Browsing by Subject "Premature birth"
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Item All trans-retinoic acid modulates hyperoxia-induced suppression of NF-kB-dependent Wnt signaling in alveolar A549 epithelial cells(Public Library of Science, 2022-08-10) Tsotakos, Nikolaos; Ahmed, Imtiaz; Umstead, Todd M.; Imamura, Yuka; Yau, Eric; Silveyra, Patricia; Chroneos, Zissis C.; Medicine, School of MedicineIntroduction: Despite recent advances in perinatal medicine, bronchopulmonary dysplasia (BPD) remains the most common complication of preterm birth. Inflammation, the main cause for BPD, results in arrested alveolarization. All trans-retinoic acid (ATRA), the active metabolite of Vitamin A, facilitates recovery from hyperoxia induced cell damage. The mechanisms involved in this response, and the genes activated, however, are poorly understood. In this study, we investigated the mechanisms of action of ATRA in human lung epithelial cells exposed to hyperoxia. We hypothesized that ATRA reduces hyperoxia-induced inflammatory responses in A549 alveolar epithelial cells. Methods: A549 cells were exposed to hyperoxia with or without treatment with ATRA, followed by RNA-seq analysis. Results: Transcriptomic analysis of A549 cells revealed ~2,000 differentially expressed genes with a higher than 2-fold change. Treatment of cells with ATRA alleviated some of the hyperoxia-induced changes, including Wnt signaling, cell adhesion and cytochrome P450 genes, partially through NF-κB signaling. Discussion/conclusion: Our findings support the idea that ATRA supplementation may decrease hyperoxia-induced disruption of the neonatal respiratory epithelium and alleviate development of BPD.Item Association of a Mediterranean Diet Pattern With Adverse Pregnancy Outcomes Among US Women(American Medical Association, 2022-12-01) Makarem, Nour; Chau, Kristi; Miller, Eliza C.; Gyamfi-Bannerman, Cynthia; Tous, Isabella; Booker, Whitney; Catov, Janet M.; Haas, David M.; Grobman, Wiliam A.; Levine, Lisa D.; McNeil, Rebecca; Merz, C. Noel Bairey; Reddy, Uma; Wapner, Ronald J.; Wong, Melissa S.; Bello, Natalie A.; Obstetrics and Gynecology, School of MedicineImportance: The Mediterranean diet pattern is inversely associated with the leading causes of morbidity and mortality, including metabolic diseases and cardiovascular disease, but there are limited data on its association with adverse pregnancy outcomes (APOs) among US women. Objective: To evaluate whether concordance to a Mediterranean diet pattern around the time of conception is associated with lower risk of developing any APO and individual APOs. Design, setting, and participants: This prospective, multicenter, cohort study, the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be, enrolled 10 038 women between October 1, 2010, and September 30, 2013, with a final analytic sample of 7798 racially, ethnically, and geographically diverse women with singleton pregnancies who had complete diet data. Data analyses were completed between June 3, 2021, and April 7, 2022. Exposures: An Alternate Mediterranean Diet (aMed) score (range, 0-9; low, 0-3; moderate, 4-5; and high, 6-9) was computed from data on habitual diet in the 3 months around conception, assessed using a semiquantitative food frequency questionnaire. Main outcomes and measures: Adverse pregnancy outcomes were prospectively ascertained and defined as developing 1 or more of the following: preeclampsia or eclampsia, gestational hypertension, gestational diabetes, preterm birth, delivery of a small-for-gestational-age infant, or stillbirth. Results: Of 7798 participants (mean [SD] age, 27.4 [5.5] years), 754 (9.7%) were aged 35 years or older, 816 (10.5%) were non-Hispanic Black, 1294 (16.6%) were Hispanic, and 1522 (19.5%) had obesity at baseline. The mean (SD) aMed score was 4.3 (2.1), and the prevalence of high, moderate, and low concordance to a Mediterranean diet pattern around the time of conception was 30.6% (n=2388), 31.2% (n=2430), and 38.2% (n=2980), respectively. In multivariable models, a high vs low aMed score was associated with 21% lower odds of any APO (adjusted odds ratio [aOR], 0.79 [95% CI, 0.68-0.92]), 28% lower odds of preeclampsia or eclampsia (aOR, 0.72 [95% CI, 0.55-0.93]), and 37% lower odds of gestational diabetes (aOR, 0.63 [95% CI, 0.44-0.90]). There were no differences by race, ethnicity, and prepregnancy body mass index, but associations were stronger among women aged 35 years or older (aOR, 0.54 [95% CI, 0.34-0.84]; P = .02 for interaction). When aMed score quintiles were evaluated, similar associations were observed, with higher scores being inversely associated with the incidence of any APO. Conclusions and relevance: This cohort study suggests that greater adherence to a Mediterranean diet pattern is associated with lower risk of APOs, with evidence of a dose-response association. Intervention studies are needed to assess whether dietary modification around the time of conception can reduce risk of APOs and their downstream associations with future development of cardiovascular disease risk factors and overt disease.Item Cost-effectiveness of low-dose aspirin for the prevention of preterm birth: a prospective study of the Global Network for Women's and Children's Health Research(Elsevier, 2023) Patterson, Jackie K.; Neuwahl, Simon; Goco, Norman; Moore, Janet; Goudar, Shivaprasad S.; Derman, Richard J.; Hoffman, Matthew; Metgud, Mrityunjay; Somannavar, Manjunath; Kavi, Avinash; Okitawutshu, Jean; Lokangaka, Adrien; Tshefu, Antoinette; Bose, Carl L.; Mwapule, Abigail; Mwenechanya, Musaku; Chomba, Elwyn; Carlo, Waldemar A.; Chicuy, Javier; Figueroa, Lester; Krebs, Nancy F.; Jessani, Saleem; Saleem, Sarah; Goldenberg, Robert L.; Kurhe, Kunal; Das, Prabir; Patel, Archana; Hibberd, Patricia L.; Achieng, Emmah; Nyongesa, Paul; Esamai, Fabian; Bucher, Sherri; Liechty, Edward A.; Bresnahan, Brian W.; Koso-Thomas, Marion; McClure, Elizabeth M.; Pediatrics, School of MedicineBackground: Premature birth is associated with an increased risk of mortality and morbidity, and strategies to prevent preterm birth are few in number and resource intensive. In 2020, the ASPIRIN trial showed the efficacy of low-dose aspirin (LDA) in nulliparous, singleton pregnancies for the prevention of preterm birth. We sought to investigate the cost-effectiveness of this therapy in low-income and middle-income countries. Methods: In this post-hoc, prospective, cost-effectiveness study, we constructed a probabilistic decision tree model to compare the benefits and costs of LDA treatment compared with standard care using primary data and published results from the ASPIRIN trial. In this analysis from a health-care sector perspective, we considered the costs and effects of LDA treatment, pregnancy outcomes, and neonatal health-care use. We did sensitivity analyses to understand the effect of the price of the LDA regimen, and the effectiveness of LDA in reducing both preterm birth and perinatal death. Findings: In model simulations, LDA was associated with 141 averted preterm births, 74 averted perinatal deaths, and 31 averted hospitalisations per 10 000 pregnancies. The reduction in hospitalisation resulted in a cost of US$248 per averted preterm birth, $471 per averted perinatal death, and $15·95 per disability-adjusted life year. Interpretation: LDA treatment in nulliparous, singleton pregnancies is a low-cost, effective treatment to reduce preterm birth and perinatal death. The low cost per disability-adjusted life year averted strengthens the evidence in support of prioritising the implementation of LDA in publicly funded health care in low-income and middle-income countries.Item Low-Dose Aspirin for the Prevention of Preterm Delivery in Nulliparous Women with a Singleton Pregnancy: A Randomised Multi-country Placebo Controlled Trial(Elsevier, 2020) Hoffman, Matthew K.; Goudar, Shivaprasad S.; Kodkany, Bhalachandra S.; Metgud, Mrityunjay; Somannavar, Manjunath; Okitawutshu, Jean; Lokangaka, Adrien; Tshefu, Antoinette; Bose, Carl L.; Mwapule, Abigail; Mwenechanya, Musaku; Chomba, Elwyn; Carlo, Waldemar A.; Chicuy, Javier; Figueroa, Lester; Garces, Ana; Krebs, Nancy F.; Jessani, Saleem; Zehra, Farnaz; Saleem, Sarah; Goldenberg, Robert L.; Kurhe, Kunal; Das, Prabir; Patel, Archana; Hibberd, Patricia L.; Achieng, Emmah; Nyongesa, Paul; Esamai, Fabian; Liechty, Edward A.; Goco, Norman; Hemingway-Foday, Jennifer; Moore, Janet; Nolen, Tracy L.; McClure, Elizabeth M.; Koso-Thomas, Marion; Miodovnik, Menachem; Silver, Robert; Derman, Richard J.; Pediatrics, School of MedicineBackground: Preterm birth remains a common cause of neonatal mortality with a disproportionate burden occurring in low and middle-income countries. Meta-analyses of low-dose aspirin to prevent preeclampsia suggest that the incidence of preterm birth may also be decreased, particularly if initiated before 16 weeks. Methods: We completed a randomised multi-country (Democratic Republic of Congo, Guatemala, India, Kenya, Pakistan, Zambia) double masked trial of aspirin (81 mg) daily compared to placebo initiated between 6 weeks and 0 days and 13 weeks and 6 days of pregnancy in nulliparous women between14 and 40 years of age with an ultrasound confirming gestational age and singleton viable pregnancy. Randomisation (1:1) was stratified by site. The primary outcome of preterm birth, defined as delivery prior to 37 weeks gestational age, was analyzed in randomised women with pregnancy outcomes at or after 20 weeks. This study is registered with ClinicalTrials.gov, number NCT02409680, and the Clinical Trial Registry, India, number CTRI/2016/05/006970. Findings: From March 2016 through June 2018, 11,976 women were assigned to aspirin (5,990 women) or placebo (5,986 women). Amongst randomised women, an evaluable birth outcome beyond 20 weeks occurred in 5787 women who received Aspirin and 5771 women who received placebo Preterm birth occurred in 11.6% of women randomised to aspirin and 13.1% randomised to placebo (Relative Risk [RR], 0.89; 95% CI, 0.81 to 0.98; Risk Difference, −0·02; 95% CI, −0·03, −0·01). Women randomised to aspirin were less likely to experience perinatal mortality (45.7/1000 vs 53.6/1000; RR, 0.86; 95%CI, 0.73 to 1.00). Other adverse maternal/neonatal events were similar between the two groups. Interpretation: In nulliparous women with singleton pregnancies, low dose aspirin initiated between 6 weeks and 0 days and 13 weeks and 6 days results in lower rates of preterm delivery before 37 weeks and perinatal mortality.Item Metformin Plus Insulin for Preexisting Diabetes or Gestational Diabetes in Early Pregnancy: The MOMPOD Randomized Clinical Trial(American Medical Association, 2023) Boggess, Kim A.; Valint, Arielle; Refuerzo, Jerrie S.; Zork, Noelia; Battarbee, Ashley N.; Eichelberger, Kacey; Ramos, Gladys A.; Olson, Gayle; Durnwald, Celeste; Landon, Mark B.; Aagaard, Kjersti M.; Wallace, Kedra; Scifres, Christina; Rosen, Todd; Mulla, Wadia; Valent, Amy; Longo, Sherri; Young, Laura; Marquis, M. Alison; Thomas, Sonia; Britt, Ashley; Berry, Diane; Obstetrics and Gynecology, School of MedicineImportance: Insulin is recommended for pregnant persons with preexisting type 2 diabetes or diabetes diagnosed early in pregnancy. The addition of metformin to insulin may improve neonatal outcomes. Objective: To estimate the effect of metformin added to insulin for preexisting type 2 or diabetes diagnosed early in pregnancy on a composite adverse neonatal outcome. Design, setting, and participants: This randomized clinical trial in 17 US centers enrolled pregnant adults aged 18 to 45 years with preexisting type 2 diabetes or diabetes diagnosed prior to 23 weeks' gestation between April 2019 and November 2021. Each participant was treated with insulin and was assigned to add either metformin or placebo. Follow-up was completed in May 2022. Intervention: Metformin 1000 mg or placebo orally twice per day from enrollment (11 weeks -<23 weeks) through delivery. Main outcome and measures: The primary outcome was a composite of neonatal complications including perinatal death, preterm birth, large or small for gestational age, and hyperbilirubinemia requiring phototherapy. Prespecified secondary outcomes included maternal hypoglycemia and neonatal fat mass at birth, and prespecified subgroup analyses by maternal body mass index less than 30 vs 30 or greater and those with preexisting vs diabetes early in pregnancy. Results: Of the 831 participants randomized, 794 took at least 1 dose of the study agent and were included in the primary analysis (397 in the placebo group and 397 in the metformin group). Participants' mean (SD) age was 32.9 (5.6) years; 234 (29%) were Black, and 412 (52%) were Hispanic. The composite adverse neonatal outcome occurred in 280 (71%) of the metformin group and in 292 (74%) of the placebo group (adjusted odds ratio, 0.86 [95% CI 0.63-1.19]). The most commonly occurring events in the primary outcome in both groups were preterm birth, neonatal hypoglycemia, and delivery of a large-for-gestational-age infant. The study was halted at 75% accrual for futility in detecting a significant difference in the primary outcome. Prespecified secondary outcomes and subgroup analyses were similar between groups. Of individual components of the composite adverse neonatal outcome, metformin-exposed neonates had lower odds to be large for gestational age (adjusted odds ratio, 0.63 [95% CI, 0.46-0.86]) when compared with the placebo group. Conclusions and relevance: Using metformin plus insulin to treat preexisting type 2 or gestational diabetes diagnosed early in pregnancy did not reduce a composite neonatal adverse outcome. The effect of reduction in odds of a large-for-gestational-age infant observed after adding metformin to insulin warrants further investigation.Item Prediction of neonatal morbidity and very preterm delivery using maternal steroid biomarkers in early gestation(PLOS, 2021-01-06) Patil, Avinash S.; Grotegut, Chad A.; Gaikwad, Nilesh W.; Dowden, Shelley D.; Haas, David M.; Obstetrics and Gynecology, School of MedicineBackground: Preterm delivery is a common pregnancy complication that can result in significant neonatal morbidity and mortality. Limited tools exist to predict preterm birth, and none to predict neonatal morbidity, from early in pregnancy. The objective of this study was to determine if the progesterone metabolites 11-deoxycorticosterone (DOC) and 16-alpha hydroxyprogesterone (16α-OHP), when combined with patient demographic and obstetric history known during the pregnancy, are predictive of preterm delivery-associated neonatal morbidity, neonatal length of stay, and risk for spontaneous preterm delivery prior to 32 weeks' gestation. Methods and findings: We conducted a cohort study of pregnant women with plasma samples collected as part of Building Blocks of Pregnancy Biobank at the Indiana University School of Medicine. The progesterone metabolites, DOC and 16α-OHP, were quantified by mass spectroscopy from the plasma of 58 pregnant women collected in the late first trimester/early second trimester. Steroid levels were combined with patient demographic and obstetric history data in multivariable logistic regression models. The primary outcome was composite neonatal morbidity as measured by the Hassan scale. Secondary outcomes included neonatal length of stay and spontaneous preterm delivery prior to 32 weeks' gestation. The final neonatal morbidity model, which incorporated antenatal corticosteroid exposure and fetal sex, was able to predict high morbidity (Hassan score ≥ 2) with an area under the ROC curve (AUROC) of 0.975 (95% CI 0.932, 1.00), while the model without corticosteroid and fetal sex predictors demonstrated an AUROC of 0.927 (95% CI 0.824, 1.00). The Hassan score was highly correlated with neonatal length of stay (p<0.001), allowing the neonatal morbidity model to also predict increased neonatal length of stay (53 [IQR 22, 76] days vs. 4.5 [2, 31] days, above and below the model cut point, respectively; p = 0.0017). Spontaneous preterm delivery prior to 32 weeks' gestation was also predicted with an AUROC of 0.94 (95% CI 0.869, 1.00). Conclusions: Plasma levels of DOC and 16α-OHP in early gestation can be combined with patient demographic and clinical data to predict significant neonatal morbidity, neonatal length of stay, and risk for very preterm delivery, though validation studies are needed to verify these findings. Early identification of pregnancies at risk for preterm delivery and neonatal morbidity allows for timely implementation of multidisciplinary care to improve perinatal outcomes.Item The efficacy of low-dose aspirin in pregnancy among women in malaria-endemic countries(Springer, 2022-04-10) Bauserman, Melissa; Leuba, Sequoia I.; Hemingway-Foday, Jennifer; Nolen, Tracy L.; Moore, Janet; McClure, Elizabeth M.; Lokangaka, Adrien; Tsehfu, Antoinette; Patterson, Jackie; Liechty, Edward A.; Esamai, Fabian; Carlo, Waldemar A.; Chomba, Elwyn; Goldenberg, Robert L.; Saleem, Sarah; Jessani, Saleem; Koso-Thomas, Marion; Hoffman, Matthew; Derman, Richard J.; Meshnick, Steven R.; Bose, Carl L.; Pediatrics, School of MedicineBackground Low dose aspirin (LDA) is an effective strategy to reduce preterm birth. However, LDA might have differential effects globally, based on the etiology of preterm birth. In some regions, malaria in pregnancy could be an important modifier of LDA on birth outcomes and anemia. Methods This is a sub-study of the ASPIRIN trial, a multi-national, randomized, placebo controlled trial evaluating LDA effect on preterm birth. We enrolled a convenience sample of women in the ASPIRIN trial from the Democratic Republic of Congo (DRC), Kenya and Zambia. We used quantitative polymerase chain reaction to detect malaria. We calculated crude prevalence proportion ratios (PRs) for LDA by malaria for outcomes, and regression modelling to evaluate effect measure modification. We evaluated hemoglobin in late pregnancy based on malaria infection in early pregnancy. Results One thousand four hundred forty-six women were analyzed, with a malaria prevalence of 63% in the DRC site, 38% in the Kenya site, and 6% in the Zambia site. Preterm birth occurred in 83 (LDA) and 90 (placebo) women, (PR 0.92, 95% CI 0.70, 1.22), without interaction between LDA and malaria (p = 0.75). Perinatal mortality occurred in 41 (LDA) and 43 (placebo) pregnancies, (PR 0.95, 95% CI 0.63, 1.44), with an interaction between malaria and LDA (p = 0.014). Hemoglobin was similar by malaria and LDA status. Conclusions Malaria in early pregnancy did not modify the effects of LDA on preterm birth, but modified the effect of LDA on perinatal mortality. This effect measure modification deserves continued study as LDA is used in malaria endemic regions.Item Treatment for Mild Chronic Hypertension during Pregnancy(Massachusetts Medical Society, 2022) Tita, Alan T.; Szychowski, Jeff M.; Boggess, Kim; Dugoff, Lorraine; Sibai, Baha; Lawrence, Kirsten; Hughes, Brenna L.; Bell, Joseph; Aagaard, Kjersti; Edwards, Rodney K.; Gibson, Kelly; Haas, David M.; Plante, Lauren; Metz, Torri; Casey, Brian; Esplin, Sean; Longo, Sherri; Hoffman, Matthew; Saade, George R.; Hoppe, Kara K.; Foroutan, Janelle; Tuuli, Methodius; Owens, Michelle Y.; Simhan, Hyagriv N.; Frey, Heather; Rosen, Todd; Palatnik, Anna; Baker, Susan; August, Phyllis; Reddy, Uma M.; Kinzler, Wendy; Su, Emily; Krishna, Iris; Nguyen, Nicki; Norton, Mary E.; Skupski, Daniel; El-Sayed, Yasser Y.; Ogunyemi, Dotum; Galis, Zorina S.; Harper, Lorie; Ambalavanan, Namasivayam; Geller, Nancy L.; Oparil, Suzanne; Cutter, Gary R.; Andrews, William W.; Chronic Hypertension and Pregnancy (CHAP) Trial Consortium; Obstetrics and Gynecology, School of MedicineBackground: The benefits and safety of the treatment of mild chronic hypertension (blood pressure, <160/100 mm Hg) during pregnancy are uncertain. Data are needed on whether a strategy of targeting a blood pressure of less than 140/90 mm Hg reduces the incidence of adverse pregnancy outcomes without compromising fetal growth. Methods: In this open-label, multicenter, randomized trial, we assigned pregnant women with mild chronic hypertension and singleton fetuses at a gestational age of less than 23 weeks to receive antihypertensive medications recommended for use in pregnancy (active-treatment group) or to receive no such treatment unless severe hypertension (systolic pressure, ≥160 mm Hg; or diastolic pressure, ≥105 mm Hg) developed (control group). The primary outcome was a composite of preeclampsia with severe features, medically indicated preterm birth at less than 35 weeks' gestation, placental abruption, or fetal or neonatal death. The safety outcome was small-for-gestational-age birth weight below the 10th percentile for gestational age. Secondary outcomes included composites of serious neonatal or maternal complications, preeclampsia, and preterm birth. Results: A total of 2408 women were enrolled in the trial. The incidence of a primary-outcome event was lower in the active-treatment group than in the control group (30.2% vs. 37.0%), for an adjusted risk ratio of 0.82 (95% confidence interval [CI], 0.74 to 0.92; P<0.001). The percentage of small-for-gestational-age birth weights below the 10th percentile was 11.2% in the active-treatment group and 10.4% in the control group (adjusted risk ratio, 1.04; 95% CI, 0.82 to 1.31; P = 0.76). The incidence of serious maternal complications was 2.1% and 2.8%, respectively (risk ratio, 0.75; 95% CI, 0.45 to 1.26), and the incidence of severe neonatal complications was 2.0% and 2.6% (risk ratio, 0.77; 95% CI, 0.45 to 1.30). The incidence of any preeclampsia in the two groups was 24.4% and 31.1%, respectively (risk ratio, 0.79; 95% CI, 0.69 to 0.89), and the incidence of preterm birth was 27.5% and 31.4% (risk ratio, 0.87; 95% CI, 0.77 to 0.99). Conclusions: In pregnant women with mild chronic hypertension, a strategy of targeting a blood pressure of less than 140/90 mm Hg was associated with better pregnancy outcomes than a strategy of reserving treatment only for severe hypertension, with no increase in the risk of small-for-gestational-age birth weight.