Contrary to the previous studies, we found no associations between GBP and PE or EC, or metabolic complications during pregnancy. The only significant finding in our study was higher SBP and DBP in GBP+ pregnant women, but these elevated blood pressures did not fulfil the diagnostic criteria for GHT. As most of the previous studies reporting a higher risk of PE among the pregnant women with GBP were based on merely a few cases reports or small case series, the reliability of their conclusions is quite doubtful. To date, there have been few large comparative case studies which conclude that GBP was “probably” associated with GHT, PE, and other pregnancy-related adverse events. For example, one study found that GBP women experienced a six-fold higher incidence of PE and a 1.5-fold higher incidence of GHT compared to the expected rates in the general female population [3]. Another study also found significantly higher rates of severe PE and cesarean delivery but the neonatal outcomes were still favorable [4]. It is noteworthy that although both of these studies included a larger number of GBP+ cases than earlier studies, the former study compared the real incidences of PE and GHT calculated with the expected incidences among the general female population from a nationwide survey reported in another study, while the latter was not a comparable matched-case study between GBP+ and GBP- pregnant cases. Therefore, we conclude that a significant association between GBP and PE or GHT has not been confirmed based on the available data.
In addition, Vabrec, et al [7]. also argued against the higher incidences of BP during pregnancy described in some studies. They suggested that the exaggeration in enrollment of controls plus active recruitment of pregnant women with GBP in those studies were able to explain the overestimations of the incidence of GBP among pregnant women. For these reasons, the reported incidence of GBP of 45:100,000 “live births” compared with 17:100,000 “women of child bearing age” used as controls in a study by Hilsinger, et al. [8] was arguable. Based on their argument on this issue, the previous agreement that the incidence of BP during pregnancy is higher than in the general female population seems unreasonable.
Although the higher incidence of BP during pregnancy is controversial, some case reports and small case series associated the occurrence of BP during pregnancy with PE, EC, GHT and GDM. How these disorders are related has been a question waiting for an explanation. Considering the pathogeneses of these pregnancy-related disorders would be helpful. For BP, the definite pathogenesis has not been clearly elucidated. The main theory currently is that BP is caused by reactivation of a herpes simplex virus (HSV) that has stayed inactively in the geniculate ganglions of the facial nerves. The other pathogeneses proposals are 1) ischemic facial neuropathy complicated with metabolic disorders such as long-standing systemic hypertension, glucose intolerance, or diabetes mellitus, 2) altered host immunity predisposing the patients to the reactivation of an HSV, or other infections, and 3) immunologically inflammatory demyelination of the facial nerve, like a variant form of Guillain-Barre syndrome.
According to the currently accepted pathogenic mechanism for PE, the inadequate intrusion of placental trophoblasts into the uterine muscles, combined with insufficient remodeling of the spiral arteries of the uterus during placental implantation cause the disorder [9]. The under development of the spiral arteries results in placental ischemia that triggers an alteration in the proportions of the T lymphocyte subpopulations, i.e. increased numbers of CD4+ and helper-17 cells but decreased regulatory T cells. Following these disproportionate number of T lymphocyte subpopulations, B lymphocytes are triggered to release autoantibodies to activate angiotensin II type I receptors. Finally, increased vascular sensitivity to angiotensin develops causing decreased renal blood flow and glomerular filtration rate, and eventually pregnancy-related systemic HT develops [10]. However, based on the available information, how GBP relates to PE is still unsettled, whether a) they share a common pathogenesis of increased vascular sensitivity to angiotensin that causes facial nerve ischemia, or b) GBP is a complication of the systemic HT associated with PE, or c) the changes in host immunity during pregnancy give rise to HSV reactivation or facial nerve demyelination resulting in BP. Our comments on this issue based on the available data are:
1) Reactivation of HSV or other human herpes viruses (HHV) is the more reasonable explanation. Because of the lowered host-defense immunity against infections during pregnancy, pregnant women are predisposed to any infection, including HHV. One study reported a cytomegalovirus infection developed four days before delivery in a pregnant woman [11]. Another study suggested that physiological changes and low host immunity against infections during the third trimester of pregnancy and early puerperium contributed to increased risk of acquiring HHV reactivation and other infections [4].
2) GBP is a complication of systemic HT that is associated with PE. This pathogenic process induces microangiopathy of the vasa nervorum which provides blood supply to the facial nerves. However, as the rising of blood pressures during PE are a transient physiological change that usually resolves shortly after childbirth, we think that the duration of high blood pressure in PE may not be long enough to cause such microvascular complications. Thence, this suggested pathogenesis should be further investigated.
3) Concurrent microvasculitis of the vasa nervorum of the facial nerves with the placental vessels are caused by immune-mediated insults. This pathogenesis also remains inconclusive and requires further study.
We believe that the lowered host-defense immunity against several infections during pregnancy is a major predisposing factor which hastens the reactivation of inactive HHV and frees them from the geniculate ganglions to cause facial neuropathy. Additionally, physiological changes during near-term pregnancies such as changes in the levels of estrogen, progesterone and corticosteroids possibly co-contribute to the occurrence of facial neuropathy by further impairing the host-defense immunity against the infections [4].
The significantly lower mean birth weight in the newborns of GBP+ women was the only abnormal neonatal development parameter found in our study. This finding possibly resulted from placental vascular insufficiency in the fetuses born from GBP+ women.
The specific parameter-matched comparative case study design was a methodological strength of our study. We intentionally matched the exact maternal age and the order of gravidity at the onset of GBP between cases and controls to limit the effects of age on metabolic disorders, and the effects of number of pregnancies on the alteration of immune response during pregnancy, respectively. The paucity of GBP cases in real practice precludes a study with large number of cases that weakens our conclusion. Future studies with larger numbers of GBP cases are needed to confirm our current findings. Moreover, we would like to suggest that as physiological and immunological changes occur among the subsequent orders of pregnancy apart from the age-dependent variations, both maternal age and the order of pregnancy need to be considered as matching parameters in future studies to strengthen the conclusions.