Clinical characterization and collagenopathic phenotyping in preterm birth due to cervical insufficiency

Preterm birth (PTB) occurs in ~5-18% of births worldwide, and in ~5–6% in Latvia. PTB in 1-2% of the cases are associated with cervical insufficiency (CI). Our previous systematic literature analysis identified 12 genes linked to CI, with the majority causing collagenopathies. Our aim for this study was to evaluate the proposed idea of CI being a subtle form of collagenopathy. Forty patients were recruited for a longitudinal cohort study at Riga Maternity Hospital. Inclusion criteria were singleton pregnancy and cervical length ≤25mm at 14-28th weeks of gestation (mean cervical length 15.8mm). Deep phenotyping of 40 patients using an extended Brighton questionnaire was performed. Clinical-exome sequencing was carried out before in 21 patients. A clinical description of 40 patients: progesterone supplementation was recommended in all cases. Seven received antibacterial therapy due to suspicion of intraamniotic infection. Cervical cerclage was placed in five cases, pessary – in 12, two patients received both. Eight pregnancies resulted in PTB at 32-37 weeks, three at 28-32, and 11 at 22-28 weeks. Eleven patients delivered at term. There was one case of perinatal death. Four patients were born preterm themselves, 19 had a positive personal history of late pregnancy loss or PTB in previous pregnancies, 11 had a positive family history of PTB. Nine patients demonstrated collagenopathic features – arthritis, joint dislocations, myalgia, and ruptures. One of these patients had variants of unknown significance/likely pathogenic variants in COL12A1 and COL1A1, one – variant in FKBP14, and one – variants in COL1A1 and LAMA4. Eight patients having possible genetic susceptibility variants did not show collagenopathic symptoms, but only CI. Outcomes for CI patients can be improved with up-to-date management of the condition. The idea of CI being a subtle form of collagenopathy is strengthened by the genetic and deep phenotyping findings, further investigations are warranted.