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.

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.

Preeclampsia and COVID-19: results from the INTERCOVID prospective longitudinal study.

BACKGROUND: It is unclear whether the suggested link between COVID-19 during pregnancy and preeclampsia is an independent association or if these are caused by common risk factors. OBJECTIVE: This study aimed to quantify any independent association between COVID-19 during pregnancy and preeclampsia and to determine the effect of these variables on maternal and neonatal morbidity and mortality. STUDY DESIGN: This was a large, longitudinal, prospective, unmatched diagnosed and not-diagnosed observational study assessing the effect of COVID-19 during pregnancy on mothers and neonates. Two consecutive not-diagnosed women were concomitantly enrolled immediately after each diagnosed woman was identified, at any stage during pregnancy or delivery, and at the same level of care to minimize bias. Women and neonates were followed until hospital discharge using the standardized INTERGROWTH-21st protocols and electronic data management system. A total of 43 institutions in 18 countries contributed to the study sample. The independent association between the 2 entities was quantified with the risk factors known to be associated with preeclampsia analyzed in each group. The outcomes were compared among women with COVID-19 alone, preeclampsia alone, both conditions, and those without either of the 2 conditions. RESULTS: We enrolled 2184 pregnant women; of these, 725 (33.2%) were enrolled in the COVID-19 diagnosed and 1459 (66.8%) in the COVID-19 not-diagnosed groups. Of these women, 123 had preeclampsia of which 59 of 725 (8.1%) were in the COVID-19 diagnosed group and 64 of 1459 (4.4%) were in the not-diagnosed group (risk ratio, 1.86; 95% confidence interval, 1.32-2.61). After adjustment for sociodemographic factors and conditions associated with both COVID-19 and preeclampsia, the risk ratio for preeclampsia remained significant among all women (risk ratio, 1.77; 95% confidence interval, 1.25-2.52) and nulliparous women specifically (risk ratio, 1.89; 95% confidence interval, 1.17-3.05). There was a trend but no statistical significance among parous women (risk ratio, 1.64; 95% confidence interval, 0.99-2.73). The risk ratio for preterm birth for all women diagnosed with COVID-19 and preeclampsia was 4.05 (95% confidence interval, 2.99-5.49) and 6.26 (95% confidence interval, 4.35-9.00) for nulliparous women. Compared with women with neither condition diagnosed, the composite adverse perinatal outcome showed a stepwise increase in the risk ratio for COVID-19 without preeclampsia, preeclampsia without COVID-19, and COVID-19 with preeclampsia (risk ratio, 2.16; 95% confidence interval, 1.63-2.86; risk ratio, 2.53; 95% confidence interval, 1.44-4.45; and risk ratio, 2.84; 95% confidence interval, 1.67-4.82, respectively). Similar findings were found for the composite adverse maternal outcome with risk ratios of 1.76 (95% confidence interval, 1.32-2.35), 2.07 (95% confidence interval, 1.20-3.57), and 2.77 (95% confidence interval, 1.66-4.63). The association between COVID-19 and gestational hypertension and the direction of the effects on preterm birth and adverse perinatal and maternal outcomes, were similar to preeclampsia, but confined to nulliparous women with lower risk ratios. CONCLUSION: COVID-19 during pregnancy is strongly associated with preeclampsia, especially among nulliparous women. This association is independent of any risk factors and preexisting conditions. COVID-19 severity does not seem to be a factor in this association. Both conditions are associated independently of and in an additive fashion with preterm birth, severe perinatal morbidity and mortality, and adverse maternal outcomes. Women with preeclampsia should be considered a particularly vulnerable group with regard to the risks posed by COVID-19.

Frequent Placental SARS-CoV-2 in Patients with COVID-19-Associated Hypertensive Disorders of Pregnancy.

INTRODUCTION: Studies described an increased frequency of hypertensive disorders of pregnancy (HDP) after a COVID-19 episode. There is limited evidence about SARS-CoV-2 viral load in placenta. This study aimed to investigate the relationship between SARS-CoV-2 viral load in the placenta and clinical development of HDP after COVID-19 throughout different periods of gestation. METHODS: This is a case-control study in women with and without gestational hypertensive disorders after SARS-CoV-2 infection diagnosed by RT-PCR during pregnancy. Patients were matched by gestational age at the moment of COVID-19 diagnosis. We performed an analysis of SARS-CoV-2 RNA levels in placenta. RESULTS: A total of 28 women were enrolled. Sixteen patients were diagnosed with COVID-19 during the third trimester and the remaining 12 patients in the other trimesters. Ten placentas (35.7%) were positive for SARS-CoV-2, 9 of them (9/14, 64.3%) belonged to the HDP group versus 1 (1/14, 7.2%) in the control group (p = 0.009). Those cases with the highest loads of viral RNA developed severe preeclampsia (PE). CONCLUSION: Among women diagnosed with COVID-19 during pregnancy, the presence of SARS-CoV-2 in the placenta was more frequent among women suffering from PE or gestational hypertension. Furthermore, the most severe cases of HDP were associated with high placental viral load, not necessarily associated with a positive nasopharyngeal RT-PCR at delivery. Our data suggest that SARS-CoV-2 infection during pregnancy could trigger gestational hypertensive disorders through persistent placental infection and resulting placental damage.

Terpenoids of the Swamp Cypress Subfamily (Taxodioideae), Cupressaceae, an Overview by GC-MS.

The resins bled from stems and in seed cones and leaves of Cryptomeria japonica, Glyptostrobus pensilis, Taxodium distichum, and T. mucronatum were characterized to provide an overview of their major natural product compositions. The total solvent extract solutions were analyzed as the free and derivatized products by gas chromatography-mass spectrometry to identify the compounds, which comprised minor mono- and sesquiterpenoids, and dominant di- and triterpenoids, plus aliphatic lipids (e.g., n-nonacosan-10-ol). Ferruginol, 7α-p-cymenylferruginol, and chamaecydin were the major characteristic markers for the Taxodioideae conifer subfamily. The mass spectrometric data can aid polar compound elucidation in environmental, geological, archeological, forensic and pharmaceutical studies.

Mulinane and Azorellane Diterpenoid Biomarkers by GC-MS from a Representative Apiaceae (Umbelliferae) Species of the Andes.

Extracts of bled resin from Azorella compacta, of the Azorelloideae family from the Andes (>4000 m), were analyzed by gas chromatography-mass spectrometry. The mass spectra of the dominant compounds of the resin and its hydrogenation products were documented. The most abundant compounds were oxygenated diterpenoids, namely mulinadien-20-oic (Δ11,13 and Δ11,14) acids, azorell-13-en-20-oic acid, 13α,14ß-dihydroxymulin-11-en-20-oic acid, and azorellanol, with a group of azorellenes and mulinadienes. The mass spectra of the novel diterpenoid hydrocarbons with the azorellane and mulinane skeletons were also presented. This study documents the molecular diversity of these diterpenoid classes, and could be of great utility for future organic geochemical, environmental, archeological, pharmaceutical, and forensic chemistry studies.

Terpenoid Compositions of Resins from Callitris Species (Cupressaceae).

The environmental fate of conifer resins and their natural product compounds as mixtures is of importance for source, alteration, and transport studies. The compound compositions of resins of the common Callitris species (Cupressaceae) based on gas chromatography-mass spectrometry have not been reported. Results show that diterpenoids were the most abundant components and callitrisic acid was present in the resin extracts of all Callitris species analyzed. Significant amounts of 4-epi-pimaric and sandaracopimaric acids, with lesser communic, ozic, and lambertianic acids, were also in the mixtures. Phenolic diterpenoids, for example, ferruginol, hinokiol, were found in trace quantities in some samples. Thus, callitrisic acid and 4-epi-pimaric acid are the characteristic diterpenoids of Callitris species that are amenable to molecular biomarker analyses in geological or environmental applications.

Threatened preterm labor is a risk factor for impaired cognitive development in early childhood.

BACKGROUND: Threatened preterm labor is a leading cause of hospital admission during pregnancy. Patients with an episode of threatened preterm labor who deliver at term are considered to have false preterm labor. However, threatened preterm labor has been proposed as a pathologic insult that is not always sufficient to induce irreversible spontaneous preterm birth but that could alter the normal course of pregnancy. OBJECTIVE: The aim of this study was to evaluate threatened preterm labor during pregnancy as a risk factor of neurodevelopmental deficits of children at 2 years of age. STUDY DESIGN: Two-year-old children who were born late preterm (n=22) or at term after threatened preterm labor (n=23) were compared with at-term control children (n=42). Neurodevelopment was evaluated at a corrected age of 24-29 months with the use of the Merrill-Palmer-Revised Scales of Development. RESULTS: Children who were born at term after threatened preterm labor had lower scores than control children on global cognitive index (95.4 vs 104.2; P=.011), cognition (95.1 vs 103.1; P=.021), fine motor (95.2 vs 103.4; P=.003), gross motor (84.7 vs 99.8; P=.001), memory (92.9 vs 100.4; P=.015), receptive language (93.9 vs 102.9; P=.03), speed of processing (105.7 vs 113.3; P=.011), and visual motor coordination (98.8 vs 106.7; P=.003) subtests. Children born at term after threatened preterm labor had an increased risk of mild neurodevelopmental delay compared with control children (odds ratio for global cognitive index, 2.06; 95% confidence interval, 1.09-3.88; P=.033). There were no significant differences in any cognitive domain between children who were born late preterm and children who were born at term after threatened preterm labor. CONCLUSIONS: Threatened preterm labor is a risk factor for impaired cognitive development at 2 years of age, even if birth occurred at term.

Takotsubo cardiomyopathy after cesarean section: A case report and literature review.

Takotsubo cardiomyopathy (TCM) is clinically identical to acute myocardial infarction. We report an unusual case of TCM and review similar cases in pregnant women. A young woman with no pre-existing cardiovascular risk factors suffered sudden dyspnea during a cesarean section. Electrocardiography (ECG) showed T-wave inversion. We observed acute lung edema and left ventricular systolic dysfunction on echocardiography. A cardiac catheterization diagnosed TCM. We reviewed 20 cases of TCM; 17 cases occurred during the post-partum period and three during pregnancy. Five of these cases had vaginal deliveries and the remaining cases had cesarean sections. Within the latter group, five cases appeared intraoperatively. With the exception of one patient with normal ECG results, all other patients progressed, with changes in ECG readings and elevation of cardiac enzyme serum levels. However, cardiac catheterization revealed that coronary arterial damage did not occur in any of the cases. After three months, each patient fully recovered.

Cervix assessment for the management of labor induction: reliability of cervical length and Bishop score determined by residents.

AIM: To evaluate the reliability of two techniques of cervical ripeness assessment at the beginning of labor induction, as assessed by inexperienced observers. METHODS: A total of 120 women were prospectively studied at admission for labor induction. Two independent physicians examined consenting women successively but separately. One experienced consultant and one of the six first-year obstetrics residents composed the pairs of observers. The trainees had very limited prior experience with cervical ultrasound scan or evaluating Bishop score. Cervical length and Bishop score were evaluated according to standard methodology. Reliability was described by intraclass correlation coefficients (ICC) and coefficients of variation (COV). Ultrasound cervical length was plotted according to the Bland-Altman method. RESULTS: The median Bishop score and mean cervical length were similar for all observers. Ultrasound cervical length and Bishop score were highly reliable when evaluated by first-year residents. Ultrasound cervical length showed the highest interobserver agreement, with ICC values over 0.9 and COV values of approximately 10% or less for all trainees. The Bishop score was also reliable, but with lower ICC and higher COV values. CONCLUSION: Bishop score and ultrasound cervical length examination for the management of labor induction are accurate and easy to learn by inexperienced first-year residents. However, cervical length showed higher reliability than the Bishop score.

Impact of Suspected Preterm Labor during Pregnancy on Cardiometabolic Profile and Neurodevelopment during Childhood: A Prospective Cohort Study Protocol.

INTRODUCTION: Suspected preterm labor (SPL), defined as the presence of regular and painful uterine contractions and cervical shortening, represents a prenatal insult with potential long-term consequences. However, despite recent evidence demonstrating suboptimal neurodevelopment at 2 years in this population, it remains underestimated as a significant risk factor for neurodevelopmental disorders or other chronic diseases. The aim of this study is to assess the impact of suspected preterm labor during pregnancy on cardiometabolic profile and neurodevelopment during childhood (6-8 years). METHODS AND ANALYSIS: Prospective cohort study including children whose mothers suffered suspected preterm labour during pregnancy and paired controls. Neurodevelopmental, cardiovascular, and metabolic assessments will be performed at 6-8 years of age. A trained psychologist will carry out the neurodevelopment assessment including intelligence, visual perception, and behavioral assessment. Body composition and physical fitness assessment will be performed by one trained pediatrician and nurse. Finally, cardiovascular evaluation, including echocardiography and blood pressure, will be performed by two pediatric cardiologists. Data regarding perinatal and postnatal characteristics, diet, lifestyle, and weekly screen time of the child will be obtained from medical history and direct interviews with families. Primary outcome measures will include body mass index and adiposity, percentage of fat mass and total and regional lean mass, bone mineral content and density, cardiorespiratory resistance, isometric muscle strength, dynamic lower body strength, systolic and diastolic blood pressure, left ventricle (LV) systolic and diastolic function, general intelligence index, visuospatial working memory span, oculomotor control test, index of emotional, and behavioral problems.

Placental Infection Associated with SARS-CoV-2 Wildtype Variant and Variants of Concern.

The original SARS-CoV-2 lineages have been replaced by successive variants of concern (VOCs) over time. The aim of this study was to perform an assessment of the placental infection by SARS-CoV-2 according to the predominant variant at the moment of COVID-19 diagnosis. This was a prospective study of SARS-CoV-2-positive pregnant women between March 2020 and March 2022. The population was divided into pregnancies affected by COVID-19 disease during 2020 (Pre-VOC group) and pregnancies affected after December 2020 by SARS-CoV-2 variants of concern (VOC group). The presence of virus was assessed by RT-PCR, and the viral variant was determined by whole genome sequencing. A total of 104 placentas were examined, among which 54 cases belonged to the Pre-VOC group and 50 cases belonged to the VOC group. Sixteen positive placental RT-PCR tests for SARS-CoV-2 were reported. The NGS analysis confirmed the SARS-CoV-2 lineage in placenta tissue. All samples corresponded to the Pre-VOC group, whereas no placental presence of SARS-CoV-2 was detected in the VOC group (16, 29.6% vs. 0, 0.0% p = 0.000). Preterm birth (9, 16.7% vs. 2, 4%; p = 0.036) and hypertensive disorders of pregnancy (14, 25.9% vs. 3, 6%; p = 0.003) were more frequent in the Pre-VOC group than in the VOC group. Finally, the VOC group was composed of 23 unvaccinated and 27 vaccinated pregnant women; no differences were observed in the sub-analysis focused on vaccination status. In summary, SARS-CoV-2-positive placentas were observed only in pregnancies infected by SARS-CoV-2 wildtype. Thus, placental SARS-CoV-2 presence could be influenced by SARS-CoV-2 variants, infection timing, or vaccination status. According to our data, the current risk of SARS-CoV-2 placental infection after maternal COVID disease during pregnancy should be updated.

Distributions and sources of polycyclic aromatic hydrocarbons in surface sediments from the Cross River estuary, S.E. Niger Delta, Nigeria.

Polycyclic aromatic hydrocarbon (PAH) analyses of surface sediments from the Cross River estuary by gas chromatography-mass spectrometry indicated natural diagenetically derived PAHs in the upper estuary, with minor and variable amounts of petrogenic and combustion-derived PAHs from human activities (lower estuary). The occurrence of significant amounts of perylene (average 23% of all PAHs) with the diagenetic natural PAHs in the middle estuary bordered by mangrove forests supports its origin from terrestrial organic matter. The natural PAHs represent the highest percentage (average 76%) of the total PAHs in this tropical environment. The traditional geochemical parameters, including the petrogenic PAHs, confirmed trace petroleum contamination in the estuary. Specific PAH ratios such as Fl/Py and Fl/(Fl+Py) also support this source contribution.

[Conservative management of cervical ectopic pregnancy]. / Tratamiento conservador de la gestación ectópica cervical.

BACKGROUND: Cervical ectopic pregnancy is a rare type of ectopic pregnancy (less than one percent of all ectopic pregnancies). OBJECTIVE: Assess the efficacy of the treatment options available. MATERIAL AND METHODS: Retrospective study of the cervical ectopic pregnancies treated in our hospital from January 2005 to December 2011. RESULTS: Three patients were diagnosed cervical ectopic pregnancy in our hospital during that period, that is, an incidence of 1.7 per 10,000 gestations. The main symptom was a moderate-to-severe genital hemorrhage. In two of the cases a single dose of 50 mg/cm2 methotrexate was administered, and in the third one, curettage and uterine arterial embolization were performed. Histerectomy was not necessary in either of the cases. CONCLUSION: Conservative management of cervical ectopic pregnancy is an effective and safe option.

Different Brain Phenotypes in Magnetic Resonance Imaging of Healthy Children after Prenatal Insults.

In this study, we used magnetic resonance imaging (MRI) to identify the different brain phenotypes within apparently healthy children and to evaluate whether these phenotypes had different prenatal characteristics. We included 65 healthy children (mean age, 10 years old) with normal neurological examinations and without structural abnormalities. We performed cluster analyses to identify the different brain phenotypes in the brain MRI images. We performed descriptive analyses, including demographic and perinatal characteristics, to assess the differences between the clusters. We identified two clusters: Cluster 1, or the "small brain phenotype" (n = 44), which was characterized by a global reduction in the brain volumes, with smaller total intracranial volumes (1044.53 ± 68.37 vs. 1200.87 ± 65.92 cm3 (p < 0.001)), total grey-matter volumes (644.65 ± 38.85 vs. 746.79 ± 39.37 cm3 (p < 0.001)), and total white-matter volumes (383.68 ± 40.17 vs. 443.55 ± 36.27 cm3 (p < 0.001)), compared with Cluster 2, or the "normal brain phenotype" (n = 21). Moreover, almost all the brain areas had decreased volumes, except for the ventricles, caudate nuclei, and pallidum areas. The risk of belonging to "the small phenotype" was 82% if the child was preterm, 76% if he/she was born small for his/her gestational age and up to 80% if the mother smoked during the pregnancy. However, preterm birth appears to be the only substantially significant risk factor associated with decreased brain volumes.

First-Trimester Sequential Screening for Preeclampsia Using Angiogenic Factors: Study Protocol for a Prospective, Multicenter, Real Clinical Setting Study.

Introduction: The incidence of preeclampsia (PE) is about 2-8%, making it one of the leading causes of perinatal morbidity and maternal mortality in the world. Early prophylactic low dose administration (150 mg) of acetylsalicylic acid is associated with a significant reduction in the incidence of early-onset PE, intrauterine growth restriction (IUGR), and neonatal mean stay in the intensive care unit (ICU). Universal implementation of a first-trimester screening system including angiogenic and antiangiogenic markers [the Placental Growth Factor (PlGF) and/or soluble fms-like Tyrosine Kinase-1 (sFlt-1)] has shown a prediction rate of 90% for early-onset PE but entails a high financial cost. The aim of this study is to determine the predictive and preventive capacity of a universal PE first-trimester two-step sequential screening model, determining the PlGF only in patients previously classified as intermediate risk by means of a multivariate model based on resources already used in the standard pregnancy control, in a real clinical setting. We hypothesize that this screening model will achieve similar diagnostic performance as the universal determination of PlGF but at a lower economic cost. Methods and Analysis: This is a prospective, multicentric, cohort study in a real-world clinical setting. Every singleton pregnancy will be recruited at the routine first pregnancy visit. In a first step, the first-trimester risk of PE will be calculated using a multivariate Gaussian distribution model, based on medical history, mean blood pressure, Pregnancy-Associated Plasma Protein A (PAPP-A), and Uterine Artery Doppler Pulsatility Index (UTPI). Patients will be classified into three risk groups for PE: (1) risk ≥ 1/50, high-risk with no further testing (blinded PlGF); (2) risk between 1/51 and 1/500, medium-risk requiring further testing; and (3) risk ≤ 1/501, low-risk with no further testing. In a second step, the PlGF will only be determined in those patients classified as intermediate risk after this first step, and then reclassified into high- or low-risk groups. Prophylactic administration of aspirin (150 mg/day) will be prescribed only in high risk patients. As a secondary objective, sFlt-1 values will be blindly determined in patients with high and intermediate risk to assess its potential performance in the screening for PE. Ethics and Dissemination: The study will be conducted in accordance with the principles of Good Clinical Practice. This study is approved by the Aragon Research Ethics Committee (CEICA) on 3 July 2020 (15/2020). Clinical Trial Registration: ClinicalTrials.gov, identifier: NCT04767438.

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.

Altered DNA methylation in human placenta after (suspected) preterm labor.

Aim: The aim of this study was to determine if alterations in DNA methylation in the human placenta would support suspected preterm labor as a pathologic insult associated with diminished placental health. Methods: We evaluated placental DNA methylation at seven loci differentially methylated in placental pathologies using targeted bisulfite sequencing, in placentas associated with preterm labor (term birth after suspected preterm labor [n = 15] and preterm birth [n = 15]), and controls (n = 15). Results: DNA methylation levels at the NCAM1 and PLAGL1 loci in placentas associated with preterm labor did differ significantly (p < 0.05) from controls. Discussion: Specific alterations in methylation patterns indicative of an unfavourable placental environment are associated with preterm labor per se and not restricted to preterm birth.

Cerebral blood perfusion and neurobehavioral performance in full-term small-for-gestational-age fetuses.

OBJECTIVE: The purpose of this study was to evaluate changes in cerebral blood perfusion and middle cerebral artery (MCA) Doppler in full-term small-for-gestational-age fetuses (SGA) and to explore their association with neonatal neurobehavioral performance. STUDY DESIGN: Frontal brain perfusion that was measured by fractional moving blood volume (FMBV) and MCA Doppler pulsatility index were assessed in 60 SGA fetuses with normal umbilical artery Doppler results that were matched with adequate-for-gestational-age fetuses. Neonates were evaluated with the Neonatal-Behavioral-Assessment-Scale (NBAS). RESULTS: The proportion of SGA fetuses with increased FMBV (35% vs 5%; P < .001) and decreased MCA Doppler pulsatility index (15% vs 1.7%; P < .01) was significantly higher. SGA fetuses showed poorer NBAS scores in all areas. Increased FMBV identified SGA fetuses with the highest risks of abnormal NBAS in social-interactive (odds ratio, 7.8), attention (odds ratio, 22.8), and state-organization (odds ratio, 25.0). Abnormal MCA Doppler identified SGA with abnormal scores in motor area (odds ratio, 10.7). CONCLUSION: Increased brain blood perfusion discriminates SGA fetuses that are at risk for abnormal neurobehavior.

A mass budget of polybrominated diphenyl ethers in San Francisco Bay, CA.

A mass budget of polybrominated diphenyl ethers (PBDEs) in San Francisco Bay is developed as a first step towards understanding the local sources and transport processes controlling PBDE fate in a highly urbanized estuary. Extensive monitoring of PBDEs in estuarine water and sediment, freshwater tributaries, air, and wastewater effluents and sludges were integrated with a mass budget model to provide a synthetic view of these emerging contaminants. The Bay inventories of BDE 47 and BDE 209 in 2006 were estimated to be 33+/-3 kg and 153+/-45 kg, respectively. Empirically derived estimates of annual inputs of BDE 47 and BDE 209 from all quantifiable external sources ranged from 11 to 28 kg/y and 22 to 24 kg/y, respectively. BDE 47 loads were dominated by wastewater while runoff from local tributaries represented the largest contributor to BDE 209 loads. Model results suggest the Bay PBDE inventory is highly sensitive to changes in external loads, with degradation and outflow being the major processes governing PBDE fate. The mass budget presented provides a framework for integrating future monitoring and modeling efforts.