The Role Of Subclinical Infection And Cytokines In Preterm Parturition

Eunice Kennedy Shriver National Institute Of Child Health & Human Development

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Abstract

I. Vaginal progesterone reduces preterm birth and adverse neonatal outcome in patients with a short cervix: an updated individual patient data meta-analysis (2025) Vaginal progesterone is an effective and safe intervention to reduce the rate of preterm birth in patients with a short cervix. Our previous meta-analysis published in 2018 was based on the reports of 5 trials and 974 women allocated to vaginal progesterone or placebo. One small trial which had contributed 8 patients (4 allocated to vaginal progesterone and 4 to placebo) to our meta-analysis was retracted and this required updating the meta-analysis. We found that after excluding the results of this trial, vaginal progesterone reduced the risk of preterm birth at less than 33 weeks (RR: 0.63, 95% CI, 0.48-0.82) and at other gestational ranges as well ranging from less than 36 to less than 32. Moreover, vaginal progesterone reduced the rate of respiratory distress syndrome, composite neonatal morbidity and mortality, and admission to the newborn intensive care unit. Subgroup analysis showed that the beneficial effects of progesterone applied to patients receiving 90-100mg, as well as 200mg of progesterone daily in the U.S. and abroad. These results support the continued use of vaginal progesterone for the prevention of preterm birth which is based on a randomized clinical trial performed by our Branch and subsequent systematic reviews and meta-analyses. II. Evidence of long-term safety (6 to 9 years of age) after prenatal exposure to vaginal progesterone to reduce the rate of preterm birth Vaginal progesterone is an effective method to reduce the rate of preterm birth and adverse neonatal outcome in both singleton and twin gestations with a short cervix in the midtrimester. An important question is whether infant exposure to this natural hormone during pregnancy has any long-term risks in terms of psychopathological and cognitive profiles. To address this question, we conducted a follow-up study of twins who had been exposed to progesterone as part of a randomized clinical trial. We studied 3 parallel groups (placebo, vaginal progesterone 200 mg/d, and vaginal progesterone 400 mg/d administered from 20 to 34 weeks of gestation or delivery). Established tools were used to assess the infants including the Child Behavior Checklist for ages 6 to 18 questionnaire and the Raven's colored progressive matrices test of nonverbal intelligence. The mean scores of the 11 psychopathological syndrome scales evaluated by the Child Behavior Checklist for ages 6 to 18 questionnaire among children exposed to vaginal progesterone 200 mg/d, 400 mg/d, or 200 and 400 mg/d were not significantly different to those among children exposed to placebo (all P values ≥.05). There were no significant differences in the mean total Child Behavior Checklist score between the vaginal progesterone groups and the placebo group ( all P values ≥.05). The mean percentiles of the Raven's test were not significantly different in children exposed to vaginal progesterone compared to those exposed to placebo. We conclude that exposure to progesterone in the second half of pregnancy for preterm birth prevention had no adverse effect on the psychopathological and cognitive profiles at 6 to 9 years of age. This information is reassuring to mothers who are prescribed progesterone for the prevention of preterm birth. III. The rapid diagnosis of intra-amniotic infection in spontaneous preterm labor Intraamniotic infection is a major cause of spontaneous premature labor and delivery. The standard diagnosis of infection is based on the identification of microorganisms in culture, and recently, with PCR to detect microbial footprints. However, both methods take time, and the results are rarely available for clinical decision-making. Nanopore sequencing technology offers real-time, long-read sequencing that can produce rapid results. We conducted a study to determine the diagnostic performance of the 16S rDNA nanopore sequencing method for the identification of microorganisms in patients with intraamniotic inflammation. We found that 16S nanopore sequencing had a sensitivity of 88.9%, specificity of 95.4%, positive predictive value of 80.0%, negative predictive value of 97.6%, positive likelihood ratio of 19.1, negative likelihood ratio of 0.1, and an accuracy of 94.2% for the identification of intraamniotic infection (prevalence, 17%). The microbial load determined by the 16S nanopore sequencing had a strong positive correlation with the intensity of an intraamniotic inflammatory response (amniotic fluid interleukin 6 concentration; Spearman's correlation 0.9; P=.002). This study shows that 16S nanopore sequencing has high diagnostic indices, predictive values, likelihood ratios, and accuracy in the diagnosis of intraamniotic infection. IV. Successful eradication of group B Streptococcus intraamniotic infection with antibiotics  Intra-amniotic infection, a major cause of the preterm labor syndrome, is a risk factor for neonatal morbidity and mortality and long-term handicap. The frequency of intra-amniotic infection in preterm prelabor rupture of membranes is 50%. Streptococcus agalactiae (GBS) is an important pathogen and causes neonatal sepsis. The conventional view has been that intra-amniotic infection due to GBS cannot be successfully treated. Yet, we have reported successful treatment of intra-amniotic infection with antimicrobial agents. A patient with prelabor rupture of membranes at 28 weeks was found to have intra-amniotic infection with GBS and was offered treatment (ceftriaxone, clarithromycin, and metronidazole) given the risk of prematurity. Serial amniocentesis reported eradication of GBS from the amniotic fluid until the patient delivered at 32 6/7 weeks of gestation, when the patient developed clinical chorioamnionitis due to E Coli. The neonate was treated with ertapenem and discharged home in good health. This case demonstrates successful treatment of invasive GBS intra-amniotic infection. V. A novel approach for the treatment of sterile intra-amniotic inflammation using homeostatic macrophages ​Preterm birth, often preceded by preterm labor, is a major cause of neonatal morbidity and mortality worldwide. Two-thirds of preterm births occurred after spontaneous premature labor. Intra-amniotic inflammation can be due to either infection or sterile intra-amniotic inflammation. This condition, discovered by our Branch, and termed sterile intra-amniotic inflammation, is diagnosed when inflammation is present in the absence of microorganisms. Successful treatment of intra-amniotic inflammation is a challenge. We have proposed that homeostatic macrophages (also called M2) could be used to prevent preterm birth and adverse neonatal outcomes caused by sterile intra-amniotic inflammation. A series of studies were undertaken to explore this hypothesis. We found that: 1) single-cell atlases of the maternal-fetal interface revealed that homeostatic maternal macrophages are reduced in human parturition; 2) administration of homeostatic macrophages to pregnant mice with intra-amniotic inflammation prevented preterm birth and reduced adverse neonatal outcomes; and 3) M2 macrophages halted premature labor by suppressing inflammatory responses in the amniotic cavity, including inflammasome activation, and mitigated placental and offspring lung inflammation. Moreover, M2 macrophages boosted gut inflammation in neonates and improved their ability to fight systemic bacterial infections. Our findings show that M2 macrophages are a promising strategy to mitigate premature labor and birth, as well as adverse neonatal outcomes resulting from sterile intra-amniotic inflammation. VI. Prediction of late onset preeclampsia using plasma proteomics One-third of preterm deliveries is due to medically-indicated conditions such as preeclampsia and fetal growth restriction. Treatment of preeclampsia once it is diagnosed is largely unsuccessful. Therefore, the goal is to identify the patients at risk so that prevention strategies can be focused on these patients. Several attempts have been made to identify protein biomarkers of preeclampsia, but findings vary with demographics, clinical characteristics, and time of sampling. In this study, we combined three independent longitudinal pregnancy cohorts (Detroit, Stanford and Oslo) resulting in 124 late-onset preeclampsia cases and 178 gestational age matched controls, and analyzed > 1000 proteins in maternal plasma sampled between 12 and 34 weeks of gestation. Differential abundance analysis of combined protein data revealed increased deviation in protein abundance trajectories throughout gestation in women destined to develop late-onset preeclampsia  compared to controls. Thirty one differentially abundant proteins were found at time interval T2 (19-27 weeks), and 48 proteins at time interval T3 (27- 34 weeks). Multi-protein random forest models assessed via cross-validation predicted late-onset preeclampsia  with an area under the ROC curve of 0.72 (0.65-0.78), 0.76 (0.71-0.81) and 0.80 (0.75-0.85) at time interval T1, T2 and T3, respectively. The results in the third trimester were confirmed using a leave-one-cohort-out analysis suggesting cross-cohort consistency, and at two other time points when the largest two cohorts were used as training sets. These findings provide robust evidence that proteomics can be used to predict late onset preeclampsia, a condition for which prediction has proven difficult and is a major cause of maternal death.Â