key: cord-1040768-3wx2l2ua
authors: Prochaska, Erica; Jang, Minyoung; Burd, Irina
title: COVID‐19 in pregnancy: Placental and neonatal involvement
date: 2020-07-17
journal: Am J Reprod Immunol
DOI: 10.1111/aji.13306
sha: e521aaf42eeffa97fd1881e717c61996b1d6d702
doc_id: 1040768
cord_uid: 3wx2l2ua

Since December 2019, severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has caused over 12 million infections and more than 550,000 deaths.(1) Morbidity and mortality appear partly due to host inflammatory response.(2) Despite rapid, global research, the effect of SARS‐CoV‐2 on the developing fetus remains unclear. Case reports indicate that vertical transmission is uncommon; however there is evidence that placental and fetal infection can occur.(3‐7) Placentas from infected patients show inflammatory, thrombotic and vascular changes that have been found in other inflammatory conditions.(8,9) This suggests that the inflammatory nature of SARS‐CoV‐2 infection during pregnancy could cause adverse obstetric and neonatal events. Exposure to intrauterine inflammation and placental changes could also potentially result in long‐term, multisystemic defects in exposed infants. This review will summarize the known literature on the placenta in SARS‐CoV‐2 infection, evidence of vertical transmission, and possible outcomes of prenatal exposure to the virus.

proinflammatory changes as SARS-CoV and MERS-CoV infections. Increased T-helper-2 (Th2) cellassociated cytokines are found in SARS-CoV-2 infections as well. 2, 11 There is widespread interest and research in developing a SARS-CoV-2 vaccine; however prior studies indicate that long-term immunity may not be achievable. In human trials, immunoglobulins IgG and IgA increased about 2 weeks after infection with human coronaviruses; however, these antibodies quickly declined. 18 Individuals who have been previously infected with human coronaviruses have little to no protection against reinfection in the subsequent season.

Maternal-fetal immunity is a rapidly expanding field of research. Our knowledge of the placenta as an immune organ has progressed significantly over recent years. The placenta is composed of fetal trophoblasts and decidua derived from maternal endometrium. 22, 23 Trophoblasts form floating and anchoring villi that interact with the decidua and the intervillous space, respectively.

Multinucleated syncytiotrophoblasts (SYN) compose the outermost layer of the villi, which comes into direct contact with maternal blood. Mononuclear cytotrophoblasts comprise the inner layer of villi. The placenta has several mechanisms to prevent transmission of viral infections to the fetus. 24 As part of the innate immune system, the SYN is a physical barrier to infections. 25 Recent research has shown that trophoblasts induce autophagy during viral infection and can also induce resistance to viruses in neighboring cells. 26, 27 The SYN contain neonatal FcRN receptors that transport maternal IgG to the fetus, thereby conferring humoral immunity. 28 Viral infections during pregnancy have a broad spectrum of placental and neonatal pathology.

Numerous viruses cause villitis and spontaneous abortion. [29] [30] [31] Congenital viral infections in the neonate can result in lifelong disabilities, sepsis, multisystem organ damage, and death. 32 Vertical transmission of viruses during pregnancy is incompletely defined. 24, 31 Potential mechanisms of fetal infection include contact between maternal endothelium and cytotrophoblasts, infected maternal macrophages, ascending urogenital infections, and spread from maternal bloodstream to fetal capillaries. Finally, maternal infections can be transmitted to the neonate during labor. 33 Review of SARS-CoV and MERS-CoV:

In November 2002, the first death from SARS-CoV occurred. SARS-CoV is believed to have originated in bats, which was transmitted to palm civets and then humans. 34 

This article is protected by copyright. All rights reserved a flu-like illness and severe pneumonia. Complications during pregnancy include maternal death, hypoxia, disseminated intravascular coagulopathy, intrauterine fetal demise, intrauterine growth restriction, preterm delivery, and spontaneous abortion. 35 Ng et al. describe placental pathology from 7 cases of SARS infection during pregnancy. 36 Placentas delivered from women who had recovered from SARS during the first trimester had normal pathology. Placentas delivered from women who had active SARS infection showed increased intervillous and subchorionic fibrin, which the authors attributed to maternal hypoxia. Placentas delivered from two women who had recovered from SARS during the third trimester had extensive fetal thrombic vasculopathy and areas of avascular fibrotic villi. The associated neonates both had intrauterine growth restriction. The authors postulate that placental hypoxia or increased thrombotic activity could have caused these pathologic findings. There have been no cases of vertical transmission during SARS infection. 35 

This article is protected by copyright. All rights reserved (PCR) results for SARS-CoV-2 in the neonate, placenta, cord blood, and vaginal secretions. 8, [40] [41] [42] [43] [44] The majority of neonates in these cases had uneventful hospitalizations. However, there are cases of neonates who have tested positive for SARS-CoV-2 after delivery, 5,6 as well as a few neonates who have had positive IgM antibodies to SARS-CoV-2. 4,45 IgM does not cross the placenta. SARS-CoV-2

IgM can appear as early as a few days after infection but peaks around 2 weeks. 46, 47 Therefore, the presence of IgM in a neonate after delivery could indicate congenital infection.

There are also reports of placental SARS-CoV-2 infection. In a case report from Switzerland, a 26-year-old woman with SARS-CoV-2 infection had preterm labor and fetal demise at 19 weeks of gestation. 7 Fetal tissue was negative for SARS-CoV-2, however, PCR of the fetal surface of the placenta was positive. Pathology of the placenta was notable for areas of inflammation, increased fibrin deposition, and funisitis. PCR of maternal blood, vaginal secretions, and urine were negative for SARS-CoV-2. Similarly, a case report from Italy describes two SARS-CoV-2 positive neonates born to SARS-CoV-2 positive mothers. 5 PCR of the placentas were positive for SARS-CoV-2, and in situ hybridization visualized SARS-CoV-2 spike proteins in the SYN layer of both specimens. Pathology was notable for chronic intervillitis. In this case series, one neonate was delivered at 35 1/7 weeks for nonreassuring fetal heart tones and required routine preterm care. Kirtsman et al. report a case of SARS-CoV-2 infection in a Canadian woman. She required urgent cesarean section for coagulopathy at 35 5/7 weeks of gestation. 6 PCR of maternal and fetal placenta, vaginal swab, breastmilk, neonatal blood, and neonatal nasopharynx were positive for SARS-CoV-2. All placental sections sampled had diffuse inflammation and early infarction. The neonate required a brief NICU admission for hypoglycemia and hypothermia. A preprinted case report from The Netherlands describes an asymptomatic pregnant woman presenting with fetal distress. 48 SARS-CoV-2 PCR was positive on the maternal and fetal side of the placenta. In situ hybridization visualized SARS-CoV-2 particles in the SYN layer. The SYN also showed signs of damage and had inflammatory infiltrates. The neonate presented with multiorgan failure but had a negative SARS-CoV-2 PCR. In another preprinted case, a woman in the second trimester tested positive for SARS-CoV-2 in the setting of preeclampsia and placental abruption. The neonate was negative for SARS-CoV-2, however SARS-CoV-2 virus was found in the SYN layer of the placenta. 49 These cases demonstrate that SARS-CoV-2 could infect the placenta. Only some reports describe neonatal SARS-CoV-2 infection in the setting of placental Accepted Article infection. These discrepancies could be due to rapid degradation of RNA after delivery. Alternatively, placental immune function could protect some neonates from SARS-CoV-2. Further observations and research are required to determine the potential mechanisms and prevention of SARS-CoV-2 vertical transmission.

As with SARS-CoV and MERS-CoV, SARS-CoV-2 infection causes inflammatory and vascular changes in the placenta (Table 1) . A recently published study of fifteen placentas from SARS-CoV-2 positive or convalescing mothers shows statistically significant increase in maternal vascular malperfusion (MVM) as compared to controls. 8 Pathological findings consistent with MVM include decidual arteriopathy, fibrinoid necrosis, and amniotic membrane arteriole hypertrophy.

Placentas from SARS-CoV-2 positive women also had significantly increased intervillous thrombi. In a case series of 20 placentas from SARS-CoV-2 patients, fetal vascular malperfusion was the most common pathology found (9 cases). 9 Intramural, nonocclusive thrombi were also noted in several placentas. Villitis was found in four cases. One placenta had chorioamnionitis and funisitis, which was delivered from a woman with pneumonia and hypoxia. While neither study tested placentas for SARS-CoV-2 infection, all associated neonates were negative for SARS-CoV-2 on PCR. These reports demonstrate that SARS-CoV-2 infection can cause inflammatory and vascular changes of the placenta. Noninfectious inflammation causes similar placental endothelial damage and thrombi in mice. 50 Alternatively, SARS-CoV-2 infection could cause hypercoagulability in the placenta as has been shown in other organs. 13 Regardless of mechanism, these placental changes could have deleterious effects on both mother and fetus. In the mouse model, endothelial and thrombotic alterations in the placenta are associated with altered vascular flow to the fetus and subsequent neural inflammation. 50 Therefore, children born to SARS-CoV-2 infected women could have similar neurologic inflammation prior to birth.

It is difficult to interpret these cases due to our limited understanding of SARS-CoV-2 pathogenesis in the placenta and neonate. Serologic testing for SARS-CoV-2 is variable at this time. 51 Furthermore, the appropriate means of screening neonates has not yet been established. IgM cutoffs are based on adult data; however, neonates produce less immunoglobulins than adults. 33 Diagnosing

This article is protected by copyright. All rights reserved congenital infections varies considerably between viruses. For example, IgG and IgM are not recommended for congenital cytomegalovirus (CMV) diagnosis. 52 other harmful effects on the neonate. For example, there is longstanding evidence that HIV exposed unaffected (HEU) infants have higher morbidity and mortality compared to peers. 53, 54 There is a growing body of research that demonstrates that HEU infants have elevated inflammatory markers, decreased CD4 counts, and decreased humoral immunity. These changes have been attributed to maternal inflammation, viremia, and immunosuppression. SARS-CoV-2 is a highly proinflammatory infection that may cause similar changes in neonatal inflammation and immunity.

Although the majority of reports on SARS-CoV-2 in pregnant women, to date, note the presence of relatively mild symptoms among this population, symptomology may not reflect the severity of inflammation provoked by infection. Maternal inflammation has been implicated in a number of neonatal outcomes in addition to neonatal immunity. As mentioned above, coronaviruses have been shown to trigger pattern recognition receptors that lead to activation of transcriptional programs, which in turn induce a proinflammatory cytokine storm, largely driven by production of IL-6. 55 Both an inflammatory and prognostic marker, IL-6 can predict disease progression in adults, as Accepted Article noted in a U.S. cohort of pregnant patients with severe to critical SARS-CoV-2 infection. 56, 57 In response to infection during pregnancy, maternal immune activation (MIA) and inflammation have been linked to a spectrum of adverse short-and long-term outcomes in infants. 58, 59 Pregnancy itself represents a unique interplay of modulated immune states that vary by stage of gestation. 60 Host response to viral infection in pregnancy induces the production of proinflammatory cytokines, like IL-1β, IL-6, and TNFα, that activate the maternal immune system and can cross the placental barrier. [61] [62] [63] Thus, even in the absence of fetal viral infection or severe maternal symptoms, placental infection can trigger a fetal inflammatory response, leading to multiorgan system damage and predisposition for negative developmental consequences ( Table 2) . [64] [65] [66] [67] [68] [69] [70] There is strong evidence to suggest that maternal inflammation associated with SARS-CoV-2 may confer long-term risk of neuropsychiatric disorders in children. MIA has been described as a "neurodevelopmental disease primer" that increases susceptibility of individuals to interacting genetic and environmental risk factors that can trigger neuro-or psychopathology later in life. 71 In particular, relationships between MIA and both autism spectrum disorder (ASD) and schizophrenia have been well established through epidemiological and animal model studies; [72] [73] [74] [75] whereas the effect of maternal infection and central nervous system (CNS) disorders like epilepsy and cerebral palsy have yet to fully defined. 76, 77 Research has also begun to suggest links between MIA and mood disorders, such as depression and bipolar affective disorder in children. 78, 79 Proposed mechanisms include the stimulation of maternal cytokines and other inflammatory mediators that can cross the placenta and interfere with neurotrophin signaling, activate astrocytes and microglia, and potentiate cellular damage in the developing CNS of the fetus. 59 Such disruptions in neuronal cell differentiation can ultimately lead to abnormal fetal brain development. 80 Certain inflammatory markers, like C-reactive protein (CRP), an acute phase reactant, have been significantly associated with risk of selected neuropsychiatric disorders in children. 81, 82 In a recent study from China, Wu et al. reported higher mean serum levels of CRP in pregnant patients with SARS-CoV-2 infection compared to uninfected pregnant patients. 83 Beyond the question of vertical transmission, the long-term risk of neuropsychiatric disorders in children exposed to SARS-CoV-2 in utero warrants longitudinal investigation.

This article is protected by copyright. All rights reserved With regard to pregnancy complications of SARS-CoV-2 infection, several cases of fetal loss and preterm delivery due to fetal distress have been reported in SARS-CoV-2 positive pregnant women; 5-7 some larger studies and systematic reviews have also suggested that the rate of preterm birth in SARS-CoV-2 patients is higher than that of the general pregnant population. [84] [85] [86] As testing capacity increases and the burden of SARS-CoV-2 infection rises among the child-bearing aged population, it is likely that even more preterm births will be reported among pregnant women with SARS-CoV-2 infection, compared to earlier reporting during the pandemic. 87 Existing literature provides substantial evidence to support an association between maternal viral infections and adverse pregnancy outcomes, including preterm labor and low birth weight. 58, 88 It is estimated that intrauterine infection may account for up to 40% of premature deliveries. 89 Intra-amniotic infection induces an inflammatory cascade that leads to the initiation of spontaneous labor. [90] [91] [92] It is important to note that the described mechanism may occur with inflammation in the absence of infectious etiology. 88 Extrauterine infections, such as malaria, have also been associated with spontaneous preterm delivery, but specific mechanisms remain to be determined. 93 Preterm labor and low birth weight are leading global causes of neonatal and under-five mortality, as well as risk factors for poor developmental outcomes in children and adults later in life. 94 Preterm infants born to mothers with SARS-CoV-2 should be monitored closely for both short-and long-term complications.

Necrotizing enterocolitis (NEC) is one of the many risks of preterm birth. This inflammatory disease of the gastrointestinal tract is a significant cause of neonatal morbidity and mortality. 95, 96, 97 Both neonatal and maternal inflammation appear to contribute to NEC pathogenesis. In NEC, immature immune function and a highly immunoreactive preterm intestinal environment are hypothesized to produce a hyper-inflammatory response to microbial stimuli, characterized by exaggerated TLR-4 signaling and decreased expression of IκB. IκB is an important regulator of nuclear κB (NF-κB), a transcription factor that upregulates production of cytokines and immunological mediators. [98] [99] [100] In animal models, fetal exposure to maternal inflammation induced by chorioamnionitis has been shown to generate higher levels of inflammatory markers, like IL-6, and 

This article is protected by copyright. All rights reserved IL-6 (10.82 pg/mL) that was higher than the reference range (0.1-2.9 pg/mL). 103 One infant with extremely elevated IL-6 levels (as high as 109.42 pg/mL) developed NEC on day 22 after birth. High levels of inflammatory markers in SARS-CoV-2 exposed neonates likely reflect a process of maternal-fetal immune activation and should be interpreted as risk factors for diseases such as NEC.

MIA and preterm birth pose an added short-term risk of bronchopulmonary dysplasia (BPD).

Although existing literature supports an association between chorioamnionitis and decreased incidence of respiratory distress syndrome in preterm infants, prenatal inflammation has been further linked to fetal pulmonary injury that can progress to BPD. [104] [105] [106] In one prospective cohort of preterm infants, histological chorioamnionitis was associated with decreased efficacy of exogenous surfactant therapy. 107,108 This reduced efficacy is attributed to inactivation and increased clearance of surfactant, which could be due to leakage of serum proteins into the alveolar space and inflammatory cytokine release. 109 A few cases of SARS-CoV-2 exposed neonates show evidence of respiratory distress. 40, 42 These presentations could be due to retained amniotic fluid or late prematurity. Alternatively, they could represent early lung damage in the setting of maternal inflammation. Longitudinal observations of long-term pulmonary sequelae in SARS-CoV-2 exposed infants are necessary.

In the present review, we have discussed the pregnancy outcomes of SARS-CoV and MERS-CoV infections and summarized available literature on placental inflammatory and thrombotic changes in SARS-CoV-2. At this time, it is uncertain whether SARS-CoV-2 can be vertically transmitted. Case reports indicate that placental and neonatal infection could occur and that maternal infection is associated with placental changes. Abundant scientific evidence demonstrates that maternal inflammation can cause a spectrum of lifelong sequelae in the offspring. Therefore, it is reasonable to speculate that the proinflammatory state of SARS-CoV-2 infection during pregnancy may precipitate negative consequences in children. In addition to potential risk of vertical transmission, SARS-CoV-2 may indirectly lead to adverse perinatal and longer-term neurodevelopmental outcomes through MIA. Further investigation of inflammatory dysregulation in pregnant women with SARS-CoV-2 and longitudinal studies of developmental outcomes in SARS-CoV-2 exposed children are needed to ensure appropriate care of these growing populations.

Johns Hopkins Coronavirus Resource Center Web site

The pathogenesis and treatment of the `Cytokine storm' in COVID-19

Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: A retrospective review of medical records

Possible vertical transmission of SARS-CoV-2 from an infected mother to her newborn

Vertical transmission of COVID-19: SARS-CoV-2 RNA on the fetal side of the placenta in pregnancies with COVID-19 positive mothers and neonates at birth

Probable congenital SARS-CoV-2 infection in a neonate born to a woman with active SARS-CoV-2 infection

Second-trimester miscarriage in a pregnant woman with SARS-CoV-2 infection

Placental pathology in COVID-19

Placental pathology in covid-19 positive mothers: Preliminary findings: Pediatric and Developmental Pathology

A novel coronavirus from patients with pneumonia in china

Clinical features of patients infected with 2019 novel coronavirus in wuhan, china

Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in covid-19

Autopsy findings and venous thromboembolism in patients with COVID-19

Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in china: Summary of a report of 72 314 cases from the chinese center for disease control and prevention

Symptoms and critical illness among obstetric patients with coronavirus disease 2019 (COVID-19) infection

COVID-19 infection among asymptomatic and symptomatic pregnant women: Two weeks of confirmed presentations to an affiliated pair of new york city hospitals

COVID-19 in children, pregnancy and neonates: A review of epidemiologic and clinical features

Nelson textbook of pediatrics

Angiotensin-converting enzyme 2: SARS-CoV-2 receptor and regulator of the renin-angiotensin system: Celebrating the 20th anniversary of the discovery of ACE2

Structural basis of receptor recognition by SARS-CoV-2

The SARS-CoV-2 receptor ACE2 expression of maternalfetal interface and fetal organs by single-cell transcriptome study

Immune responses at the maternal-fetal interface

Placenta: The forgotten organ

The placenta as a barrier to viral infections

Autophagy as a mechanism of antiviral defense at the maternal-fetal interface

Human trophoblasts confer resistance to viruses implicated in perinatal infection

IgG placental transfer in healthy and pathological pregnancies

Chronic inflammation of the placenta: Definition, classification, pathogenesis, and clinical significance

Detection of cytomegalovirus, herpes virus simplex, and parvovirus b19 in spontaneous abortion placentas

Cellular and molecular mechanisms of viral infection in the human placenta. Pathogens and disease

Congenital infections

Vertical transmission of SARS-CoV-2: What is the optimal definition?

Origin and evolution of pathogenic coronaviruses

Accepted Article This article is protected by copyright. All rights reserved

Potential maternal and infant outcomes from coronavirus 2019-nCoV (SARS-CoV-2) infecting pregnant women: Lessons from SARS, MERS, and other human coronavirus infections

The placentas of patients with severe acute respiratory syndrome: A pathophysiological evaluation

SARS and MERS: Recent insights into emerging coronaviruses

Sars-CoV-2 in the context of past coronaviruses epidemics: Consideration for prenatal care

MERS-CoV infection in a pregnant woman in Korea

Infants born to mothers with a new coronavirus (COVID-19)

Maternal and neonatal outcomes of pregnant women with COVID-19 pneumonia: A case-control study

Unlikely SARS-CoV-2 vertical transmission from mother to child: A case report

Placental pathology in covid-19 positive mothers: Preliminary findings: Accepted Article This article is protected by copyright. All rights reserved Pediatric and Developmental Pathology

Clinical course of coronavirus disease-2019 in pregnancy

Antibodies in infants born to mothers with COVID-19 pneumonia

Kinetics of SARS-CoV-2 specific IgM and IgG responses in COVID-19 patients

Antibody responses to SARS-CoV-2 in patients with COVID-19

SARS-CoV-2 placental infection and inflammation leading to fetal distress and neonatal multi-organ failure in an asymptomatic woman

SARS-CoV-2 infection of the placenta

Placental malperfusion in response to intrauterine inflammation and its connection to fetal sequelae

Developing a national strategy for serology (antibody testing) in the united states

for-Accepted Article This article is protected by copyright. All rights reserved serology-antibody-testing-in-the-US

Remington and Klein's infectious diseases of the fetus and newborn infant

HIV-exposed uninfected children: A growing population with a vulnerable immune system?

HIV-exposed, uninfected infants: New global challenges in the era of paediatric HIV elimination. The Lancet Infectious Diseases

Effect of TLR agonist on infections bronchitis virus replication and cytokine expression in embryonated chicken eggs

Clinical course of severe and critical COVID-19 in hospitalized pregnancies: A US cohort study

Immunological environment shifts during pregnancy may affect the risk of developing severe complications in COVID-19 patients

Intrauterine infection and preterm delivery

The fetal origins of mental illness

Accessed Accepted Article This article is protected by copyright. All rights reserved

The role of cytokines in mediating effects of prenatal infection on the fetus: Implications for schizophrenia

Prenatal infection and risk for schizophrenia: IL-1beta, IL-6, and TNFalpha inhibit cortical neuron dendrite development

IL-1 signaling mediates intrauterine inflammation and chorio-decidua neutrophil recruitment and activation

Viral infection of the placenta leads to fetal inflammation and sensitization to bacterial products predisposing to preterm labor

Chorioamnionitis: A multiorgan disease of the fetus?

Chorioamnionitis as a risk factor for retinopathy of prematurity: A systematic review and meta-analysis

Maternal inflammation exacerbates neonatal hyperoxia-induced kidney injury in rat offspring

Prenatal and postnatal inflammation in relation to cortisol levels in preterm infants at 18 months corrected age

LPS-induced maternal inflammation promotes fetal leukocyte recruitment and prenatal organ infiltration in mice

Histological chorioamnionitis shapes the neonatal transcriptomic immune response

Maternal immune activation: Implications for neuropsychiatric disorders

Activation of the maternal immune system alters cerebellar development in the offspring

Specific neurodevelopmental damage in mice offspring following maternal inflammation during pregnancy

Inflammation in pregnancy: Its roles in reproductive physiology, obstetrical complications, and fetal injury

Immune involvement in schizophrenia and autism: Etiology, pathology and animal models

Maternal immune activation and abnormal brain development across CNS disorders

Chorioamnionitis and cerebral palsy in term and near-term infants

Association between prenatal exposure to maternal infection and offspring mood disorders: A review of the literature

Animal models of maternal immune activation in depression research

Accepted Article This article is protected by copyright. All rights reserved

Immunological stress at the maternal-foetal interface: A link between neurodevelopment and adult psychopathology

Elevated maternal C-reactive protein and autism in a national birth cohort

Maternal C-reactive protein and cytokine levels during pregnancy and the risk of selected neuropsychiatric disorders in offspring: A systematic review and meta-analysis

Clinical manifestation and laboratory characteristics of SARS-CoV-2 infection in pregnant women

A snapshot of the covid-19 pandemic among pregnant women in france

Rates of maternal and perinatal mortality and vertical transmission in pregnancies complicated by severe acute respiratory syndrome coronavirus 2 (SARS-co-V-2) infection: A systematic review

Maternal and neonatal outcomes associated with COVID-19 infection: A systematic review

Dallas County Health and Human Services. 2019 novel coronavirus (COVID-19) summary

Intrauterine infection and preterm labor

Accepted Article This article is protected by copyright. All rights reserved 89

Preterm labor: One syndrome, many causes

A new model for inflammationinduced preterm birth: The role of platelet-activating factor and toll-like receptor-4

Activation of TLR3 in the trophoblast is associated with preterm delivery

Circulating cytokines associated with poor pregnancy outcomes in beninese exposed to infection with plasmodium falciparum

Perinatal outcomes from preterm and early term births in a multicenter cohort of low risk nulliparous women

Necrotizing enterocolitis

Experimental necrotizing enterocolitis induces neuroinflammation in the neonatal brain

Neurodevelopmental outcomes of neonates with medically and surgically treated necrotizing enterocolitis

Accepted Article This article is protected by copyright. All rights reserved

Toll-like receptor-4 inhibits enterocyte proliferation via impaired beta-catenin signaling in necrotizing enterocolitis

Developmentally regulated I B expression in intestinal epithelium and susceptibility to flagellin-induced inflammation

Necrotizing enterocolitis: New insights into pathogenesis and mechanisms

Fetal exposure to maternal inflammation interrupts murine intestinal development and increases susceptibility to neonatal intestinal injury

Chorioamnionitis as a risk factor for necrotizing enterocolitis: A systematic review and meta-analysis

The immunologic status of newborns born to SARS-CoV2-infected mothers in wuhan, china. The Journal of Allergy and Clinical Immunology

Chorioamnionitis and early lung inflammation in infants in whom bronchopulmonary dysplasia develops

Seminars in fetal & neonatal medicine. Seminars in fetal & neonatal medicine

Intravenous lipopolysaccharide-induced pulmonary maturation and structural changes in fetal sheep. American Accepted Article This article is protected by copyright

Chorioamnionitis alters the response to surfactant in preterm infants

Surfactant replacement therapy: From biological basis to current clinical practice

Histological chorioamnionitis and respiratory outcome in preterm infants

This article is protected by copyright. All rights reserved Tables: Table 1 . Pathologic and infectious findings in placentas. Forty-five total cases are included ( In situ hybridization visualization