Magnesium Sulfate Before Preterm Birth for Neuroprotection: An Updated Cochrane Systematic Review.

OBJECTIVE: To systematically review the evidence for the effectiveness and safety of magnesium sulfate as a fetal neuroprotective agent when given to individuals at risk of preterm birth. DATA SOURCES: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (through March 17, 2023), and reference lists of relevant studies. METHODS OF STUDY SELECTION: Randomized controlled trials (RCTs) assessing magnesium sulfate for fetal neuroprotection in pregnant participants at risk of imminent preterm birth were eligible. Two authors assessed RCTs for inclusion, extracted data, and evaluated risk of bias, trustworthiness, and evidence certainty (GRADE [Grading of Recommendations Assessment, Development and Evaluation]). TABULATION, INTEGRATION, AND RESULTS: We included six RCTs (5,917 pregnant participants and 6,759 fetuses at less than 34 weeks of gestation at randomization). They were conducted in high-income countries (two in the United States, two across Australia and New Zealand, and one each in Denmark and France) and commenced between 1995 and 2018. Primary outcomes: up to 2 years of corrected age, magnesium sulfate compared with placebo reduced the risk of cerebral palsy (risk ratio [RR] 0.71, 95% CI, 0.57-0.89; six RCTs, 6,107 children) and death or cerebral palsy (RR 0.87, 95% CI, 0.77-0.98; six RCTs, 6,481 children) (high-certainty evidence). Magnesium sulfate had little or no effect on death up to 2 years of corrected age (moderate-certainty evidence) or these outcomes at school age (low-certainty evidence). Although there was little or no effect on death or cardiac or respiratory arrest for pregnant individuals (low-certainty evidence), magnesium sulfate increased adverse effects severe enough to stop treatment (RR 3.21, 95% CI, 1.88-5.48; three RCTs, 4,736 participants; moderate-certainty evidence). Secondary outcome: magnesium sulfate reduced the risk of severe neonatal intraventricular hemorrhage (moderate-certainty evidence). CONCLUSION: Magnesium sulfate for preterm fetal neuroprotection reduces cerebral palsy and death or cerebral palsy for children. Further research is required on longer-term benefits and harms for children, effect variation by participant and treatment characteristics, and the generalizability of findings to low- and middle-income countries. SYSTEMATIC REVIEW REGISTRATION: The review protocol was based on a standard Cochrane Pregnancy and Childbirth template and our previous Cochrane Systematic Review (doi: 10.1002/14651858.CD004661.pub3; published before the introduction of PROSPERO).

Optimizing Opioid Prescription Quantity After Cesarean Delivery: A Randomized Controlled Trial.

OBJECTIVE: To test whether an individualized opioid-prescription protocol (IOPP) with a shared decision-making component can be used without compromising postcesarean pain management. METHODS: In this multicenter randomized controlled noninferiority trial, we compared IOPP with shared decision making with a fixed quantity of opioid tablets at hospital discharge. We recruited at 31 centers participating in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Study participants had uncomplicated cesarean births. Follow-up occurred through 12 weeks postdischarge. Individuals with complicated cesarean births or history of opioid use in the pregnancy were excluded. Participants were randomized 1:1 to IOPP with shared decision making or fixed quantity (20 tablets of 5 mg oxycodone). In the IOPP group, we calculated recommended tablet quantity based on opioid use in the 24 hours before discharge. After an educational module and shared decision making, participants selected a quantity of discharge tablets (up to 20). The primary outcome was moderate to severe pain (score 4 or higher [possible range 0-10]) on the BPI (Brief Pain Inventory) at 1 week after discharge. A total sample size of 5,500 participants was planned to assess whether IOPP with shared decision making was not inferior to the fixed quantity of 20 tablets. RESULTS: From September 2020 to March 2022, 18,990 individuals were screened and 5,521 were enrolled (n=2,748 IOPP group, n=2,773 fixed-quantity group). For the primary outcome, IOPP with shared decision making was not inferior to fixed quantity (59.5% vs 60.1%, risk difference 0.67%; 95% CI, -2.03% to 3.37%, noninferiority margin -5.0) and resulted in significantly fewer tablets received (median 14 [interquartile range 4-20] vs 20, P<.001) through 90 days postpartum. CONCLUSION: Compared with fixed quantity, IOPP with shared decision making was noninferior for outpatient postcesarean analgesia at 1 week postdischarge and resulted in fewer prescribed opioid tablets at discharge. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT04296396.

Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus.

BACKGROUND: Magnesium sulphate is a common therapy in perinatal care. Its benefits when given to women at risk of preterm birth for fetal neuroprotection (prevention of cerebral palsy for children) were shown in a 2009 Cochrane review. Internationally, use of magnesium sulphate for preterm cerebral palsy prevention is now recommended practice. As new randomised controlled trials (RCTs) and longer-term follow-up of prior RCTs have since been conducted, this review updates the previously published version. OBJECTIVES: To assess the effectiveness and safety of magnesium sulphate as a fetal neuroprotective agent when given to women considered to be at risk of preterm birth. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) on 17 March 2023, as well as reference lists of retrieved studies. SELECTION CRITERIA: We included RCTs and cluster-RCTs of women at risk of preterm birth that assessed prenatal magnesium sulphate for fetal neuroprotection compared with placebo or no treatment. All methods of administration (intravenous, intramuscular, and oral) were eligible. We did not include studies where magnesium sulphate was used with the primary aim of preterm labour tocolysis, or the prevention and/or treatment of eclampsia. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed RCTs for inclusion, extracted data, and assessed risk of bias and trustworthiness. Dichotomous data were presented as summary risk ratios (RR) with 95% confidence intervals (CI), and continuous data were presented as mean differences with 95% CI. We assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: We included six RCTs (5917 women and their 6759 fetuses alive at randomisation). All RCTs were conducted in high-income countries. The RCTs compared magnesium sulphate with placebo in women at risk of preterm birth at less than 34 weeks' gestation; however, treatment regimens and inclusion/exclusion criteria varied. Though the RCTs were at an overall low risk of bias, the certainty of evidence ranged from high to very low, due to concerns regarding study limitations, imprecision, and inconsistency. Primary outcomes for infants/children: Up to two years' corrected age, magnesium sulphate compared with placebo reduced cerebral palsy (RR 0.71, 95% CI 0.57 to 0.89; 6 RCTs, 6107 children; number needed to treat for additional beneficial outcome (NNTB) 60, 95% CI 41 to 158) and death or cerebral palsy (RR 0.87, 95% CI 0.77 to 0.98; 6 RCTs, 6481 children; NNTB 56, 95% CI 32 to 363) (both high-certainty evidence). Magnesium sulphate probably resulted in little to no difference in death (fetal, neonatal, or later) (RR 0.96, 95% CI 0.82 to 1.13; 6 RCTs, 6759 children); major neurodevelopmental disability (RR 1.09, 95% CI 0.83 to 1.44; 1 RCT, 987 children); or death or major neurodevelopmental disability (RR 0.95, 95% CI 0.85 to 1.07; 3 RCTs, 4279 children) (all moderate-certainty evidence). At early school age, magnesium sulphate may have resulted in little to no difference in death (fetal, neonatal, or later) (RR 0.82, 95% CI 0.66 to 1.02; 2 RCTs, 1758 children); cerebral palsy (RR 0.99, 95% CI 0.69 to 1.41; 2 RCTs, 1038 children); death or cerebral palsy (RR 0.90, 95% CI 0.67 to 1.20; 1 RCT, 503 children); and death or major neurodevelopmental disability (RR 0.81, 95% CI 0.59 to 1.12; 1 RCT, 503 children) (all low-certainty evidence). Magnesium sulphate may also have resulted in little to no difference in major neurodevelopmental disability, but the evidence is very uncertain (average RR 0.92, 95% CI 0.53 to 1.62; 2 RCTs, 940 children; very low-certainty evidence). Secondary outcomes for infants/children: Magnesium sulphate probably reduced severe intraventricular haemorrhage (grade 3 or 4) (RR 0.76, 95% CI 0.60 to 0.98; 5 RCTs, 5885 infants; NNTB 92, 95% CI 55 to 1102; moderate-certainty evidence) and may have resulted in little to no difference in chronic lung disease/bronchopulmonary dysplasia (average RR 0.92, 95% CI 0.77 to 1.10; 5 RCTs, 6689 infants; low-certainty evidence). Primary outcomes for women: Magnesium sulphate may have resulted in little or no difference in severe maternal outcomes potentially related to treatment (death, cardiac arrest, respiratory arrest) (RR 0.32, 95% CI 0.01 to 7.92; 4 RCTs, 5300 women; low-certainty evidence). However, magnesium sulphate probably increased maternal adverse effects severe enough to stop treatment (average RR 3.21, 95% CI 1.88 to 5.48; 3 RCTs, 4736 women; moderate-certainty evidence). Secondary outcomes for women: Magnesium sulphate probably resulted in little to no difference in caesarean section (RR 0.96, 95% CI 0.91 to 1.02; 5 RCTs, 5861 women) and postpartum haemorrhage (RR 0.94, 95% CI 0.80 to 1.09; 2 RCTs, 2495 women) (both moderate-certainty evidence). Breastfeeding at hospital discharge and women's views of treatment were not reported. AUTHORS' CONCLUSIONS: The currently available evidence indicates that magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus, compared with placebo, reduces cerebral palsy, and death or cerebral palsy, in children up to two years' corrected age, and probably reduces severe intraventricular haemorrhage for infants. Magnesium sulphate may result in little to no difference in outcomes in children at school age. While magnesium sulphate may result in little to no difference in severe maternal outcomes (death, cardiac arrest, respiratory arrest), it probably increases maternal adverse effects severe enough to stop treatment. Further research is needed on the longer-term benefits and harms for children, into adolescence and adulthood. Additional studies to determine variation in effects by characteristics of women treated and magnesium sulphate regimens used, along with the generalisability of findings to low- and middle-income countries, should be considered.

Prediction of COVID-19 Severity at Delivery after Asymptomatic or Mild COVID-19 during Pregnancy.

OBJECTIVE: This study aimed to develop a prediction model that estimates the probability that a pregnant person who has had asymptomatic or mild coronavirus disease 2019 (COVID-19) prior to delivery admission will progress in severity to moderate, severe, or critical COVID-19. STUDY DESIGN: This was a secondary analysis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-positive patients who delivered from March through December 2020 at hospitals across the United States. Those eligible for this analysis presented for delivery with a current or previous asymptomatic or mild SARS-CoV-2 infection. The primary outcome was moderate, severe, or critical COVID-19 during the delivery admission through 42 days postpartum. The prediction model was developed and internally validated using stratified cross-validation with stepwise backward elimination, incorporating only variables that were known on the day of hospital admission. RESULTS: Of the 2,818 patients included, 26 (0.9%; 95% confidence interval [CI], 0.6-1.3%) developed moderate-severe-critical COVID-19 during the study period. Variables in the prediction model were gestational age at delivery admission (adjusted odds ratio [aOR], 1.15; 95% CI, 1.08-1.22 per 1-week decrease), a hypertensive disorder in a prior pregnancy (aOR 3.05; 95% CI, 1.25-7.46), and systolic blood pressure at admission (aOR, 1.04; 95% CI, 1.02-1.05 per mm Hg increase). This model yielded an area under the receiver operating characteristic curve of 0.82 (95% CI, 0.72-0.91). CONCLUSION: Among individuals presenting for delivery who had asymptomatic-mild COVID-19, gestational age at delivery admission, a hypertensive disorder in a prior pregnancy, and systolic blood pressure at admission were predictive of delivering with moderate, severe, or critical COVID-19. This prediction model may be a useful tool to optimize resources for SARS-CoV-2-infected pregnant individuals admitted for delivery. KEY POINTS: · Three factors were associated with delivery with more severe COVID-19.. · The developed model yielded an area under the receiver operating characteristic curve of 0.82 and model fit was good.. · The model may be useful tool for SARS-CoV-2 infected pregnancies admitted for delivery..

Gestational Weight Gain and Neonatal Biometry during the COVID-19 Pandemic: A Multicenter Observational Cohort.

OBJECTIVE: This study aimed to test the hypothesis that being pregnant and delivering during the coronavirus disease 2019 (COVID-19) pandemic was associated with changes in gestational weight gain (GWG) or frequency of small- (SGA) or large-for-gestational-age (LGA) neonates. STUDY DESIGN: Secondary analysis of a multicenter observational cohort comparing pregnant people who delivered during the COVID-19 pandemic (June-December 2020) to people who delivered prior to the pandemic (March-December 2019). Those with multiple gestations, fetuses with major congenital anomalies, implausible GWG values, unavailable body mass index (BMI), or who were severe acute respiratory syndrome coronavirus-2-positive were excluded. The primary outcome was frequency of optimal recommended GWG based on prepregnancy BMI. Neonatal outcomes included birth weight, ponderal index, and frequency of SGA, LGA, and small head circumference for live births. Multivariable regression analysis was used to assess associations between exposure to the pandemic and outcomes. RESULTS: A total of 10,717 pregnant people were included in our analysis. A total of 4,225 pregnant people were exposed to the pandemic and 6,492 pregnant people delivered prior to the COVID-19 pandemic. Pregnant people exposed to the pandemic were older and more likely to have gestational diabetes. The frequency of appropriate GWG was 28.0% during the pandemic and 27.6% before the pandemic (adjusted odds ratio [aOR]: 1.02, 95% confidence interval [CI]: 0.93-1.11). Excessive GWG was more likely (54.9 vs. 53.1%; aOR: 1.08, 95% CI: 1.001-1.17), and inadequate GWG was less likely during the pandemic (17.0 vs. 19.3%; aOR: 0.86, 95% CI: 0.77-0.95). The frequency of SGA was 5.4% during the pandemic and 6.1% before the pandemic (aOR: 0.90, 95% CI: 0.76-1.06), and the frequency of LGA was 16.0% during the pandemic versus 15.0% before the pandemic (aOR: 1.06, 95% CI: 0.95-1.18). Other neonatal outcomes including birth weight percentile (62.1 [35.8-83.2] vs. 60.2 [34.4-82.2]; adjusted mean difference (aMD) = 1.50, 95% CI: -0.28 to 3.29), ponderal index (2.6 g/cm3 [2.4-2.8] in both groups; aMD = 0.01, 95% CI: 0.00-0.02), and small head circumference for livebirths (<10th percentile [8.2 vs. 8.1%; aOR: 1.03, 95% CI: 0.89-1.19], <3rd percentile [3.5 vs. 3.1%; aOR: 1.16, 95% CI: 0.93-1.44]) were similar between groups as well. CONCLUSION: Being pregnant and delivering during the COVID-19 pandemic was associated with a higher likelihood of excessive GWG and a lower likelihood of inadequate GWG. KEY POINTS: · Delivering during the COVID-19 pandemic was associated with higher likelihood of excessive GWG.. · Delivering during the COVID-19 pandemic was associated with lower likelihood of inadequate GWG.. · COVID-19 pandemic was not associated with changes in frequency of SGA or LGA..

Neurodevelopmental Outcomes After Late Preterm Antenatal Corticosteroids: The ALPS Follow-Up Study.

Importance: The Antenatal Late Preterm Steroids (ALPS) trial changed clinical practice in the United States by finding that antenatal betamethasone at 34 to 36 weeks decreased short-term neonatal respiratory morbidity. However, the trial also found increased risk of neonatal hypoglycemia after betamethasone. This follow-up study focused on long-term neurodevelopmental outcomes after late preterm steroids. Objective: To evaluate whether administration of late preterm (34-36 completed weeks) corticosteroids affected childhood neurodevelopmental outcomes. Design, Setting, and Participants: Prospective follow-up study of children aged 6 years or older whose birthing parent had enrolled in the multicenter randomized clinical trial, conducted at 13 centers that participated in the Maternal-Fetal Medicine Units (MFMU) Network cycle from 2011-2016. Follow-up was from 2017-2022. Exposure: Twelve milligrams of intramuscular betamethasone administered twice 24 hours apart. Main Outcome and Measures: The primary outcome of this follow-up study was a General Conceptual Ability score less than 85 (-1 SD) on the Differential Ability Scales, 2nd Edition (DAS-II). Secondary outcomes included the Gross Motor Function Classification System level and Social Responsiveness Scale and Child Behavior Checklist scores. Multivariable analyses adjusted for prespecified variables known to be associated with the primary outcome. Sensitivity analyses used inverse probability weighting and also modeled the outcome for those lost to follow-up. Results: Of 2831 children, 1026 enrolled and 949 (479 betamethasone, 470 placebo) completed the DAS-II at a median age of 7 years (IQR, 6.6-7.6 years). Maternal, neonatal, and childhood characteristics were similar between groups except that neonatal hypoglycemia was more common in the betamethasone group. There were no differences in the primary outcome, a general conceptual ability score less than 85, which occurred in 82 (17.1%) of the betamethasone vs 87 (18.5%) of the placebo group (adjusted relative risk, 0.94; 95% CI, 0.73-1.22). No differences in secondary outcomes were observed. Sensitivity analyses using inverse probability weighting or assigning outcomes to children lost to follow-up also found no differences between groups. Conclusion and Relevance: In this follow-up study of a randomized clinical trial, administration of antenatal corticosteroids to persons at risk of late preterm delivery, originally shown to improve short-term neonatal respiratory outcomes but with an increased rate of hypoglycemia, was not associated with adverse childhood neurodevelopmental outcomes at age 6 years or older.

Effects of follicle-stimulating hormone on energy balance and tissue metabolic health after loss of ovarian function.

Loss of ovarian function imparts increased susceptibility to obesity and metabolic disease. These effects are largely attributed to decreased estradiol (E2), but the role of increased follicle-stimulating hormone (FSH) in modulating energy balance has not been fully investigated. Previous work that blocked FSH binding to its receptor in mice suggested this hormone may play a part in modulating body weight and energy expenditure after ovariectomy (OVX). We used an alternate approach to isolate the individual and combined contributions of FSH and E2 in mediating energy imbalance and changes in tissue-level metabolic health. Female Wistar rats were ovariectomized and given the gonadotropin releasing hormone (GnRH) antagonist degarelix to suppress FSH production. E2 and FSH were then added back individually and in combination for a period of 3 wk. Energy balance, body mass composition, and transcriptomic profiles of individual tissues were obtained. In contrast to previous studies, suppression and replacement of FSH in our paradigm had no effect on body weight, body composition, food intake, or energy expenditure. We did, however, observe organ-specific effects of FSH that produced unique transcriptomic signatures of FSH in retroperitoneal white adipose tissue. These included reductions in biological processes related to lipogenesis and carbohydrate transport. In addition, rats administered FSH had reduced liver triglyceride concentration (P < 0.001), which correlated with FSH-induced changes at the transcriptomic level. Although not appearing to modulate energy balance after loss of ovarian function in rats, FSH may still impart tissue-specific effects in the liver and white adipose tissue that might affect the metabolic health of those organs.NEW & NOTEWORTHY We find no effect of follicle-stimulating hormone (FSH) on energy balance using a novel model in which rats are ovariectomized, subjected to gonadotropin-releasing hormone antagonism, and systematically given back FSH by osmotic pump. However, tissue-specific effects of FSH on adipose tissue and liver were observed in this study. These include unique transcriptomic signatures induced by the hormone and a stark reduction in hepatic triglyceride accumulation.

Postpartum pharmacologic thromboprophylaxis and complications in a US cohort.

BACKGROUND: Venous thromboembolism accounts for approximately 9% of pregnancy-related deaths in the United States. National guidelines recommend postpartum risk stratification and pharmacologic prophylaxis in at-risk individuals. Knowledge on modern rates of postpartum pharmacologic thromboprophylaxis and its associated risks is limited. OBJECTIVE: This study aimed to describe the rate of, and factors associated with, initiation of postpartum pharmacologic prophylaxis for venous thromboembolism, and to assess associated adverse outcomes. STUDY DESIGN: This was a secondary analysis of a multicenter cohort of individuals delivering on randomly selected days at 17 US hospitals (2019-2020). Medical records were reviewed by trained and certified personnel. Those with an antepartum diagnosis of venous thromboembolism, receiving antepartum anticoagulation, or known SARS-CoV-2 infection were excluded. The primary outcome was use of postpartum pharmacologic thromboprophylaxis. Secondary outcomes included bleeding complications, surgical site infection, hospital readmission, and venous thromboembolism through 6 weeks postpartum. The rate of thromboprophylaxis administration was assessed by mode of delivery, institution, and continuance to the outpatient setting. Multivariable regression models were developed using k-fold cross-validation with stepwise backward elimination to evaluate factors associated with thromboprophylaxis administration. Univariable and multivariable logistic models with propensity score covariate adjustment were performed to assess the association between thromboprophylaxis administration and adverse outcomes. RESULTS: Of 21,114 individuals in the analytical cohort, 11.9% (95% confidence interval, 11.4%-12.3%) received postpartum pharmacologic thromboprophylaxis; the frequency of receipt was 29.8% (95% confidence interval, 28.7%-30.9%) following cesarean and 3.5% (95% confidence interval, 3.2%-3.8%) following vaginal delivery. Institutional rates of prophylaxis varied from 0.21% to 34.8%. Most individuals (83.3%) received thromboprophylaxis only as inpatients. In adjusted analysis, cesarean delivery (adjusted odds ratio, 19.17; 95% confidence interval, 16.70-22.00), hysterectomy (adjusted odds ratio, 15.70; 95% confidence interval, 4.35-56.65), and obesity (adjusted odds ratio, 3.45; 95% confidence interval, 3.02-3.95) were the strongest factors associated with thromboprophylaxis administration. Thromboprophylaxis administration was not associated with surgical site infection (0.9% vs 0.6%; odds ratio, 1.48; 95% confidence interval, 0.80-2.74), bleeding complications (0.2% vs 0.1%; odds ratio, 2.60; 95% confidence interval, 0.99-6.80), or postpartum readmission (0.9% vs 0.3%; adjusted odds ratio, 1.38; 95% confidence interval, 0.68-2.81). The overall rate of venous thromboembolism was 0.06% (95% confidence interval, 0.03%-0.10%) and was higher in those receiving prophylaxis (0.2%) compared with those not receiving prophylaxis (0.04%). CONCLUSION: Approximately 1 in 10 patients received postpartum pharmacologic thromboprophylaxis in this US cohort. Rates of prophylaxis varied widely by institution. Cesarean delivery, hysterectomy, and obesity were predominant factors associated with postpartum thromboprophylaxis administration.

The Beneficial Effects of Antenatal Magnesium (BEAM) Sulfate Trial.

The BEAM Trial.

Association of Mild Iodine Insufficiency during Pregnancy with Child Neurodevelopment in Patients with Subclinical Hypothyroidism or Hypothyroxinemia.

OBJECTIVE: Our objective was to evaluate whether iodine status in pregnant patients with either subclinical hypothyroidism or hypothyroxinemia in the first half of pregnancy is associated with measures of behavior and neurodevelopment in children through the age of 5 years. STUDY DESIGN: This is a secondary analysis of a multicenter study consisting of two randomized, double-masked, placebo-controlled treatment trials conducted in parallel. Patients with a singleton gestation before 20 weeks' gestation underwent thyroid screening using serum thyrotropin and free thyroxine. Participants with subclinical hypothyroidism or hypothyroxinemia were randomized to levothyroxine replacement or an identical placebo. At randomization, maternal urine was collected and stored for subsequent urinary iodine excretion analysis. Urinary iodine concentrations greater than 150 µg/L were considered iodine sufficient, and concentrations of 150 µg/L or less were considered iodine insufficient. The primary outcome was a full-scale intelligence quotient (IQ) score at the age of 5 years, the general conceptual ability score from the Differential Ability Scales-II at the age of 3 if IQ was not available, or death before 3 years. RESULTS: A total of 677 pregnant participants with subclinical hypothyroidism and 526 with hypothyroxinemia were randomized. The primary outcome was available in 1,133 (94%) of children. Overall, 684 (60%) of mothers were found to have urinary iodine concentrations >150 µg/L. Children of iodine-sufficient participants with subclinical hypothyroidism had similar primary outcome scores when compared to children of iodine-insufficient participants (95 [84-105] vs. 96 [87-109], P adj = 0.73). After adjustment, there was also no difference in IQ scores among children of participants with hypothyroxinemia at 5 to 7 years of age (94 [85 - 102] and 91 [81 - 100], Padj 1/4 0.11). Treatment with levothyroxine was not associated with neurodevelopmental or behavioral outcomes regardless of maternal iodine status (p > 0.05). CONCLUSION: Maternal urinary iodine concentrations ≤150 µg/L were not associated with abnormal cognitive or behavioral outcomes in offspring of participants with either subclinical hypothyroidism or hypothyroxinemia. KEY POINTS: · Most pregnant patients with subclinical thyroid disease are iodine sufficient.. · Mild maternal iodine insufficiency is not associated with lower offspring IQ at 5 years.. · Iodine supplementation in subclinical thyroid disease is unlikely to improve IQ..

Desirability of outcome ranking for obstetrical trials: illustration and application to the ARRIVE trial.

BACKGROUND: In randomized trials, 1 primary outcome is typically chosen to evaluate the consequences of an intervention, whereas other important outcomes are relegated to secondary outcomes. This issue is amplified for many obstetrical trials in which an intervention may have consequences for both the pregnant person and the child. In contrast, desirability of outcome ranking, a paradigm shift for the design and analysis of clinical trials based on patient-centric evaluation, allows multiple outcomes-including from >1 individual-to be considered concurrently. OBJECTIVE: This study aimed to describe desirability of outcome ranking methodology tailored to obstetrical trials and to apply the methodology to maternal-perinatal paired (dyadic) outcomes in which both individuals may be affected by an intervention but may experience discordant outcomes (eg, an obstetrical intervention may improve perinatal but worsen maternal outcomes). STUDY DESIGN: This secondary analysis applies the desirability of outcome ranking methodology to data from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network ARRIVE trial. The original analysis found no substantial difference in the primary (perinatal composite) outcome, but a decreased risk of the secondary outcome of cesarean delivery with elective induction at 39 weeks. In the present desirability-of-outcome-ranking analysis, dyadic outcomes ranging from spontaneous vaginal delivery without severe neonatal complication (most desirable) to cesarean delivery with perinatal death (least desirable) were classified into 8 categories ranked by overall desirability by experienced investigators. Distributions of the desirability of outcome ranking were compared by estimating the probability of having a more desirable dyadic outcome with elective induction at 39 weeks of gestation than with expectant management. To account for various perspectives on these outcomes, a complementary analysis, called the partial credit strategy, was used to grade outcomes on a 100-point scale and estimate the difference in overall treatment scores between groups using a t test. RESULTS: All 6096 participants from the trial were included. The probability of a better dyadic outcome for a randomly selected patient who was randomized to elective induction was 53% (95% confidence interval, 51-54), implying that elective induction led to a better overall outcome for the dyad when taking multiple outcomes into account concurrently. Furthermore, the desirability-of-outcome-ranking probability of averting cesarean delivery with elective induction was 52% (95% confidence interval, 51-53), which was not at the expense of an operative vaginal delivery or a poorer outcome for the perinate (ie, survival with a severe neonatal complication or perinatal death). Randomization to elective induction was also advantageous in most of the partial credit score scenarios. CONCLUSION: Desirability-of-outcome-ranking methodology is a useful tool for obstetrical trials because it provides a concurrent view of the effect of an intervention on multiple dyadic outcomes, potentially allowing for better translation of data for decision-making and person-centered care.

New design strategies for ultra-specific CRISPR-Cas13a-based RNA detection with single-nucleotide mismatch sensitivity.

An increasingly pressing need for clinical diagnostics has required the development of novel nucleic acid-based detection technologies that are sensitive, fast, and inexpensive, and that can be deployed at point-of-care. Recently, the RNA-guided ribonuclease CRISPR-Cas13 has been successfully harnessed for such purposes. However, developing assays for detection of genetic variability, for example single-nucleotide polymorphisms, is still challenging and previously described design strategies are not always generalizable. Here, we expanded our characterization of LbuCas13a RNA-detection specificity by performing a combination of experimental RNA mismatch tolerance profiling, molecular dynamics simulations, protein, and crRNA engineering. We found certain positions in the crRNA-target-RNA duplex that are particularly sensitive to mismatches and establish the effect of RNA concentration in mismatch tolerance. Additionally, we determined that shortening the crRNA spacer or modifying the direct repeat of the crRNA leads to stricter specificities. Furthermore, we harnessed our understanding of LbuCas13a allosteric activation pathways through molecular dynamics and structure-guided engineering to develop novel Cas13a variants that display increased sensitivities to single-nucleotide mismatches. We deployed these Cas13a variants and crRNA design strategies to achieve superior discrimination of SARS-CoV-2 strains compared to wild-type LbuCas13a. Together, our work provides new design criteria and Cas13a variants to use in future easier-to-implement Cas13-based RNA detection applications.

Validation of Three Models for Prediction of Blood Transfusion during Cesarean Delivery Admission.

OBJECTIVE: Prediction of blood transfusion during delivery admission allows for clinical preparedness and risk mitigation. Although prediction models have been developed and adopted into practice, their external validation is limited. We aimed to evaluate the performance of three blood transfusion prediction models in a U.S. cohort of individuals undergoing cesarean delivery. STUDY DESIGN: This was a secondary analysis of a multicenter randomized trial of tranexamic acid for prevention of hemorrhage at time of cesarean delivery. Three models were considered: a categorical risk tool (California Maternal Quality Care Collaborative [CMQCC]) and two regression models (Ahmadzia et al and Albright et al). The primary outcome was intrapartum or postpartum red blood cell transfusion. The CMQCC algorithm was applied to the cohort with frequency of risk category (low, medium, high) and associated transfusion rates reported. For the regression models, the area under the receiver-operating curve (AUC) was calculated and a calibration curve plotted to evaluate each model's capacity to predict receipt of transfusion. The regression model outputs were statistically compared. RESULTS: Of 10,785 analyzed individuals, 3.9% received a red blood cell transfusion during delivery admission. The CMQCC risk tool categorized 1,970 (18.3%) individuals as low risk, 5,259 (48.8%) as medium risk, and 3,556 (33.0%) as high risk with corresponding transfusion rates of 2.1% (95% confidence interval [CI]: 1.5-2.9%), 2.2% (95% CI: 1.8-2.6%), and 7.5% (95% CI: 6.6-8.4%), respectively. The AUC for prediction of blood transfusion using the Ahmadzia and Albright models was 0.78 (95% CI: 0.76-0.81) and 0.79 (95% CI: 0.77-0.82), respectively (p = 0.38 for difference). Calibration curves demonstrated overall agreement between the predicted probability and observed likelihood of blood transfusion. CONCLUSION: Three models were externally validated for prediction of blood transfusion during cesarean delivery admission in this U.S. COHORT: Overall, performance was moderate; model selection should be based on ease of application until a specific model with superior predictive ability is developed. KEY POINTS: · A total of 3.9% of individuals received a blood transfusion during cesarean delivery admission.. · Three models used in clinical practice are externally valid for blood transfusion prediction.. · Institutional model selection should be based on ease of application until further research identifies the optimal approach..

Researching COVID to enhance recovery (RECOVER) pregnancy study: Rationale, objectives and design.

IMPORTANCE: Pregnancy induces unique physiologic changes to the immune response and hormonal changes leading to plausible differences in the risk of developing post-acute sequelae of SARS-CoV-2 (PASC), or Long COVID. Exposure to SARS-CoV-2 during pregnancy may also have long-term ramifications for exposed offspring, and it is critical to evaluate the health outcomes of exposed children. The National Institutes of Health (NIH) Researching COVID to Enhance Recovery (RECOVER) Multi-site Observational Study of PASC aims to evaluate the long-term sequelae of SARS-CoV-2 infection in various populations. RECOVER-Pregnancy was designed specifically to address long-term outcomes in maternal-child dyads. METHODS: RECOVER-Pregnancy cohort is a combined prospective and retrospective cohort that proposes to enroll 2,300 individuals with a pregnancy during the COVID-19 pandemic and their offspring exposed and unexposed in utero, including single and multiple gestations. Enrollment will occur both in person at 27 sites through the Eunice Kennedy Shriver National Institutes of Health Maternal-Fetal Medicine Units Network and remotely through national recruitment by the study team at the University of California San Francisco (UCSF). Adults with and without SARS-CoV-2 infection during pregnancy are eligible for enrollment in the pregnancy cohort and will follow the protocol for RECOVER-Adult including validated screening tools, laboratory analyses and symptom questionnaires followed by more in-depth phenotyping of PASC on a subset of the overall cohort. Offspring exposed and unexposed in utero to SARS-CoV-2 maternal infection will undergo screening tests for neurodevelopment and other health outcomes at 12, 18, 24, 36 and 48 months of age. Blood specimens will be collected at 24 months of age for SARS-CoV-2 antibody testing, storage and anticipated later analyses proposed by RECOVER and other investigators. DISCUSSION: RECOVER-Pregnancy will address whether having SARS-CoV-2 during pregnancy modifies the risk factors, prevalence, and phenotype of PASC. The pregnancy cohort will also establish whether there are increased risks of adverse long-term outcomes among children exposed in utero. CLINICAL TRIALS.GOV IDENTIFIER: Clinical Trial Registration: http://www.clinicaltrials.gov. Unique identifier: NCT05172011.

Standard experimental paradigm designs and data exclusion practices in cognitive psychology can inadvertently introduce systematic "shadow" biases in participant samples.

Standard cognitive psychology research practices can introduce inadvertent sampling biases that reduce the reliability and generalizability of the findings. Researchers commonly acknowledge and understand that any given study sample is not perfectly generalizable, especially when implementing typical experimental constraints (e.g., limiting recruitment to specific age ranges or to individuals with normal color vision). However, less obvious systematic sampling constraints, referred to here as "shadow" biases, can be unintentionally introduced and can easily go unnoticed. For example, many standard cognitive psychology study designs involve lengthy and tedious experiments with simple, repetitive stimuli. Such testing environments may 1) be aversive to some would-be participants (e.g., those high in certain neurodivergent symptoms) who may self-select not to enroll in such studies, or 2) contribute to participant attrition, both of which reduce the sample's representativeness. Likewise, standard performance-based data exclusion efforts (e.g., minimum accuracy or response time) or attention checks can systematically remove data from participants from subsets of the population (e.g., those low in conscientiousness). This commentary focuses on the theoretical and practical issues behind these non-obvious and often unacknowledged "shadow" biases, offers a simple illustration with real data as a proof of concept of how applying attention checks can systematically skew latent/hidden variables in the included population, and then discusses the broader implications with suggestions for how to manage and reduce, or at a minimum acknowledge, the problem.

Genetic Predisposition to Adverse Neurodevelopmental Outcome of Extremely Low Birth Weight Infants.

OBJECTIVE: This study aimed to evaluate whether there are genetic variants associated with adverse neurodevelopmental outcomes in extremely low birth weight (ELBW) infants. STUDY DESIGN: We conducted a candidate gene association study in two well-defined cohorts of ELBW infants (<1,000 g). One cohort was for discovery and the other for replication. The discovery case-control analysis utilized anonymized DNA samples and evaluated 1,614 single-nucleotide polymorphisms (SNPs) in 145 genes concentrated in inflammation, angiogenesis, brain development, and oxidation pathways. Cases were children who died by age one or who were diagnosed with cerebral palsy (CP) or neurodevelopmental delay (Bayley II mental developmental index [MDI] or psychomotor developmental index [PDI] < 70) by 18 to 22 months. Controls were survivors with normal neurodevelopment. We assessed significant epidemiological variables and SNPs associated with the combined outcome of CP or death, CP, mental delay (MDI < 70) and motor delay (PDI < 70). Multivariable analyses adjusted for gestational age at birth, small for gestational age, sex, antenatal corticosteroids, multiple gestation, racial admixture, and multiple comparisons. SNPs associated with adverse neurodevelopmental outcomes with p < 0.01 were selected for validation in the replication cohort. Successful replication was defined as p < 0.05 in the replication cohort. RESULTS: Of 1,013 infants analyzed (452 cases, 561 controls) in the discovery cohort, 917 were successfully genotyped for >90% of SNPs and passed quality metrics. After adjusting for covariates, 26 SNPs with p < 0.01 for one or more outcomes were selected for replication cohort validation, which included 362 infants (170 cases and 192 controls). A variant in SERPINE1, which encodes plasminogen activator inhibitor (PAI1), was associated with the combined outcome of CP or death in the discovery analysis (p = 4.1 × 10-4) and was significantly associated with CP or death in the replication cohort (adjusted odd ratio: 0.4; 95% confidence interval: 0.2-1.0; p = 0.039). CONCLUSION: A genetic variant in SERPINE1, involved in inflammation and coagulation, is associated with CP or death among ELBW infants. KEY POINTS: · Early preterm and ELBW infants have dramatically increased risks of CP and developmental delay.. · A genetic variant in SERPINE1 is associated with CP or death among ELBW infants.. · The SERPINE1 gene encodes the serine protease inhibitor plasminogen activator inhibitor..