番茄社区

MONTREAL -- Two of the most common disorders of pregnancy, preeclampsia and preterm birth, remain deeply puzzling, but they are slowly yielding their secrets, researcher suggested here.

A team at Ohio State University and Nationwide Children's Hospital in Columbus, Ohio, have previously suggested that preeclampsia is a disorder characterized by abnormally folded proteins -- similar to Alzheimer's and prion diseases.

To prove that preeclampsia is a protein-folding disorder, OSU's , and colleagues examined proteasome activity (protein complexes that degrade unneeded or damaged proteins) in two cohorts, hypothesizing that increases in this activity would reflect the presence of abnormal proteins. They presented their findings at the (SRI) annual meeting.

A feasibility cohort consisted of 48 women, half of which had severe preeclampsia, 20 were healthy pregnant controls, and 10 were nonpregnant controls. Berryman's team found that compared to pregnant controls, women with severe preeclampsia had higher levels of 20S, the protein subunit and core particle of the proteasome (P<0.001) and higher proteasome activity (P<0.001).

"Pregnancy represents a status of increased proteostatic stress," said Berryman at the presentation. "Upregulation in proteasome level and activity in preeclampsia may result form a maladaptive or perhaps insufficient response of the maternal organism to counteract misfolded protein excess."

To test this theory against other high-risk pregnancy conditions, a validation cohort was comprised of 115 women with either mild or severe preeclampsia, spontaneous preterm birth, and women with gestational or chronic hypertension, and found that only women with severe preeclampsia had a marked elevation in proteasome activity and elevated levels of plasma proteasome compared to mild preeclampsia and other pregnancy disorders.

Berryman admitted that while their findings showed the mechanism to degrade the abnormal protein was increased, they didn't yet know why that was the case.

"Is the proteasome increased because it's trying to respond to the excess protein burden or is it already increased and it's not able to keep up?" she said. "We have to keep looking into that and trying to figure out where in the pathway is the breakdown that's causing the build up."

, of Stanford University in Palo Alto, Calif., who was not involved with the study, said that misfolded proteins may be another byproduct of inflammation that causes placental dysfunction.

"Misfolded protein is another one in a long line of observations of something that's wrong, but I haven't seen any suggestion that there is a therapeutic approach to misfolded proteins," he told 番茄社区. "The holy grail is, can we predict preeclampsia with a screening test. Almost all research in preeclampsia has failed that acid test."

Vaginal Microbiome and Preterm Birth

Another study reported found that women delivering preterm were more likely to show a vaginal microbiome in the first trimester dominated by Lactobacillus iners bacteria, pointing toward a possible marker of increased risk and perhaps therapeutic intervention.

Among 30 women delivering preterm, 50% showed an L. iners-dominated microbiome at 12 weeks gestation, compared with 12% of 101 delivering at term (P<0.01), , of Imperial College London, reported.

Women whose vaginal microbiome was dominated by L. crispatus bacteria at 12 weeks were significantly more likely to deliver at term (P<0.001).

"The vaginal microbiome plays an important role in pregnancy outcome, where L. iners is pathogenic and L. crispatus is protective," said Kindinger at the presentation.

Composition of the vaginal microbiome played the largest role in the risk of preterm birth, even when other risk factors were involved. Alongside the 72 pregnant women with a history of preterm birth, researchers also examined 59 pregnant women who had cervical conization treatment to excise cervical intraepithelial neoplasia (CIN, a pre-cancerous growth on the cervix).

Prior research had shown that pre-pregnancy cervical treatment for CIN doubles the risk of future preterm birth by increasing the rate of vaginal dysbiosis (or imbalances in the microbiome). But when compared to a cohort of women with a preterm birth, rates of preterm birth in the current pregnancy were significantly lower among the cervical treatment group (10% vs 33%, P<0.01).

Instead, Kindinger and colleagues found that if a woman in the preterm birth group had a vaginal microbiome dominated by L. iners bacteria prior to 24 weeks gestation, her risk of preterm birth was 2.4 times greater (compared to 1.2 times greater in the cervical treatment group).

"The interaction between the cervix and the microbiome is important when considering preterm birth risk," said Kindinger. "But we reject the hypothesis that pregnancies after cervical treatment have a higher incidence of vaginal dysbiosis."

Druzin said that the idea that the composition of the vaginal microbiome is associated with preterm labor is nothing new, and "continues at a rapid pace," but reiterated that the problem that remains is what can be done about it.

"There's a high risk of recurrence in preterm birth and vaginal microbiome doesn't go back to previous 'normal' microbiome, so maybe they have some kind of host defense mechanism that doesn't allow them to repopulate with the normal flora," said Druzin.

He added that these observational studies may show associations, but ultimately not causation.

"At the end of the day, we need to take all this stuff and put it into clinical context to find out whether it's cause and effect. If it's just an association, that's not strong evidence," Druzin noted.