In this first prospective, population-based study evaluating the association between PE, GH and subsequent hypothyroidism, no clear association was found, although the risk appeared to be somewhat increased for nulliparous women with late PE.
One previous study has found that women with PE have higher TSH concentrations in late pregnancy than normotensive mothers [9
]. Some studies have found that thyroid dysfunction in early pregnancy might increase the risk of PE, especially late PE [10
], but others have not [12
]. Similarly, women with history of recurrent PE have been found to have elevated levels of TSH [9
], a finding that has not been confirmed by others [19
]. We observed an association between late PE and hypothyroidism, which is a novel finding.
The increased risk for thyroid dysfunction among women with PE is thought to be mediated through antiangiogenic proteins, secreted in high amounts in hypertensive pregnancies [2
]. These proteins act as antagonists for VEGF and PlGF, causing endothelial dysfunction and capillary regression in several tissues, including the thyroid [2
]. This is thought to play an important role in the subsequent morbidity observed in PE patients [20
]. The effect of antiangiogenic proteins on thyroid function has been shown among cancer patients receiving tyrosine kinase inhibitors, which also act through VEGF antagonism and can produce a condition resembling PE [5
]. In the thyroid tissue, up to 60% of capillaries may regress during treatment with anti-VEGF agents, but the phenomenon is reversible [21
]. Still 30% patients receiving tyrosine kinase inhibitors have increased risk for temporary or persistent hypothyroidism [22
], possibly due to destructive thyroiditis. The association is dose-effective with higher risk observed with prolonged treatment with the inhibitors [22
Our observed association between late PE and subsequent hypothyroidism among nulliparous women was unexpected and needs to be validated in other studies. Women with early PE have generally higher levels of antiangiogenic proteins than those with late PE [4
], but exposure time might be shorter than among those with late PE. The study by Ashoor et al. [11
] suggested that women developing late PE have higher TSH and lower fT4 in early pregnancy. We did additional testing in NFBC 1986 to check if women with late PE had higher TSH levels or more thyroid autoantibodies than normotensive women, but we observed no differences (data not shown), suggesting that underlying thyroid dysfunction might not be the cause. Why the association with late PE and hypothyroidism was statistically significant only in nulliparous women is unknown. Interestingly, the association was stronger in pregnancies with male fetuses. One previous study has shown that fetal gender is important in the peripheral microvascular response of women with PE, with women with male fetuses and PE having a poor response [27
]. This might suggest that fetal gender might affect the antiangiogenic protein release and possibly even later disease risk [28
]. Studies also suggest that microchimerism might be an important risk factor for Hashimotos thyroiditis [29
], and women with PE might have higher feto-maternal trafficking than normotensive women [30
In the current study we also found that women with PE and GH had higher fT3 concentrations in early pregnancy than normotensive women, and those with GH had higher TSH concentrations. No differences were seen in fT4 concentrations or rates of thyroid antibody positivity. Our findings could reflect increased release of fT3 from the thyroid or increased fT4 to fT3 turnover. The higher TSH concentration among women with GH was an interesting finding as women with GH usually have lower levels of sFLt1 than those with PE [4
], suggesting that cases with PE should be more susceptible to hypothyroidism than cases with GH. Age and parity might contribute to these findings, as women with GH were somewhat older and less often nulliparous than those with PE. Age has been found to be a significant risk factor for autoimmune-based hypothyroidism [31
Interestingly, our data suggest an increased risk of hypothyroidism among euthyroid, thyroid antibody negative women with PE who should have low risk for hypothyroidism. Although non-significant, the elevated risk estimate for this group suggests a potential independent role for PE. Similar association was not seen among those with GH. These findings may suggest an effect related to sFlt1 during pregnancy complicated by PE.
Based on the hypothesis that elevated levels of sFlt1 lead to destructive thyroiditis, cases of recurrent PE should have increased risk for subsequent hypothyroidism, as they are exposed recurrently to high levels of sFlt1 [4
], but this was not evident in our study.
Our study has some advantages and limitations. The data is based on large, prospective population based cohorts with extensive data collection during the index pregnancy and follow-up using high-quality Finnish registries with complete population coverage. Our data on hypertensive complications during the NFBC index pregnancies is reliable, based on measurements and diagnoses made during routine visits to MWCs which all Finnish women attend and recurrence of complications could be defined using the registries. Data on recurrent PE was scarce, resulting in limited power in those analyses.
Data on hypothyroidism is based on three registers which allowed verification and accurate identification of cases with hypothyroidism over a long follow-up time (from 20 to 40 years). This setting has a limitation, however, since it only includes cases with verified thyroid disease. Therefore we may be lacking information on subclinical disease with no symptoms or treatment and this would underestimate the prevalence of hypothyroidism in the population. These limitations may explain why our results differ from those by Levine et al., who measured TSH concentrations in women with history of PE and found they had elevated TSH concentrations during follow-up [9
]. In our study, it was not possible to obtain TSH or thyroid hormone concentrations at the end of the follow-up.
Based on our results, we conclude that PE or GH have no clear association with subsequent overt symptomatic hypothyroidism, but due to the limitations of the study, the association with subclinical hypothyroidism could not be resolved. Our finding of a 1.8-fold increased risk of long-term hypothyroidisms in nulliparous women with late PE needs to be confirmed in other populations.