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OBJECTIVE: With inconsistencies regarding the possible effect of hyperemesis gravidarum on the course of pregnancy, this research aimed to study the association between hyperemesis gravidarum and pregnancy outcomes, while also addressing the trimester of diagnosis and severity. METHODS: A retrospective cohort study was performed, including all singleton deliveries of mothers from the largest health maintenance organization in the country, in a single tertiary hospital between 1991 and 2021. The incidence of adverse pregnancy outcomes was compared between pregnancies with and without hyperemesis gravidarum diagnosis. Multivariable generalized estimation equation binary models were used to study the association between maternal hyperemesis gravidarum, trimester of diagnosis and hyperemesis gravidarum severity and the studied outcomes. RESULTS: The study population included 232 476 pregnancies, of which 3227 (1.4%) were complicated with hyperemesis gravidarum. Women with hyperemesis gravidarum were more likely to deliver preterm (adj. OR = 1.33, 95% CI: 1.18-1.50), a newborn with low birthweight (adj. OR = 1.52, 95% CI: 1.16-1.98, only if diagnosed in the second trimester), and to have a cesarean delivery (adj. OR = 1.20, 95% CI: 1.09-1.32). They were less likely to deliver small gestational age newborn (adj. OR = 0.82, 95% CI: 0.69-0.99) and their offspring to experience perinatal mortality (adj. OR = 0.54, 95% CI: 0.31-0.93, among mild cases only). A dose-response association was observed between preterm birth and hyperemesis gravidarum (adj. OR = 1.26; 95% CI: 1.11-1.44, for mild cases and adj. OR = 2.04; 95% CI: 1.31-3.19, for severe cases). CONCLUSIONS: Hyperemesis gravidarum is associated with an increased risk for adverse pregnancy outcomes including mainly preterm delivery in a dose-response manner and when diagnosed during the second trimester.
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Ehlers-Danlos syndromes (EDS) are a group of connective tissue disorders caused by mutations in collagen and collagen-interacting genes. We delineate a novel form of EDS with vascular features through clinical and histopathological phenotyping and genetic studies of a three-generation pedigree, displaying an apparently autosomal dominant phenotype of joint hypermobility and frequent joint dislocations, atrophic scarring, prolonged bleeding time and age-related aortic dilatation and rupture. Coagulation tests as well as platelet counts and function were normal. Reticular dermis displayed highly disorganized collagen fibers and transmission electron microscopy (TEM) revealed abnormally shaped fibroblasts and endothelial cells, with high amount and irregular shape of extracellular matrix (ECM) substance, especially near blood vessels. Genetic analysis unraveled a heterozygous mutation in THBS2 (NM_003247.5:c.2686T>C, p.Cys896Arg). We generated CRISPR/Cas9 knock-in (KI) mice, bearing the heterozygous human mutation in the mouse ortholog. The KI mice demonstrated phenotypic traits correlating with those observed in the human subjects, as evidenced by morphologic, histologic, and TEM analyses, in conjunction with bleeding time assays. Our findings delineate a novel form of human EDS with classical-like elements combined with vascular features, caused by a heterozygous THBS2 missense mutation. We further demonstrate a similar phenotype in heterozygous THBS2Cys896Arg KI mice, in line with previous studies in Thbs2 homozygous null-mutant mice. Notably, THBS2 encodes Thrombospondin-2, a secreted homotrimeric matricellular protein that directly binds the ECM-shaping Matrix Metalloproteinase 2 (MMP2), mediating its clearance. THBS2 loss-of-function attenuates MMP2 clearance, enhancing MMP2-mediated proteoglycan cleavage, causing ECM abnormalities similar to those seen in the human and mouse disease we describe.