The alarmin S100A12 causes sterile inflammation of the human chorioamniotic membranes and preterm birth and neonatal mortality in mice†

Abstract Sterile inflammation is triggered by danger signals or alarmins released upon cellular stress or necrosis. Sterile inflammation occurring in the amniotic cavity (i.e. sterile intra-amniotic inflammation) is frequently observed in women with spontaneous preterm labor resulting in preterm birth, the leading cause of neonatal morbidity and mortality worldwide, and is associated with increased amniotic fluid concentrations of alarmins. However, the mechanisms whereby alarmins induce sterile intra-amniotic inflammation are still under investigation. Herein, we investigated the mechanisms whereby the alarmin S100A12 induces inflammation of the human chorioamniotic membranes in vitro and used a mouse model to establish a causal link between this alarmin and adverse perinatal outcomes. We report that S100A12 initiates sterile inflammation in the chorioamniotic membranes by upregulating the expression of inflammatory mediators such as pro-inflammatory cytokines and pattern recognition receptors. Importantly, S100A12 induced the priming and activation of inflammasomes, resulting in the activation of caspase-1 and the subsequent release of mature IL-1β by the chorioamniotic membranes. This alarmin also caused the activation of the chorioamniotic membranes by promoting MMP-2 activity and collagen degradation. Lastly, the ultrasound-guided intra-amniotic injection of S100A12 at specific concentrations observed in the majority of women with sterile intra-amniotic inflammation induced preterm birth (rates: 17% at 200 ng/sac; 25% at 300 ng/sac; 25% at 400 ng/sac) and neonatal mortality (rates: 22% at 200 ng/sac; 44% at 300 ng/sac; 31% at 400 ng/sac), demonstrating a causal link between this alarmin and adverse perinatal outcomes. Collectively, our findings shed light on the inflammatory responses driven by alarmins in the chorioamniotic membranes, providing insight into the immune mechanisms leading to preterm birth in women with sterile intra-amniotic inflammation.

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The alarmin interleukin-1α causes preterm birth through the NLRP3 inflammasome

MHR Basic science of reproductive medicine ◽

10.1093/molehr/gaaa054 ◽

2020 ◽

Vol 26 (9) ◽

pp. 712-726 ◽

Cited By ~ 1

Author(s):

K Motomura ◽

R Romero ◽

V Garcia-Flores ◽

Y Leng ◽

Y Xu ◽

...

Keyword(s):

Preterm Birth ◽

Neonatal Mortality ◽

Nlrp3 Inflammasome ◽

Clinical Condition ◽

Neonatal Morbidity ◽

Causal Link ◽

Pathological Process ◽

Amniotic Cavity ◽

Protein Levels ◽

Pyrin Domain

Abstract Sterile intra-amniotic inflammation is a clinical condition frequently observed in women with preterm labor and birth, the leading cause of neonatal morbidity and mortality worldwide. Growing evidence suggests that alarmins found in amniotic fluid, such as interleukin (IL)-1α, are central initiators of sterile intra-amniotic inflammation. However, the causal link between elevated intra-amniotic concentrations of IL-1α and preterm birth has yet to be established. Herein, using an animal model of ultrasound-guided intra-amniotic injection of IL-1α, we show that elevated concentrations of IL-1α cause preterm birth and neonatal mortality. Additionally, using immunoblotting techniques and a specific immunoassay, we report that the intra-amniotic administration of IL-1α induces activation of the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome in the fetal membranes, but not in the decidua, as evidenced by a concomitant increase in the protein levels of NLRP3, active caspase-1, and IL-1β. Lastly, using Nlrp3−/− mice, we demonstrate that the deficiency of this inflammasome sensor molecule reduces the rates of preterm birth and neonatal mortality caused by the intra-amniotic injection of IL-1α. Collectively, these results demonstrate a causal link between elevated IL-1α concentrations in the amniotic cavity and preterm birth as well as adverse neonatal outcomes, a pathological process that is mediated by the NLRP3 inflammasome. These findings shed light on the mechanisms underlying sterile intra-amniotic inflammation and provide further evidence that this clinical condition can potentially be treated by targeting the NLRP3 inflammasome.

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Comparison of adverse perinatal outcomes between Asians and Caucasians: a population-based retrospective cohort study in Ontario

BMC Pregnancy and Childbirth ◽

10.1186/s12884-020-03467-w ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Na Zeng ◽

Erica Erwin ◽

Wendy Wen ◽

Daniel J. Corsi ◽

Shi Wu Wen ◽

...

Keyword(s):

Cohort Study ◽

Birth Weight ◽

Preterm Birth ◽

Cesarean Section ◽

Gestational Age ◽

Retrospective Cohort Study ◽

Retrospective Cohort ◽

Perinatal Outcomes ◽

Population Based ◽

Adverse Perinatal Outcomes

Abstract Background Racial disparities in adverse perinatal outcomes have been studied in other countries, but little has been done for the Canadian population. In this study, we sought to examine the disparities in adverse perinatal outcomes between Asians and Caucasians in Ontario, Canada. Methods We conducted a population-based retrospective cohort study that included all Asian and Caucasian women who attended a prenatal screening and resulted in a singleton birth in an Ontario hospital (April 1st, 2015-March 31st, 2017). Generalized estimating equation models were used to estimate the independent adjusted relative risks and adjusted risk difference of adverse perinatal outcomes for Asians compared with Caucasians. Results Among 237,293 eligible women, 31% were Asian and 69% were Caucasian. Asians were at an increased risk of gestational diabetes mellitus, placental previa, early preterm birth (< 32 weeks), preterm birth, emergency cesarean section, 3rd and 4th degree perineal tears, low birth weight (< 2500 g, < 1500 g), small-for-gestational-age (<10th percentile, <3rd percentile), neonatal intensive care unit admission, and hyperbilirubinemia requiring treatment, but had lower risks of preeclampsia, macrosomia (birth weight > 4000 g), large-for-gestational-age neonates, 5-min Apgar score < 7, and arterial cord pH ≤7.1, as compared with Caucasians. No difference in risk of elective cesarean section was observed between Asians and Caucasians. Conclusion There are significant differences in several adverse perinatal outcomes between Asians and Caucasians. These differences should be taken into consideration for clinical practices due to the large Asian population in Canada.

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Fertility Treatments and the Risk of Preterm Birth Among Women with Subfertility: A Linked-Data Retrospective Cohort Study

10.21203/rs.3.rs-206714/v1 ◽

2021 ◽

Author(s):

Jessica N Sanders ◽

Sara E Simonsen ◽

Christina A Porucznik ◽

Ahmad O Hammoud ◽

Ken Smith ◽

...

Keyword(s):

Cohort Study ◽

Preterm Birth ◽

In Vitro Fertilization ◽

Retrospective Cohort ◽

Fetal Death ◽

Perinatal Outcomes ◽

Birth Certificates ◽

Vitro Fertilization ◽

Fertility Treatments

Abstract Background: In vitro fertilization (IVF) births contribute to a considerable proportion of preterm birth (PTB) each year. However, there is no formal surveillance of adverse perinatal outcomes for less invasive fertility treatments. The study objective was to determine the effect of fertility treatment (in vitro fertilization, intrauterine insemination, usually with ovulation drugs (IUI), or ovulation drugs alone) on preterm birth, compared to no treatment in subfertile women.Methods: The Fertility Experiences Study (FES) is a retrospective cohort study conducted at the University of Utah between April 2010 and September 2012. Women with a history of primary subfertility self-reported treatment data via survey and interviews. Participant data were linked to birth certificates and fetal death records to asses for perinatal outcomes, particularly preterm birth.Results: A total 487 birth certificates and 3 fetal death records were linked as first births for study participants who completed questionnaires. Among linked births, 19% had a PTB. After adjustment for maternal age, paternal age, maternal education, annual income, religious affiliation, female or male fertility diagnosis, and duration of subfertility, the odds ratios and 95% confidence intervals (CI) for PTB were 2.17 (CI: 0.99, 4.75) for births conceived using ovulation drugs, 3.17 (CI: 1.4, 7.19) for neonates conceived using IUI and 4.24 (CI: 2.05, 8.77) for neonates conceived by IVF, compared to women with subfertility who used no treatment during the month of conception. A reported diagnosis of female factor infertility increased the adjusted odds of having a PTB 2.99 (CI: 1.5, 5.97). Duration of pregnancy attempt was not independently associated with PTB. In restricting analyses to singleton gestation, odds ratios remained elevated but were not significant for any type of treatment.Conclusion: IVF, IUI, and ovulation drugs were all associated with a higher incidence of preterm birth and low birth weight, predominantly related to multiple gestation births.

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Perinatal Outcomes of Twin Pregnancies With Preterm Premature Rupture of the Membranes at 24–34 Weeks’ Gestation

10.21203/rs.3.rs-669989/v1 ◽

2021 ◽

Author(s):

Shuwei Zhou ◽

Yajun Yang ◽

XiaoYan Zhang ◽

Xiaoling Mu ◽

Quan Quan ◽

...

Keyword(s):

Neonatal Death ◽

Latency Period ◽

Perinatal Outcomes ◽

Neonatal Morbidity ◽

Premature Rupture Of Membranes ◽

Premature Rupture ◽

Factors Associated ◽

Preterm Premature Rupture ◽

Adverse Perinatal Outcomes ◽

Twin Pregnancies

Abstract Objective: To describe the perinatal outcomes of twin pregnancies with preterm premature rupture of membranes (PPROM) before 34 weeks’ gestation and identify factors associated with discharge without severe or moderate-severe neonatal morbidity.Methods: This study was conducted as a retrospective analysis of twin pregnancies with PPROM occurring at 24 0/7 to 33 6/7 weeks’ gestation. Perinatal outcomes were assessed by gestational age (GA) at PPROM. Factors associated with discharge without severe or moderate-severe neonatal morbidity were identified using logistic regression analysis.Results: Of the 180 pregnancies (360 foetuses), only 17 (9.4%) women remained pregnant 7 days after PPROM. There were 10 (2.8%) cases of prenatal or neonatal death; 303 (84.2%) and 177 (49.2%) neonates were discharged without severe or moderate-severe morbidity, respectively. As GA at PPROM increased, the adverse obstetric and neonatal outcomes decreased, especially after 32 weeks. The GA at PPROM and latency period were both significantly associated with discharge without severe or moderate-severe neonatal morbidity. Pregnancy complications and 5-min Apgar score < 7 increased severe neonatal morbidity.Conclusion: As GA at PPROM increased, the risk of adverse perinatal outcomes decreased. GA at PPROM and latency period were significantly associated with discharge without severe or moderate-severe neonatal morbidity.

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Adverse perinatal outcomes of chlamydia infections: an ongoing challenge

Journal of Perinatal Medicine ◽

10.1515/jpm-2021-0519 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Yael Eliner ◽

Moti Gulersen ◽

Amos Grunebaum ◽

Erez Lenchner ◽

Liron Bar-El ◽

...

Keyword(s):

Preterm Birth ◽

Neonatal Intensive Care ◽

Low Birthweight ◽

Perinatal Outcomes ◽

The United States ◽

Chlamydia Infection ◽

Suspected Sepsis ◽

Bonferroni Adjustment ◽

Neonatal Ventilation ◽

Adverse Perinatal Outcomes

Abstract Objectives Chlamydia trachomatis is one of the most common sexually transmitted diseases in the world, but there are limited data on its impact on perinatal outcomes. Our objective was to investigate the association between chlamydia infections and adverse perinatal outcomes. Methods This is a retrospective analysis of the United States Centers for Disease Control and Prevention natality live birth database for the years 2016–2019. The rates of adverse perinatal outcomes were compared between patients with a chlamydia infection during pregnancy and patients without such infection, using Pearson’s chi-square test with the Bonferroni adjustment. A multivariate logistic regression was then used to adjust outcomes for potential confounders. Results Chlamydia infections were associated with small, but statistically significant, increased odds of preterm birth (<37 weeks), early preterm birth (<32 weeks), low birthweight (<2,500 g), congenital anomalies, low 5-min Apgar score (<7), neonatal intensive care unit admission, immediate neonatal ventilation, prolonged (>6 h) neonatal ventilation, and neonatal antibiotic treatment for suspected sepsis. Conclusions Chlamydia infections during pregnancy are associated with adverse perinatal outcomes. These results call for increased education regarding the potential risks of pregnancies with a chlamydia infection, as well as for increased antenatal surveillance and post-natal pediatric assessment in these pregnancies.

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G06: Adoptive transfer of in vitro M2‐polarized macrophages prevents preterm birth and neonatal mortality

American Journal of Reproductive Immunology ◽

10.1111/aji.05_13118 ◽

2019 ◽

Vol 81 (S1) ◽

pp. 24-25

Keyword(s):

Preterm Birth ◽

Neonatal Mortality ◽

Adoptive Transfer

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Associations between first-trimester uterine artery Doppler velocimetry indices and adverse perinatal outcomes in women conceiving via in vitro fertilization

The Journal of Maternal-Fetal & Neonatal Medicine ◽

10.1080/14767058.2016.1182979 ◽

2016 ◽

Vol 30 (6) ◽

pp. 684-688 ◽

Cited By ~ 2

Author(s):

Hakan Timur ◽

Mehmet Çinar ◽

Necati Hançerlioğullari ◽

Mihriban Alkan ◽

Hasan Ali İnal ◽

...

Keyword(s):

In Vitro Fertilization ◽

Uterine Artery ◽

Perinatal Outcomes ◽

First Trimester ◽

Doppler Velocimetry ◽

Uterine Artery Doppler ◽

Vitro Fertilization ◽

Adverse Perinatal Outcomes

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Treatment of vulvovaginal candidiasis in preparation programs for in vitro fertilization

Medical Council ◽

10.21518/2079-701x-2021-13-77-83 ◽

2021 ◽

pp. 77-83

Author(s):

A. Yu. Romanov ◽

A. G. Syrkasheva ◽

I. V. Kuznetsova

Keyword(s):

Topical Therapy ◽

Perinatal Outcomes ◽

First Trimester ◽

Vulvovaginal Candidiasis ◽

Reproductive Age ◽

Preparation Programs ◽

Vitro Fertilization ◽

History Of ◽

Adverse Perinatal Outcomes

Vulvovaginal candidiasis (VVC) is considered as the second most common cause of vaginitis after bacterial vaginosis. About three quarters of women of reproductive age have a history of at least one episode of VVC, and about a half of women have two or more episodes. Candida albicans is responsible for85% to 90% of vulvovaginal candidiasis. There are uncomplicated and complicated forms of VVC. Uncomplicated forms are not severe cases caused by C. albicans. Complicated forms are cases caused by other Candida species, severe cases, cases that develop during pregnancy or associated with other diseases such as diabetes mellitus or immunosuppressive conditions. Reccurent cases are also complicated ones. Therapeutic schemes should depend on the form of the VVC. Short-term topical therapy or a single oral dose are effective in 90% of uncomplicated cases. Complicated forms of VVC require longer treatment. Oral fluconazole can be administered three times with a break of 72 hours. Topical azoles can be administered daily for at least 1 week. So, sertaconazole in the form of suppositories is used once intravaginally. The data on the use of probiotics in the treatment of VVC today are contradictory and heterogeneous. Treatment of VVC during pregnancy, especially in the first trimester, may be associated with adverse perinatal outcomes. On the other hand, during pregnancy, VVC can be more severe than in non-pregnant women, especially in the second half of pregnancy. In addition, the risk of transmission to a newborn is about 50%. Thus, the identification and treatment of VVC is one of the important tasks in pregnancy planning, including assisted reproduction.

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Benefits of not smoking during pregnancy for Australian Aboriginal and Torres Strait Islander women and their babies: a retrospective cohort study using linked data

BMJ Open ◽

10.1136/bmjopen-2019-032763 ◽

2019 ◽

Vol 9 (11) ◽

pp. e032763 ◽

Cited By ~ 1

Author(s):

Carol McInerney ◽

Ibinabo Ibiebele ◽

Jane B Ford ◽

Deborah Randall ◽

Jonathan M Morris ◽

...

Keyword(s):

Preterm Birth ◽

Gestational Age ◽

Small For Gestational Age ◽

Lower Risk ◽

Perinatal Death ◽

Perinatal Outcomes ◽

Smoking During Pregnancy ◽

Relative Risks ◽

South Wales ◽

Adverse Perinatal Outcomes

ObjectivesTo provide evidence for targeted smoking cessation policy, the aim of this study was to compare pregnancy outcomes of Aboriginal mothers who reported not smoking during pregnancy with Aboriginal mothers who reported smoking during pregnancy.DesignPopulation based retrospective cohort study using linked data.SettingNew South Wales, the most populous Australian state.Population18 154 singleton babies born to 13 477 Aboriginal mothers between 2010 and 2014 were identified from routinely collected New South Wales datasets. Aboriginality was determined from birth records and from four linked datasets through an Enhanced Reporting of Aboriginality algorithm.ExposureNot smoking at any time during pregnancy.Main outcome measuresUnadjusted and adjusted relative risks (aRR) and 95% CIs from modified Poisson regression were used to examine associations between not smoking during pregnancy and maternal and perinatal outcomes including severe morbidity, inter-hospital transfer, perinatal death, preterm birth and small-for-gestational age. Population attributable fractions (PAFs) were calculated using adjusted relative risks.ResultsCompared with babies born to mothers who smoked during pregnancy, babies born to non-smoking mothers had a lower risk of all adverse perinatal outcomes including perinatal death (aRR=0.58, 95% CI 0.44 to 0.76), preterm birth (aRR=0.58, 95% CI 0.53 to 0.64) and small-for-gestational age (aRR=0.35, 95% CI 0.32 to 0.39). PAFs (%) were 27% for perinatal death, 26% for preterm birth and 48% for small-for-gestational-age. Compared with women who smoked during pregnancy (n=8919), those who did not smoke (n=9235) had a lower risk of being transferred to another hospital (aRR=0.76, 95% CI 0.66 to 0.89).ConclusionsBabies born to women who did not smoke during pregnancy had a lower risk of adverse perinatal outcomes. Rates of adverse outcomes among Aboriginal non-smokers were similar to those among the general population. These results quantify the proportion of adverse perinatal outcomes due to smoking and highlight why effective smoking cessation programme are urgently required for this population.

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