In this large population-based cohort study, offspring born to women with term pruritus exhibited higher rates of long-term neuropsychiatric morbidity, specifically developmental and neurodegenerative disorders, compared to offspring born to women without pruritus.
The association between pruritus during pregnancy and pregnancy complications has been investigated in the past [6,7]. ICP, one of the conditions that causes pruritus during pregnancy, was shown to increase the risk for immediate adverse pregnancy outcomes such as preterm birth, respiratory distress syndrome, meconium-stained amniotic fluid, fetal asphyxia, preeclampsia, and stillbirth [11,12], and long-term maternal morbidity, as well as increasing the risk for diseases of the digestive system, cholelithiasis, cholecystitis, and hypothyroidism . Other pruritic conditions during pregnancy have also been studied, among them pemphigoid gestationis, which was associated with immediate adverse pregnancy outcomes, such as small-for-gestational-age offspring and preterm birth, suggesting low-grade placental insufficiency. Other pruritic dermatoses of pregnancy were not found to be associated with pregnancy complications .
The fetal environment plays a critical role in early neural processes and can impact fetal brain structure and function and increase long-term susceptibility to neurodevelopmental and neuropsychiatric disorders . For example, an increase in the level of maternal and fetal serum bile acids, as seen in ICP , can cross the blood brain barrier via diffusion or by bile acid transporters , and has been reported to interact with receptors involved with neurotransmission. Further, an elevation of bile acids has been found in various neuropsychiatric disorders. It is worth mentioning that while several neuropsychiatric disorders have been correlated with elevated bile acids, others were shown to improve by the supplementation of specific bile acids , Another pruritus-causing disease that may inflict damage through neuroinflammation is pemphigoid gestationis, an autoimmune disease where the underlying mechanism is the breakdown of immunotolerance against a protein called BP180, which is expressed both on the skin and in the central nervous system , This may lead to autoimmune activity in the brain and thus to neuroinflammation, which may result in neurodevelopmental morbidity.
Our study has several limitations. As an inherent limitation of any observational epidemiologic study, our study cannot infer a causative relationship between pruritus during pregnancy and neuropsychiatric morbidity in the offspring, but rather can only demonstrate association between the two. In addition, numerous factors influence neuropsychiatric development, hence we cannot rule out the possibility of bias due to uncontrolled unknown confounders. Another limitation of our study is that our database is based on childhood hospitalization, while many of the neuropsychiatric morbidities that we evaluated hay have been treated in an ambulatory setting. We therefore believe that the true prevalence of the neuropsychiatric morbidities assessed is actually higher than our data shows. An additional limitation concerns the actual maternal exposure. As "pruritus" is a term comprising several different diseases with different pathophysiologies, the data does not distinguish between the various pruritic diseases. It is therefore highly likely that only the diseases known to cause pregnancy complications are the ones correlated to our findings, and the association between pruritus and long-term neuropsychiatric morbidity in the offspring may have been stronger if pruritus from benign conditions were excluded.
A significant strength of our study is the fact that all preterm deliveries were excluded from the analysis, hence eliminating a significant confounder of long-term neuropsychiatric morbidity . Moreover, controlling for the age at birth within the term deliveries eliminated early-term deliveries which has also been associated with long-term neuropsychiatric morbidity in the offspring . Another strength of this study is the large and unselected population included, with a long follow-up period that was possible due to the fact that SUMC is the only hospital in the entire region.
In conclusion, in our study, pruritus during pregnancy was found to be associated with a higher risk for long-term neuropsychiatric morbidity in the offspring, specifically neurodegenerative and neurodevelopmental disorders. More studies are needed in order to confirm our findings in varying populations, include cases diagnosed and treated in a community setting, and to further investigate specifically which pruritus-causing diseases are related to neuropsychiatric morbidity. Furthermore, pregnant women with pruritus during pregnancy should consider consulting with their physicians and the long-term neuropsychiatric surveillance of the children should be increased.