Skeletal consequences of preterm birth in pigs as a model for preterm infants.

Preterm birth affects about 10% of all live births with many resultant health challenges, including metabolic bone disease of prematurity (MBDP), which is characterized by elevated alkaline phosphatase, suppressed phosphate, and deficient skeletal development. Because of the lack of an animal model, very little is known about bone structure, strength, and quality after preterm birth. This study investigated the utility of a pig model to replicate clinical features of preterm birth, including MBDP, and sought to determine if early postnatal administration of IGF-1 was an effective treatment. Preterm pigs, born by caesarean section at 90% gestation, were reared in intensive care facilities (respiratory, thermoregulatory, and nutritional support) and compared with sow-reared term pigs born vaginally. Preterm pigs were systemically treated with vehicle or IGF-1 (recombinant human IGF-1/BP-3, 2.25 mg/kg/d). Tissues were collected at postnatal days 1, 5, and 19 (the normal weaning period in pigs). Most bone-related outcomes were affected by preterm birth throughout the study period, whereas IGF-1 supplementation had almost no effect. By day 19, alkaline phosphatase was elevated, phosphate and calcium were reduced, and the bone resorption marker C-terminal crosslinks of type I collagen was elevated in preterm pigs compared to term pigs. Preterm pigs also had decrements in femoral cortical cross-sectional properties, consistent with reduced whole-bone strength. Thus, the preterm pig model replicates many features of preterm bone development in infants, including features of MBDP, and allows for direct interrogation of skeletal tissues, enhancing the field's ability to examine underlying mechanisms.

Premature birth interrupts a critical period of skeletal development as the majority of fetal bone mineral accumulation occurs during the last gestational trimester, leaving preterm infants at increased risk for low bone mineral density and fractures. Although there are some data on growth in bone mass in preterm infants, very little is known about bone structural properties, quality, and strength during development after preterm birth. In this study, we sought to evaluate the pig as a model for postnatal skeletal development after premature birth. Preterm pigs born after approximately 90% of the full gestation period were compared to full-term control pigs through day 19 of life. Levels of 2 blood markers used to diagnose osteoporosis of prematurity were replicated in the pig model. Bone properties related to strength were reduced even when accounting for their smaller body size, possibly suggesting elevated fracture risk in preterm infants. Based on the similarities between the preterm pig model and preterm human infants, the pig model may prove to be useful to study factors and interventions affecting postnatal bone development after preterm birth.

Arachidonic acid and docosahexaenoic acid levels correlate with the inflammation proteome in extremely preterm infants.

BACKGROUND & AIM: Clinical trials supplementing the long-chain polyunsaturated fatty acids (LCPUFAs) docosahexaenoic acid (DHA) and arachidonic acid (AA) to preterm infants have shown positive effects on inflammation-related morbidities, but the molecular mechanisms underlying these effects are not fully elucidated. This study aimed to determine associations between DHA, AA, and inflammation-related proteins during the neonatal period in extremely preterm infants. METHODS: A retrospective exploratory study of infants (n = 183) born below 28 weeks gestation from the Mega Donna Mega trial, a randomized multicenter trial designed to study the effect of DHA and AA on retinopathy of prematurity. Serial serum samples were collected after birth until postnatal day 100 (median 7 samples per infant) and analyzed for phospholipid fatty acids and proteins using targeted proteomics covering 538 proteins. Associations over time between LCPUFAs and proteins were explored using mixed effect modeling with splines, including an interaction term for time, and adjusted for gestational age, sex, and center. RESULTS: On postnatal day one, 55 proteins correlated with DHA levels and 10 proteins with AA levels. Five proteins were related to both fatty acids, all with a positive correlation. Over the first 100 days after birth, we identified 57 proteins to be associated with DHA and/or AA. Of these proteins, 41 (72%) related to inflammation. Thirty-eight proteins were associated with both fatty acids and the overall direction of association did not differ between DHA and AA, indicating that both LCPUFAs similarly contribute to up- and down-regulation of the preterm neonate inflammatory proteome. Primary examples of this were the inflammation-modulating cytokines IL-6 and CCL7, both being negatively related to levels of DHA and AA in the postnatal period. CONCLUSIONS: This study supports postnatal non-antagonistic and potentially synergistic effects of DHA and AA on the inflammation proteome in preterm infants, indicating that supplementation with both fatty acids may contribute to limiting the disease burden in this vulnerable population. CLINICAL REGISTRATION NUMBER: ClinicalTrials.gov (NCT03201588).

Effectiveness of Vitamin D supplementation in combination with calcium on risk of maternal and neonatal outcomes: A quasi-experimental clinical trial.

Objectives: We examined the effectiveness of combining Vitamin D supplementation with calcium on maternal and neonatal outcomes, as opposed to using Vitamin D supplements alone. Materials and Methods: Pregnant women in their third trimester were divided into two groups. The control group received a daily dose of 1000 IU of Vitamin D, but, the experimental group received a combined daily dosage of 1000 IU of Vitamin D and 500 mg of calcium, until delivery. Results: The women in the Vitamin D + calcium group were less likely to develop gestational diabetes (2.78%; vs. 19.51%; P = 0.0318), preeclampsia (2.78% vs. 26.83%; P = 0.004), newly onset gestational hypertension (11.11% vs. 46.34%; P = 0.001), proteinuria (5.56% vs. 39.02%; P = 0.0004), and impaired glucose tolerance (2.78% vs. 21.95%; P = 0.0163) and had lower blood pressure at 20th and 39th weeks of gestation. The newborns in the Vitamin D + calcium group were less likely to experience low birth weight (5.71% vs. 31.58%; P = 0.0066), low birth length (5.71% vs. 44.74%; P = 0.0007), were less likely to be admitted to the neonatal intensive care unit (14.29% vs. 42.11%; P = 0.0105), have a larger head circumference (35.00 vs. 33.63; P < 0.0001), longer gestational age at birth (40.0 vs. 37.56 weeks; P < 0.0001), and higher APGAR scores (9.58 vs. 6.31; P < 0.0001.) compared to Vitamin D group, respectively. Conclusions: Taking Vitamin D and calcium by pregnant women in the third trimester is an effective treatment to decrease maternal, fetal, and neonatal outcomes.

Transition to Motherhood of Puerperal Women With Preterm Birth in a Challenging Lifetime: Transition Theory-Based Study.

Background and purpose: Although the transition process to motherhood of mothers who gave birth preterm has been examined using other theories, no studies have yet utilized Meleis's Transition Theory (TT). The aim of this study was to examine the transition process of mothers who gave birth preterm according to Meleis's TT. Methods: This study is a holistic single-pattern qualitative case study. The qualitative research paradigm was used based on the 32-item Qualitative Research Reporting Consolidated Criteria checklist, a guide for qualitative studies. Face-to-face interviews were conducted with 10 preterm mothers using a semistructured interview form between February 2019 and December 2021. The thematic analysis analysis method was used for the data obtained. After the data were transcribed, all the documents were read, and the data were deciphered. Using the notes, the codings were themed as titles and subtitles according to Meleis' TT. Results: Three main themes were determined using Meleis' TT: facilitators and inhibitors of the transition process, response patterns to motherhood, and nursing care. Visiting the baby in the intensive care unit, touching, and expressing milk for the baby were found to be important milestones in the mothers' transition process. Conclusion: Mothers faced numerous problems after premature birth and required support to cope with the transition process. They attempted to adapt to the transition to motherhood with the support of nurses, husbands, and families. Implications for practice: The researchers stated that may assist a healthy transition process by supporting health professionals to understand the problems faced by mothers during the transition to motherhood and to provide nursing care according to mothers' needs.

Effective and simple interventions to improve outcomes for preterm infants worldwide: The FIGO PremPrep-5 initiative.

Preterm birth remains the leading cause of mortality among under-5's and is a major contributor to the reduction in quality-of-life adjusted years and reduction in human capital. Globally, there are many interventions and care bundles that aim to reduce the impact of preterm birth once preterm labor has ensued and into the neonatal period; not all of these are applicable in all settings. Here, we introduce the FIGO PremPrep-5 initiative, which aims to disseminate key information on the most simple and effective interventions with the aim of increasing implementation globally. Before delivery, we recommend a course of antenatal corticosteroids, and intrapartum magnesium sulfate. At delivery, we recommend delayed cord clamping. Postnatally, we recommend early feeding with breast milk and immediate kangaroo care. While there are many other interventions that may improve outcomes at the time of labor and after preterm birth, these are clinically effective and relatively inexpensive options that can be practiced in most settings and supplemented with more advanced care. We include examples of a training video and infographics that will be used for dissemination.

A retrospective, longitudinal cohort study of trends and risk factors for preterm birth in the Northern Territory, Australia.

BACKGROUND: Preterm birth (PTB) is the single most important cause of perinatal mortality and morbidity in high income countries. In Australia, 8.6% of babies are born preterm but substantial variability exists between States and Territories. Previous reports suggest PTB rates are highest in the Northern Territory (NT), but comprehensive analysis of trends and risk factors are lacking in this region. The objective of this study was to characterise temporal trends in PTB among First Nations and non-First Nations mothers in the Top End of the NT over a 10-year period and to identify perinatal factors associated with the risk of PTB. METHODS: This was a retrospective population-based cohort study of all births in the Top End of the NT over the 10-year period from January 1st, 2008, to December 31st, 2017. We described maternal characteristics, obstetric complications, birth characteristics and annual trends in PTB. The association between the characteristics and the risk of PTB was determined using univariate and multivariate generalised linear models producing crude risk ratios (cRR) and adjusted risk ratios (aRR). Data were analysed overall, in First Nations and non-First Nations women. RESULTS: During the decade ending in 2017, annual rates of PTB in the Top End of the NT remained consistently close to 10% of all live births. However, First Nations women experienced more than twice the risk of PTB (16%) compared to other women (7%). Leading risk factors for PTB among First Nations women as compared to other women included premature rupture of membranes (RR 12.33; 95% CI 11.78, 12.90), multiple pregnancy (RR 7.24; 95% CI 6.68, 7.83), antepartum haemorrhage (RR 4.36; 95% CI 3.93, 4.84) and pre-existing diabetes (RR 4.18; 95% CI 3.67, 4.76). CONCLUSIONS: First Nations women experience some of the highest PTB rates globally. Addressing specific pregnancy complications provides avenues for intervention, but the story is complex and deeper exploration is warranted. A holistic approach that also acknowledges the influence of socio-demographic influences, such as remote dwelling and disadvantage on disease burden, will be required to improve perinatal outcomes.

The association of preconceptional folic acid supplementation with gestational age and preterm birth risk in twin pregnancies: a prospective cohort study in China.

PURPOSE: This study aims to explore the association of maternal preconceptional folic acid (FA) supplementation with gestational age and preterm birth in twin pregnancies, and whether the association varies by chorionicity or conception mode. METHODS: From November 2018 to December 2021, the information of FA supplementation and pregnancy outcomes were collected in twin pregnant women. The linear regression models and the logistic regression were used to test the association of preconceptional FA supplementation with gestational age at delivery and preterm birth and premature rupture of membranes (PROM). RESULTS: A total of 416 twin pregnancies were included. Compared with no use in twins, maternal preconceptional FA use was associated with a 0.385-week longer gestational age (95% CI 0.019-0.751) and lower risk of preterm birth < 36 weeks (adjusted OR 0.519; 95% CI 0.301-0.895) and PROM (adjusted OR 0.426; 95% CI 0.215-0.845). The protective effect on preterm birth < 36 weeks and PROM is similar whether taking FA supplements alone or multivitamins. However, the associations varied by chorionicity and conception mode of twins or compliance with supplementation. The positive associations between preconceptional FA use and gestational age only remained significant among twins via assisted reproductive technology or dichorionic diamniotic twins. Significant protective effects on preterm birth < 36 weeks and PROM were only found among women who took FA at least 4 times a week before conception. CONCLUSION: Maternal preconceptional FA supplementation was associated with longer gestation duration and lower risk of preterm birth < 36 weeks and PROM in twin pregnancies. To improve the success of their pregnancies, reproductive women should start taking FA supplements well before conception and with good compliance.

Omega-3 fatty acid supply in pregnancy for risk reduction of preterm and early preterm birth.

This clinical practice guideline on the supply of the omega-3 docosahexaenoic acid and eicosapentaenoic acid in pregnant women for risk reduction of preterm birth and early preterm birth was developed with support from several medical-scientific organizations, and is based on a review of the available strong evidence from randomized clinical trials and a formal consensus process. We concluded the following. Women of childbearing age should obtain a supply of at least 250 mg/d of docosahexaenoic+eicosapentaenoic acid from diet or supplements, and in pregnancy an additional intake of ≥100 to 200 mg/d of docosahexaenoic acid. Pregnant women with a low docosahexaenoic acid intake and/or low docosahexaenoic acid blood levels have an increased risk of preterm birth and early preterm birth. Thus, they should receive a supply of approximately 600 to 1000 mg/d of docosahexaenoic+eicosapentaenoic acid, or docosahexaenoic acid alone, given that this dosage showed significant reduction of preterm birth and early preterm birth in randomized controlled trials. This additional supply should preferably begin in the second trimester of pregnancy (not later than approximately 20 weeks' gestation) and continue until approximately 37 weeks' gestation or until childbirth if before 37 weeks' gestation. Identification of women with inadequate omega-3 supply is achievable by a set of standardized questions on intake. Docosahexaenoic acid measurement from blood is another option to identify women with low status, but further standardization of laboratory methods and appropriate cutoff values is needed. Information on how to achieve an appropriate intake of docosahexaenoic acid or docosahexaenoic+eicosapentaenoic acid for women of childbearing age and pregnant women should be provided to women and their partners.

Preterm-Born Young Women Have Weaker Hand Grip Strength Compared to Their Full-Term-Born Peers.

Prematurity has been linked to lower muscular fitness and increased morbidity across the human lifespan. Hand grip strength is widely used as a measure of muscle strength. Previous studies have shown inconsistent results regarding the role of vitamin D in hand grip strength. Here, we investigated hand grip strength and the effects of a yearlong vitamin D supplementation in healthy preterm-born young adults. We recruited 38 young adults born preterm at either ≤32 weeks' gestation or <34 weeks' gestation and weighing <1500 g, as well as 39 gender- and age-matched controls, for this study. Anthropometric measurements, hand grip strengths, and vitamin D concentrations were recorded. These investigations were repeated after a yearlong vitamin D supplementation intervention. There was a significant difference in the age- and gender-specific hand grip strength ranks between the preterm- and full-term-born young adults: 57.9% and 30.7%, respectively, were below average (p = 0.009). In the preterm-born group, the females had significantly lower hand grip strengths compared to their full-term-born peers, with a mean difference of -3.46 kg (95% CI: -6.68 to -0.247; p = 0.035). In a linear regression analysis, the preterm-born female adult height was negatively associated with hand grip strength (R2 = 0.24, F (1.43) = 13.61, p < 0.001). The vitamin D concentrations were increased after the supplementation period, with no association with hand grip strength. According to our results, preterm-born young females are at risk for lower muscle strength, independent of their current vitamin D status.

Vitamin D Status as an Important Predictor of Preterm Birth in a Cohort of Black Women.

Vitamin D deficiency (25 (OH)D < 20 ng/mL) is a modifiable risk factor that has been associated with an increased risk of preterm birth (PTB) (<37 weeks gestation). Black women are at a high risk for vitamin D deficiency due to higher melanin levels. Vitamin D sufficiency may be protective against PTB risk in Black women. Black participants between 8 and 25 weeks of gestation were included in this nested case-control study. The sample consisted of women who had either PTBs (n = 57) or term births, were selected based on maternal age compared to those who had PTBs (n = 118), and had blood samples available between 8 and 25 weeks of gestation. The women completed questionnaires about depressive symptoms and smoking behavior and had blood collected to determine their vitamin D levels. Gestational age at birth, hypertensive disorders, and body mass index (BMI) were collected from the medical records. The odds of PTB were increased by 3.34 times for participants with vitamin D deficiency after adjusting for hypertensive disorders of pregnancy and depressive symptoms. Vitamin D assessment and supplementation may be an important intervention for preventing PTB in pregnant Black women.

Myoinositols Prevent Gestational Diabetes Mellitus and Related Complications: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Although gestational diabetes mellitus (GDM) has several short- and long-term adverse effects on the mother and the offspring, no medicine is generally prescribed to prevent GDM. The present systematic review and meta-analysis aimed to investigate the effect of inositol supplementation in preventing GDM and related outcomes. Systematic search was performed in CENTRAL, MEDLINE, and Embase until 13 September 2023. Eligible randomized controlled trials (RCTs) compared the efficacy of inositols to placebo in pregnant women at high risk for GDM. Our primary outcome was the incidence of GDM, whereas secondary outcomes were oral glucose tolerance test (OGTT) and maternal and fetal complications. (PROSPERO registration number: CRD42021284939). Eight eligible RCTs were identified, including the data of 1795 patients. The incidence of GDM was halved by inositols compared to placebo (RR = 0.42, CI: 0.26-0.67). Fasting, 1-h, and 2-h OGTT glucose levels were significantly decreased by inositols. The stereoisomer myoinositol also reduced the risk of insulin need (RR = 0.29, CI: 0.13-0.68), preeclampsia or gestational hypertension (RR = 0.38, CI: 0.2-0.71), preterm birth (RR = 0.44, CI: 0.22-0.88), and neonatal hypoglycemia (RR = 0.12, CI: 0.03-0.55). Myoinositol decrease the incidence of GDM in pregnancies high-risk for GDM. Moreover, myoinositol supplementation reduces the risk of insulin need, preeclampsia or gestational hypertension, preterm birth, and neonatal hypoglycemia. Based on the present study 2-4 g myoinositol canbe suggested from the first trimester to prevent GDM and related outcomes.

DHA, nutrient intake, and maternal characteristics as predictors of pregnancy outcomes in a randomised clinical trial of DHA supplementation.

PURPOSE: To investigate the relationships among docosahexaenoic acid (DHA) intake, nutrient intake, and maternal characteristics on pregnancy outcomes in a phase III randomised clinical trial designed to determine the effect of a DHA dose of 1000 mg/day compared to 200 mg/day on early preterm birth (<34 weeks gestation). METHODS: A secondary aim of the phase III randomised trial was to explore the relationships among pregnancy outcomes (maternal red blood cell phospholipid (RBC-PL) DHA at delivery, preterm birth, gestational age at delivery, labor type, birth anthropometric measures, low birth weight, gestational diabetes, pre-eclampsia, and admission to a neonatal intensive care unit) in participants (n = 1100). We used Bayesian multiple imputation and linear and logistic regression models to conduct an analysis of five general classes of predictor variables collected during the trial: a) DHA intake, b) nutrient intake from food and supplements, c) environmental exposure to tobacco and alcohol, d) maternal demographics, and e) maternal medical history. RESULTS: DHA supplementation lowered the risk of preterm birth and NICU admission, and increased gestation and birth weight as observed in the primary analysis. Higher maternal RBC-PL-DHA at delivery was associated with DHA supplementation and formal education of a bachelor's degree or higher. DHA supplementation and maternal age were associated with a higher risk of gestational diabetes. Total vitamin A intake was associated with longer gestation, while fructose and intake of the long chain omega-6 fatty acid, arachidonic acid, were associated with shorter gestation. Risk of preterm birth was associated with a history of low birth weight, preterm birth, pre-eclampsia, and NICU admission. CONCLUSION: Bayesian models provide a comprehensive approach to relationships among DHA intake, nutrient intake, maternal characteristics, and pregnancy outcomes. We observed previously unreported relationships between gestation duration and fructose, vitamin A, and arachidonic acid that could be the basis for future research. TRIAL REGISTRATION NUMBER AND DATE: ClinicalTrials.gov (NCT02626299); December 10, 2015.

The effect of selenium supplementation in pregnant women on maternal, fetal, and newborn outcomes: a systematic review and meta-analysis.

OBJECTIVE: Low maternal selenium status has been associated with poor pregnancy outcomes, including preterm birth. This study aimed to evaluate available evidence of the effects of selenium supplementation during pregnancy on preterm birth and related maternal, fetal, and newborn outcomes. DATA SOURCES: MEDLINE, Embase, CINAHL, Global Index Medicus, and the Cochrane Library were systematically searched on June 23, 2022, without language or time restrictions. STUDY ELIGIBILITY CRITERIA: Randomized controlled trials and nonrandomized interventional studies were included if they compared the effects of selenium supplementation with placebo or no treatment among pregnant women. The review protocol was registered in the International Prospective Register of Systematic Reviews (identification number: CRD42022383669). METHODS: For outcomes reported by ≥1 study, a meta-analysis was conducted. Because of the small number of studies and high clinical heterogeneity between populations, random-effects models were used. The Risk of Bias 2 and Risk Of Bias In Non-randomized Studies - of Interventions tools were used to assess study quality, and Grading of Recommendations Assessment, Development, and Evaluation analysis was used to determine the certainty of evidence for each outcome. RESULTS: Literature searches identified 5105 unique records, and 32 studies met the eligibility criteria. Of note, 11 reports were not included for analysis following research integrity assessments. Moreover, 10 trials and 3 observational studies met the inclusion criteria; however, only 8 trials (1851 women) and 1 prospective cohort study (71,728 women) reported on at least 1 review outcome. Our results could not determine the effect of selenium supplementation on preterm birth at <37 weeks of gestation (relative risk, 0.65; 95% confidence interval, 0.26-1.63; very low certainty evidence) and <34 weeks of gestation (relative risk, 1.05; 95% confidence interval, 0.59-1.44; very low certainty evidence). CONCLUSION: There is limited evidence on the effects of selenium supplementation during pregnancy. Further trials, with larger sample sizes, more representative populations, and reliable assessment of maternal selenium status at trial entry, are required.

Characterizing light-dark cycles in the Neonatal Intensive Care Unit: a retrospective observational study.

Objectives: To characterize bedside 24-h patterns in light exposure in the Neonatal Intensive Care Unit (NICU) and to explore the environmental and individual patient characteristics that influence these patterns in this clinical setting. Methods: We conducted a retrospective cohort study that included 79 very preterm infants who stayed in an incubator with a built-in light sensor. Bedside light exposure was measured continuously (one value per minute). Based on these data, various metrics (including relative amplitude, intradaily variability, and interdaily stability) were calculated to characterize the 24-h patterns of light exposure. Next, we determined the association between these metrics and various environmental and individual patient characteristics. Results: A 24-h light-dark cycle was apparent in the NICU with significant differences in light exposure between the three nurse shifts (p < 0.001), with the highest values in the morning and the lowest values at night. Light exposure was generally low, with illuminances rarely surpassing 75 lux, and highly variable between patients and across days within a single patient. Furthermore, the season of birth and phototherapy had a significant effect on 24-h light-dark cycles, whereas no effect of bed location and illness severity were observed. Conclusion: Even without an official lighting regime set, a 24-h light-dark cycle was observed in the NICU. Various rhythmicity metrics can be used to characterize 24-h light-dark cycles in a clinical setting and to study the relationship between light patterns and health outcomes.

Road to Equity in Maternal and Child Health: Honoring the Past and Blazing New Paths.

PURPOSE: This paper is a historical account of an initiative, as recalled by the authors who were directly involved, that brought to the forefront the long-standing and unjust reproductive health inequities in the United States. It is composed of three distinct but interrelated parts that together map the past, present, and future of addressing racial inequities in Maternal and Child Health. DESCRIPTION: This paper is composed of three distinct but interrelated parts that together map the past, present, and future of addressing racial inequities in Maternal and Child Health. Part I recounts the history and achievements of a Centers for Disease for Control and Prevention initiative in the 1980-90's, led by the Prematurity Research Group in the Division of Reproductive Health, Pregnancy and Infant Health Branch. This initiative stimulated a paradigm shift in how we understand and address black infant mortality and the inequities in this outcome. Part II illustrates examples of some exemplary programmatic and policy legacies that stemmed either directly or indirectly from the Centers for Disease for Control and Prevention paradigm shift. Part III provides a discussion of how effectively the current practice in Maternal and Child Health applies this paradigm to address inequities and proposes a path for accelerating Title V agencies' progress toward birth equity. ASSESSMENT: This CDC initiative was transformative in that it raised the visibility of African American researchers, moved the field from a focus on traditional epidemiologic risks such as personal health promotion and medical interventions, to include racism as a risk factor for inequitable birth outcomes. The paradigm examined the specific roles of historical and structural racism, and the racialized, contextualized, and temporal exposures that are unique to Black women's experiences in the United States. CONCLUSION: The initiative radically changed the narratives about the underlying factors contributing to inequities in birth outcomes of Black women, altered the way we currently approach addressing inequities, and holds the keys for transforming practice to a more holistic and systematic approach to building sustained organizational structures in maternal and child health that accelerate the achievement of birth equity.

Plasticity of thalamocortical axons is regulated by serotonin levels modulated by preterm birth.

Sensory inputs are conveyed to distinct primary areas of the neocortex through specific thalamocortical axons (TCA). While TCA have the ability to reorient postnatally to rescue embryonic mistargeting and target proper modality-specific areas, how this remarkable adaptive process is regulated remains largely unknown. Here, using a mutant mouse model with a shifted TCA trajectory during embryogenesis, we demonstrated that TCA rewiring occurs during a short postnatal time window, preceded by a prenatal apoptosis of thalamic neurons-two processes that together lead to the formation of properly innervated albeit reduced primary sensory areas. We furthermore showed that preterm birth, through serotonin modulation, impairs early postnatal TCA plasticity, as well as the subsequent delineation of cortical area boundary. Our study defines a birth and serotonin-sensitive period that enables concerted adaptations of TCA to primary cortical areas with major implications for our understanding of brain wiring in physiological and preterm conditions.

Arrest of mouse preterm labor until term delivery by combination therapy with atosiban and mundulone, a natural product with tocolytic efficacy.

There is a lack of FDA-approved tocolytics for the management of preterm labor (PL). In prior drug discovery efforts, we identified mundulone and mundulone acetate (MA) as inhibitors of in vitro intracellular Ca2+-regulated myometrial contractility. In this study, we probed the tocolytic potential of these compounds using human myometrial samples and a mouse model of preterm birth. In a phenotypic assay, mundulone displayed greater efficacy, while MA showed greater potency and uterine-selectivity in the inhibition of intracellular-Ca2+ mobilization. Cell viability assays revealed that MA was significantly less cytotoxic. Organ bath and vessel myography studies showed that only mundulone exerted inhibition of myometrial contractions and that neither compounds affected vasoreactivity of ductus arteriosus. A high-throughput combination screen identified that mundulone exhibits synergism with two clinical-tocolytics (atosiban and nifedipine), and MA displayed synergistic efficacy with nifedipine. Of these combinations, mundulone+atosiban demonstrated a significant improvement in the in vitro therapeutic index compared to mundulone alone. The ex vivo and in vivo synergism of mundulone+atosiban was substantiated, yielding greater tocolytic efficacy and potency on myometrial tissue and reduced preterm birth rates in a mouse model of PL compared to each single agent. Treatment with mundulone after mifepristone administration dose-dependently delayed the timing of delivery. Importantly, mundulone+atosiban permitted long-term management of PL, allowing 71% dams to deliver viable pups at term (>day 19, 4-5 days post-mifepristone exposure) without visible maternal and fetal consequences. Collectively, these studies provide a strong foundation for the development of mundulone as a single or combination tocolytic for management of PL.

The effects of adherence to recommended antenatal services on adverse pregnancy outcomes in Northwest Ethiopia: multilevel and propensity score matching (PSM) modeling.

Introduction: Adverse pregnancy outcomes are a personal and social crisis caused by easily preventable pregnancy-related problems. Despite that, studies on the effectiveness of adherence to the continuity of antenatal care (ANC) services are scarce. Therefore, this study aims to determine the effectiveness of the continuity of ANC services and the determinants of adverse pregnancy outcomes. Methods: A prospective follow-up study design was conducted from March 2020 to January 2021 in Northwest Ethiopia among randomly selected study subjects. Data were collected by trained data collectors using pre-tested structured questionnaires and analyzed using STATA Software version 14. A multilevel regression model was used to identify determinant factors, whereas the propensity score matching (PSM) model was used to look at the effectiveness of adherence to ANC services on adverse pregnancy outcomes. Results: Among 2,198 study participants, 26.8% had adverse pregnancy outcomes, with 95% CI: 24.9-28.7 [abortion (6.1%; 95% CI: 5.1-7.1), low birth weight (11.5%; 95% CI: 10.2-12.9), and preterm birth (10.9; 95% CI: 9.6-12.3)]. Determinant factors were iron-folic acid supplementation (AOR = 0.52; 95% CI: 0.41, 0.68), delayed initiation of ANC visits at 4-6 months (AOR = 0.5; 95% CI: 0.32, 0.8), initiation of ANC visits after 6 months (AOR = 0.2; 95% CI: 0.06, 0.66), received four ANC visits (AOR = 0.36; 95% CI: 0.24, 0.49), an average time of rupture of the amniotic membrane of between 1 and 12 h (AOR = 0.66; 95% CI: 0.45, 0.97), and pregnancy-related problems (AOR = 1.89; 95% CI: 1.24, 2.9). As a treatment effect, completion of a continuum of visit-based ANC (ATET; ß = -0.1, 95% CI: -0.15, -0.05), and continuum of care via space dimension (ATET; ß = -0.11, 95% CI: -0.15, -0.07) were statistically significant on the reduction of adverse pregnancy outcomes. Conclusion: In the study area, the rate of adverse pregnancy outcomes was high. Even though adherence to the continuity of ANC services via time and space dimensions is effective in the prevention of adverse pregnancy outcomes, programmatically important factors were also detected. Therefore, key strategies for promoting the uptake of antenatal services and strengthening iron-folic acid supplementation are strongly recommended.

Antenatal depression and adverse birth outcomes among pregnant women living with HIV in Dar es Salaam, Tanzania.

BACKGROUND: Women who experience antenatal depression may be at increased risk of adverse birth outcomes. Few studies have examined this association among women living with HIV (WHIV). METHODS: We conducted a prospective cohort study of 2298 pregnant WHIV on antiretroviral therapy (ART) in Dar es Salaam, Tanzania, who were participants in a randomized trial of vitamin D3 supplementation. Depressive symptoms were assessed at 12-27 weeks gestation using the Hopkins Symptoms Checklist (HSCL-25). Generalized estimating equations to account for twins were used to assess the relative risks of adverse birth outcomes. RESULTS: Approximately 67 % of the women in our study population reported symptoms consistent with depression. We observed a 4.0 % prevalence of stillbirth and a 25.1 % prevalence of preterm birth. We found that low social support, higher education, and more recent initiation of ART were associated with a greater risk of antenatal depression. There was no association of antenatal depression with risk of fetal loss, stillbirth, low birth weight, birth weight, preterm birth, gestational age at delivery, or small-for-gestational age. LIMITATIONS: Depression was self-reported and only collected at one timepoint in pregnancy. Our findings may not be generalizable to all WHIV. CONCLUSIONS: Our findings illustrate the high risk of both depression and adverse birth outcomes among WHIV and underscore the need for interventions to improve their mental health and the health of their infants; however, the relationship between depression and birth outcomes remains unclear. Further research on this topic is merited, particularly examining the chronicity and timing of depression in pregnancy.

Development and internal validation of a non-invasive clinical tool to predict sufficient omega-3 levels in early pregnancy.

BACKGROUND: Complications from preterm birth (PTB) are the leading cause of death and disability in those under five years. Whilst the role of omega-3 (n-3) supplementation in reducing PTB is well-established, growing evidence suggests supplementation use in those replete may increase the risk of early PTB. AIM: To develop a non-invasive tool to identify individuals with total n-3 serum levels above 4.3% of total fatty acids in early pregnancy. METHODS: We conducted a prospective observational study recruiting 331 participants from three clinical sites in Newcastle, Australia. Eligible participants (n = 307) had a singleton pregnancy between 8 and 20 weeks' gestation at recruitment. Data on factors associated with n-3 serum levels were collected using an electronic questionnaire; these included estimated intake of n-3 (including food type, portion size, frequency of consumption), n-3 supplementation, and sociodemographic factors. The optimal cut-point of estimated n-3 intake that predicted mothers with total serum n-3 levels likely above 4.3% was developed using multivariate logistic regression, adjusting for maternal age, body mass index, socioeconomic status, and n-3 supplementation use. Total serum n-3 levels above 4.3% was selected as previous research has demonstrated that mothers with these levels are at increased risk of early PTB if they take additional n-3 supplementation during pregnancy. Models were evaluated using various performance metrics including sensitivity, specificity, area under receiver operator characteristic (AUROC) curve, true positive rate (TPR) at 10% false positive rate (FPR), Youden Index, Closest to (0,1) Criteria, Concordance Probability, and Index of Union. Internal validation was performed using 1000-bootstraps to generate 95% confidence intervals for performance metrics generated. RESULTS: Of 307 eligible participants included for analysis, 58.6% had total n-3 serum levels above 4.3%. The optimal model had a moderate discriminative ability (AUROC 0.744, 95% CI 0.742-0.746) with 84.7% sensitivity, 54.7% specificity and 37.6% TPR at 10% FPR. CONCLUSIONS: Our non-invasive tool was a moderate predictor of pregnant women with total serum n-3 levels above 4.3%; however, its performance is not yet adequate for clinical use. TRIAL REGISTRATION: This trial was approved by the Hunter New England Human Research Ethics Committee of the Hunter New England Local Health District (Reference 2020/ETH00498 on 07/05/2020 and 2020/ETH02881 on 08/12/2020).