. do not find any increased incidence of preeclampsia in subclinical hypothyroid women [3]. Medici M et al. [25] have found that biochemical hyperthyroidism but not hypothyroidism during early pregnancy is associated with an increased risk of hypertensive disorders.

Therefore, the relationships between thyroid dysfunction and pregnancy outcomes in preeclampsia still needs to be clarified. It is known that the placental dysfunction is more likely to occur in the early onset preeclampsia at < 34 weeks of gestation [26, 27] and early onset preeclampsia conferred a substantially higher risk of cardiovascular [28], respiratory, central nervous system, renal, hepatic, and other morbidity [29]. However, in most previous studies, thyroid hormones were measured before 20 weeks of pregnancy. Associations of thyroid hormones measured in the second half of pregnancy in different subtypes of preeclampsia (mild and severe preeclamptic women as well as early onset and late onset women) and neonatal outcomes of pregnancy (rates of preterm birth and low neonatal birth weight) remained unclear and were investigated in the study.

In this retrospective case-control study, we found that patients with severe preeclampsia, early onset preeclampsia or thyroid dysfunction had higher risk of adverse maternal and fetal outcomes such as preterm birth and low neonatal birth weight. Our data show that the rates of preterm birth and thyroid dysfunction were the highest in the patients with EPE. Although we could not find significant differences between EPE and PIH groups in the rates of thyroid dysfunction (71.9% vs. 56.7%), giving more emphasis on the thyroid hormones in those patients with EPE might reduce some adverse maternal and fetal outcomes.

Preeclampsia is one of the major causes of maternal and perinatal death [33]. To better manage this disease, we need to improve our knowledge to better identify patients with preeclampsia at increased risk for adverse outcomes. In this study, most maternal adverse outcomes happened in patients with SPE or EPE. We found that BNP was significantly higher in these two groups which was in accordance with the symptoms. However, we did not find any difference among these groups in blood lipids. Most previous studies have found that thyroid dysfunction occurs more frequently in women with preeclampsia than in normal pregnant women [8, 18], and is associated with many adverse pregnant outcomes such as spontaneous abortion, intrauterine fetal death, preterm birth, and low birth weight etc. [3, 7, 11‐13, 16, 17, 34] Our results are in accordance with these previous studies.

Hypothyroidism has been shown to have various vascular pathogenic effects, including endothelial cell dysfunction [35] which is also a pathophysiological basis of gestational hypertension. A study including 16,364 singleton births hypothyroid mothers in Finland found that maternal hypothyroidism was associated with higher risks of gestational hypertension (OR = 1.20, 95% CI [1.10–1.30]), severe preeclampsia (OR = 1.38, 95% CI [1.15–1.65]), preterm births (OR = 1.25, 95% CI [1.16–1.34]), major congenital anomalies (OR = 1.14, 95%CI [1.06–1.22]), and neonatal intensive care unit admission (OR = 1.23, 95% CI [1.17–1.29]) [36]. Surks et al. [37] showed that increased maternal serum TSH (higher than 10 mIU/L) was associated with increased risk of stillbirth. A study including 25,756 women conducted by Casey and colleagues [3] revealed that subclinical hypothyroidism in pregnancies was associated with a 3-fold increased risk of placental abruption (relative risk 3.0, 95% CI [1.1–8.2]). The risk of preterm birth was almost 2-fold higher in women with subclinical hypothyroidism than in those without (relative risk, 1.8, 95% CI [1.1–2.9]). Another study showed that the incidence of premature birth, low birth weight and neonatal asphyxia was significantly higher in pregnant women with hyperthyroidism than that in normal pregnant women [38]. In our study, only two types of thyroid dysfunction - i.e. hypothyroidism and FT3 and FT4 both below the normal lower limit - were found to be significantly associated with increased risk of low neonatal birth weight. The rate of hyperthyroidism was rare in this population. It might be due to the small sample size of our study or the racial differences of different studies.

Many studies focused only on the first trimester [9, 19, 25, 39, 40], and did not include all preeclampsia types [41]. The present study investigated thyroid hormones of women with gestational hypertension in the second half trimester and compared various types of preeclampsia according to the severity and the gestational age. Our results were also in consistency with other studies in the second half trimester. A study including 6031 mothers showed that after normalization of the thyroid hormones with appropriate treatment in women developing hypothyroidism in the first trimester, there was no significant difference in the risk of developing preeclampsia compared with the normal pregnant women. However, if the women developed hypothyroidism in the third trimester, they still had a 2.18-fold higher risk of developing preeclampsia [34]. A prospective study in China [42] including 3398 pregnant women found that isolated maternal hypothyroxinemia (IMH) in the first trimester did not increase the risk of adverse outcomes irrespective of whether women received L-thyroxine treatment or not. However, IMH identified in the second trimester was associated with a significantly increased risk of adverse pregnancy outcomes. The results suggest that thyroid function follow-up during the second trimester is necessary, even if thyroid function is normal during the first trimester. Therefore, comprehensive monitoring of thyroid hormones throughout the whole pregnancy and early treatment are very important to reduce the risk of preterm birth and low birth weight. Consequently, the rate of neonatal intensive care unit will be decreased and the burden to the family and the society will also be reduced. Thus, it might be helpful to test thyroid hormones in women with preeclampsia in all three stages, treatment should be initiated as early as possible by thyroid dysfunction to avoid adverse pregnant outcomes.

Our study had a few limitations. First, as a retrospective investigation, we could only analyze variables that were appropriately documented, and we were not able to investigate those patients without results of thyroid hormones. Second, this was a single center study with a small sample size, so the sensitivity and specificity of results were not quite satisfactory. With the popularity of thyroid function tests, we will get more accurate and precise data in China. Due to the retrospective design and the small size of our study, currently we cannot determine whether thyroid dysfunction in the first half trimester or in the second half trimester have a greater effect on maternal and fetal pregnancy outcomes. Data are also lacking regarding whether the treatment is obligatory for patients with FT3 and FT4 both under the lower limit but normal TSH to prevent adverse neonatal outcomes. Certainly, further studies are needed to widen our understanding on thyroid dysfunction and neonatal outcomes.

Our data indicate that more severe and early onset preeclampsia, as well as thyroid dysfunction were associated with significantly increased risk of neonatal adverse outcomes such as preterm birth and low neonatal birth weight. Therefore, monitoring thyroid hormones in women with preeclampsia might help to predict and consequently reduce the adverse neonatal outcomes.