Timing of Maternal COVID-19 Vaccine and Antibody Concentrations in Infants Born Preterm.

Importance: COVID-19 vaccine-derived antibodies in pregnant people may protect infants from severe infection in the first 6 months of life via transplacental antibody transfer. Few data exist on maternally derived SARS-CoV-2 antibodies in preterm compared with full-term infants in association with vaccination timing. Objective: To compare SARS-CoV-2 anti-Spike (anti-S) antibody levels in preterm and full-term infants in the context of vaccine dose timing before delivery. Design, Setting, and Participants: This prospective cohort study enrolled pregnant individuals and collected paired maternal and cord blood samples at delivery at the University of Washington between February 1, 2021, and January 31, 2023. Participants who had received at least 2 doses of a messenger RNA COVID-19 vaccine before delivery and did not have a history of prior COVID-19 infection or detectable anti-SARS-CoV-2 nucleocapsid antibodies were included. Exposures: Timing of the last vaccine dose and preterm or full-term gestational age at delivery. Main Outcomes and Measures: Paired maternal and cord samples were tested for anti-S antibody, and linear regression was used to evaluate associations between preterm delivery and anti-S antibody levels. Covariates included timing of last dose, number of doses, insurance status, and immunosuppressing medications. Results: A total of 220 participants (median [IQR] age, 34 [32-37] years; 212 [96.4%] female) with 36 preterm and 184 full-term deliveries were studied. Before delivery, 121 persons received 2 vaccine doses and 99 persons received 3 or more vaccine doses. The geometric mean concentration of maternal anti-S antibodies was 674 (95% CI, 577-787) after 2 doses and 8159 (95% CI, 6636-10 032) after 3 or more doses (P < .001). The cord anti-S antibody geometric mean concentration was 1000 (95% CI, 874-1144) after 2 doses and 9992 (95% CI, 8381-11 914) after 3 or more doses (P < .001). After adjustment for vaccine timing and number of doses before delivery, no association was found between preterm delivery and cord anti-S antibody levels (ß = 0.44; 95% CI, -0.06 to 0.94). Conclusions and Relevance: In this prospective cohort study of pregnant individuals with preterm and full-term deliveries, receipt of 3 or more compared with 2 doses of COVID-19 vaccine before delivery resulted in 10-fold higher cord anti-S antibody levels. Maternal antibody concentration appeared more important than delivery gestational age in determining cord anti-S antibody levels. The number of doses and timing considerations for COVID-19 vaccine in pregnancy should include individuals at risk for preterm delivery.

Normative spatiotemporal fetal brain maturation with satisfactory development at 2 years.

Maturation of the human fetal brain should follow precisely scheduled structural growth and folding of the cerebral cortex for optimal postnatal function1. We present a normative digital atlas of fetal brain maturation based on a prospective international cohort of healthy pregnant women2, selected using World Health Organization recommendations for growth standards3. Their fetuses were accurately dated in the first trimester, with satisfactory growth and neurodevelopment from early pregnancy to 2 years of age4,5. The atlas was produced using 1,059 optimal quality, three-dimensional ultrasound brain volumes from 899 of the fetuses and an automated analysis pipeline6-8. The atlas corresponds structurally to published magnetic resonance images9, but with finer anatomical details in deep grey matter. The between-study site variability represented less than 8.0% of the total variance of all brain measures, supporting pooling data from the eight study sites to produce patterns of normative maturation. We have thereby generated an average representation of each cerebral hemisphere between 14 and 31 weeks' gestation with quantification of intracranial volume variability and growth patterns. Emergent asymmetries were detectable from as early as 14 weeks, with peak asymmetries in regions associated with language development and functional lateralization between 20 and 26 weeks' gestation. These patterns were validated in 1,487 three-dimensional brain volumes from 1,295 different fetuses in the same cohort. We provide a unique spatiotemporal benchmark of fetal brain maturation from a large cohort with normative postnatal growth and neurodevelopment.

Biological and pathological mechanisms leading to the birth of a small vulnerable newborn.

The pathway to a thriving newborn begins before conception and continues in utero with a healthy placenta and the right balance of nutrients and growth factors that are timed and sequenced alongside hormonal suppression of labour until a mature infant is ready for birth. Optimal nutrition that includes adequate quantities of quality protein, energy, essential fats, and an extensive range of vitamins and minerals not only supports fetal growth but could also prevent preterm birth by supporting the immune system and alleviating oxidative stress. Infection, illness, undernourishment, and harmful environmental exposures can alter this trajectory leading to an infant who is too small due to either poor growth during pregnancy or preterm birth. Systemic inflammation suppresses fetal growth by interfering with growth hormone and its regulation of insulin-like growth factors. Evidence supports the prevention and treatment of several maternal infections during pregnancy to improve newborn health. However, microbes, such as Ureaplasma species, which are able to ascend the cervix and cause membrane rupture and chorioamnionitis, require new strategies for detection and treatment. The surge in fetal cortisol late in pregnancy is essential to parturition at the right time, but acute or chronically high maternal cortisol levels caused by psychological or physical stress could also trigger labour onset prematurely. In every pathway to the small vulnerable newborn, there is a possibility to modify the course of pregnancy by supporting improved nutrition, protection against infection, holistic maternal wellness, and healthy environments.

Machine learning for accurate estimation of fetal gestational age based on ultrasound images.

Accurate estimation of gestational age is an essential component of good obstetric care and informs clinical decision-making throughout pregnancy. As the date of the last menstrual period is often unknown or uncertain, ultrasound measurement of fetal size is currently the best method for estimating gestational age. The calculation assumes an average fetal size at each gestational age. The method is accurate in the first trimester, but less so in the second and third trimesters as growth deviates from the average and variation in fetal size increases. Consequently, fetal ultrasound late in pregnancy has a wide margin of error of at least ±2 weeks' gestation. Here, we utilise state-of-the-art machine learning methods to estimate gestational age using only image analysis of standard ultrasound planes, without any measurement information. The machine learning model is based on ultrasound images from two independent datasets: one for training and internal validation, and another for external validation. During validation, the model was blinded to the ground truth of gestational age (based on a reliable last menstrual period date and confirmatory first-trimester fetal crown rump length). We show that this approach compensates for increases in size variation and is even accurate in cases of intrauterine growth restriction. Our best machine-learning based model estimates gestational age with a mean absolute error of 3.0 (95% CI, 2.9-3.2) and 4.3 (95% CI, 4.1-4.5) days in the second and third trimesters, respectively, which outperforms current ultrasound-based clinical biometry at these gestational ages. Our method for dating the pregnancy in the second and third trimesters is, therefore, more accurate than published methods.

Pregnancy outcomes and vaccine effectiveness during the period of omicron as the variant of concern, INTERCOVID-2022: a multinational, observational study.

BACKGROUND: In 2021, we showed an increased risk associated with COVID-19 in pregnancy. Since then, the SARS-CoV-2 virus has undergone genetic mutations. We aimed to examine the effects on maternal and perinatal outcomes of COVID-19 during pregnancy, and evaluate vaccine effectiveness, when omicron (B.1.1.529) was the variant of concern. METHODS: INTERCOVID-2022 is a large, prospective, observational study, involving 41 hospitals across 18 countries. Each woman with real-time PCR or rapid test, laboratory-confirmed COVID-19 in pregnancy was compared with two unmatched women without a COVID-19 diagnosis who were recruited concomitantly and consecutively in pregnancy or at delivery. Mother and neonate dyads were followed until hospital discharge. Primary outcomes were maternal morbidity and mortality index (MMMI), severe neonatal morbidity index (SNMI), and severe perinatal morbidity and mortality index (SPMMI). Vaccine effectiveness was estimated, adjusted by maternal risk profile. FINDINGS: We enrolled 4618 pregnant women from Nov 27, 2021 (the day after WHO declared omicron a variant of concern), to June 30, 2022: 1545 (33%) women had a COVID-19 diagnosis (median gestation 36·7 weeks [IQR 29·0-38·9]) and 3073 (67%) women, with similar demographic characteristics, did not have a COVID-19 diagnosis. Overall, women with a diagnosis had an increased risk for MMMI (relative risk [RR] 1·16 [95% CI 1·03-1·31]) and SPMMI (RR 1·21 [95% CI 1·00-1·46]). Women with a diagnosis, compared with those without a diagnosis, also had increased risks of SNMI (RR 1·23 [95% CI 0·88-1·71]), although the lower bounds of the 95% CI crossed unity. Unvaccinated women with a COVID-19 diagnosis had a greater risk of MMMI (RR 1·36 [95% CI 1·12-1·65]). Severe COVID-19 symptoms in the total sample increased the risk of severe maternal complications (RR 2·51 [95% CI 1·84-3·43]), perinatal complications (RR 1·84 [95% CI 1·02-3·34]), and referral, intensive care unit (ICU) admission, or death (RR 11·83 [95% CI 6·67-20·97]). Severe COVID-19 symptoms in unvaccinated women increased the risk of MMMI (RR 2·88 [95% CI 2·02-4·12]) and referral, ICU admission, or death (RR 20·82 [95% CI 10·44-41·54]). 2886 (63%) of 4618 total participants had at least a single dose of any vaccine, and 2476 (54%) of 4618 had either complete or booster doses. Vaccine effectiveness (all vaccines combined) for severe complications of COVID-19 for all women with a complete regimen was 48% (95% CI 22-65) and 76% (47-89) after a booster dose. For women with a COVID-19 diagnosis, vaccine effectiveness of all vaccines combined for women with a complete regimen was 74% (95% CI 48-87) and 91% (65-98) after a booster dose. INTERPRETATION: COVID-19 in pregnancy, during the first 6 months of omicron as the variant of concern, was associated with increased risk of severe maternal morbidity and mortality, especially among symptomatic and unvaccinated women. Women with complete or boosted vaccine doses had reduced risk for severe symptoms, complications, and death. Vaccination coverage among pregnant women remains a priority. FUNDING: None.

Placental transcriptomic signatures of spontaneous preterm birth.

BACKGROUND: Spontaneous preterm birth accounts for most preterm births and leads to significant morbidity in the newborn and childhood period. This subtype of preterm birth represents an increasing proportion of all preterm births when compared with medically indicated preterm birth, yet it is understudied in omics analyses. The placenta is a key regulator of fetal and newborn health, and the placental transcriptome can provide insight into pathologic changes that lead to spontaneous preterm birth. OBJECTIVE: This analysis aimed to identify genes for which placental expression was associated with spontaneous preterm birth (including early preterm and late preterm birth). STUDY DESIGN: The ECHO PATHWAYS consortium extracted RNA from placental samples collected from the Conditions Affecting Neurocognitive Development and Learning in Early Childhood and the Global Alliance to Prevent Prematurity and Stillbirth studies. Placental transcriptomic data were obtained by RNA sequencing. Linear models were fit to estimate differences in placental gene expression between term birth and spontaneous preterm birth (including gestational age subgroups defined by the American College of Obstetricians and Gynecologists). Models were adjusted for numerous confounding variables, including labor status, cohort, and RNA sequencing batch. This analysis excluded patients with induced labor, chorioamnionitis, multifetal gestations, or medical indications for preterm birth. Our combined cohort contained gene expression data for 14,023 genes in 48 preterm and 540 term samples. Genes and pathways were considered statistically significantly different at false discovery rate-adjusted P value of <.05. RESULTS: In total, we identified 1728 genes for which placental expression was associated with spontaneous preterm birth with more differences in expression in early preterm samples than late preterm samples when compared with full-term samples. Of those, 9 genes were significantly decreased in both early and late spontaneous preterm birth, and the strongest associations involved placental expression of IL1B, ALPL, and CRLF1. In early and late preterm samples, we observed decreased expression of genes involved in immune signaling, signal transduction, and endocrine function. CONCLUSION: This study provides a comprehensive assessment of the differences in the placental transcriptome associated with spontaneous preterm birth with robust adjustment for confounding. Results of this study are in alignment with the known etiology of spontaneous preterm birth, because we identified multiple genes and pathways for which the placental and chorioamniotic membrane expression was previously associated with prematurity, including IL1B. We identified decreased expression in key signaling pathways that are essential for placental growth and function, which may be related to the etiology of spontaneous preterm birth. We identified increased expression of genes within metabolic pathways associated exclusively with early preterm birth. These signaling and metabolic pathways may provide clinically targetable pathways and biomarkers. The findings presented here can be used to understand underlying pathologic changes in premature placentas, which can inform and improve clinical obstetrics practice.

Effects of prenatal exposure to maternal COVID-19 and perinatal care on neonatal outcome: results from the INTERCOVID Multinational Cohort Study.

BACKGROUND: The effect of COVID-19 in pregnancy on maternal outcomes and its association with preeclampsia and gestational diabetes mellitus have been reported; however, a detailed understanding of the effects of maternal positivity, delivery mode, and perinatal practices on fetal and neonatal outcomes is urgently needed. OBJECTIVE: To evaluate the impact of COVID-19 on fetal and neonatal outcomes and the role of mode of delivery, breastfeeding, and early neonatal care practices on the risk of mother-to-child transmission. STUDY DESIGN: In this cohort study that took place from March 2020 to March 2021, involving 43 institutions in 18 countries, 2 unmatched, consecutive, unexposed women were concomitantly enrolled immediately after each infected woman was identified, at any stage of pregnancy or delivery, and at the same level of care to minimize bias. Women and neonates were followed up until hospital discharge. COVID-19 in pregnancy was determined by laboratory confirmation and/or radiological pulmonary findings or ≥2 predefined COVID-19 symptoms. The outcome measures were indices of neonatal and perinatal morbidity and mortality, neonatal positivity and its correlation with mode of delivery, breastfeeding, and hospital neonatal care practices. RESULTS: A total of 586 neonates born to women with COVID-19 diagnosis and 1535 neonates born to women without COVID-19 diagnosis were enrolled. Women with COVID-19 diagnosis had a higher rate of cesarean delivery (52.8% vs 38.5% for those without COVID-19 diagnosis, P<.01) and pregnancy-related complications, such as hypertensive disorders of pregnancy and fetal distress (all with P<.001), than women without COVID-19 diagnosis. Maternal diagnosis of COVID-19 carried an increased rate of preterm birth (P≤.001) and lower neonatal weight (P≤.001), length, and head circumference at birth. In mothers with COVID-19 diagnosis, the length of in utero exposure was significantly correlated to the risk of the neonate testing positive (odds ratio, 4.5; 95% confidence interval, 2.2-9.4 for length of in utero exposure >14 days). Among neonates born to mothers with COVID-19 diagnosis, birth via cesarean delivery was a risk factor for testing positive for COVID-19 (odds ratio, 2.4; 95% confidence interval, 1.2-4.7), even when severity of maternal conditions was considered and after multivariable logistic analysis. In the subgroup of neonates born to women with COVID-19 diagnosis, the outcomes worsened when the neonate also tested positive, with higher rates of neonatal intensive care unit admission, fever, gastrointestinal and respiratory symptoms, and death, even after adjusting for prematurity. Breastfeeding by mothers with COVID-19 diagnosis and hospital neonatal care practices, including immediate skin-to-skin contact and rooming-in, were not associated with an increased risk of newborn positivity. CONCLUSION: In this multinational cohort study, COVID-19 in pregnancy was associated with increased maternal and neonatal complications. Cesarean delivery was significantly associated with newborn COVID-19 diagnosis. Vaginal delivery should be considered the safest mode of delivery if obstetrical and health conditions allow it. Mother-to-child skin-to-skin contact, rooming-in, and direct breastfeeding were not risk factors for newborn COVID-19 diagnosis, thus well-established best practices can be continued among women with COVID-19 diagnosis.

A review of ex vivo placental perfusion models: an underutilized but promising method to study maternal-fetal interactions.

Studying the placenta can provide information about the mechanistic pathways of pregnancy disease. However, analyzing placental tissues and manipulating placental function in real-time during pregnancy is not feasible. The ex vivo placental perfusion model allows observing important aspects of the physiology and pathology of the placenta, while maintaining its viability and functional integrity, and without causing harm to mother or fetus. In this review, we describe and compare setups for this technically complex model and summarize outcomes from various published studies. We hope that our review will encourage wider use of ex vivo placental perfusion, which in turn would generate more knowledge to improve pregnancy outcomes.

Diabetes mellitus, maternal adiposity, and insulin-dependent gestational diabetes are associated with COVID-19 in pregnancy: the INTERCOVID study.

BACKGROUND: Among nonpregnant individuals, diabetes mellitus and high body mass index increase the risk of COVID-19 and its severity. OBJECTIVE: This study aimed to determine whether diabetes mellitus and high body mass index are risk factors for COVID-19 in pregnancy and whether gestational diabetes mellitus is associated with COVID-19 diagnosis. STUDY DESIGN: INTERCOVID was a multinational study conducted between March 2020 and February 2021 in 43 institutions from 18 countries, enrolling 2184 pregnant women aged ≥18 years; a total of 2071 women were included in the analyses. For each woman diagnosed with COVID-19, 2 nondiagnosed women delivering or initiating antenatal care at the same institution were also enrolled. The main exposures were preexisting diabetes mellitus, high body mass index (overweight or obesity was defined as a body mass index ≥25 kg/m2), and gestational diabetes mellitus in pregnancy. The main outcome was a confirmed diagnosis of COVID-19 based on a real-time polymerase chain reaction test, antigen test, antibody test, radiological pulmonary findings, or ≥2 predefined COVID-19 symptoms at any time during pregnancy or delivery. Relationships of exposures and COVID-19 diagnosis were assessed using generalized linear models with a Poisson distribution and log link function, with robust standard errors to account for model misspecification. Furthermore, we conducted sensitivity analyses: (1) restricted to those with a real-time polymerase chain reaction test or an antigen test in the last week of pregnancy, (2) restricted to those with a real-time polymerase chain reaction test or an antigen test during the entire pregnancy, (3) generating values for missing data using multiple imputation, and (4) analyses controlling for month of enrollment. In addition, among women who were diagnosed with COVID-19, we examined whether having gestational diabetes mellitus, diabetes mellitus, or high body mass index increased the risk of having symptomatic vs asymptomatic COVID-19. RESULTS: COVID-19 was associated with preexisting diabetes mellitus (risk ratio, 1.94; 95% confidence interval, 1.55-2.42), overweight or obesity (risk ratio, 1.20; 95% confidence interval, 1.06-1.37), and gestational diabetes mellitus (risk ratio, 1.21; 95% confidence interval, 0.99-1.46). The gestational diabetes mellitus association was specifically among women requiring insulin, whether they were of normal weight (risk ratio, 1.79; 95% confidence interval, 1.06-3.01) or overweight or obese (risk ratio, 1.77; 95% confidence interval, 1.28-2.45). A somewhat stronger association with COVID-19 diagnosis was observed among women with preexisting diabetes mellitus, whether they were of normal weight (risk ratio, 1.93; 95% confidence interval, 1.18-3.17) or overweight or obese (risk ratio, 2.32; 95% confidence interval, 1.82-2.97). When the sample was restricted to those with a real-time polymerase chain reaction test or an antigen test in the week before delivery or during the entire pregnancy, including missing variables using imputation or controlling for month of enrollment, the observed associations were comparable. CONCLUSION: Diabetes mellitus and overweight or obesity were risk factors for COVID-19 diagnosis in pregnancy, and insulin-dependent gestational diabetes mellitus was associated with the disease. Therefore, it is essential that women with these comorbidities are vaccinated.

Validation of community health worker identification of maternal puerperal sepsis using a clinical diagnostic algorithm in Bangladesh and Pakistan.

BACKGROUND: Puerperal sepsis (PP sepsis) is a leading cause of maternal mortality globally. The majority of maternal sepsis cases and deaths occur at home and remain undiagnosed and under-reported. In this paper, we present findings from a nested case-control study in Bangladesh and Pakistan which sought to assess the validity of community health worker (CHW) identification of PP sepsis using a clinical diagnostic algorithm with physician assessment and classification used as the gold standard. METHODS: Up to 300 postpartum women were enrolled in each of the 3 sites 1) Sylhet, Bangladesh (n = 278), 2) Karachi, Pakistan (n = 278) and 3) Matiari, Pakistan (n = 300). Index cases were women with suspected PP Sepsis as diagnosed by CHWs clinical assessment of one or more of the following signs and symptoms: temperature (recorded fever ≥38.1°C, reported history of fever, lower abdominal or pelvic pain, and abnormal or foul-smelling discharge. Each case was matched with 3 control women who were diagnosed by CHWs to have no infection. Cases and controls were assessed by trained physicians using the same algorithm implemented by the CHWs. Using physician assessment as the gold standard, Kappa statistics for reliability and diagnostic validity (sensitivity and specificity) are presented with 95% CI. Sensitivity and specificity were adjusted for verification bias. RESULTS: The adjusted sensitivity and specificity of CHW identification of PP sepsis across all sites was 82% (Karachi: 78%, Matiari: 78%, Sylhet: 95%) and 90% (Karachi: 95%, Matiari: 85%, Sylhet: 90%) respectively. CHW-Physician agreement was highest for moderate and high fever (range across sites: K = 0.84-0.97) and lowest for lower abdominal pain (K = 0.30-0.34). The clinical signs and symptoms for other conditions were reported infrequently, however, the CHW-physician agreement was high for all symptoms except severe headache/ blurred vision (K = 0.13-0.38) and reported "lower abdominal pain without fever" (K = 0.39-0.57). CONCLUSION: In all sites, CHWs with limited training were able to identify signs and symptoms and to classify cases of PP sepsis with high validity. Integrating postpartum infection screening into existing community-based platforms and post-natal visits is a promising strategy to monitor women for PP sepsis - improving delivery of cohesive maternal and child health care in low resource settings.

Maternal and Neonatal Morbidity and Mortality Among Pregnant Women With and Without COVID-19 Infection: The INTERCOVID Multinational Cohort Study.

Importance: Detailed information about the association of COVID-19 with outcomes in pregnant individuals compared with not-infected pregnant individuals is much needed. Objective: To evaluate the risks associated with COVID-19 in pregnancy on maternal and neonatal outcomes compared with not-infected, concomitant pregnant individuals. Design, Setting, and Participants: In this cohort study that took place from March to October 2020, involving 43 institutions in 18 countries, 2 unmatched, consecutive, not-infected women were concomitantly enrolled immediately after each infected woman was identified, at any stage of pregnancy or delivery, and at the same level of care to minimize bias. Women and neonates were followed up until hospital discharge. Exposures: COVID-19 in pregnancy determined by laboratory confirmation of COVID-19 and/or radiological pulmonary findings or 2 or more predefined COVID-19 symptoms. Main Outcomes and Measures: The primary outcome measures were indices of (maternal and severe neonatal/perinatal) morbidity and mortality; the individual components of these indices were secondary outcomes. Models for these outcomes were adjusted for country, month entering study, maternal age, and history of morbidity. Results: A total of 706 pregnant women with COVID-19 diagnosis and 1424 pregnant women without COVID-19 diagnosis were enrolled, all with broadly similar demographic characteristics (mean [SD] age, 30.2 [6.1] years). Overweight early in pregnancy occurred in 323 women (48.6%) with COVID-19 diagnosis and 554 women (40.2%) without. Women with COVID-19 diagnosis were at higher risk for preeclampsia/eclampsia (relative risk [RR], 1.76; 95% CI, 1.27-2.43), severe infections (RR, 3.38; 95% CI, 1.63-7.01), intensive care unit admission (RR, 5.04; 95% CI, 3.13-8.10), maternal mortality (RR, 22.3; 95% CI, 2.88-172), preterm birth (RR, 1.59; 95% CI, 1.30-1.94), medically indicated preterm birth (RR, 1.97; 95% CI, 1.56-2.51), severe neonatal morbidity index (RR, 2.66; 95% CI, 1.69-4.18), and severe perinatal morbidity and mortality index (RR, 2.14; 95% CI, 1.66-2.75). Fever and shortness of breath for any duration was associated with increased risk of severe maternal complications (RR, 2.56; 95% CI, 1.92-3.40) and neonatal complications (RR, 4.97; 95% CI, 2.11-11.69). Asymptomatic women with COVID-19 diagnosis remained at higher risk only for maternal morbidity (RR, 1.24; 95% CI, 1.00-1.54) and preeclampsia (RR, 1.63; 95% CI, 1.01-2.63). Among women who tested positive (98.1% by real-time polymerase chain reaction), 54 (13%) of their neonates tested positive. Cesarean delivery (RR, 2.15; 95% CI, 1.18-3.91) but not breastfeeding (RR, 1.10; 95% CI, 0.66-1.85) was associated with increased risk for neonatal test positivity. Conclusions and Relevance: In this multinational cohort study, COVID-19 in pregnancy was associated with consistent and substantial increases in severe maternal morbidity and mortality and neonatal complications when pregnant women with and without COVID-19 diagnosis were compared. The findings should alert pregnant individuals and clinicians to implement strictly all the recommended COVID-19 preventive measures.

International gestational age-specific centiles for blood pressure in pregnancy from the INTERGROWTH-21st Project in 8 countries: A longitudinal cohort study.

BACKGROUND: Gestational hypertensive and acute hypotensive disorders are associated with maternal morbidity and mortality worldwide. However, physiological blood pressure changes in pregnancy are insufficiently defined. We describe blood pressure changes across healthy pregnancies from the International Fetal and Newborn Growth Consortium for the 21st Century (INTERGROWTH-21st) Fetal Growth Longitudinal Study (FGLS) to produce international, gestational age-specific, smoothed centiles (third, 10th, 50th, 90th, and 97th) for blood pressure. METHODS AND FINDINGS: Secondary analysis of a prospective, longitudinal, observational cohort study (2009 to 2016) was conducted across 8 diverse urban areas in Brazil, China, India, Italy, Kenya, Oman, the United Kingdom, and the United States of America. We enrolled healthy women at low risk of pregnancy complications. We measured blood pressure using standardised methodology and validated equipment at enrolment at <14 weeks, then every 5 ± 1 weeks until delivery. We enrolled 4,607 (35%) women of 13,108 screened. The mean maternal age was 28·4 (standard deviation [SD] 3.9) years; 97% (4,204/4,321) of women were married or living with a partner, and 68% (2,955/4,321) were nulliparous. Their mean body mass index (BMI) was 23.3 (SD 3.0) kg/m2. Systolic blood pressure was lowest at 12 weeks: Median was 111.5 (95% CI 111.3 to 111.8) mmHg, rising to a median maximum of 119.6 (95% CI 118.9 to 120.3) mmHg at 40 weeks' gestation, a difference of 8.1 (95% CI 7.4 to 8.8) mmHg. Median diastolic blood pressure decreased from 12 weeks: 69.1 (95% CI 68.9 to 69.3) mmHg to a minimum of 68.5 (95% CI 68.3 to 68.7) mmHg at 19+5 weeks' gestation, a change of -0·6 (95% CI -0.8 to -0.4) mmHg. Diastolic blood pressure subsequently increased to a maximum of 76.3 (95% CI 75.9 to 76.8) mmHg at 40 weeks' gestation. Systolic blood pressure fell by >14 mmHg or diastolic blood pressure by >11 mmHg in fewer than 10% of women at any gestational age. Fewer than 10% of women increased their systolic blood pressure by >24 mmHg or diastolic blood pressure by >18 mmHg at any gestational age. The study's main limitations were the unavailability of prepregnancy blood pressure values and inability to explore circadian effects because time of day was not recorded for the blood pressure measurements. CONCLUSIONS: Our findings provide international, gestational age-specific centiles and limits of acceptable change to facilitate earlier recognition of deteriorating health in pregnant women. These centiles challenge the idea of a clinically significant midpregnancy drop in blood pressure.

Female genital tuberculosis in Pakistan - A retrospective review of 10-year laboratory data and analysis of 32 cases.

Background: Female genital tuberculosis (FGTB) is an underobserved clinical entity owing to diagnostic challenges stemming from difficulty of obtaining diagnostic specimens and paucibacillary nature of the disease. Yet, FGTB is a cause of infertility, pelvic pain, or menstrual irregularities in high-burden countries. To assess laboratory and microbiology diagnostic utilization for FGTB in Pakistan, we have collected data from 2007 to 2016 to inform the need for improved laboratory diagnostics. The objectives of this study were to determine the proportion of FGTB as culture-confirmed extrapulmonary tuberculosis (EPTB) and to describe the characteristics of women with culture-confirmed FGTB in a nationwide laboratory network in Pakistan. Method: A retrospective database was established by accessing laboratory archives and analyzed by sex and source to determine extrapulmonary cases among women. Data were checked for quality, and after removing patient identifiers and duplicate samples, frequencies were calculated in MS Excel. Clinical characteristics of patients were derived from a linked hospital database for those patients who were diagnosed and managed at the affiliated university hospital in Karachi, Pakistan. Results: Over 10 years, 410,748 mycobacterial cultures were received from multiple geographic sites throughout Pakistan and processed at the study laboratory. The overall mean culture positivity rate was 5.9% ± 3.5%, while the mean culture positivity rate among females was 2.8% ± 0.8%. Among female culture-confirmed tuberculosis cases, the pulmonary-to-EPTB ratio of infection was 5. Over 10 years, a total of 32 FGTB cases were reported on the basis of positive cultures for Mycobacterium tuberculosis; 3 (9.4%) were rifampin resistant. Conclusions: FGTB currently constitutes a small but significant proportion of culture-confirmed EPTB. A fewer number of laboratory requisitions suggest the need to increase awareness and testing. The advent of high-sensitivity molecular testing on extrapulmonary specimens has the potential to improve diagnostic accuracy and improved detection of FGTB cases in high-burden regions.

Sequential Ensemble-Decision Aliquot Ranking Isolation and Fluorescence In Situ Hybridization Identification of Rare Cells from Blood by Using Concentrated Peripheral Blood Mononuclear Cells.

Isolation and analysis of circulating rare cells is a promising approach for early detection of cancer and other diseases and for prenatal diagnosis. Isolation of rare cells is usually difficult due to their heterogeneity as well as their low abundance in peripheral blood. We previously reported a two-stage ensemble-decision aliquot ranking platform (S-eDAR) for isolating circulating tumor cells from whole blood with high throughput, high recovery rate (>90%), and good purity (>70%), allowing detection of low surface antigen-expressing cancer cells linked to metastasis. However, due to the scarcity of these cells, large sample volumes and large quantities of antibodies were required to isolate sufficient cells for downstream analysis. Here, we drastically increased the number of nucleated cells analyzed by first concentrating peripheral blood mononuclear cells (PBMCs) from whole blood by density gradient centrifugation. The S-eDAR platform was capable of isolating rare cells from concentrated PBMCs (108/mL, equivalent to processing ∼20 mL of whole blood in the 1 mL sample volume used by our instrument) at a high recovery rate (>85%). We then applied the S-eDAR platform for isolating rare fetal nucleated red blood cells (fNRBCs) from concentrated PBMCs spiked with umbilical cord blood cells and confirmed fNRBC recovery by immunostaining and fluorescence in situ hybridization, demonstrating the potential of the S-eDAR system for isolating rare fetal cells from maternal PBMCs to improve noninvasive prenatal diagnosis.

Fetal growth velocity standards from the Fetal Growth Longitudinal Study of the INTERGROWTH-21st Project.

BACKGROUND: Human growth is susceptible to damage from insults, particularly during periods of rapid growth. Identifying those periods and the normative limits that are compatible with adequate growth and development are the first key steps toward preventing impaired growth. OBJECTIVE: This study aimed to construct international fetal growth velocity increment and conditional velocity standards from 14 to 40 weeks' gestation based on the same cohort that contributed to the INTERGROWTH-21st Fetal Growth Standards. STUDY DESIGN: This study was a prospective, longitudinal study of 4321 low-risk pregnancies from 8 geographically diverse populations in the INTERGROWTH-21st Project with rigorous standardization of all study procedures, equipment, and measurements that were performed by trained ultrasonographers. Gestational age was accurately determined clinically and confirmed by ultrasound measurement of crown-rump length at <14 weeks' gestation. Thereafter, the ultrasonographers, who were masked to the values, measured the fetal head circumference, biparietal diameter, occipitofrontal diameter, abdominal circumference, and femur length in triplicate every 5 weeks (within 1 week either side) using identical ultrasound equipment at each site (4-7 scans per pregnancy). Velocity increments across a range of intervals between measures were modeled using fractional polynomial regression. RESULTS: Peak velocity was observed at a similar gestational age: 16 and 17 weeks' gestation for head circumference (12.2 mm/wk), and 16 weeks' gestation for abdominal circumference (11.8 mm/wk) and femur length (3.2 mm/wk). However, velocity growth slowed down rapidly for head circumference, biparietal diameter, occipitofrontal diameter, and femur length, with an almost linear reduction toward term that was more marked for femur length. Conversely, abdominal circumference velocity remained relatively steady throughout pregnancy. The change in velocity with gestational age was more evident for head circumference, biparietal diameter, occipitofrontal diameter, and femur length than for abdominal circumference when the change was expressed as a percentage of fetal size at 40 weeks' gestation. We have also shown how to obtain accurate conditional fetal velocity based on our previous methodological work. CONCLUSION: The fetal skeleton and abdomen have different velocity growth patterns during intrauterine life. Accordingly, we have produced international Fetal Growth Velocity Increment Standards to complement the INTERGROWTH-21st Fetal Growth Standards so as to monitor fetal well-being comprehensively worldwide. Fetal growth velocity curves may be valuable if one wants to study the pathophysiology of fetal growth. We provide an application that can be used easily in clinical practice to evaluate changes in fetal size as conditional velocity for a more refined assessment of fetal growth than is possible at present (https://lxiao5.shinyapps.io/fetal_growth/). The application is freely available with the other INTERGROWTH-21st tools at https://intergrowth21.tghn.org/standards-tools/.

Achieving accurate estimates of fetal gestational age and personalised predictions of fetal growth based on data from an international prospective cohort study: a population-based machine learning study.

Background: Preterm birth is a major global health challenge, the leading cause of death in children under 5 years of age, and a key measure of a population's general health and nutritional status. Current clinical methods of estimating fetal gestational age are often inaccurate. For example, between 20 and 30 weeks of gestation, the width of the 95% prediction interval around the actual gestational age is estimated to be 18-36 days, even when the best ultrasound estimates are used. The aims of this study are to improve estimates of fetal gestational age and provide personalised predictions of future growth. Methods: Using ultrasound-derived, fetal biometric data, we developed a machine learning approach to accurately estimate gestational age. The accuracy of the method is determined by reference to exactly known facts pertaining to each fetus-specifically, intervals between ultrasound visits-rather than the date of the mother's last menstrual period. The data stem from a sample of healthy, well-nourished participants in a large, multicentre, population-based study, the International Fetal and Newborn Growth Consortium for the 21st Century (INTERGROWTH-21st). The generalisability of the algorithm is shown with data from a different and more heterogeneous population (INTERBIO-21st Fetal Study). Findings: In the context of two large datasets, we estimated gestational age between 20 and 30 weeks of gestation with 95% confidence to within 3 days, using measurements made in a 10-week window spanning the second and third trimesters. Fetal gestational age can thus be estimated in the 20-30 weeks gestational age window with a prediction interval 3-5 times better than with any previous algorithm. This will enable improved management of individual pregnancies. 6-week forecasts of the growth trajectory for a given fetus are accurate to within 7 days. This will help identify at-risk fetuses more accurately than currently possible. At population level, the higher accuracy is expected to improve fetal growth charts and population health assessments. Interpretation: Machine learning can circumvent long-standing limitations in determining fetal gestational age and future growth trajectory, without recourse to often inaccurately known information, such as the date of the mother's last menstrual period. Using this algorithm in clinical practice could facilitate the management of individual pregnancies and improve population-level health. Upon publication of this study, the algorithm for gestational age estimates will be provided for research purposes free of charge via a web portal. Funding: Bill & Melinda Gates Foundation, Office of Science (US Department of Energy), US National Science Foundation, and National Institute for Health Research Oxford Biomedical Research Centre.

INTERGROWTH-21st Project international INTER-NDA standards for child development at 2 years of age: an international prospective population-based study.

OBJECTIVES: To describe the construction of the international INTERGROWTH-21st Neurodevelopment Assessment (INTER-NDA) standards for child development at 2 years by reporting the cognitive, language, motor and behaviour outcomes in optimally healthy and nourished children in the INTERGROWTH-21st Project. DESIGN: Population-based cohort study, the INTERGROWTH-21st Project. SETTING: Brazil, India, Italy, Kenya and the UK. PARTICIPANTS: 1181 children prospectively recruited from early fetal life according to the prescriptive WHO approach, and confirmed to be at low risk of adverse perinatal and postnatal outcomes. PRIMARY MEASURES: Scaled INTER-NDA domain scores for cognition, language, fine and gross motor skills and behaviour; vision outcomes measured on the Cardiff tests; attentional problems and emotional reactivity measured on the respective subscales of the preschool Child Behaviour Checklist; and the age of acquisition of the WHO gross motor milestones. RESULTS: Scaled INTER-NDA domain scores are presented as centiles, which were constructed according to the prescriptive WHO approach and excluded children born preterm and those with significant postnatal/neurological morbidity. For all domains, except negative behaviour, higher scores reflect better outcomes and the threshold for normality was defined as ≥10th centile. For the INTER-NDA's cognitive, fine motor, gross motor, language and positive behaviour domains these are ≥38.5, ≥25.7, ≥51.7, ≥17.8 and ≥51.4, respectively. The threshold for normality for the INTER-NDA's negative behaviour domain is ≤50.0, that is, ≤90th centile. At 22-30 months of age, the cohort overlapped with the WHO motor milestone centiles, showed low postnatal morbidity (<10%), and vision outcomes, attentional problems and emotional reactivity scores within the respective normative ranges. CONCLUSIONS: From this large, healthy and well-nourished, international cohort, we have constructed, using the WHO prescriptive methodology, international INTER-NDA standards for child development at 2 years of age. Standards, rather than references, are recommended for population-level screening and the identification of children at risk of adverse outcomes.

The role of the IL-1 system in pregnancy and the use of IL-1 system markers to identify women at risk for pregnancy complications†.

The interleukin (IL)-1 system plays a major role in immune responses and inflammation. The IL-1 system components include IL-1α, IL-1ß, IL-1 receptor type 1 and IL-1 receptor type 2 (decoy receptor), IL-1 receptor accessory protein, and IL-1 receptor antagonist (IL-1Ra). These components have been shown to play a role in pregnancy, specifically in embryo-maternal communication for implantation, placenta development, and protection against infections. As gestation advances, maternal tissues experience increasing fetal demand and physical stress and IL-1ß is induced. Dependent on the levels of IL-1Ra, which regulates IL-1ß activity, a pro-inflammatory response may or may not occur. If there is an inflammatory response, prostaglandins are synthesized that may lead to myometrial contractions and the initiation of labor. Many studies have examined the role of the IL-1 system in pregnancy by independently measuring plasma, cervical, and amniotic fluid IL-1ß or IL-1Ra levels. Other studies have tested for polymorphisms in IL-1ß and IL-1Ra genes in women experiencing pregnancy complications such as early pregnancy loss, in vitro fertilization failure, pre-eclampsia and preterm delivery. Data from those studies suggest a definite role for the IL-1 system in successful pregnancy outcomes. However, as anticipated, the results varied among different experimental models, ethnicities, and disease states. Here, we review the current literature and propose that measurement of IL-1Ra in relation to IL-1 may be useful in predicting the risk of poor pregnancy outcomes.

Late weaning and maternal closeness, associated with advanced motor and visual maturation, reinforce autonomy in healthy, 2-year-old children.

We studied neurodevelopmental outcomes and behaviours in healthy 2-year old children (N = 1306) from Brazil, India, Italy, Kenya and the UK participating in the INTERGROWTH-21st Project. There was a positive independent relationship of duration of exclusive breastfeeding (EBF) and age at weaning with gross motor development, vision and autonomic physical activities, most evident if children were exclusively breastfed for ≥7 months or weaned at ≥7 months. There was no association with cognition, language or behaviour. Children exclusively breastfed from birth to <5 months or weaned at >6 months had, in a dose-effect pattern, adjusting for confounding factors, higher scores for "emotional reactivity". The positive effect of EBF and age at weaning on gross motor, running and climbing scores was strongest among children with the highest scores in maternal closeness proxy indicators. EBF, late weaning and maternal closeness, associated with advanced motor and vision maturation, independently influence autonomous behaviours in healthy children.

Maternal serum glycosylated fibronectin as a short-term predictor of preeclampsia: a prospective cohort study.

BACKGROUND: Preeclampsia is a major pregnancy complication that results in significant maternal and infant mortality, most of which occurs in low and middle-income countries. The accurate and timely diagnosis of preeclampsia is critical in management of affected pregnancies to reduce maternal and fetal/neonatal morbidity and mortality, yet difficulties remain in establishing the rigorous diagnosis of preeclampsia based on clinical parameters alone. Biomarkers that detect biochemical disease have been proposed as complements or alternatives to clinical criteria to improve diagnostic accuracy. This cohort study assessed the performance of several biomarkers, including glycosylated fibronectin (GlyFn), to rule-in or rule-out preeclampsia within 4 weeks in a cohort of women at increased risk for preeclampsia. METHODS: 151 women with risk factors for or clinical signs and symptoms of preeclampsia were selected from a prospective cohort. Maternal serum samples were collected between 20 and 37 weeks of gestation. Clinical suspicion of preeclampsia was defined as presence of new-onset proteinuria, or clinical symptoms of preeclampsia. Subjects with a clinical diagnosis of preeclampsia at the time of enrollment were excluded. GlyFn, pregnancy-associated plasma protein-A2 (PAPPA2), placental growth factor (PlGF), and soluble fms-like tyrosine kinase-1 (sFlt-1) were measured by immunoassay. GlyFn was also determined using a rapid point-of care (POC) test format. Receiver-operating characteristic (ROC) curves derived from logistic regression analysis were used to determine the classification performance for each analyte. RESULTS: 32 of 151 (21%) women developed a clinical diagnosis of preeclampsia within 4 weeks. All biomarkers exhibited good classification performance [GlyFn (area under the curve (AUROC) = 0.94, 91% sensitivity, 86% specificity); PAPPA2 AUC = 0.92, 87% sensitivity, 77% specificity; PlGF AUC = 0.90, 81% sensitivity, 83% specificity; sFlt-1 AUC = 0.92, 84% sensitivity, 91% specificity. The GlyFn immunoassay and the rapid POC test showed a correlation of r = 0.966. CONCLUSIONS: In this prospective cohort, serum biomarkers of biochemical disease were effective in short-term prediction of preeclampsia, and the performance of GlyFn in particular as a POC test may meet the needs of rapid and accurate triage and intervention.