Impact of SARS-CoV-2 Infection on Unvaccinated Pregnant Women: Non-Reassuring Fetal Heart Rate Tracing Because of Placentitis.

In 2020, a new coronavirus, called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in China. SARS-CoV-2 infection has been shown to be highly morbid in pregnant women, being a risk factor for several obstetric conditions leading to increased maternal and neonatal mortality. A few studies since 2020 have shown SARS-CoV-2 maternal-fetal transmission and noted placental abnormalities grouped under the term placentitis. We hypothesized that these placental lesions could be responsible for abnormalities in placental exchange and therefore abnormalities in cardiotocographic monitoring, leading to premature fetal extraction. The objective is to identify the clinical, biochemical, and histological determinants associated with the occurrence of non-reassuring fetal heart rate (NRFHR) outside labor in fetuses of SARS-CoV-2-infected mothers. We conducted a retrospective multicenter case series of the natural history of maternal SARS-CoV-2 infections resulting in fetal delivery outside labor due to NRFHR. Collaboration was sought with the maternity hospitals in the CEGORIF, the APHP and Brussels hospitals. The investigators were contacted by e-mail on three successive occasions over a period of one year. Data from 17 mothers and 17 fetuses were analyzed. Most women had a mild SARS-CoV-2 infection; only two women presented severe infection. No woman was vaccinated. We found a substantial proportion of maternal coagulopathy at birth: elevation of APTT ratio (62%), thrombocytopenia (41%) and liver cytolysis (58.3%). Iatrogenic prematurity was noted in 15 of 17 fetuses, and 100% were born by cesarean delivery due to emergency criteria. One male neonate died on the day of birth due to peripartum asphyxia. Three cases of maternal-fetal transmission were recorded following WHO criteria. Placental analysis in 15 cases revealed eight cases of SARS-CoV-2 placentitis, causing placental insufficiency. In total, 100% of the placentas analyzed showed at least one lesion suggestive of placentitis. SARS-CoV-2 maternal infection during pregnancy is likely to generate neonatal morbidity in relation to placental damage resulting in placental insufficiency. This morbidity may be the consequence of induced prematurity as well as acidosis in the most severe situations. Placental damage occurred in unvaccinated women and in women with no identified risk factor, in contrast to severe maternal clinical forms.

Mother-to-child transmission of SARS-CoV-2 infection in high-income countries: a systematic review and meta-analysis of prospective observational studies.

Mother-to-child transmission of SARS-CoV-2 has been reported since the onset of the COVID-19 pandemic. We conducted a study to summarize evidence on the risk of mother-to-child transmission in the first 30 days after birth in high-income countries and to evaluate the association between preventive measures and the risk of infection for the neonate. A systematic review and meta-analysis were undertaken following PRISMA guidelines. The National Library of Medicine, Web of Science, and Excerpta Medica databases were screened on February 26, 2022. All prospective observational studies addressing the frequency of infection in infants born to mothers SARS-CoV-2 positive were included. Twenty-six studies were included, reporting data of 2653 mothers with SARS-CoV-2 and 2677 neonates. The proportion meta-analysis pointed out an overall estimate of SARS-CoV-2 infection among infants of 2.3% (95% CI: 1.4-3.2%). Data from studies with (1.4%, 95% CI: 0.8-2) and without (1.3%, 95% CI: 0.0-2.7%) rooming-in provided similar risk of infection. Adopting at least two prevention measures during rooming-in resulted in a rate of mother-to-child infection of 1.0% (95%CI: 0.3-1.7%). The results of this study show a low rate of perinatal infection, support the rooming-in and confirm the effectiveness of preventive measures in reducing the risk of mother-to-child viral transmission.

Vaccination is preventing development of placental pathologies in SARS-CoV-2 infected pregnant patients.

INTRODUCTION: The coronavirus disease (COVID-19) has created a serious health problem in pregnant people. We aimed to address whether vaccination can prevent development of placental disease in SARS-CoV-2 infected mothers. METHODS: We reported the pathology findings obtained from routine histopathological examination of placentas of overall 38 cases. RESULTS: We found low prevalence of placental pathology in vaccinated pregnant people with active SARS-CoV-2 infection in comparison to those unvaccinated cases. CONCLUSION: Based on our findings, SARS-CoV-2 vaccination can prevent development of placental pathological lesions and may lower the risk of serious illness in pregnant people.

The effect of coronavirus disease 2019 on newborns.

PURPOSE OF REVIEW: To evaluate the available literature regarding effects of coronavirus disease 2019 (COVID-19) on newborns, ranging from effects related to in utero and perinatal exposure to maternal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, to pandemic-related stress and socioeconomic changes. RECENT FINDINGS: Several large studies and national registries have shown that the risk of vertical transmission from SARS-CoV-2-infected mothers to newborns is rare and does not appear to be related to postnatal care policies such as mother-newborn separation and breastfeeding. Newborns exposed to SARS-CoV-2 in utero are at higher risk for preterm delivery for reasons still under investigation. When newborns do acquire SARS-CoV-2 infection, their disease course is usually mild. Long-term follow-up data are lacking, but preliminary reports indicate that, similarly to prior natural disasters, being born during the pandemic may be associated with developmental risk. SUMMARY: Although risk of vertical or perinatal transmission is low across a range of postnatal care practices, early indicators suggest developmental risk to the generation born during the pandemic. Long-term follow-up data are critically needed to determine the developmental impact of in utero and early life exposure to SARS-CoV-2 and the COVID-19 pandemic.

Effect of COVID-19 on Pregnancy and Neonate's Vital Parameters: A Systematic Review.

Background: COVID-19 is a new pandemic, which was declared by the World Health Organization in 2019 as a threat to public health. According to numerous reports, it can have negative consequences for pregnant women, labour, and neonates born to infected mothers. The aim of this paper was to gather the evidence and to present a summary of the results of studies concerning COVID-19 in pregnant women and their neonates. Methods: Articles from prestigious journals covering the period from 2020 to February 2023, relevant review papers, and original research articles from PubMed were analysed. In order to analyse the available research literature, the Web of Science, Scopus, and PubMed databases were used, in which the search for articles was conducted using terms ("pregnancy," "coronavirus," "SARS-CoV-2," and "newborn") and using PRISMA (Preferred Reporting Items for Systemic Reviews and Meta-Analysis) guidelines for clinical trials. Meta-analyses and systematic reviews (2022-2023) on symptoms, neonatal course, and risk of COVID-19 infection have been summarized. Summary of meta-analyses and systematic reviews (2022-2023) on the effect and adverse reaction of the COVID-19 vaccination is presented. Results: As a result of the research conducted, it was confirmed that in most pregnant women, no serious signs of the infection were observed, although isolated cases of death related to COVID-19 in pregnant women were reported. Several authors called attention to the more severe course of the infection in pregnant women with obesity. It seemed that no vertical transmission from mother to child was occurring. Nevertheless, the information was not clinching. The condition of the neonates born to mothers with COVID-19 was in most cases described as normal; however, some papers reported deaths of infected neonates. Conclusions: Due to insufficient data, further research is necessary. Further studies and follow-up are recommended, which would make possible an assessment of remote effects of COVID-19 on pregnancy and vital parameters of the newborn.

The effects of COVID-19 on placental morphology.

The impact of the COVID-19 infection, caused by Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), during the pandemic has been considerably more severe in pregnant women than non-pregnant women. Therefore, a review detailing the morphological alterations and physiological changes associated with COVID-19 during pregnancy and the effect that these changes have on the feto-placental unit is of high priority. This knowledge is crucial for these mothers, their babies and clinicians to ensure a healthy life post-pandemic. Hence, we review the placental morphological changes due to COVID-19 to enhance the general understanding of how pregnant mothers, their placentas and unborn children may have been affected by this pandemic. Based on current literature, we deduced that COVID-19 pregnancies were oxygen deficient, which could further result in other pregnancy-related complications like preeclampsia and IUGR. Therefore, we present an up-to-date review of the COVID-19 pathophysiological implications on the placenta, covering the function of the placenta in COVID-19, the effects of this virus on the placenta, its functions and its link to other gestational complications. Furthermore, we highlight the possible effects of COVID-19 therapeutic interventions on pregnant mothers and their unborn children. Based on the literature, we strongly suggest that consistent surveillance for the mothers and infants from COVID-19 pregnancies be prioritised in the future. Though the pandemic is now in the past, its effects are long-term, necessitating the monitoring of clinical manifestations in the near future.

Prevalence and impact of SARS-CoV-2 infection on maternal and infant health in African populations: protocol of a multicentre prospective cohort study (MA-CoV project).

INTRODUCTION: Pregnant women are currently considered a vulnerable population to SARS-CoV-2 infection, with increased risk of severe COVID-19, preterm birth and maternal mortality. There is, however, a paucity of data on the burden of maternal SARS-CoV-2 infection in sub-Saharan countries. The objective of this study is to determine the prevalence and health effects of maternal SARS-CoV-2 infection in selected sites from Gabon and Mozambique. METHODS AND ANALYSIS: MA-CoV (MAternal CoVid) is an observational, multicentre prospective cohort study where 1000 pregnant women (500 per country) will be enrolled at the antenatal clinic visits. Participants will undergo monthly follow-up at each antenatal care visit, delivery and postpartum visit. The primary study outcome is the prevalence of SARS-CoV-2 infection during pregnancy. The clinical presentation of COVID-19 in pregnancy will also be characterised, and incidence of infection during pregnancy will be evaluated, as well as the risk factors of maternal and neonatal morbidity and mortality associated with SARS-CoV-2 infection and the risk of mother to child transmission of SARS-CoV-2. SARS-CoV-2 infection screening will be performed through PCR diagnosis. ETHICS AND DISSEMINATION: The protocol was reviewed and approved by the Comité National d'Éthique pour la Recherche au Gabon, Comité Nacional de Bioética para Saúde de Moçambique and the Ethics Committee of the Hospital Clinic of Barcelona (Spain). Project results will be presented to all stakeholders and published in open access journals. TRIAL REGISTRATION NUMBER: NCT05303168.

Residual risk of mother-to-child transmission of HBV despite timely Hepatitis B vaccination: a major challenge to eliminate hepatitis B infection in Cambodia.

BACKGROUND: In countries with intermediate or high hepatitis B virus (HBV) endemicity, mother-to-child transmission (MTCT) represents the main route of chronic HBV infection. There is a paucity of information on HBV MTCT in Cambodia. This study aimed to investigate the prevalence of HBV infection among pregnant women and its MTCT rate in Siem Reap, Cambodia. METHODS: This longitudinal study included two parts, study-1 to screen HBsAg among pregnant women and study-2 to follow up babies of all HBsAg-positive and one-fourth of HBsAg-negative mothers at their delivery and six-month post-partum. Serum or dried blood spot (DBS) samples were collected to examine HBV sero-markers by chemiluminescent enzyme immunoassay (CLEIA), and molecular analyses were performed on HBsAg-positive samples. Structured questionnaires and medical records were used to examine the risk factors for HBV infection. MTCT rate was calculated by HBsAg positivity of 6-month-old babies born to HBsAg-positive mothers and ascertained by the homology of HBV genomes in mother-child pair at 6-month-old. RESULTS: A total of 1,565 pregnant women were screened, and HBsAg prevalence was 4.28% (67/1565). HBeAg positivity was 41.8% and was significantly associated with high viral load (p < 0.0001). Excluding subjects who dropped out due to restrictions during COVID-19, one out of 35 babies born to HBsAg-positive mothers tested positive for HBsAg at 6 months of age, despite receiving timely HepB birth dose and HBIG, followed by 3 doses of HepB vaccine. Hence the MTCT rate was 2.86%. The mother of the infected baby was positive for HBeAg and had a high HBV viral load (1.2 × 109 copies/mL). HBV genome analysis showed 100% homology between the mother and the child. CONCLUSIONS: Our findings illustrate the intermediate endemicity of HBV infection among pregnant women in Siem Reap, Cambodia. Despite full HepB vaccination, a residual risk of HBV MTCT was observed. This finding supports the recently updated guidelines for the prevention of HBV MTCT in 2021, which integrated screening and antiviral prophylaxis for pregnant women at risk of HBV MTCT. Furthermore, we strongly recommend the urgent implementation of these guidelines nationwide to effectively combat HBV in Cambodia.

Routine placental histopathology findings from women testing positive for SARS-CoV-2 during pregnancy: Retrospective cohort comparative study.

OBJECTIVE: To assess the impact of maternal Coronavirus disease 2019 (COVID-19) infection on placental histopathological findings in an unselected population and evaluate the potential effect on the fetus, including the possibility of vertical transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). DESIGN: Retrospective cohort comparative study of placental histopathological findings in patients with COVID-19, compared with controls. SETTING: During the COVID-19 pandemic, placentas were studied from women at University College Hospital London who reported and/or tested positive for COVID-19. POPULATION: Of 10 508 deliveries, 369 (3.5%) women had COVID-19 during pregnancy, with placental histopathology available for 244 women. METHODS: Retrospective review of maternal and neonatal characteristics, where placental analysis had been performed. This was compared with available, previously published, histopathological findings from placentas of unselected women. MAIN OUTCOME MEASURES: Frequency of placental histopathological findings and relevant clinical outcomes. RESULTS: Histological abnormalities were reported in 117 of 244 (47.95%) cases, with the most common diagnosis being ascending maternal genital tract infection. There was no statistically significant difference in the frequency of most abnormalities compared with controls. There were four cases of COVID-19 placentitis (1.52%, 95% CI 0.04%-3.00%) and one possible congenital infection, with placental findings of acute maternal genital tract infection. The rate of fetal vascular malperfusion (FVM), at 4.5%, was higher compared with controls (p = 0.00044). CONCLUSIONS: In most cases, placentas from pregnant women infected with SARS-CoV-2 virus do not show a significantly increased frequency of pathology. Evidence for transplacental transmission of SARS-CoV-2 is lacking from this cohort. There is a need for further study into the association between FVM, infection and diabetes.

Maternal respiratory viral infections during pregnancy and offspring's neurodevelopmental outcomes: A systematic review.

Maternal infections during pregnancy, as cytomegalovirus and zika, have been consistently associated with severe newborn neurodevelopmental conditions, mainly related to vertical transmission and congenital infection. However, little is known about the neurodevelopmental consequences of maternal respiratory viral infections, which are the most prevalent infections during pregnancy. The recent COVID-19 pandemic has increased the interest in understanding the consequences of infections in offspring's development. This systematic review explores whether maternal gestational viral respiratory infections are associated with neurodevelopmental deviations in children below 10 years-old. The search was conducted in Pubmed, PsychInfo and Web of Science databases. 13 articles were revised, including information about maternal infection (Influenza, SARS-CoV-2 and unspecified respiratory infections) and offspring's neurodevelopment (global development, specific functions, temperament and behavioral/emotional aspects). Controversial results were reported regarding maternal respiratory infections during pregnancy and infants' neurodevelopment. Maternal infections seem to be associated with subtle alterations in some offspring's developmental subdomains, as early motor development, and attentional, behavioral/emotional minor problems. Further studies are needed to determine the impact of other psychosocial confounding factors.

Entry, egress and vertical transmission of SARS-CoV-2.

The high infectivity and pathogenicity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have caused the COVID-19 outbreak, one of the most devastating pandemics in more than a century. This pandemic has already left a trail of destruction, including enormous loss of life, a global economic slump, and widespread psychological damage. Despite assiduous world-wide endeavors, an effective cure for COVID-19 is still lacking. Surprisingly, infected neonates and children have relatively mild clinical manifestations and a much lower fatality rate than elderly adults. Recent studies have unambiguously demonstrated the vertical transmission of SARS-CoV-2 from infected pregnant women to fetuses, which creates yet another challenge for disease prevention. In this review, we will summarize the molecular mechanism for entry of SARS-CoV-2 into host cells, the basis for the failure of the lungs and other organs in severe acute cases, and the evidence for congenital transmission.

Consequences of the SARS-CoV-2 pandemic in the perinatal period.

PURPOSE OF REVIEW: To provide an update on the consequences of severe acute respiratory syndrome (SARS)-CoV-2 infection on the health and perinatal outcomes of pregnant women and their infants. RECENT FINDINGS: The severity of SARS-CoV-2 infection is greater in pregnant compared to nonpregnant women as measured by rates of admission to intensive care units, mechanical ventilation, mortality, and morbidities including myocardial infarction, venous thromboembolic and other thrombotic events, preeclampsia, preterm labor, and preterm birth. The risk of transmission from mother-to-infant is relatively low (1.5-5%) as quantitated by neonatal SARS-CoV-2 testing. Infants appear to be at higher risk of testing positive for SARS-CoV-2 if the mother has tested positive within 1 week of delivery or is herself symptomatic at the time of maternity admission. The rate of positivity is not higher in infants who room in with the mother compared to infants who are initially separated and cared for in a SARS-CoV-2-free environment. Infants who test positive in the hospital have no or mild signs of disease, most of which may be attributable to prematurity, and rarely require readmission for clinical signs consistent with COVID-19. SUMMARY: Pregnant women should take precautions to avoid infection with SARS-CoV-2. Infants born to mothers who test positive for SARS-CoV-2 can receive normal neonatal care in-hospital with their mothers if mother and staff adhere to recommended infection control practices.

Perinatal COVID-19: guideline development, implementation, and challenges.

PURPOSE OF REVIEW: The aim of this review was to describe the process of and challenges in developing national guidance for management of infants born to mothers with COVID-19. RECENT FINDINGS: Beginning in January 2020, infection with the novel coronavirus SARS-CoV-2 spread across the USA, causing the illness COVID-19. As pregnant women began to present for delivery while sick with COVID-19, the American Academy of Pediatrics (AAP) convened a writing group in March 2020 to develop guidance for the management of their newborns. The initial guidance was developed emergently and was forced to rely on extremely limited data from China. The initial guidance advocated for a conservative approach that included temporary physical separation of infected mother and newborn. To address the knowledge deficit, the AAP sponsored a volunteer registry to collect data on perinatal infection and management. As data have emerged informing the natural history of COVID-19, the performance of PCR-based diagnostics, the value of infection control measures and the risk of infant disease, AAP has issued serial updates to newborn guidance. SUMMARY: Evolving knowledge on the epidemiology of perinatal COVID-19 has informed newborn guidance. The most recent guidance focuses on the use of infection control measures to support maternal-newborn contact and breastfeeding.

Maternal and perinatal outcomes with COVID-19: A systematic review of 108 pregnancies.

INTRODUCTION: The pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has exposed vulnerable populations to an unprecedented global health crisis. The knowledge gained from previous human coronavirus outbreaks suggests that pregnant women and their fetuses are particularly susceptible to poor outcomes. The objective of this study was to summarize the clinical manifestations and maternal and perinatal outcomes of COVID-19 during pregnancy. MATERIAL AND METHODS: We searched databases for all case reports and series from 12 February to 4 April 2020. Multiple terms and combinations were used including COVID-19, pregnancy, maternal mortality, maternal morbidity, complications, clinical manifestations, neonatal morbidity, intrauterine fetal death, neonatal mortality and SARS-CoV-2. Eligibility criteria included peer-reviewed publications written in English or Chinese and quantitative real-time polymerase chain reaction (PCR) or dual fluorescence PCR-confirmed SARS-CoV-2 infection. Unpublished reports, unspecified date and location of the study or suspicion of duplicate reporting, cases with suspected COVID-19 that were not confirmed by a laboratory test, and unreported maternal or perinatal outcomes were excluded. Data on clinical manifestations, maternal and perinatal outcomes including vertical transmission were extracted and analyzed. RESULTS: Eighteen articles reporting data from 108 pregnancies between 8 December 2019 and 1 April 2020 were included in the current study. Most reports described women presenting in the third trimester with fever (68%) and coughing (34%). Lymphocytopenia (59%) with elevated C-reactive protein (70%) was observed and 91% of the women were delivered by cesarean section. Three maternal intensive care unit admissions were noted but no maternal deaths. One neonatal death and one intrauterine death were also reported. CONCLUSIONS: Although the majority of mothers were discharged without any major complications, severe maternal morbidity as a result of COVID-19 and perinatal deaths were reported. Vertical transmission of the COVID-19 could not be ruled out. Careful monitoring of pregnancies with COVID-19 and measures to prevent neonatal infection are warranted.

The COVID-19 Pandemic and Pregnancy: Impact on Mothers and Newborns.

The severe acute respiratory syndrome coronavirus 2 pandemic has markedly, and likely permanently, changed health care. This includes changing the obstetric and perinatal care of mothers and infants, and by extension, the care of their families. Infection during pregnancy is associated with an increased risk for severe coronavirus disease 2019 illness and related complications that can significantly impact maternal health and the health of the neonate. Viral transmission from mother to fetus is possible, but rare during pregnancy, and current health care policies focusing on maternal masking, and hand washing allows infected mothers to safely care for neonates (including nursing or feeding with expressed breast milk). The newly developed vaccines have been shown to be safe and effective for pregnant and breast-feeding mothers, with measurable antibody levels in cord blood and breast milk potentially providing a level of passive immunity to neonates. While studies looking at short-term outcomes for neonates have been reassuring, it is critical that we continue to work to understand and improve the care of pregnant woman and newborns with coronavirus disease 2019 to optimize long term outcomes. Although the knowledge base continues to evolve, the available evidence influencing the care of pregnant women and their infants is summarized in this focused review.

Outcomes in neonates born to mothers with COVID-19 during the second wave in India.

COVID-19 pandemic has affected all age groups globally including pregnant women and their neonates. The aim of the study was to understand outcomes in neonates of mothers with COVID-19 during the first and second waves of COVID-19 pandemic. A retrospective analysis of 2524 neonates born to SARS-CoV-2-infected mothers was conducted during the first wave (n = 1782) and second wave (n = 742) of the COVID-19 pandemic at five study sites of the PregCovid registry in Maharashtra, India. A significant difference was noted in preterm birth, which was higher in the second wave (15.0%, 111/742) compared to the first wave (7.8%, 139/1782) (P < 0.001). The proportion of neonates requiring NICU admission was significantly higher in the second wave (19.0%, 141/742) as compared to that in the first wave (14.8%, 264/1782) (P < 0.05). On comparing regional differences, significantly higher neonatal complications were reported from Mumbai metropolitan region (P < 0.05). During the second wave of COVID-19, birth asphyxia and prematurity were 3.8- and 2.1-fold higher respectively (P < 0.001). Neonatal resuscitation at birth was significantly higher in second wave (3.4%, 25/742 vs 1.8%, 32/1782) (P < 0.05). The prevalence of SARS-CoV-2 infection in neonates was comparable (4.2% vs 4.6%) with no significant difference between the two waves. CONCLUSION: Higher incidence of adverse outcomes in neonates born to SARS-CoV-2-infected mothers in the second wave of COVID-19 as compared to the first wave. TRIAL REGISTRATION: PregCovid study is registered with the Clinical Trial Registry of India (CTRI/2020/05/025423, Registered on 28/05/2020). WHAT IS KNOWN: • The second wave of COVID-19 was more lethal to pregnant women than the first wave. Newborns are at risk of developing complications. WHAT IS NEW: • Birth asphyxia, prematurity, and neonatal resuscitation at birth were significantly higher in the second wave as compared to those in the first wave of the COVID-19 pandemic in India.

SARS-CoV-2 Transplacental Transmission: A Rare Occurrence? An Overview of the Protective Role of the Placenta.

The outbreak of the coronavirus disease 2019 (COVID-19) pandemic, caused by novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in a global public health crisis, causing substantial concern especially to the pregnant population. Pregnant women infected with SARS-CoV-2 are at greater risk of devastating pregnancy complications such as premature delivery and stillbirth. Irrespective of the emerging reported cases of neonatal COVID-19, reassuringly, confirmatory evidence of vertical transmission is still lacking. The protective role of the placenta in limiting in utero spread of virus to the developing fetus is intriguing. The short- and long-term impact of maternal COVID-19 infection in the newborn remains an unresolved question. In this review, we explore the recent evidence of SARS-CoV-2 vertical transmission, cell-entry pathways, placental responses towards SARS-CoV-2 infection, and its potential effects on the offspring. We further discuss how the placenta serves as a defensive front against SARS-CoV-2 by exerting various cellular and molecular defense pathways. A better understanding of the placental barrier, immune defense, and modulation strategies involved in restricting transplacental transmission may provide valuable insights for future development of antiviral and immunomodulatory therapies to improve pregnancy outcomes.