Cases Of Spontaneous Preterm Birth Research Articles

Placental SARS-CoV-2 infection and its implications for increased risk of adverse pregnancy outcomes.

Pregnant women are at increased risk of COVID-19. This could be explained through the prism of physiologic and immunologic changes in pregnancy. In addition, certain immunological reactions originate in the placenta in response to viral infections. This study aimed to investigate whether SARS-CoV-2 can infect the human placenta and discuss its implications in the pathogenesis of adverse pregnancy outcomes. We conducted a retrospective cohort study in which we collected placental specimens from pregnant women who had a laboratory-confirmed SARS-CoV-2 infection. We performed RNA in situ hybridization (RNA-ISH) assay on formalin-fixed paraffin-embedded (FFPE) tissues to establish the in vivo evidence for placental infectivity by this corona virus. In addition, we infected trophoblast isolated from uninfected term human placenta with SARS-CoV-2 variants to further provide in vitro evidence for such an infectivity. There was a total of 21 cases enrolled, which included five cases of spontaneous preterm birth (SPTB) and two intrauterine fetal demises (IUFDs). Positive staining of positive-sense strand (PSS) of SARS-CoV-2 virions was detected in 15 placentas including four SPTB and both IUFDs. In vitro infection assay demonstrated that SARS-CoV-2 virions were highly capable of infecting both cytotrophoblast and syncytiotrophoblast. This study implies that placental SARS-CoV-2 infection may be associated with an increased risk of adverse obstetrical outcomes.

Prescription Opioid Exposure During Pregnancy and Risk of Spontaneous Preterm Delivery

Opioid exposure during pregnancy has been associated with preterm birth, but prior studies have not differentiated between spontaneous and indicated preterm birth or fully investigated these associations as functions of opioid dose. To determine whether prescription opioid use during pregnancy is associated with spontaneous preterm birth and whether the association is dose-dependent. This case-control study examined a retrospective cohort of pregnant patients enrolled in Tennessee Medicaid. Enrollment files were linked to health care encounters, hospital discharge information, birth certificate data, and prescription fills. Eligible participants were pregnant people ages 15 to 44 years without opioid use disorder who experienced birth of a single fetus at 24 weeks gestation or greater between 2007 and 2019 with linked birth certificate data. Cases of spontaneous preterm birth were matched with up to 10 controls based on pregnancy start date, race, ethnicity, age at delivery within 2 years, and history of prior preterm birth. Cases and matched controls were continuously enrolled in TennCare for at least 90 days prior to the index date (case delivery date). Total opioid MME filled during the 60 days prior to the index date. The primary outcome was spontaneous preterm birth determined by a validated algorithm using birth certificate data. Conditional logistic regression was used to estimate the association between spontaneous preterm birth and total opioid morphine milligram equivalents (MME) dispensed, adjusting for parity, prepregnancy body mass index, education level, tobacco use, hepatitis infections, and pain indications. A total of 25 391 cases (median [IQR] age, 23 [20-28] years; 127 Asian [0.5%], 9820 Black [38.7%], 664 Hispanic [2.6%]; 14 748 non-Hispanic White [58.1%]) with spontaneous preterm birth were identified and matched with 225 696 controls (median [IQR] age, 23 [20-27] years; 229 Asian [0.1%], 89 819 Black [39.8%], 3590 Hispanic [1.6%]; 132 002 non-Hispanic White [58.5%]) (251 087 patients total), with 18 702 patients (7.4%) filling an opioid prescription in the 60 days prior to the index date. Each doubling of nonzero opioid MME was associated with a 4% increase in the odds of spontaneous preterm birth compared with no opioid exposure (adjusted odds ratio, 1.04; 95% CI, 1.01-1.08). In this case-control study, a positive association was found between total prescription opioid dose dispensed and the odds of spontaneous preterm birth. These findings support guidance to minimize opioid exposure during pregnancy and prescribe the lowest dose necessary.

Maternal Vitamin D Insufficiency Early in Pregnancy Is Associated with Increased Risk of Preterm Birth in Ethnic Minority Women in Canada

BackgroundMaternal vitamin D insufficiency (plasma 25-hydroxyvitamin D [25(OH)D] <75 nmol/L) may play a role in ethnic disparities in rates of preterm and spontaneous preterm births. ObjectiveWe explored the relation between maternal plasma 25(OH)D concentration in the first trimester (8–14 wk of gestation) and the risk of preterm and spontaneous preterm births (<37 wk of gestation) by ethnicity. MethodsWe designed a case-control study that included 120 cases of preterm birth (<37 wk of gestation) and 360 term controls (≥37 wk of gestation) of singleton pregnancies from the 3D cohort, a multicenter study in 2456 pregnant women in Quebec, Canada. Plasma 25(OH)D was measured by LC–mass spectrometry. We compared the distribution of vitamin D status between cases and controls for 8 ethnic minority subgroups. We explored the association between maternal plasma 25(OH)D concentration and preterm and spontaneous preterm births with the use of splines in logistic regression by ethnicity. ResultsThe distributions of maternal vitamin D status (<50, 50–75, and >75 nmol/L) were different in preterm and spontaneous preterm birth cases compared with controls but only in women of ethnic minority (P-trend = 0.003 and 0.024, respectively). Among ethnic subgroups, sub-Saharan Africans (P-trend = 0.030) and Arab-West Asians (P-trend = 0.045) showed an inverse relation between maternal vitamin D status and the risk of preterm birth. Maternal plasma 25(OH)D concentrations of 30 nmol/L were associated with 4.05 times the risk of preterm birth in the total ethnic minority population (95% CI: 1.16, 14.12; P = 0.028) relative to participants with a concentration of 75 nmol/L. In contrast, there was no such association among nonethnic women (OR: 0.94; 95% CI: 0.48, 1.82; P = 0.85). There was no association when we considered only spontaneous preterm births in the total ethnic minority population (OR: 1.75; 95% CI: 0.39, 7.79; P = 0.46). ConclusionVitamin D insufficiency is associated with an increased risk of preterm birth in ethnic minority women in Canada.

Natural copper isotopic abnormity in maternal serum at early pregnancy associated to risk of spontaneous preterm birth

Spontaneous preterm birth (SPB) has drawn public attention due to its increasing incidence and adverse effects on fetal growth. Effect of copper (Cu) imbalance in maternal bodies on the risk of SPB remains a subject of debate, and the related mechanisms are still unraveled. Here we applied natural stable copper isotopes to explore the underlying association and mechanism of copper imbalance with SPB using a nested case-control study. We collected maternal sera at the early pregnancy stage and then measured their copper isotopic ratio (65Cu/63Cu, expressed as δ65Cu) as well as physiological and biochemical indexes from women with and without delivering SPB. We found that SPB cases had no significant difference in serum copper level from their controls, but their serum copper was significantly isotopically heavier than the controls (δ65Cu value = 0.15 ± 0.34 ‰ versus −0.15 ± 0.17 ‰, P = 0.0149). Compared with the controls with lower δ65Cu values, the crude odds ratio (OR) associated with SPB risk increased to 4.00 (95 % confidence interval (CI): 1.37–11.70) and the adjusted OR reached up to 11.35 (95 % CI: 1.35–95.60). Furthermore, via the copper isotopic fractionation, we revealed that dietary intake and blood ceruloplasmin may play more important roles than blood lipids and mother-to-child transmission in the copper imbalance associated with SPB. Further studies will be needed to understand the mechanisms of isotope fractionation related to reproductive health.

Breaking Down the Barrier: The Role of Cervical Infection and Inflammation in Preterm Birth

Approximately 40% of cases of spontaneous preterm birth (sPTB) are associated with ascending intrauterine infections. The cervix serves as a physical and immunological gatekeeper, preventing the ascent of microorganisms from the vagina to the amniotic cavity. The cervix undergoes remodeling during pregnancy. It remains firm and closed from the start until the late third trimester of pregnancy and then dilates and effaces to accommodate the passage of the fetus during delivery. Remodeling proceeds appropriately and timely to maintain the pregnancy until term delivery. However, risk factors, such as acute and chronic infection and local inflammation in the cervix, may compromise cervical integrity and result in premature remodeling, predisposing to sPTB. Previous clinical studies have established bacterial (i.e., chlamydia, gonorrhea, mycoplasma, etc.) and viral infections (i.e., herpesviruses and human papillomaviruses) as risk factors of PTB. However, the exact mechanism leading to PTB is still unknown. This review focuses on: (1) the epidemiology of cervical infections in pregnant patients; (2) cellular mechanisms that may explain the association of cervical infections to premature cervical ripening and PTB; (3) endogenous defense mechanisms of the cervix that protect the uterine cavity from infection and inflammation; and (4) potential inflammatory biomarkers associated with cervical infection that can serve as prognostic markers for premature cervical ripening and PTB. This review will provide mechanistic insights on cervical functions to assist in managing cervical infections during pregnancy.

A specific bacterial DNA signature in the vagina of Australian women in midpregnancy predicts high risk of spontaneous preterm birth (the Predict1000 study)

Intrauterine infection accounts for a quarter of the cases of spontaneous preterm birth; however, at present, it is not possible to efficiently identify pregnant women at risk to deliver preventative treatments. This study aimed to establish a vaginal microbial DNA test for Australian women in midpregnancy that will identify those at increased risk of spontaneous preterm birth. A total of 1000 women with singleton pregnancies were recruited in Perth, Australia. Midvaginal swabs were collected between 12 and 23 weeks' gestation. DNA was extracted for the detection of 23 risk-related microbial DNA targets by quantitative polymerase chain reaction. Obstetrical history, pregnancy outcome, and demographics were recorded. After excluding 64 women owing to losses to follow-up and insufficient sample for microbial analyses, the final cohort consisted of 936 women of predominantly white race (74.3%). The overall preterm birth rate was 12.6% (118 births); the spontaneous preterm birth rate at <37 weeks' gestation was 6.2% (2.9% at ≤34 weeks' gestation), whereas the preterm premature rupture of the membranes rate was 4.2%. No single individual microbial target predicted increased spontaneous preterm birth risk. Conversely, women who subsequently delivered at term had higher amounts of Lactobacillus crispatus, Lactobacillus gasseri, or Lactobacillus jensenii DNA in their vaginal swabs (13.8% spontaneous preterm birth vs 31.2% term; P=.005). In the remaining women, a specific microbial DNA signature was identified that was strongly predictive of spontaneous preterm birth risk, consisting of DNA from Gardnerella vaginalis (clade 4), Lactobacillus iners, and Ureaplasma parvum (serovars 3 and 6). Risk prediction was improved if Fusobacterium nucleatum detection was included in the test algorithm. The final algorithm, which we called the Gardnerella Lactobacillus Ureaplasma (GLU) test, was able to detect women at risk of spontaneous preterm birth at <37 and ≤34 weeks' gestation, with sensitivities of 37.9% and 44.4%, respectively, and likelihood ratios (plus or minus) of 2.22 per 0.75 and 2.52 per 0.67, respectively. Preterm premature rupture of the membranes was more than twice as common in GLU-positive women. Adjusting for maternal demographics, ethnicity, and clinical history did not improve prediction. Only a history of spontaneous preterm birth was more effective at predicting spontaneous preterm birth than a GLU-positive result (odds ratio, 3.6). We have identified a vaginal bacterial DNA signature that identifies women with a singleton pregnancy who are at increased risk of spontaneous preterm birth and may benefit from targeted antimicrobial therapy.

905: Release of placental exosomes is reduced in spontaneous preterm births

Feto-maternal signaling is considered to contribute to the timing of birth. Exosomes originating from the placenta may transport signals to maternal tissues where they deposit protein and RNA cargo into target cells. Our previous results indicate that tissues including the placenta secrete lower levels of exosomes into blood under pathological conditions. We hypothesize that differential secretion of placental exosomes and expression of exosome contents will reflect the underlying physiology of spontaneous preterm birth (SPTB). We performed a case-control study comparing levels of placental exosomes in maternal plasma samples obtained following hospital admission from SPTB cases to term delivery and medically-indicated preterm delivery (MPTB)controls. Exosomes were isolated by ultracentrifugation, and nanoparticle analysis was performed to demonstrate that the majority of isolated microvesicles were in the size range consistent with exosomes. Western blots were performed utilizing antibodies against syncytin-1, a placenta-specific protein, and levels of placental exosomes were normalized to TSG-101 (an exosome marker) levels in the plasma samples (Figure 1). Levels of placental exosomes were measured in 16 SPTB cases (20-34 weeks), 10 MPTB (20-34 weeks), and 16 uncomplicated term delivery controls (38-39 weeks). Nanoparticle detection and electron microscopy showed that intact exosomes (range 40–100 nm) were enriched. Relative levels of placental exosomes (syncytin-1 label normalized to TSG 101) were similar in term delivery controls (established at 1.000) and MPTB (1.174+0.626) but were significantly lower in SPTB cases (0.493+0.205, P=0.036, Figure 2). Shedding of placental exosomes into maternal blood was lower in SPTB cases compared to term delivery and MPTB controls. It will be important to compare maternal plasma exosome levels earlier in pregnancy and the proteomic and RNA signatures in SPTB cases and term delivery controls. These studies have the potential to identify novel pathways by which the fetus contributes to the timing of birth.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

15: Markers of placental dysfunction and spontaneous preterm birth

Placental dysfunction is an understudied potential cause of spontaneous preterm birth (SPTB). Levels of pregnancy-associated plasma protein-A1 (PAPP-A1, a growth-promoting enzyme that cleaves insulin-like growth factor binding protein-1 and -4 [IGFBP1 and IGFBP4]) are decreased, and levels of PAPP-A2 (which downregulates trophoblast differentiation) are increased in maternal serum samples from other pregnancy complications associated with placental dysfunction, including preeclampsia and fetal growth restriction. We sought to compare maternal plasma and placental levels of PAPP-A1, PAPP-A2, IGFBP1, and IGFBP4 across birth outcomes. We performed a case-control study comparing levels of PAPP-A1, PAPP-A2, IGFBP1, and IGFBP4 in maternal plasma and placenta biopsy samples obtained from 20 early SPTB cases (< 32 weeks), 20 term deliveries (38-40 weeks), and 20 medically-indicated preterm births (MPTB, < 32 weeks). Protein levels were measured by enzyme-linked immunosorbent assay. Protein levels were stratified by neonatal sex. Demographics of the study groups are presented in Table 1. Maternal plasma and placental levels of PAPP-A1, PAPP-A2, IGFBP1, and IGFBP4 are presented in Table 2. Among the 60 women in the cohort, placental levels of PAPP-A1 and PAPP-A2 differed by birth outcome (P< .001). Maternal plasma levels of PAPP-A1 and PAPP-A2 were lower in SPTB compared to MPTB and term deliveries (P=0.003 and < 0.001). Placental levels of IGFBP4 were significantly greater in MPTB compared to SPTB and term deliveries (P< 0.001). Mothers of male fetuses had significantly lower plasma levels of IGFBP1 and IGFBP4 compared to females. Plasma levels of PAPP-A1 and PAPP-A2 did not differ by sex. This study demonstrates differential expression of placental proteins that influence trophoblast invasion and differentiation in SPTB cases. Additional studies investigating functional pathways that involve these proteins, such as the sonic hedgehog pathway and insulin-like growth factor axis, in relation to SPTB are warranted.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Cervicovaginal microbial communities deficient in Lactobacillus species are associated with second trimester short cervix

The cervix functions as a barrier to ascending pathogens in pregnancy. Short cervical length and lack of cervicovaginal Lactobacillus species are risk factors for spontaneous preterm birth; however, whether they interact to increase risk remains unknown. We sought to examine the relationship between cervicovaginal microbiota and short cervix as well as their combined impact on spontaneous preterm birth risk. This was a secondary analysis of a prospective nested, case-control pregnancy study. Cervical swabs were collected between 16 and 20 weeks of gestation. Cervical length was measured per standard clinical care during a clinically indicated ultrasound at approximately 20 weeks of gestation. Cervicovaginal microbiota were analyzed with 16S ribosomal RNA gene sequencing and classified into community state types among 67 cases of spontaneous preterm birth, 47 cases of medically indicated preterm birth, and 358 cases of term births. Logistic regression was used to model associations of community state type IV, a community characterized by a paucity of Lactobacillus species and a wide array of anaerobic bacteria, and short cervix (<25 mm) as well as to model the association of a combination of short cervix and community state type IV with the odds of spontaneous preterm birth. Among the 472 women in the data set, there were 38 with short cervix (8.1%) and 177 with community state type IV (37.5%). Short cervix was associated with spontaneous preterm birth (adjusted odds ratio, 15.59; 95% confidence interval, 6.77-35.92). Women with community state type IV had higher odds of short cervix (adjusted odds ratio, 2.17; 95% confidence interval, 1.04-4.53) as well as spontaneous preterm birth (adjusted odds ratio, 1.97; 95% confidence interval, 1.06-3.65). While the interaction of community state type IV and short cervix was not significant (P= .771), women with both short cervix and community state type IV (n= 20) had higher odds of spontaneous preterm birth compared with women with both normal cervical length and community state types I, II, III, or V (n= 277) (adjusted odds ratio, 21.8; 95% confidence interval, 6.78-70.2). Community state type IV, characterized by a diverse set of strict and facultative anaerobes and a paucity of Lactobacillus species, is associated with increased odds of short cervix. Women with both community state type IV and short cervix have higher odds of spontaneous preterm birth than women with either factor alone. Determining the cascade of events leading to premature cervical shortening, including dysbiosis, may be critical in preventing spontaneous preterm birth.

Cervicovaginal fluid proteomic analysis to identify potential biomarkers for preterm birth

Spontaneous preterm birth is a leading cause of neonatal morbidity and mortality. Early identification of at-risk women by reliable screening tests could reduce the spontaneous preterm birth rate, but conventional methods such as obstetrical history and maternal cervical length screening identify only a minority of spontaneous preterm birth cases. Cervicovaginal fluid might prove to be a useful, readily available biological fluid for identifying spontaneous preterm birth biomarkers. The objective of the study was to identify cervicovaginal fluid biomarkers of early spontaneous preterm birth in a high-risk cohort of pregnant women with a history of spontaneous preterm birth using targeted and shotgun proteomic analyses. A nested case control study (cases were spontaneous preterm birth <34 weeks in the current pregnancy; controls were spontaneous labor and delivery at 39-41 weeks) was performed using cervicovaginal fluid samples collected at 3 study visits (100/7 to 186/7 weeks, 190/7 to 236/7 weeks, and 280/7 to 316/7 weeks). All participants had a history of at least 1 prior spontaneous preterm birth. Targeted proteomic analysis was performed using a stable isotope-labeled proteome derived from endocervical and vaginal mucosal cells. This served as a standard to quantitate candidate protein levels in individual cervicovaginal fluid samples from the second and third study visits using liquid chromatography-multiple reaction monitoring mass spectrometry. The ratio of endogenous peptide area/stable isotope-labeled proteome-derived peptide area was used to measure levels of 42 peptides in 22 proteins. To maximize biomarker discovery in the cervicovaginal fluid samples, shotgun proteomic analysis also was performed utilizing liquid chromatography and ion trap mass spectrometry. A validation study was performed in second-trimester cervicovaginal fluid samples from an independent study group (12 spontaneous preterm birth cases, 19 term delivery controls) using enzyme-linked immunosorbent assay for 5 proteins expressed at higher levels in spontaneous preterm birth cases compared with controls in targeted or shotgun proteomic analyses. For targeted proteomics, cervicovaginal fluid samples from 33 cases and 32 controls at 190/7 to 236/7 weeks and 16 cases and 14 controls at 280/7 to 316/7 weeks from the same pregnancies were analyzed. When samples were compared between cases and controls, the relative abundance of 5 proteins was greater (P= .02-.05) in cases at both visits, while the relative abundance of 1 protein was lower (P= .03) in cases at both visits. For shotgun proteomics analyses, cervicovaginal fluid samples were pooled for 9 spontaneous preterm birth cases and 9 term delivery controls at each study visit. Shotgun proteomics yielded 28 proteins that were detected at levels >2 times higher and 1 protein that was detected at a level <0.5 times lower in spontaneous preterm birth cases compared with controls at all 3 study visits. Validation enzyme-linked immunosorbent assay for 5 proteins that were detected at higher levels in cervicovaginal fluid samples from spontaneous preterm birth cases compared with term delivery controls in proteomics analyses did not demonstrate statistically significant differences between spontaneous preterm birth cases and controls. Potential biomarkers of spontaneous preterm birth were identified by targeted and shotgun proteomics analyses in cervicovaginal fluid samples from high-risk, asymptomatic women. Many of the proteins detected at higher levels in cervicovaginal fluid samples from spontaneous preterm birth cases are extracellular matrix proteins and/or regulate cell membrane physiology. These proteins have substantial biological interest, but validation enzyme-linked immunosorbent assay for 5 of these proteins did not yield clinically useful biomarkers for spontaneous preterm birth.

Cervicovaginal microbiota and local immune response modulate the risk of spontaneous preterm delivery

Failure to predict and understand the causes of preterm birth, the leading cause of neonatal morbidity and mortality, have limited effective interventions and therapeutics. From a cohort of 2000 pregnant women, we performed a nested case control study on 107 well-phenotyped cases of spontaneous preterm birth (sPTB) and 432 women delivering at term. Using innovative Bayesian modeling of cervicovaginal microbiota, seven bacterial taxa were significantly associated with increased risk of sPTB, with a stronger effect in African American women. However, higher vaginal levels of β-defensin-2 lowered the risk of sPTB associated with cervicovaginal microbiota in an ethnicity-dependent manner. Surprisingly, even in Lactobacillus spp. dominated cervicovaginal microbiota, low β-defensin-2 was associated with increased risk of sPTB. These findings hold promise for diagnostics to accurately identify women at risk for sPTB early in pregnancy. Therapeutic strategies could include immune modulators and microbiome-based therapeutics to reduce this significant health burden.

Preterm birth in relation to the bisphenol A replacement, bisphenol S, and other phenols and parabens

IntroductionPreterm birth continues to be a significant public heath concern and is a leading cause of perinatal and infant mortality. Environmental exposures to phenols and parabens are suspected to potentially contribute to the pathology of preterm birth, yet limited human studies have characterized the extent to which these toxicants are associated with birth outcomes. MethodsWe examined the associations between phenols, parabens, and preterm birth, within pregnant women who were recruited early in gestation into the LIFECODES cohort at Brigham and Women's Hospital in Boston, Massachusetts. Urine samples were collected at up to 4 time points in pregnancy and analyzed for phenols and parabens. We selected 130 cases of preterm birth (defined as delivery before 37 weeks gestation), and 350 random controls. We categorized preterm birth subtypes based on clinical presentation and identified 75 cases of spontaneous preterm birth (characterized by spontaneous preterm labor and/or preterm premature rupture of membranes), and 37 cases of placental preterm birth (characterized by preeclampsia and/or intrauterine growth restriction). We used multivariate logistic regression with visit specific and geometric averages of phenols and parabens to determine associations with preterm birth. ResultsWe observed moderate variability in urinary phenol and paraben concentrations over pregnancy with intraclass correlation coefficients ranging between 0.45 and 0.68. Regression analyses indicated mostly null associations. We observed inverse associations, notably between 2,5-dichlorophenol and overall preterm birth (adjusted odds ratio [95% confidence interval, CI]: 0.79 [0.67 – 0.94]), and this relationship was consistent by study visit. Conversely, ethyl paraben was associated with increased risk for placental preterm birth (adjusted odds ratio [95% CI]: 1.47 [1.14 – 1.91]). Bisphenol-S detection at visit 4 was associated with overall preterm birth (adjusted odds ratio [95% CI]: 2.05 [1.09, 3.89]). ConclusionsWhile the findings from this study largely indicate null associations, we observed some relationships between select phenols, parabens and preterm birth, which warrants further investigation of these toxicants and birth outcomes.

Tensile Mechanical Properties and Dynamic Collagen Fiber Re-Alignment of the Murine Cervix are Dramatically Altered Throughout Pregnancy.

The cervix is a unique organ able to dramatically change its shape and function by serving as a physical barrier for the growing fetus and then undergoing dramatic dilation allowing for delivery of a term infant. As a result, the cervix endures changing mechanical forces from the growing fetus. There is an emerging concept that the cervix may change or remodel "early" in many cases of spontaneous preterm birth (sPTB). However, the mechanical role of the cervix in both normal and preterm birth remains unclear. Therefore, the primary objective of this study was to determine the mechanical and structural responses of murine cervical tissue throughout a normal gestational time course. In this study, both tissue structural and material properties were determined via a quasi-static tensile load-to-failure test, while simultaneously obtaining dynamic collagen fiber re-alignment via cross-polarization imaging. This study demonstrated that the majority of the mechanical properties evaluated decreased at midgestation and not just at term, while collagen fiber re-alignment occurred earlier in the loading curve for cervices at term. This suggests that although structural changes in the cervix occur throughout gestation, the differences in material properties function in combination with collagen fiber re-alignment as mechanical precursors to regulate term gestation. This work lays a foundation for investigating cervical biomechanics and the role of the cervix in preterm birth.

Maternal Vitamin D Insufficiency Early in Pregnancy Is Associated with Increased Risk of Preterm Birth in Ethnic Minority Women in Canada.

Background: Maternal vitamin D insufficiency (plasma 25-hydroxyvitamin D [25(OH)D] <75 nmol/L) may play a role in ethnic disparities in rates of preterm and spontaneous preterm births.Objective: We explored the relation between maternal plasma 25(OH)D concentration in the first trimester (8-14 wk of gestation) and the risk of preterm and spontaneous preterm births (<37 wk of gestation) by ethnicity.Methods: We designed a case-control study that included 120 cases of preterm birth (<37 wk of gestation) and 360 term controls (≥37 wk of gestation) of singleton pregnancies from the 3D cohort, a multicenter study in 2456 pregnant women in Quebec, Canada. Plasma 25(OH)D was measured by LC-mass spectrometry. We compared the distribution of vitamin D status between cases and controls for 8 ethnic minority subgroups. We explored the association between maternal plasma 25(OH)D concentration and preterm and spontaneous preterm births with the use of splines in logistic regression by ethnicity.Results: The distributions of maternal vitamin D status (<50, 50-75, and >75 nmol/L) were different in preterm and spontaneous preterm birth cases compared with controls but only in women of ethnic minority (P-trend = 0.003 and 0.024, respectively). Among ethnic subgroups, sub-Saharan Africans (P-trend = 0.030) and Arab-West Asians (P-trend = 0.045) showed an inverse relation between maternal vitamin D status and the risk of preterm birth. Maternal plasma 25(OH)D concentrations of 30 nmol/L were associated with 4.05 times the risk of preterm birth in the total ethnic minority population (95% CI: 1.16, 14.12; P = 0.028) relative to participants with a concentration of 75 nmol/L. In contrast, there was no such association among nonethnic women (OR: 0.94; 95% CI: 0.48, 1.82; P = 0.85). There was no association when we considered only spontaneous preterm births in the total ethnic minority population (OR: 1.75; 95% CI: 0.39, 7.79; P = 0.46).Conclusion: Vitamin D insufficiency is associated with an increased risk of preterm birth in ethnic minority women in Canada.

Associations of maternal PLA2G4C and PLA2G4D polymorphisms with the risk of spontaneous preterm birth in a Chinese population.

Preterm birth is the leading cause of mortality and morbidity in infants. Its etiology is multifactorial with genes and immune homeostasis. The authors investigated whether prostaglandin (PG) synthesis related single nucleotide polymorphisms (SNPs) PLA2G4C rs1366442 and PLA2G4D rs4924618 were associated with the risk of spontaneous preterm birth (SPTB) in a Chinese population of 114 cases of SPTB and 250 controls of term delivery. The risk associations were determined by odds ratios (ORs) and their 95% confidence intervals (CIs) calculated using multivariate logistic regression. Homology modeling was performed to elucidate potential mechanism of the SNP function. The maternal AT/TT genotype of PLA2G4D rs4924618 was associated with a reduced risk of SPTB (OR, 0.61; 95% CI, 0.37–0.99), while no significant association between PLA2G4C rs1366442 and SPTB risk was identified. Structure and sequence analysis revealed that the amino acid substitution introduced by this SNP located at the conserved central core of the catalytic domain of cytosolic phospholipase A2 δ and was close to the active site. These findings suggested that the polymorphism of PLA2G4D rs4924618 may have a protective influence on the SPTB susceptibility in a Chinese population, supporting a role for genetics in the association between PG synthesis and preterm birth.

Maternal plasma miRNAs as biomarkers during mid-pregnancy to predict later spontaneous preterm birth: a pilot study

More than 10% of babies are born too early resulting in over 15 million preterm births and more than one million new-born deaths globally. Although women with a previous spontaneous preterm birth (SPTB) are considered at high risk for recurrence, the majority occur in women without prior history. Prediction of SPTB risk allows for improved care and potential for targeting novel and existing therapeutics to prevent SPTB, which may result in improved outcomes for infant and mother. In this pilot study, a miRNA array was used to analyse plasma from healthy women in their first pregnancy at 20 weeks of gestation who then went on to deliver either at term or experience SPTB at 28–32 weeks. We identified specific miRNA expression profiles that differentiated between those mothers who delivered at term or delivered following SPTB. miR302b, miR1253 and a clustering of miR548 miRNAs were underexpressed in SPTB cases compared to term controls. Conversely, miR223 was elevated in mothers that later experienced a SPTB. The circulating miRNAs identified in the present study may therefore be attractive candidates as non-invasive biomarkers for the early prediction of SPTB. Further larger studies are now warranted to investigate the potential clinical utility of these markers.

Maternal IGF1 and IGF1R polymorphisms and the risk of spontaneous preterm birth.

The insulin-like growth factor (IGF) pathway was involved in the occurrence of spontaneous preterm birth (SPTB), but little is known regarding the relationship between genetic variations in IGF pathway and the risk of SPTB. We aimed to investigate the associations of IGF1 rs972936 and IGF1 receptor (IGF1R) rs2229765 polymorphisms with SPTB risk in a Chinese population. A total of 114 cases of SPTB and 250 controls of term delivery were included from Guangzhou Women and Children's Medical Center, China. The odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were calculated using multivariate logistic regression. We found that the GA and GA/AA genotypes of IGF1 rs972936 were associated with an increased risk of SPTB, and the adjusted ORs (95% CI) were 1.74 (1.01-3.02) and 1.75 (1.04-2.93) respectively. Women carrying GA and GA/AA genotypes of IGF1R rs2229765 had a reduced risk compared to those with the GG genotype (0.60 [0.37-0.98] and 0.64 [0.40-1.00] respectively). There were significant interactions between IGF1 rs972936 and GDM status (P for interaction=.02), as well as between IGF1R rs2229765 and pre-pregnancy BMI (P for interaction <.001) on the risk of SPTB. Our findings suggest that polymorphisms of IGF1 rs972936 and IGF1R rs2229765 were associated with the risk of SPTB in Chinese pregnant women and these effects depend on the maternal metabolic status.

Neonatal outcomes following preterm birth classified according to placental features

Preterm birth has staggering health implications, and yet the causes of most cases are still unknown. Placental features have been understudied as an etiology for preterm birth, and the association between placental pathologic lesions and neonatal outcomes are incompletely understood. We sought to characterize births according to placental pathology and relate these to adverse neonatal outcomes. We studied 20,091 births (15,710 term and 4381 preterm) with placental evaluations. Births were classified according to the presence or absence of placental lesions consistent with malperfusion (vasculopathy, infarct, advanced villous maturation, perivillous fibrin, fibrin deposition) and intrauterine inflammation/infection (chorioamnionitis, funisitis, vasculitis). Outcomes were gestational week of delivery, birthweight z-score, neonatal respiratory distress syndrome, and intraventricular hemorrhage. Among all preterm births, evidence of placental malperfusion was identified more often than inflammation/infection (50.6% vs 27.3%, P< .0001). Placental malperfusion was associated with reduced fetal growth (adjusted birthweight z-score, -0.83, P < .0001) and lesions of inflammation/infection were associated with earlier delivery (adjusted difference -2.08 weeks, P < .0001) than those with no lesions. When both placental lesions were present, earlier delivery (adjusted difference -2.28 weeks, P < .0001) and reduced fetal growth (adjusted birthweight z-score difference, -0.24, P= .001) were observed more often than when neither lesion was present. Findings were similar when restricted to cases of spontaneous preterm birth. Intraventricular hemorrhage was higher in preterm births with malperfusion lesions than cases with no lesions (7.6% vs 3.4%; odds ratio, 1.98; confidence interval, 1.18-3.32), accounting for gestational age and other covariates. Placental pathology provides important insight into subtypes of preterm birth with adverse neonatal outcomes. Co-occurrence of malperfusion and inflammation/infection, especially among spontaneous preterm births, may be a novel pattern of placental injury linked to severe adverse outcomes.

Ureaplasma parvum genotype, combined vaginal colonisation with Candida albicans, and spontaneous preterm birth in an Australian cohort of pregnant women.

BackgroundDetection of Ureaplasma, Mycoplasma and Candida spp. in the vagina during pregnancy has previously been associated with preterm birth (PTB). However, the prevalence of these microorganisms and the associated obstetric risks (likely to be population-specific) have not been determined in Australian women; furthermore, in the case of Ureaplasma spp., very few studies have attempted characterisation at the species level and none have examined genotype/serovar status to further refine risk assessment.MethodsIn order to address these issues we sampled the vaginal fluid of 191 pregnant Australian women at three time points in pregnancy. Culture methods were used for detection of Ureaplasma spp. and Candida spp., and real-time PCR was used for speciation of U. parvum and U. urealyticum, non-albicans Candida spp., Mycoplasma hominis and Mycoplasma genitalium. High-resolution melt PCR was used to genotype U. parvum. Data on various lifestyle factors (including sex during pregnancy and smoking), antimicrobial use and pregnancy outcome were collected on all participants. Chi-square tests were used to assess the association of vaginal microorganisms with PTB.ResultsDetection of Ureaplasma spp. was higher among spontaneous PTB cases, specifically in the presence of U. parvum [77 % preterm (95 % confidence interval (CI) 50–100 %) vs. 36 % term (CI: 29–43 %), p = 0.004], but not U. urealyticum. The association with PTB strengthened when U. parvum genotype SV6 was detected (54 % preterm (CI: 22–85 %) vs. 15 % term (CI: 10–20 %), p = 0.002); this genotype was also present in 80 % (4/5) of cases of PTB <34 weeks gestation. When present with Candida albicans in the same sample, the association with PTB remained strong for both U. parvum [46 % preterm (CI: 15–78 %) vs. 13 % term (CI: 8–18 %), p = 0.005] and U. parvum genotype SV6 [39 % preterm (CI: 8–69 %) vs. 7 % term (CI: 3–11 %), p = 0.003]. With the exception of Candida glabrata, vaginal colonisation status for all organisms was stable throughout pregnancy. Smoking significantly increased the likelihood of detection of all target organisms.ConclusionsThese data suggest that the presence of different species and serovars of Ureaplasma spp. in the vagina confers an increased risk of spontaneous PTB, findings which may be useful in risk assessment for identifying women who would benefit from antimicrobial treatment.

Cervical elastography during pregnancy: a critical review of current approaches with a focus on controversies and limitations.

In normal pregnancy, the cervix functions as a protective mechanical barrier that must remain tight and closed. Premature remodeling and consecutive shortening occur in many cases of spontaneous preterm birth. Although the complex underlying physiology of normal and abnormal cervical remodeling is not fully understood, it is clear that cervical softening occurs prior to delivery, and inappropriate timing seems to be associated with preterm delivery. Also, degree of cervical softness is a component of the Bishop score currently used clinically to predict successful induction of labor. Therefore, the assessment of changes in cervical stiffness with ultrasound elastography techniques might be useful in the prediction of preterm delivery or successful induction of labor. Two different approaches for cervical elastography for quantitative determination of the physical properties of the pregnant cervix have been developed: strain elastography and shear wave elastography. Recently, several feasibility studies showed the reliability of these cervical elastography techniques for the prediction of preterm delivery and successful labor induction. In this review, we contrast strain elastography, which determines only relative values of tissue stiffness because the applied transducer pressure is unknown, with shear wave elastography, which provides, in principle at least, a more objective description of tissue softness. While more promising preliminary results involving these approaches to assessing cervical softness have been recently published, current limitations in technical implementation need to be addressed before elastography techniques will become clinically useful. We discuss these limitations and present challenges for future studies and equipment development.