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American Journal of Obstetrics and... May 2024Antenatal betamethasone and dexamethasone are prescribed to women who are at high risk of premature birth to prevent neonatal respiratory distress syndrome. The current...
Optimization of the betamethasone and dexamethasone dosing regimen during pregnancy: a combined placenta perfusion and pregnancy physiologically-based pharmacokinetic modeling approach.
BACKGROUND
Antenatal betamethasone and dexamethasone are prescribed to women who are at high risk of premature birth to prevent neonatal respiratory distress syndrome. The current treatment regimens, effective to prevent neonatal RDS, may be suboptimal. Recently, concerns have been raised regarding possible adverse long-term neurological outcomes due to high fetal drug exposures. Data from non-human primates and sheep suggest maintaining a fetal plasma concentration above 1 ng/mL for 48 hours to retain efficacy, while avoiding undesirable high fetal plasma levels.
OBJECTIVE
We aimed to re-evaluate the current betamethasone and dexamethasone dosing strategies to assess estimated fetal exposure and provide new dosing proposals that meet the efficacy target but avoid excessive peak exposures.
STUDY DESIGN
A pregnancy physiologically-based pharmacokinetic model was used to predict fetal drug exposures. To allow prediction of the extent of betamethasone and dexamethasone exposure in the fetus, placenta perfusion experiments were conducted to determine placental transfer. Placental transfer rates were integrated in the PBPK model to predict fetal exposure and model performance was verified using published maternal and fetal PK data. The verified pregnancy physiologically-based pharmacokinetic models were then used to simulate alternative dosing regimens to establish a model-informed dose.
RESULTS
Ex vivo data showed that both drugs extensively cross the placenta. For betamethasone 15.7 ± 1.7% and for dexamethasone 14.4 ± 1.5% of the initial maternal perfusate concentration reached the fetal circulations at the end of the 3-hour perfusion period. Pregnancy physiologically-based pharmacokinetic models that include these ex vivo-derived placental transfer rates, accurately predicted maternal and fetal exposures resulting from current dosing regimens. The dose simulations suggest that for betamethasone intramuscular a dose reduction from 2 dosages 11.4 mg, 24 hours apart, to 4 dosages 1.425 mg, 12 hours apart would avoid excessive peak exposures and still meet the fetal response threshold. For dexamethasone, the dose may be reduced from four times 6 mg every 12 hours to 8 times 1.5 mg every 6 hours.
CONCLUSION
A combined placenta perfusion and pregnancy physiologically-based pharmacokinetic modeling approach adequately predicted both maternal and fetal drug exposures of two antenatal corticosteroids. Strikingly, our PBPK simulations suggest that drug doses might be reduced drastically to still meet earlier proposed efficacy targets and minimize peak exposures. We propose the provided model-informed dosing regimens are used to support further discussion on an updated antenatal corticosteroid scheme and design of clinical trials to confirm the effectiveness and safety of lower doses.
PubMed: 38763343
DOI: 10.1016/j.ajog.2024.05.012 -
Journal of Health, Population, and... May 2024This study examined the neonatal mortality for newborn of women who delivered by caesarean section or vaginally using a prospective cohort.
BACKGROUND
This study examined the neonatal mortality for newborn of women who delivered by caesarean section or vaginally using a prospective cohort.
METHODS
A total of 6,989 live births registered from 2016 to 2018, were followed for neonatal survival from the selected slums of Dhaka (North and South) and Gazipur city corporations, where icddr,b maintained the Health and Demographic Surveillance System (HDSS). Neonatal mortality was compared by maternal and newborn characteristics and mode of delivery using z-test. Logistic regression model performed for neonatal mortality by mode of delivery controlling selected covariates and reported adjusted odd ratios (aOR) with 95% confidence interval (CI).
RESULTS
Out of 6,989 live births registered, 27.7% were caesarean and the rest were vaginal delivery; of these births, 265 neonatal deaths occurred during the follow-up. The neonatal mortality rate was 2.7 times higher (46 vs. 17 per 1,000 births) for vaginal than caesarean delivered. Until 3rd day of life, the mortality rate was very high for both vaginal and caesarean delivered newborn; however, the rate was 24.8 for vaginal and 6.3 per 1,000 live births for caesarean delivered on the 1st day of life. After adjusting the covariates, the odds of neonatal mortality were higher for vaginal than caesarean delivered (aOR: 2.63; 95% CI: 1.82, 3.85). Additionally, the odds were higher for adolescent than elderly adult mother (aOR: 1.60; 95% CI: 1.03, 2.48), for multiple than singleton birth (aOR: 5.40; 95% CI: 2.82, 10.33), for very/moderate (aOR: 5.13; 95% CI: 3.68, 7.15), and late preterm birth (aOR: 1.48; 95% CI: 1.05, 2.08) than term birth; while the odds were lower for girl than boy (aOR: 0.74; 95% CI: 0.58, 0.96), and for 5th wealth quintile than 1st quintile (aOR: 0.59, 95% CI: 0.38, 0.91).
CONCLUSION
Our study found that caesarean delivered babies had significantly lower neonatal mortality than vaginal delivered. Therefore, a comprehensive delivery and postnatal care for vaginal births needed a special attention for the slum mothers to ensure the reduction of neonatal mortality.
Topics: Humans; Female; Bangladesh; Infant Mortality; Infant, Newborn; Cesarean Section; Prospective Studies; Adult; Pregnancy; Infant; Poverty Areas; Male; Young Adult; Delivery, Obstetric; Adolescent
PubMed: 38762527
DOI: 10.1186/s41043-024-00563-x -
European Journal of Obstetrics,... May 2024In singleton-pregnant women, abnormal maternal apolipoprotein levels have been confirmed as a risk factor for preterm birth. However, there are currently no studies on...
OBJECTIVE
In singleton-pregnant women, abnormal maternal apolipoprotein levels have been confirmed as a risk factor for preterm birth. However, there are currently no studies on the relationship of the related research in twin-pregnant women.
METHODS
This single-center retrospective study included 743 dichorionic twin-pregnant women who delivered between January 2019 and December 2020. Twins delivered before 37 weeks gestation were categorized as the preterm group, while those delivered at or after 37 weeks gestation were classified as the term group. Maternal serum apolipoprotein A1 (ApoA1) levels, apolipoprotein B (ApoB) levels, and the ApoB/ApoA1 ratio were measured in the first trimester(6-14 weeks), the second trimester(18-28 weeks) and the third trimester(after 28 weeks). We conducted SPSS analysis to evaluate the correlation between ApoA1 levels, ApoB levels, the ApoB/ApoA1 ratio and preterm birth.
RESULTS
Among the 743 included dichorionic twin-pregnant women, 53.57 % (398/743) delivered preterm. Compared with the term group, the ApoA1 levels in the third trimester were lower (p < 0.001), while the Apo B/ApoA1 ratio was higher in the second (p = 0.01) and third trimesters in the preterm group (p = 0.001). When preterm birth was categorized as iatrogenic and spontaneous preterm birth, the results were similar. In the analysis stratified by prepregnancy BMI, a higher risk of preterm birth was associated with low ApoA1 levels and a high Apo B/ApoA1 ratio in the second and third trimesters only among the subgroup of overweight/obese dichorionic twin-pregnant women.
CONCLUSIONS
Low ApoA1 levels and a high Apo B/ApoA1 ratio during the second and third trimesters were associated with a high incidence of preterm birth for overweight/obese dichorionic twin-pregnant women.
PubMed: 38761531
DOI: 10.1016/j.ejogrb.2024.05.013 -
BMJ Open May 2024To systematically map evidence to answer the research question: DESIGN: Scoping review. (Review)
Review
OBJECTIVE
To systematically map evidence to answer the research question: DESIGN: Scoping review.
SETTING
Primary care.
ELIGIBILITY CRITERIA
English-language quantitative or mixed-methods studies published between 2012 and 2022.
DATA SOURCES
Medline, Embase, Scopus and Web of Science Social Sciences Citation Index, and grey literature.
RESULTS
22 eligible studies were identified, covering general practice (n=14), dental health (n=4), child mental health (MN) services (n=3) and immunisation (n=1). Only eight studies (36%) controlled for variables associated with healthcare need (eg, age, birth weight and long-term conditions). In these, evidence of horizontal inequity in primary care use was reported for CYP living in deprived areas in England, with and without complex needs. Horizontal inequity was also identified in primary care MN referrals for CYP in England identifying as mixed-race, Asian or black ethnicity, compared with their white British peers. No evidence of horizontal inequity was observed, however, in primary care use for CYP in England exposed to parental depression, or for CYP children from low-income households in Scotland. Increasing CYP's age was associated with decreasing primary care use across included studies. No studies were found regarding CYP from Gypsy or Traveller communities, children in care, or those with disabilities or special educational needs.
CONCLUSIONS
There is evidence that socioeconomic factors impact on CYP's primary care use, in particular age, ethnicity and deprivation. However, better quality evidence is required to evaluate horizontal inequity in use and address knowledge gaps regarding primary care use for vulnerable CYP populations and the impact of policy and practice related 'supply side' of primary care.
Topics: Humans; Primary Health Care; Child; United Kingdom; Caregivers; Adolescent; Healthcare Disparities; Child, Preschool; Health Services Needs and Demand; Child Health Services
PubMed: 38760051
DOI: 10.1136/bmjopen-2023-078505 -
PLoS Neglected Tropical Diseases May 2024In response to the 2015-2016 Zika virus (ZIKV) outbreak and the causal relationship established between maternal ZIKV infection and adverse infant outcomes, we conducted...
BACKGROUND
In response to the 2015-2016 Zika virus (ZIKV) outbreak and the causal relationship established between maternal ZIKV infection and adverse infant outcomes, we conducted a cohort study to estimate the incidence of ZIKV infection in pregnancy and assess its impacts in women and infants.
METHODOLOGY/PRINCIPAL FINDINGS
From May 2018-January 2020, we prospectively followed pregnant women recruited from 134 participating hospitals in two non-adjacent provinces in northeastern Thailand. We collected demographic, clinical, and epidemiologic data and blood and urine at routine antenatal care visits until delivery. ZIKV infections were confirmed by real-time reverse transcriptase polymerase chain reaction (rRT-PCR). Specimens with confirmed ZIKV underwent whole genome sequencing. Among 3,312 women enrolled, 12 (0.36%) had ZIKV infections, of which two (17%) were detected at enrollment. Ten (83%, 3 in 2nd and 7 in 3rd trimester) ZIKV infections were detected during study follow-up, resulting in an infection rate of 0.15 per 1,000 person-weeks (95% CI: 0.07-0.28). The majority (11/12, 91.7%) of infections occurred in one province. Persistent ZIKV viremia (42 days) was found in only one woman. Six women with confirmed ZIKV infections were asymptomatic until delivery. Sequencing of 8 ZIKV isolates revealed all were of Asian lineage. All 12 ZIKV infected women gave birth to live, full-term infants; the only observed adverse birth outcome was low birth weight in one (8%) infant. Pregnancies in 3,300 ZIKV-rRT-PCR-negative women were complicated by 101 (3%) fetal deaths, of which 67 (66%) had miscarriages and 34 (34%) had stillbirths. There were no differences between adverse fetal or birth outcomes of live infants born to ZIKV-rRT-PCR-positive mothers compared to live infants born to ZIKV-rRT-PCR-negative mothers.
CONCLUSIONS/SIGNIFICANCE
Confirmed ZIKV infections occurred infrequently in this large pregnancy cohort and observed adverse maternal and birth outcomes did not differ between mothers with and without confirmed infections.
PubMed: 38758964
DOI: 10.1371/journal.pntd.0012176 -
Medicine May 2024To explore the influence of perinatal-related factors on meconium aspiration syndrome (MAS) in full-term neonates and construct a nomogram prediction model for risk... (Observational Study)
Observational Study
To explore the influence of perinatal-related factors on meconium aspiration syndrome (MAS) in full-term neonates and construct a nomogram prediction model for risk stratification of neonatal MAS and adoption of preventive measures. A total of 424 newborns and their mothers who were regularly examined at our hospital between January 2020 and December 2023 who had meconium-contaminated amniotic fluid during delivery were retrospectively selected as participants. Neonates were divided into MAS and non-MAS groups based on whether MAS occurred within 3 days after birth. Data from the 2 groups were analyzed, and factors influencing MAS were screened using multivariate logistic regression analysis. The R3.4.3 software was used to construct a nomogram prediction model for neonatal MAS risk. Receiver operating characteristic (ROC) curve analysis and the Hosmer-Lemeshow goodness-of-fit test were used to evaluate the performance of the model, and its clinical effectiveness was evaluated using a decision curve. Among the 424 neonates with meconium-stained amniotic fluid, 51 developed MAS within 3 days of birth (12.03%). Multivariate logistic regression analysis showed that a low amniotic fluid index before delivery (OR = 2.862, P = .019), advanced gestational age (OR = 0.526, P = .034), cesarean section (OR = 2.650, P = .013), severe amniotic fluid contamination (OR = 4.199, P = .002), low umbilical cord blood pH (OR = 2.938, P = .011), and low neonatal Apgar 1-min score (OR = 3.133, P = .006) were influencing factors of MAS in full-term neonates. Based on the above indicators, a nomogram prediction model for MAS risk of full-term newborns was constructed. The area under the ROC curve of the model was 0.931. The model was also tested for goodness-of-fit deviation (χ2 = 3.465, P = .903). Decision curve analysis found that the model was clinically effective in predicting the net benefit of MAS risk in neonates with meconium-stained amniotic fluid. The construction of a column chart prediction model for neonatal MAS risk based on prenatal amniotic fluid index, gestational age, delivery method, amniotic fluid contamination level, newborn umbilical blood pH value, and Apgar 1-min score has a certain application value.
Topics: Humans; Meconium Aspiration Syndrome; Infant, Newborn; Female; Nomograms; Retrospective Studies; Male; Amniotic Fluid; Pregnancy; Risk Assessment; Risk Factors; ROC Curve; Gestational Age; Logistic Models; Apgar Score; Cesarean Section; Meconium; Adult
PubMed: 38758867
DOI: 10.1097/MD.0000000000038279 -
JAMA Network Open May 2024Linking prenatal drug exposures to both infant behavior and adult cognitive outcomes may improve early interventions.
IMPORTANCE
Linking prenatal drug exposures to both infant behavior and adult cognitive outcomes may improve early interventions.
OBJECTIVE
To assess whether neonatal physical, neurobehavioral, and infant cognitive measures mediate the association between prenatal cocaine exposure (PCE) and adult perceptual reasoning IQ.
DESIGN, SETTING, AND PARTICIPANTS
This study used data from a longitudinal, prospective birth cohort study with follow-up from 1994 to 2018 until offspring were 21 years post partum. A total of 384 (196 PCE and 188 not exposed to cocaine [NCE]) infants and mothers were screened for cocaine or polydrug use. Structural equation modeling was performed from June to November 2023.
EXPOSURES
Prenatal exposures to cocaine, alcohol, marijuana, and tobacco assessed through urine and meconium analyses and maternal self-report.
MAIN OUTCOMES AND MEASURES
Head circumference, neurobehavioral assessment, Bayley Scales of Infant Development, Fagan Test of Infant Intelligence score, Wechsler Perceptual Reasoning IQ, Home Observation for Measurement of the Environment (HOME) score, and blood lead level.
RESULTS
Among the 384 mothers in the study, the mean (SD) age at delivery was 27.7 (5.3) years (range, 18-41 years), 375 of 383 received public assistance (97.9%) and 336 were unmarried (87.5%). Birth head circumference (standardized estimate for specific path association, -0.05, SE = 0.02; P = .02) and 1-year Bayley Mental Development Index (MDI) (standardized estimate for total of the specific path association, -0.05, SE = 0.02; P = .03) mediated the association of PCE with Wechsler Perceptual Reasoning IQ, controlling for HOME score and other substance exposures. Abnormal results on the neurobehavioral assessment were associated with birth head circumference (β = -0.20, SE = 0.08; P = .01). Bayley Psychomotor Index (β = 0.39, SE = 0.05; P < .001) and Fagan Test of Infant Intelligence score (β = 0.16, SE = 0.06; P = .01) at 6.5 months correlated with MDI at 12 months.
CONCLUSIONS AND RELEVANCE
In this cohort study, a negative association of PCE with adult perceptual reasoning IQ was mediated by early physical and behavioral differences, after controlling for other drug and environmental factors. Development of infant behavioral assessments to identify sequelae of prenatal teratogens early in life may improve long-term outcomes and public health awareness.
Topics: Humans; Female; Pregnancy; Prenatal Exposure Delayed Effects; Adult; Intelligence; Infant; Cocaine; Prospective Studies; Male; Young Adult; Adolescent; Infant Behavior; Longitudinal Studies; Infant, Newborn; Child Development
PubMed: 38758554
DOI: 10.1001/jamanetworkopen.2024.11905 -
Archives of Medical Science : AMS 2024Necrotizing enterocolitis (NEC) poses a significant threat to preterm infants, with nonspecific early manifestations complicating timely diagnosis. Therefore, this study...
INTRODUCTION
Necrotizing enterocolitis (NEC) poses a significant threat to preterm infants, with nonspecific early manifestations complicating timely diagnosis. Therefore, this study aimed to develop a novel scoring system for early diagnosis of NEC, incorporating clinical and laboratory data with urinary caveolin-1 levels.
MATERIAL AND METHODS
A single-center prospective cohort study was conducted at a tertiary hospital in East Java, Indonesia. NEC diagnosis was established by Bell's criteria and proven gut dysbiosis. Urinary levels of claudin-2, caveolin-1, and epidermal growth factor (EGF) were assessed as potential indicators of tight junction disruption. The selected urine biomarker cutoff value was determined using symbolic classification analysis and combined with clinical and laboratory parameters from Bell's criteria to create an NEC scoring system, validated with the Aiken index. Sensitivity and specificity analyses were performed.
RESULTS
Thirty-four neonates, comprising NEC, preterm non-NEC, and term infants, were included. qPCR analysis highlighted elevated , , , and levels in NEC patients, indicating a gut dysbiosis trend. Among 3 biomarkers, caveolin-1 ≥ 17.81 ng/dl on day 3 demonstrated 72.86% negative predictive value and 87.50% positive predictive value. The combined scoring system which comprised abdominal cellulitis, distension, radiology, advanced resuscitation at birth, prematurity or low birthweight, platelet count, sepsis, orogastric retention, metabolic acidosis and caveolin-1 findings exhibited an AUC of 0.922 (95% CI: 0.81-1.00, < 0.001), with ≥ 1.81 as the cutoff, offering 93% sensitivity and 94% specificity.
CONCLUSIONS
Urine caveolin-1 on day 3 signifies enterocyte tight junction damage and the acute phase of NEC in premature infants. The proposed scoring system demonstrates good performance in predicting NEC incidence in preterm infants.
PubMed: 38757010
DOI: 10.5114/aoms/173390 -
Journal of Dairy Science May 2024We investigated the short- and long-term effects of different forage types supplemented in preweaning dairy calves on growth performance, blood metabolites, rumen...
We investigated the short- and long-term effects of different forage types supplemented in preweaning dairy calves on growth performance, blood metabolites, rumen fermentation, bacterial community, and milk production during first lactation. Sixty healthy 1-mo-old female Holstein calves were blocked by birth date and body weight and randomly assigned to one of 3 groups (n = 20): normal milk and pelleted starter feeding (CON), supplemented with chopped oat hay [75.0 g/d/calf (dry matter (DM) basis); OAH], or alfalfa hay [75.0 g/d/calf (DM basis); ALF]. The forage supplementation started when calves were 30 d old (D1 of the experimental period) and ended when they were 73 d old (D44 of the experimental period when calves were weaned. Milk and feed intakes and fecal consistency scores were recorded daily. Growth performance, rumen fluid, and blood samples were collected bi-weekly. After weaning, all the calves were integrated with the same barn and diets. After calving, the milk production was recorded daily. During the experimental period, the OAH group had greater solid feed and total DM intakes and greater rumen pH than the CON group (P ≤ 0.04), but had lower forage intake and crude protein digestibility than the ALF group (P ≤ 0.04). The ALF group had higher rumen pH and blood β-hydroxybutyrate concentration (P ≤ 0.04), lower fecal score (P = 0.02), and greater ether extract digestibility (P = 0.02) than the CON group. The ALF and OAH groups had lower concentrations of ruminal total volatile fatty acids (P = 0.01). Still, the ALF group had a greater proportion of acetate and a relative abundance of cellulose degradation-related bacteria (Lachnoclostridium_1 and Oribacterium) and a lower relative abundance of inflammation-related bacteria (Erysipelotrichaceae_UCG-009) in the rumen compared with CON. Interestingly, the average milk production from 6 to 200 d in milk (DIM) was greater in the ALF group (P < 0.01) even though no significant effects were found on the rumen fermentation parameters and blood metabolites at 200 DIM. Generally, alfalfa hay supplementation in preweaning dairy calves had positive effects in the short- and long-term in terms of rumen development, health status, and future milk production.
PubMed: 38754819
DOI: 10.3168/jds.2023-24244 -
PLOS Global Public Health 2024Women in malaria-endemic areas receive sulphadoxine-pyrimethamine (SP) as Intermittent Preventive Treatment in Pregnancy (IPTp) to reduce malaria. While...
Intermittent preventive treatment with sulphadoxine-pyrimethamine but not dihydroartemisinin-piperaquine modulates the relationship between inflammatory markers and adverse pregnancy outcomes in Malawi.
Women in malaria-endemic areas receive sulphadoxine-pyrimethamine (SP) as Intermittent Preventive Treatment in Pregnancy (IPTp) to reduce malaria. While dihydroartemisinin-piperaquine (DP) has superior antimalarial properties as IPTp, SP is associated with superior fetal growth. As maternal inflammation influences fetal growth, we investigated whether SP alters the relationship between inflammation and birth outcomes. We measured C-reactive protein (CRP) and alpha-1-acid glycoprotein (AGP) at enrollment (16-28 gestation weeks (gw)), visit 3 (24-36 gw) and delivery in 1319 Malawian women randomized to receive monthly SP, DP, or DP and single-dose azithromycin (AZ) in the IMPROVE trial (NCT03208179). Logistic regression was used to assess the relationship between adverse outcomes, inflammation, and treatment arm. Elevated AGP at enrollment was associated with adverse birth outcome (aRR 1.40, 95% CI: 1.15, 1.70), with similar associations observed across treatment arms, exceptions being that elevated AGP was associated with low maternal weight gain in SP recipients (aRR 1.94, 95% CI: 1.36, 2.76) and with small for gestational age in DP+AZ recepients (aRR 1.49, 95% CI 1.02, 2.17). At visit 3 there were few associations between inflammation andoutcomes. At delivery, women with elevated AGP receiving either DP or DP+AZ had an increased risk of adverse birth outcomes (aRR 1.60, 95% CI: 1.28, 2.00), including low birth weight, pre-term birth and foetal loss, this was not seen in women receiving SP (aRR 0.82, 95% CI: 0.54, 1.26). The risk of an association between elevated AGP and adverse birth outcome was higher in those receiving DP or DP+AZ compared to those receiving SP (aRR 1.95, 95% CI: 1.21, 3.13). No clear associations between CRP and adverse outcomes were observed. AGP identified women at risk of adverse pregnancy outcomes. SP modifies the relationship between inflammatory biomarkers and adverse outcomes. Our findings provide insights into potential mechanisms by which SP may improve pregnancy outcomes.
PubMed: 38753813
DOI: 10.1371/journal.pgph.0003198