Daniel W. Skupski

Objective: Foetal‐neonatal alloimmune thrombocytopaenia (FNAIT) is a rare disease, most commonly caused by maternal alloantibodies to human platelet antigen (HPA)‐1a that can result in severe bleeding. The present study was designed to determine the frequency of higher risk for HPA‐1a alloimmunisation and development of FNAIT among a racially and ethnically diverse cohort of pregnant women. Design: Longitudinal, prospective, non‐interventional, natural history study. Setting: Conducted across 28 sites in North America and Europe. Population: Pregnant women (≥ 18 years) with no history of FNAIT. Methods: Blood samples were collected at 10–14 weeks' gestation and a sequential screening algorithm applied: maternal HPA‐1a/1b genotyping, human leukocyte antigen [HLA]‐DRB3*01:01 allele status, anti‐HPA‐1a antibody status and foetal HPA‐1 genotype. Main Outcome Measures: Number of women at higher risk for HPA‐1a alloimmunisation (i.e., those who are HPA‐1b/b, HLA‐DRB3*01:01 positive, anti‐HPA‐1a antibody negative and carrying an HPA‐1a‐positive foetus) that alloimmunise. Results: Of the 14 114 participants screened, 1.7% were HPA‐1b/1b genotype, which varied according to race and geography. Of 24 women at higher risk for FNAIT, five were lost to follow‐up with no post‐partum test for alloimmunisation. At Week 10 post‐partum, 2/19 higher risk participants (11%; 95% confidence interval [CI]: 1.3%, 33.1%) demonstrated anti‐HPA‐1a antibodies, while 17 remained negative. Pre‐existing anti‐HPA‐1a antibodies were identified in 18 other HPA‐1bb, DRB3*01:01 positive women at screening. Conclusions: This prospective study confirms the rarity of a population at higher risk for HPA‐1a alloimmunisation and FNAIT, describes the risk among Black and Asian women, and establishes a rigorous methodology to assess for risk of HPA‐1a immunisation.

Objective: Foetal-neonatal alloimmune thrombocytopaenia (FNAIT) is a rare disease most commonly caused by maternal alloantibodies to human platelet antigen (HPA)-1a that can result in severe bleeding. The present study was designed to determine the frequency of higher risk for HPA-1a alloimmunisation and development of FNAIT among a racially and ethnically diverse cohort of pregnant women. Design: Longitudinal, prospective, non-interventional, natural history study. Setting: Conducted across 28 sites in North America and Europe. Population: Pregnant women (≥18 years) with no history of FNAIT. Methods: Blood samples were collected at 10-14 weeks’ gestation and a sequential screening algorithm applied: maternal HPA-1a/1b genotyping, human leukocyte antigen [HLA]-DRB3*01:01 allele status, anti-HPA-1a antibody status, and foetal HPA-1 genotype. Main Outcome Measures: Number of women at higher risk for HPA-1a alloimmunisation (i.e., those who are HPA-1b/b, HLA-DRB3*01:01 positive, anti-HPA-1a antibody negative, and carrying an HPA-1a-positive foetus) that alloimmunise. Results: Of the 14,114 participants screened, 1.7% were HPA-1b/1b genotype, which varied according to race and geography. Of 24 women at higher risk for FNAIT, five were lost to follow-up with no post-partum test for alloimmunisation. At week 10 post-partum, 2/19 higher risk participants (11%; 95% confidence interval [CI]: 1.3%, 33.1%) demonstrated anti-HPA-1a antibodies, while 17 remained negative. Pre-existing anti-HPA-1a antibodies were identified in 18 other higher risk women at screening. Conclusions: This prospective study confirms the rarity of a population at higher risk for HPA-1a alloimmunisation and FNAIT, describes the risk among Black and Asian women, and establishes a rigorous methodology to assess for risk of FNAIT.

Background/objective: Approximately one-third of pregnant individuals in the U.S. are affected by obesity, which can adversely impact the in utero environment and offspring. This study aimed to investigate the differences in urine metabolomics between children exposed and unexposed to maternal obesity. Methods: In a study nested within a larger pregnancy cohort of women–offspring pairs, we measured untargeted metabolomics using liquid chromatography–mass spectrometry in urine samples from 68 children at 4–8 years of age. We compared metabolite levels between offspring exposed to maternal obesity (body mass index [BMI] ≥ 30.0 kg/m²) vs. unexposed (maternal BMI 18.5–24.9 kg/m²) and matched them on covariates, using two-sample t-tests, with additional sensitivity analyses based on children’s BMI. This study reports statistically significant results (p ≤ 0.05) and potentially noteworthy findings (fold change > 1 or 0.05 < p < 0.15), considering compounds’ involvement in common pathways or similar biochemical families. Results: The mean (SD) maternal age at study enrollment was 28.0 (6.3) years, the mean child age was 6.6 (0.8) years, 56% of children were male, and 38% of children had a BMI in the overweight/obese range (BMI ≥ 85th percentile). Children exposed to maternal obesity had lower levels of 5-hydroxyindole sulfate and 7-hydroxyindole sulfate and higher levels of secondary bile acids. Phenylacetic acid derivatives were lower in offspring exposed to obesity and in offspring who had a current BMI in the overweight/obese range. Exposure to maternal obesity was associated with lower levels of androgenic steroid dehydroepiandrosterone sulfate (DHEA-S). Conclusions: In this preliminary study, children exposed to maternal obesity in utero had differences in microbiome-related metabolites in urine suggestive of altered microbial catabolism of tryptophan and acetylated peptides. Some of these differences were partially attributable to the offspring’s current BMI status. This study highlights the potential of urine metabolomics to identify biomarkers and pathways impacted by in utero exposure to maternal obesity.

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.

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. Registration: NCT05172024

Background: Customized fetal growth charts assume birthweight at term to be normally distributed across the population with a constant coefficient of variation at earlier gestational ages. Thus, standard deviation used for computing percentiles (e.g., 10^th, 90^th) is assumed to be proportional to the customized mean, although this assumption has never been formally tested. Methods: In a secondary analysis of NICHD Fetal Growth Studies-Singletons (12 U.S. sites, 2009–2013) using longitudinal sonographic biometric data (n = 2288 pregnancies), we investigated the assumptions of normality and constant coefficient of variation by examining behavior of the mean and standard deviation, computed following the Gardosi method. We then created a more flexible model that customizes both mean and standard deviation using heteroscedastic regression and calculated customized percentiles directly using quantile regression, with an application in a separate study of 102, 012 deliveries, 37–41 weeks. Results: Analysis of term optimal birthweight challenged assumptions of proportionality and that values were normally distributed: at different mean birthweight values, standard deviation did not change linearly with mean birthweight and the percentile computed with the normality assumption deviated from empirical percentiles. Composite neonatal morbidity and mortality rates in relation to birthweight < 10^th were higher for heteroscedastic and quantile models (10.3% and 10.0%, respectively) than the Gardosi model (7.2%), although prediction performance was similar among all three (c-statistic 0.52–0.53). Conclusions: Our findings question normality and constant coefficient of variation assumptions of the Gardosi customization method. A heteroscedastic model captures unstable variance in customization characteristics which may improve detection of abnormal growth percentiles. Trial registration: ClinicalTrials.gov identifier: NCT00912132.

Article A Celebration of Professor Joachim Dudenhausen was published on February 28, 2023 in the journal Journal of Perinatal Medicine (volume 0, issue 0).

Objectives: To apply scientometric methodology to characterize influential articles in the Journal of Perinatal Medicine (JPM). Methods: We performed a cross-sectional study of all JPM articles indexed in Clarivate Web of Science (WOS), NIH Open Citation Collection, and Altmetric Explorer databases (1973–2022). We identified articles cited ≥100 times in WOS and articles with highest Relative Citation Ratios (RCR, a metric of influence based on citations) and highest Altmetric Attention Scores (AAS, a metric of engagement with social media and public platforms). We performed descriptive analysis to characterize influential articles based on citation rates vs. highest AAS, and quantile regression with bootstrapping to estimate the median differences (95% confidence intervals). Results: We identified 4095 JPM articles that were indexed in the WOS, of which 3,959 (96.7%) had RCRs and 939 (22.9%) had AASs. The study cohort included 34 articles cited ≥100 times and the 34 top-RCR and 34 top-AAS articles, representing 83 unique articles. These influential articles had median 67 citations (IQR 17–114), median RCR 3.4 (IQR 1.7–5.0), and median AAS 14 (IQR 3–28). The majority were observational studies and reviews. Compared to top-AAS articles, top-cited articles had higher median citations (117 [IQR 111–147] vs. 13 [IQR 5–62]; median difference 104.0, 95% CI 86.6–121.4) and citations per year (7.3 [IQR 4.9–10.6] vs. 2.3 [0.7–4.6]; median difference 5.5 [95% CI 3.1–7.9]). Results were similar for top-RCR vs. top-AAS articles. Conclusions: We identified influential articles during 50 years of JPM, providing insight into the impact of the journal and providing a template for future studies of academic journals.

Objectives: Improvement in the antenatal diagnosis of placenta accreta spectrum (PAS) would allow preparation for delivery in a referral center, leading to decreased maternal morbidity and mortality. Our objectives were to assess the performance of classic ultrasound signs and to determine the value of novel ultrasound signs in the detection of PAS.Methods: This was a retrospective cohort study of women with second‐trimester placenta previa who underwent third‐trimester transvaginal ultrasound and all women with PAS in seven medical centers. A retrospective image review for signs of PAS was conducted by three maternal–fetal medicine physicians. Classic signs of PAS were defined as placental lacunae, bladder‐wall interruption, myometrial thinning and subplacental hypervascularity. Novel signs were defined as small placental lacunae, irregular placenta–myometrium interface (PMI), vascular PMI, non‐tapered placental edge and placental bulge towards the bladder. PAS was diagnosed based on difficulty in removing the placenta or pathological examination of the placenta. Multivariate regression analysis was performed and receiver‐operating‐characteristics (ROC) curves were generated to assess the performance of combined novel signs, combined classic signs and a model combining classic and novel signs.Results: A total of 385 cases with placenta previa were included, of which 55 had PAS (28 had placenta accreta, 11 had placenta increta and 16 had placenta percreta). The areas under the ROC curves for classic markers, novel markers and a model combining classic and novel markers for the detection of PAS were 0.81 (95% CI, 0.75–0.88), 0.84 (95% CI, 0.77–0.90) and 0.88 (95% CI, 0.82–0.94), respectively. A model combining classic and novel signs performed better than did the classic or novel markers individually (P = 0.03). An increasing number of signs was associated with a greater likelihood of PAS. With the presence of 0, 1, 2 and ≥ 3 classic ultrasound signs, PAS was present in 5%, 24%, 57% and 94% of cases, respectively.Conclusions: We have confirmed the value of classic ultrasound signs of PAS. The use of novel ultrasound signs in combination with classic signs improved the detection of PAS. These findings have clinical implications for the detection of PAS and may help guide the obstetric management of patients diagnosed with these placental disorders. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.