Recurrent Spontaneous Preterm Birth Research Articles

Vaginal microbiota and spontaneous preterm birth in pregnant women at high risk of recurrence

We describe vaginal microbiota, including Gardnerella species and sexually transmitted infections (STIs), during pregnancy and their associations with recurrent spontaneous preterm birth (sPTB). We performed a prospective cohort study in a tertiary referral centre in the Netherlands, among pregnant women with previous sPTB <34 weeks' gestation. Participants collected three vaginal swabs in the first and second trimester. Vaginal microbiota was profiled with 16S rDNA sequencing. Gardnerella species and STI's were tested with qPCR. Standard care was provided according to local protocol, including screening and treatment for bacterial vaginosis (BV), routine progesterone administration and screening for cervical length shortening. Of 154 participants, 26 (16.9 %) experienced recurrent sPTB <37 weeks' gestation. Microbiota composition was not associated with sPTB. During pregnancy, the share of Lactobacillus iners-dominated microbiota increased at the expense of diverse microbiota between the first and second trimester. This change coincided with treatment for BV, demonstrating a similar change in microbiota composition after treatment. In this cohort of high-risk women, we did not find an association between vaginal microbiota composition and recurrent sPTB. This should be interpreted with care, as these women were offered additional preventive therapies to reduce sPTB according to national guidelines including progesterone and BV treatment. The increase observed in L. iners dominated microbiota and the decrease in diverse microbiota mid-gestation was most likely mediated by BV treatment. Our findings suggest that in recurrent sPTB occurring despite several preventive therapies, the microbe-related etiologic contribution might be limited.

Progesterone therapy for prevention of recurrent spontaneous preterm birth in a minority patient population: a retrospective study

BackgroundPreterm birth is a leading cause of infant morbidity and mortality worldwide. The burden of prematurity underscores the need for effective risk reduction strategies. The purpose of this study is to evaluate the efficacy of progesterone therapy, both intramuscular 17-α-hydroxyprogesterone caproate (IM 17-OHPC) and vaginal progesterone, in the prevention of recurrent spontaneous preterm birth (sPTB). The co-primary outcomes included: recurrent spontaneous PTB < 37 and < 34 weeks’ gestation.MethodsThis retrospective cohort study included 637 pregnant patients that delivered at any of the three hospitals within the Los Angeles County healthcare system between October 2015 and June 2021. We compared frequencies of measured variables between each of the progesterone treated groups to no treatment using Pearson chi-squared tests and independent t-tests for categorical and continuous variables, respectively. We estimated crude and adjusted associations between each specific treatment (versus no treatment) and primary outcomes using logistic regression.ResultsRecurrent sPTB < 37 weeks’ gestation occurred in 22.3% (n = 64) of those in the no treatment group, 29.1% (n = 86, p = .077) in the 17-OHPC group, and 14.3% (n = 6, p = 0.325) in the vaginal progesterone group. Recurrent sPTB < 34 weeks’ gestation was 6.6% (n = 19) in the no treatment group, 11.8% (n = 35, p = .043) in the 17-OHPC group, and 7.1% (n = 3, p = 1) in the vaginal progesterone group. Among all participants, neither 17-OHPC nor vaginal progesterone was significantly associated with a reduction in recurrent sPTB at any time point. Among those with a short cervix, IM 17-OHPC was positively associated with recurrent sPTB < 37 weeks’ gestation (aOR 5.61; 95% CI 1.16, 42.9).ConclusionsProgesterone therapy of any type did not reduce the risk of recurrent sPTB < 34 or < 37 weeks’ gestation compared to no progesterone therapy.

The dosing regimen for 17-hydroxyprogesterone caproate was suboptimal: lessons for future pharmacotherapy for pregnant women

BackgroundMakena (17-hydroxyprogesterone caproate) was FDA approved for prevention of recurrent spontaneous preterm birth in 2011 under the accelerated approval pathway but fundamental pharmacokinetic or pharmacodynamic (phase1 and phase 2) studies were not performed. At the time, there were no dose-response or concentration-response data. The therapeutic concentration was not known. The lack of such data questions whether the dosing regimen for 17-hydroxyprogesterone caproate was optimized. ObjectiveThe purpose of this study was to evaluate the dosing regimen for 17-hydroxyprogesterone by analyzing three data sets that evaluated 17-hydroxyprogesterone caproate pharmacology: the Maternal-Fetal Medicine Omega 3 study, the Obstetric-Fetal Pharmacology Research Units study and the Obstetrical-Fetal Pharmacology Research Centers study. If an inappropriate dosing regimen could be identified, such information could inform future studies of pharmacotherapy in pregnancy. Study DesignData from the Omega 3 study were utilized to determine if plasma concentration was related to spontaneous preterm birth risk and if a threshold concentration could be identified. Data from the Obstetric-Fetal Pharmacology Research Units study were used to determine the half-life of 17-hydroxyprogesterone caproate and to develop a model to simulate drug concentrations with various dosing regimens. Data from the Obstetrical-Fetal Pharmacology Research Centers study were used to determine the relationship between dose and safety outcomes. ResultsAnalysis of the Omega 3 dataset indicated that the risk of spontaneous preterm birth decreased as the log of 17-hydroxyprogesterone caproate increased [odds ratio (95%CI) 0.04 (0.00 - 0.90)]. A steady state concentration> 9 ng/ml (equivalent to > 8 ng/ml at 25-28 weeks) was associated with the lowest risk of spontaneous preterm birth [hazard ratio (95%CI) 0.52 (0.27-0.98, p=0.04)]; this concentration was not achieved in 25% of subjects receiving the 250 mg weekly dose. In the Obstetrical-Fetal Pharmacology Research Units study, the adjusted half-life (median and IQR) of 17-hydroxyprogesterone caproate was 14.0 (11.5-17.2) days. Simulations indicated that with the 250 mg weekly dose, > 5 weekly injections were required to reach the 9 ng/ml target; however, those with the shortest half-life (corresponding to higher clearance), never reached the targeted 9 ng/ml concentration. In 75% of subjects, a loading dose of 500 mg weekly for 2 weeks followed by 250 mg weekly achieved and maintained the 9 ng/ml concentration within two weeks but in those 25% with the shortest half-life, concentrations exceeded the 9 ng/ml target for only 3 weeks. In the Obstetrical-Fetal Pharmacology Research Centers study, all 65 subjects receiving a weekly dose of 500 mg exceeded the 9 ng/ml steady state. ConclusionsThe dosing regimen for 17-hydoxyprogesterone caproate was inadequate. There is a significant inverse relationship between drug concentration and spontaneous preterm birth. Risk is lowest when concentration exceeds 9 ng/ml but 25% of women receiving the 250 mg weekly dose will never reach and maintain this concentration. The drug’s long half-life necessitates a loading dose to achieve therapeutic concentrations rapidly. The omission of basic pharmacologic studies to determine the proper dosing may have compromised the effectiveness of 17-hydroxyprogesterone caproate. Future pharmacotherapy trials in pregnancy must first complete fundamental pharmacology studies.

Research progress on the STAT signaling pathway in pregnancy and pregnancy-associated disorders.

Signal transducer and activator of transcription (STAT) proteins, pivotal regulators of signaling cascades, undergo activation in response to the stimulation of cytokines and growth factors, and participate in biological processes, including inflammation, immune responses, cell proliferation, and differentiation. During the process of pregnancy, STAT signaling is involved in regulating embryonic implantation, endometrial decidualization, and establishing and maintaining maternal-fetal immune tolerance. Increasing evidence suggests that aberrant STAT signaling contributes to the occurrence and development of pregnancy disorders, including repeated implantation failure (RIF), preeclampsia (PE), recurrent spontaneous abortion (RSA), preterm birth (PTB) and gestational diabetes mellitus (GDM). Elucidating the molecular mechanisms of the STAT signaling pathway holds promise for further understanding the establishment and maintenance of normal pregnancy, and thereby providing potent targets and strategic avenues for the prevention and management of ailments associated with pregnancy. In this review, we summarized the roles of the STAT signaling pathway and its related regulatory function in embryonic implantation, endometrial decidualization, and maternal-fetal immune tolerance. In conclusion, in-depth research on the mechanism of the STAT signaling pathway not only enhances our understanding of normal pregnancy processes but also offers STAT-based therapeutic approaches to protect women from the burden of pregnancy-related disorders.

1179 Risk of recurrent spontaneous preterm birth among those with persistent cervical HPV infection

1179 Risk of recurrent spontaneous preterm birth among those with persistent cervical HPV infection

DOCK1 insufficiency disrupts trophoblast function and pregnancy outcomes via DUSP4-ERK pathway.

Abnormal trophoblast function is associated with diseases such as recurrent spontaneous abortion, pre-eclampsia, and preterm birth, and endangers maternal and fetal health. However, the underlying regulatory mechanisms remain unclear. In this study, we found DOCK1 expression is decreased in the placental villi of patients with recurrent spontaneous abortion, and that its expression determined the invasive properties of extravillous trophoblasts (EVTs), highlighting a previously unknown role of DOCK1 in regulating EVT function. Furthermore, DOCK1 deficiency disturbed the ubiquitinated degradation of DUSP4, leading to its accumulation. This caused inactivation of the ERK signaling pathway, resulting in inadequate EVT migration and invasion. DOCK1 was implicated in regulating the ubiquitin levels of DUSP4, possibly by modulating the E3 ligase enzyme HUWE1. The results of our in vivo experiments confirmed that the DOCK1 inhibitor TBOPP caused miscarriage in mice by inactivating the DUSP4/ERK pathway. Collectively, our results revealed the crucial role of DOCK1 in the regulation of EVT function via the DUSP4-ERK pathway and a basis for the development of novel treatments for adverse pregnancy outcomes caused by trophoblast dysfunction.

Role Of Low Dose Aspirin In Preventing Preterm Birth In Patients With Previous History Of Preterm Delivery

Objective: Preterm birth (PTB) occurs between 24-37 weeks of gestation. The important risk factor for PTB is a previous PTB and currently progesterone is used for the management of recurrent spontaneous PTB. Some studies have shown good outcomes but recent studies revealed that the use of vaginal progesterone was not related to a decreased likelihood of PTB or neonatal adverse effects. Thus, the controversy in the literature suggests multiple underlying pathological mechanisms involved in the progression of PTB. This study aims to determine the role of low-dose aspirin in the prevention of preterm birth in patients with a previous history of preterm delivery. Methodology: In this randomized controlled trial, a total of 172 patients fulfilling the inclusion criteria were selected from the inpatient and outpatient departments. Patients were divided randomly into two groups (group A and group B), using random number tables. In Group A, low-dose aspirin (75mg) was given while group B was taken as a control group. Patients were called every 8 weeks in the outpatient department for the assessment of compliance and side effects of the drug. The data were entered and analyzed by using SPSS v25.0. Chi-square was used to compare the two groups for incidence of preterm birth. Relative risk (along with a 95% confidence interval) for the decrease in the incidence of preterm birth with the use of aspirin was calculated. Results: The age of participants included in the study was 18 to 40 years. The mean age of patients in group A was 33.85±5.210 years and in group B was 32.86±4.139 years. The mean fetal birth weight in group A was 2281.1962±363.125 grams and in group B was 2271.4344±374.797 grams. In the low-dose aspirin group, 10(11.6%) had preterm birth and 31(36.0%) in the control group with a p-value of 0.001, which is statistically significant. The risk of having preterm birth with low-dose aspirin was 1.801 times less than controls. Conclusion: aspirin in low dose given before 14 weeks of gestation decrease spontaneous preterm birth as compared to the control group in a woman with a history of previous preterm birth which was spontaneous

Placental histology for targeted risk assessment of recurrent spontaneous preterm birth

Spontaneous preterm birth significantly increases the risk for a recurrent preterm birth (rPTB). Few identifiable clinical risk factors exist in counseling of rPTB. Furthermore, treatment with progesterone supplementation has not consistently prevented preterm birth in high-risk patients, but may be effective in a subset of such patients. Placental pathology from a prior pregnancy may be used to predict which patients will experience rPTB, or to identify a subset more likely to respond to treatment with antenatal progesterone. To determine if histologic patterns are associated with rPTB among patients with an index spontaneous preterm birth. A secondary objective was to determine if placental histologic types and/or progesterone receptor density in the decidua is associated with response to progesterone supplementation with intramuscular 17 hydroxyprogesterone caproate (17-OHPC). This was a retrospective cohort study at a single institution of singleton pregnancies with an index spontaneous preterm birth and subsequent birth within the same hospital system between 2009 and 2019. Patients were included if placental pathology was available in the index spontaneous preterm birth. Logistic regression was utilized to determine independent association of four histologic types (acute inflammation (AI), maternal vascular malperfusion (MVM), fetal vascular malperfusion, chronic inflammation (CI)) with rPTB. For the secondary endpoint, 17-OHPC response was defined as achievement of > 3 weeks beyond the gestational age at delivery in the index pregnancy. Patients who delivered < 3 weeks from index pregnancy but > 39 weeks were excluded. Logistic regression was used to assess the independent association of placental histology with 17-OHPC response. Sensitivity analyses were completed utilizing only patients with an index birth < 36 weeks, and then excluding those with medically indicated preterm birth in a subsequent pregnancy. A nested case-control immunohistochemical study was done among 20 patients with a subsequent term and 20 patients with a subsequent spontaneous preterm birth. The percent of cells in the maternal decidua positive for progesterone receptor (PR) was correlated with subsequent pregnancy outcome. A total of 352 patients were included. AI was the most common histologic type seen among patients with spontaneous preterm birth (44.1%), followed by CI (40.9%) and MVM (31.3%). No histologic type was independently associated with rPTB. 155 patients received 17-OHPC in a second pregnancy. Low grade AI was significantly associated with decreased likelihood of 17-OHPC response. Low grade MVM in those with index pregnancy delivered at < 36 weeks was significantly associated with over 4 times increased likelihood of 17-OHPC response when excluding those with an iatrogenic subsequent preterm birth. Progesterone receptor staining was not associated with recurrent preterm birth. While AI was prevalent among spontaneous preterm births, over half of spontaneous preterm births were not associated with AI. Low grade AI was associated with significantly decreased response to 17-OHPC supplementation. Low grade MVM was associated with 4 fold increase likelihood of 17-OHPC response among those with index deliveries < 36 weeks. Further work is needed to determine whether placental pathological examination can be utilized to target treatment in subsequent pregnancies to prevent rPTB.

OP03_3. Aspirin and recurrent preterm birth, aspirin use in pregnancy could reduce the risk of recurrent spontaneous preterm birth: A Swedish register-based cohort study

OP03_3. Aspirin and recurrent preterm birth, aspirin use in pregnancy could reduce the risk of recurrent spontaneous preterm birth: A Swedish register-based cohort study

Longitudinal change in cervical length following vaginal or abdominal cervical cerclage: a randomized comparison

Cervical cerclage has been shown to reduce the risk of recurrent spontaneous preterm birth in a high-risk patient population; however, the mechanism is not well understood. Transabdominal cerclage is superior to low and high vaginal cerclage in reducing early spontaneous preterm birth and fetal loss in women with previous failed vaginal cerclage. Cervical length measurements are commonly used to monitor high-risk women and may explain the mechanism of success. This study aimed to evaluate the rate of change in longitudinal cervical length after randomized placement of low transvaginal, high transvaginal, or transabdominal cerclage in women with a previous failed vaginal cerclage. This was a planned analysis of longitudinal transvaginal ultrasound cervical length measurements from patients enrolled in the Vaginal Randomised Intervention of Cerclage trial, a randomized controlled trial comparing transabdominal cerclage or high transvaginal cerclage with low transvaginal cerclage. Cervical length measurements at specific gestational ages were compared over time and between groups, using generalized estimating equations fitted using the maximum-likelihood random-effects estimator. In addition, cervical length measurements were compared in women with transabdominal cerclage placed before and during pregnancy. The diagnostic accuracy of cervical length as a predictor of spontaneous preterm birth at <32 weeks of gestation was explored. This study included 78 women who underwent longitudinal cervical length assessment (70% of the analyzed cohort) with a history of failed cerclage, of whom 25 (32%) were randomized to low transvaginal cerclage, 26 (33%) to high transvaginal cerclage, and 27 (35%) to transabdominal cerclage. Abdominal cerclage was superior to low (P=.008) and high (P=.001) vaginal cerclage at maintaining cervical length over the surveillance period (14 to 26 weeks of gestation) (+0.08 mm/week, 95% confidence interval, -0.40 to 0.22; P=.580). On average, the cervical length was 1.8 mm longer by the end of the 12-week surveillance period in women with transabdominal cerclage (+1.8 mm; 95% confidence interval, -7.89 to 4.30; P=.564). High vaginal cerclage was no better than low cervical cerclage in the prevention of cervical shortening; the cervix shortened by 13.2 mm over 12 weeks in those with low vaginal cerclage (95% confidence interval, -21.7 to -4.7; P=.002) and by 20 mm over 12 weeks in those with high vaginal cerclage (95% confidence interval, -33.1 to -7.4; P=.002). Preconception transabdominal cerclage resulted in a longer cervix than those performed during pregnancy; this difference was significant after 22 weeks of gestation (48.5 mm vs 39.6 mm; P=.039). Overall, cervical length was an excellent predictor of spontaneous preterm birth at <32 weeks of gestation (receiver operating characteristic curve, 0.92; 95% confidence interval, 0.82-1.00). In women with a previous failed cervical cerclage, in the next pregnancy, the cervical length in women treated with vaginal cerclage funneled and shortened over time, whereas there was preservation of cervical length in women who receive transabdominal cerclage. Cervical length remained longer in transabdominal procedures performed before pregnancy than in transabdominal procedures performed during pregnancy. Overall, cervical length was an excellent predictor of spontaneous preterm birth in our cohort. Our findings may explain the mechanism of benefit for transabdominal cerclage, with its high placement better maintaining the structural integrity of the cervix at the level of the internal os.

Society for Maternal-Fetal Medicine Statement: Response to the Food and Drug Administration’s withdrawal of 17-alpha hydroxyprogesterone caproate

On April 5, 2023, the US Food and Drug Administration withdrew the approval of 17-alpha hydroxyprogesterone caproate, effective immediately, because of the lack of evidence that it reduces the risk of recurrent spontaneous preterm birth. This decision withdraws approval for all formulations of 17-alpha hydroxyprogesterone caproate (both intramuscular and subcutaneous) and applies to both brand name (Makena) and generic versions of the medication. We agree with the Food and Drug Administration determination and discourage continued prescribing of 17-alpha hydroxyprogesterone caproate, including through compounding pharmacies. We do not recommend changing indications for cerclage, indications for vaginal progesterone in patients with a short cervix, or recommendations against activity restriction based on the Food and Drug Administration withdrawal of 17-alpha hydroxyprogesterone caproate from the market. We recommend that discussion of the use of vaginal progesterone for primary prevention of recurrent preterm birth without input of cervical length or in those with a cervical length of ≥25 mm includes a shared decision-making process, especially if a progesterone formulation for preterm birth prevention was received in a previous pregnancy. The Food and Drug Administration determined that it would be inappropriate to delay the effective date of the withdrawal to allow patients currently receiving 17-alpha hydroxyprogesterone caproate to finish treatment. We agree with the Food and Drug Administration that there is no evidence of benefit with continued treatment. Patients currently receiving 17-alpha hydroxyprogesterone caproate can be counseled that the Food and Drug Administration's Center for Drug Evaluation and Research has not identified evidence of harm from discontinuation before 37 weeks of gestation.

The effectiveness of vaginal progesterone in reducing preterm birth in high-risk patients diagnosed with short cervical length after 24 weeks: A retrospective cohort study.

To assess the impact of progesterone treatment on maternal and neonatal outcomes in women with a history of preterm birth and short cervical length diagnosed after 24 weeks of gestation. A retrospective cohort study included women with a history of preterm birth and a transvaginal sonographic cervical length measurement of ≤ 25 mm, diagnosed between 24+0 and 33+6 weeks of gestation. Exclusion criteria included prior progesterone treatment, cervical cerclage, or pessary. The study population was divided into the progesterone treatment group and the non-treatment group. The study included 104 women, with 46.2% (48/104) receiving progesterone treatment and 53.8% (56/104) not receiving treatment. The rate of spontaneous preterm birth before 37 weeks of gestation was 43% (24/56) in the non-treatment group and 31% (15/48) in the progesterone treatment group (P = 0.14); the rate of spontaneous preterm birth before 34 weeks was 7% (4/56) in the non-treatment group and 0% (0/48) in the progesterone treatment group (P = 0.05). Progesterone treatment was associated with a significant decrease in neonatal intensive care unit admissions (OR 0.20, 95% CI 0.05-0.74) and in the neonatal hospitalization period (mean difference in days 2.43, 95% CI 0.44-4.42). The risk of recurrent spontaneous preterm birth was highest (71%) among women with two or more previous preterm deliveries who did not receive progesterone treatment, and lowest (24%) among women with one previous preterm delivery who received progesterone treatment. Progesterone treatment was associated with a reduction in rates of spontaneous preterm birth before 34 weeks of gestation, neonatal intensive care unit admission, and neonatal length of stay in high-risk patients, even when initiated after 24 weeks of gestation.

Vaginal progesterone compared to intramuscular 17-alpha-hydroxyprogesterone caproate for prevention of recurrent spontaneous preterm birth in singleton gestations: a systematic review and meta-analysis

Vaginal progesterone compared to intramuscular 17-alpha-hydroxyprogesterone caproate for prevention of recurrent spontaneous preterm birth in singleton gestations: a systematic review and meta-analysis

Frequency of cerclage in consecutive pregnancies of women with history of preterm birth.

Serial cervical length screening is performed in women with a history of preterm birth to determine indication for cerclage placement. Our aim is to evaluate the frequency of cerclage placement in consecutive pregnancies with preterm birth history to determine whether performing serial cervical length screening for women with a history of late (34-36 6/7 weeks) spontaneous preterm birth (SPTB) should be reconsidered. Retrospective evaluation of cerclage frequency and gestational age of delivery for consecutive singleton births for 69,671 women whose first birth was a SPTB. History of late SPTB was associated with a lower frequency of cerclage than history of early SPTB (0.83% vs 4.88%, OR 0.16, 95% CI 0.14-0.18). Rates of recurrent SPTB were lower for women with history of late SPTB than those with history of early SPTB (13.45%, 3.74% early, 9.71% late vs 20.69%, 9.12% early, 11.57% late). Women with a history of late PTB have a lower risk of recurrent PTB than those with a history of early PTB but constitute most of those undergoing serial cervical length screening for potential cerclage placement. Practice guidelines for screening women with a history of late PTB should be re-evaluated.

Previous term emergency caesarean section is a risk factor for recurrent spontaneous preterm birth; a retrospective cohort study

ObjectivesEmergency caesarean sections (EmCS), particularly those performed in the second stage of labour, have been associated with a risk of subsequent preterm birth. More worrying is that the risk of sPTB recurrence appears to be high in women who have had a second stage EmCS and a subsequent sPTB. However, there is a paucity of evidence regarding the risk of recurrence in women who have had a prior term EmCS at any stage of labour followed by a sPTB. This study aims to investigate the relationship between all term in labour EmCS and the risk of recurrent spontaneous preterm birth (sPTB).Study Design.This is an observational, retrospective cohort study conducted at St Thomas’ Hospital, a tertiary-level maternity hospital in London, United Kingdom. 259 women were included; 59 women with a term in labour EmCS preceding a sPTB (EmCS group) and 200 women with a prior sPTB only (control group). The initial EmCS was further categorised into first stage (FS)-EmCS or second stage (SS)-EmCS. Primary outcome was sPTB in Pregnancy C < 37 weeks’ gestation. Secondary outcomes included sPTB < 34 weeks’ and < 24 weeks’ gestation. Results54% (32/59) of the EmCS group had a recurrent sPTB < 37 weeks compared to 20% (40/200) of the control women (p < 0.0001) with a relative risk of 2.71 [95%CI 1.87–3.87]). Of women who had a SS-EmCS and a subsequent PTB, 61.9% (13/21) had a further sPTB (RR 3.0 [95%CI, 1.8–4.5] compared to control women). In addition, there is nearly a 6-fold increased risk of a recurrent sPTB or midtrimester loss < 24 weeks’ gestation in these women (RR 5.65 [95%CI2.6–12.0]). ConclusionsIn women who have had a previous sPTB in which a term in labour EmCS is a risk factor, the risk of a further sPTB is much higher than in those women where a prior sPTB is the sole risk factor. Furthermore, EmCS at both the first and second stage of labour are associated with a increased risk of recurrent sPTB. Further work should ascertain which women who have had a prior term EmCS are at risk of sPTB and recurrence, and how best to identify and treat them.

Immunobiology of Gestational Diabetes Mellitus in Post-Medawar Era.

Although the concepts related to fetal immune tolerance proposed by Sir Peter Medawar in the 1950s have not withstood the test of time, they revolutionized our current understanding of the immunity at the maternal-fetal interface. An important extension of the original Medawar paradigm is the investigation into the underlying mechanisms for adverse pregnancy outcomes, including recurrent spontaneous abortion, preterm birth, preeclampsia and gestational diabetes mellitus (GDM). Although a common pregnancy complication with systemic symptoms, GDM still lacks understanding of immunological perturbations associated with the pathological processes, particularly at the maternal-fetal interface. GDM has been characterized by low grade systemic inflammation that exacerbates maternal immune responses. In this regard, GDM may also entail mild autoimmune pathology by dysregulating circulating and uterine regulatory T cells (Tregs). The aim of this review article is to focus on maternal-fetal immunological tolerance phenomenon and discuss how local or systemic inflammation has been programmed in GDM. Specifically, this review addresses the following questions: Does the inflammatory or exhausted Treg population affecting the Th17:Treg ratio lead to the propensity of a pro-inflammatory environment? Do glycans and glycan-binding proteins (mainly galectins) contribute to the biology of immune responses in GDM? Our understanding of these important questions is still elementary as there are no well-defined animal models that mimic all the features of GDM or can be used to better understand the mechanistic underpinnings associated with this common pregnancy complication. In this review, we will leverage our preliminary studies and the literature to provide a conceptualized discussion on the immunobiology of GDM.

Effectiveness of 17-OHP for Prevention of Recurrent Preterm Birth: A Retrospective Cohort Study.

17-α-hydroxyprogesterone caproate (17-OHP) has been recommended by professional societies for the prevention of recurrent preterm birth, but subsequent clinical studies have reported conflicting efficacy results. This study aimed to contribute to the evidence base regarding the effectiveness of 17-OHP in clinical practice using real-world data. A total of 4,422 individuals meeting inclusion criteria representing recurrent spontaneous preterm birth (sPTB) were identified in a database of insurance claims, and 568 (12.8%) received 17-OHP. Crude and propensity score-matched recurrence rates and risk ratios (RRs) for the association of receiving 17-OHP on recurrent sPTB were calculated. Raw sPTB recurrence rates were higher among those treated versus not treated; after propensity score matching, no association was detected (26.3 vs. 23.8%, RR = 1.1, 95% CI: 0.9-1.4). We failed to identify a beneficial effect of 17-OHP for the prevention of spontaneous recurrent preterm birth in our observational, U.S. based cohort. · We observed higher risk for sPTB in the group receiving 17-OHP in the unmatched analysis. · After propensity-score matching, we still failed to identify a beneficial effect of 17-OHP on sPTB. · Sensitivity analyses demonstrated robustness to the inclusion criteria and modeling assumptions..

A Possible Mechanism of Action of 17α-Hydroxyprogesterone Caproate: Enhanced IL-10 Production.

The rate of recurrent spontaneous preterm birth (PTB) was reduced by 33% in the Maternal-Fetal Medicine Unit (MFMU) Network trial of 17α-hydroxyprogesterone caproate (17-OHPC), but the mechanism of action, 17 years later, remains elusive. The robustness of the interleukin-10 (IL-10) response to lipopolysaccharide (LPS) stimulation of leukocytes in pregnant women with a prior PTB correlates with gestational age at delivery. This study sought to determine if there is a relationship between the concentration of 17-OHPC and response to LPS stimulation. We performed a secondary analysis of data from the Omega-3 MFMU trial which evaluated the effectiveness of omega-3 fatty acid supplementation in reducing recurrent PTB. We utilized previously characterized data from a subanalyses of the Omega-3 trial of IL-10 and tumor necrosis factor alpha (TNF-α) levels from peripheral blood mononuclear cells stimulated with LPS. Blood was obtained from enrolled women at 16 to 22 weeks' gestation (baseline) and 25 to 28 weeks' gestation (posttreatment). All women received 17-OHPC and plasma 17-OHPC concentrations were measured at 25 to 28 weeks' gestation. We analyzed these data to determine if there was a relationship between 17-OHPC concentration and cytokine production. We then performed an in vitro study to determine if 17-OHPC could directly alter cytokine production by THP-1-derived macrophages. In the clinical samples, we found that 17-OHPC plasma concentrations were correlated with the quantity of the LPS-stimulated production of IL-10. TNF-α production after LPS stimulation was unrelated to 17-OHPC concentration. In the in vitro study, we demonstrate a 17-OHPC concentration dependent increase in IL-10 production. In women receiving 17-OHPC for PTB prevention, we demonstrate a relationship between plasma 17-OHPC and LPS-stimulated IL-10 production by circulating leukocytes. We also demonstrate that, in vitro, 17-OHPC treatment affects IL-10 production by LPS-stimulated macrophages. Collectively, these findings support an immunomodulatory mechanism of action of 17-OHPC in the prevention of recurrent PTB. · 17-OHPC plasma concentrations and LPS-stimulated IL-10 levels correlate in clinical samples in women at risk for recurrent preterm birth.. · 17-OHPC can modulate the response of LPS-stimulated macrophages to increase IL-10 production.. · There was no relationship between TNF-α and plasma concentration of 17-OHPC in clinical samples or in vitro..

Revisiting the placental clock: Early corticotrophin-releasing hormone rise in recurrent preterm birth.

ObjectiveTo determine if maternal plasma CRH and preterm birth history were associated with recurrent preterm birth risk in a high-risk cohort.Study designSecondary analysis of pregnant women with a prior preterm birth ≤35 weeks receiving 17-alpha hydroxyprogesterone caproate for the prevention of recurrent spontaneous preterm birth. All women with a 24-week blood sample were included. Maternal plasma CRH level at 24- and 32-weeks’ gestation was measured using both enzyme-linked immunosorbent assay (ELISA) and extracted radioimmunoassay (RIA) technologies. The primary outcome was spontaneous preterm birth <37 weeks. The association of CRH, prior preterm birth history, and the two combined was assessed in relation to recurrent preterm birth risk.ResultsRecurrent preterm birth in this cohort of 169 women was 24.9%. Comparing women who subsequently delivered <37 versus ≥37 weeks, mean levels of CRH measured by RIA were significantly different at 24 weeks (111.1±87.5 vs. 66.1±45.4 pg/mL, P = .002) and 32 weeks (440.9±275.6 vs. 280.2±214.5 pg/mL, P = .003). The area under the receiver operating curve (AUC) at 24 and 32 weeks for (1) CRH level was 0.68 (95% CI 0.59–0.78) and 0.70 (95% CI 0.59–0.81), (2) prior preterm birth history was 0.75 (95% CI 0.67–0.83) and 0.78 (95% CI 0.69–0.87), and (3) combined was 0.81 (95% CI 0.73–0.88, P = .001) and 0.81 (95% CI 0.72–0.90, P = .01) respectively for delivery <37 weeks. CRH measured by ELISA failed to correlate with gestational age or other clinical parameters.ConclusionIn women with a prior preterm birth, CRH levels were higher and had an earlier rise in women who experienced recurrent preterm birth. Second trimester CRH may be useful in identifying a sub-group of women with preterm birth due to early activation of the placenta-fetal adrenal axis. Assay methodology is a variable that contributes to difficulties in reproducibility of CRH levels in the obstetric literature.

Maternal selenium levels and whole genome screen in recurrent spontaneous preterm birth population: A nested case control study

ObjectiveTo establish if low maternal selenium (Se) was associated with sPTB in women with recurrent sPTB and identify genetic link with maternal Se levels. DesignNested case-control study. SettingTertiary Maternity Hospital. PopulationPlasma and whole blood from pregnant women with history of early sPTB/PPROM < 34+0 and European ancestry were obtained at 20 weeks (range 15–24 weeks). ‘Cases’ were recurrent PTB/PPROM < 34+0 weeks and term (≥37+0) deliveries were classified as ‘high-risk controls.’ Women with previous term births and index birth ≥ 39 weeks were ‘low-risk controls’. MethodsMaternal plasma Se measured by ICP-MS was used as a continuous phenotype in a GWAS analysis. Se was added to a logistic regression model using PTB predictor variables. Main outcome measuresMaternal Se concentration, recurrent early sPTB/PPROM. Results53/177 high-risk women had a recurrent sPTB/PPROM < 34+0weeks and were 2.7 times more likely to have a Se level < 83.3 ppm at 20weeks of pregnancy compared with low-risk term controls (n = 179), (RR 2.7, 95%CI 1.5–4.8; p = .001). One SNP from a non-coding region (FOXN3 intron variant, rs55793422) reached genome-wide significance level (p = 3.73E−08). Targeted analysis of Se gene variant did not show difference between preterm and term births. (χ2 test, OR = 0.95; 95%CI = 0.59–1.56; p = 0.82). When Se levels were added to a clinical prediction model, only an additional 5% of cases (n = 3) and 0.6% (n = 1) of controls were correctly identified. ConclusionsLow plasma Se is associated with sPTB risk but is not sufficiently predictive at individual patient level. We did not find a genetic association between maternal Se levels and Se-related genes.