SARS‐CoV‐2—Placental effects and association with stillbirth

SARS‐CoV‐2 has had a significant impact on pregnancy outcomes due to the effects of the virus and the altered healthcare environment. Stillbirth has been relatively hidden during the COVID‐19 pandemic, but a clear link between SARS‐CoV‐2 and poor fetal outcome emerged in the Alpha and Delta waves. A small minority of women/birthing people who contracted COVID‐19 developed SARS‐CoV‐2 placentitis. In many reported cases this was linked to intrauterine fetal death, although there are cases of delivery just before imminent fetal demise and we shall discuss how some cases are sub‐clinical. What is surprising, is that SARS‐CoV‐2 placentitis is often not associated with severe maternal COVID‐19 infection and this makes it difficult to predict. The worst outcomes seem to be with diffuse placental disease which occurs within 21 days of COVID‐19 diagnosis. Poor outcomes are often pre‐dated by reduced fetal movements but are not associated with ultrasound changes. In some cases, there has also been maternal thrombocytopenia, or coagulation abnormalities, which may provide a clue as to which pregnancies are at risk of fetal demise if a further variant of concern is to emerge. In future, multidisciplinary collaboration and cross‐boundary working must be prioritised, to identify quickly such a phenomenon and provide clinicians with clear guidance for reducing fetal death and associated poor outcomes. While we wait to see if COVID‐19 brings a future variant of concern, we must focus on appropriate future management of women who have had SARS‐CoV‐2 placentitis. As a placental condition with an infectious aetiology, SARS‐CoV‐placentitis is unlikely to recur in a subsequent pregnancy and thus a measured approach to subsequent pregnancy management is needed.


| SA R S -C oV-2 A N D PR EGNA NC Y
The first reports of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the coronavirus disease it caused (COVID- 19), emerged in 2019. 1 There are over 640 million cases and over 6.6 million deaths from COVID-19. 2 The economic and societal impact of COVID-19 infection and the myriad measures put in place to limit its spread has affected the daily lives of women in general, 3 and impacted maternal and neonatal health in particular.The peak of the pandemic saw fewer women accessing maternity care due to reduction in services or a desire to avoid places perceived to be associated with risk of infection. 4he general story of maternal and fetal health has been that outcomes have worsened, with increases in maternal deaths and stillbirths, and significant disparities between high-and low-resource settings. 5Pregnant compared with non-pregnant women are more likely to be admitted to intensive care.Risk factors for severe disease include non-white ethnicity, high body mass index (BMI), older age and pre-existing medical co-morbidities. 6Other important factors are the prevalent SARS-CoV-2 variant and the introduction of vaccines.Abstract SARS-CoV-2 has had a significant impact on pregnancy outcomes due to the effects of the virus and the altered healthcare environment.Stillbirth has been relatively hidden during the COVID-19 pandemic, but a clear link between SARS-CoV-2 and poor fetal outcome emerged in the Alpha and Delta waves.A small minority of women/birthing people who contracted COVID-19 developed SARS-CoV-2 placentitis.In many reported cases this was linked to intrauterine fetal death, although there are cases of delivery just before imminent fetal demise and we shall discuss how some cases are sub-clinical.What is surprising, is that SARS-CoV-2 placentitis is often not associated with severe maternal COVID-19 infection and this makes it difficult to predict.The worst outcomes seem to be with diffuse placental disease which occurs within 21 days of COVID-19 diagnosis.Poor outcomes are often predated by reduced fetal movements but are not associated with ultrasound changes.In some cases, there has also been maternal thrombocytopenia, or coagulation abnormalities, which may provide a clue as to which pregnancies are at risk of fetal demise if a further variant of concern is to emerge.In future, multidisciplinary collaboration and cross-boundary working must be prioritised, to identify quickly such a phenomenon and provide clinicians with clear guidance for reducing fetal death and associated poor outcomes.While we wait to see if COVID-19 brings a future variant of concern, we must focus on appropriate future management of women who have had SARS-CoV-2 placentitis.As a placental condition with an infectious aetiology, SARS-CoV-placentitis is unlikely to recur in a subsequent pregnancy and thus a measured approach to subsequent pregnancy management is needed.

K E Y W O R D S placental histopathology, SARS-CoV-2, stillbirth
The variants of concern, which can increase transmissibility and virulence and can affect disease presentation and decrease effectiveness of public health measures, thus far have been Alpha, Beta, Gamma, Delta and Omicron (Table 1).The currently circulating variant of concern is Omicron. 7The Alpha and Delta variants have been associated with worse maternal and perinatal outcome than the wild-type variant; in a UK-based cohort study the odds of moderate or severe infection were increased during the Alpha variant (adjusted odds ratio [aOR] 1.98, 95% CI 1.66-2.37)and still further during the Delta variant (aOR 2.66, 95% CI 2.21-3.20). 8The risk of severe respiratory disease with Omicron is similar to that with the previous wild-type variant of 2020 and is largely restricted to the unvaccinated population. 9Among the pregnant population, those admitted to hospital since the vaccine became available are predominantly the unvaccinated (93%). 10accines were introduced for pregnant women more quickly in some parts of the world than others; pregnant women were not included in initial trials or recommendations. 11,12In the UK, m-RNA vaccines were recommended for pregnant women from April 2021, 10 whereas in the USA they were granted an emergency licence in December 2020 but were only recommended in June 2021. 13This led to vaccine hesitancy among the pregnant population globally. 11,12,14However, poor perinatal outcomes are reduced with vaccination, including a 15% reduction in stillbirth. 12

| STI L L BIRTH DU R I NG COV ID -19 00 -022
There were 2 million stillbirths in 2019, a global stillbirth rate of 13.9 per 1000 live births, with the lowest income countries experiencing 22.7 stillbirths per 1000 live births compared with 3.0 in the richest nations. 15Measuring stillbirth is challenging, even outside of a pandemic, in part due to variation in definition and lack of robust data collection in many settings. 15We know stillbirths increased during the COVID-19 pandemic (OR 1.28, 95% CI 1.07-1.54); 5however, gaining this clarity was challenging, as stillbirth is a relatively uncommon event, particularly in high-income countries.
Due to the relatively low prevalence of stillbirth, large datasets are required to identify any relation between SARS-CoV-2 and stillbirth.It is challenging to set up bespoke data collection rapidly, and when relying on existing national data collection systems, there can be significant delays in getting complete data, 10 resulting in years elapsing before publication.Furthermore, it is difficult to unpick the relations between, for example, timing of vaccine and stillbirth, as when looking at things on this scale, it is not possible or practical to visit the medical notes.It is therefore important to have multiple study designs from multiple countries and multiple sources, which can increase the certainty of the evidence.
For stillbirth the emerging story at the start of the pandemic was that in Spain, 16 Denmark 17 and Germany 18 there was no increase in stillbirth rate, and this was supported by

Pregnancy following a previous diagnosis of SARS-CoV-2 placentitis:
• If a woman has a pregnancy where histiocytic intervillositis and/or significantly increased perivillous fibrin(oid) deposition is evident on placental examination, it is vital to establish whether this is linked to SARS-CoV-2 infection.This can be accomplished by demonstrating the presence of the virus in the affected placenta by immunohistochemistry or in situ hybridisation (with specialist placental pathologist review where necessary).• If the link is clear, and the woman has no previous history of these phenomena, it is reasonable to attribute the placental findings and any poor fetal outcome to SARS-CoV-2 placentitis complicating maternal COVID-19 infection and the subsequent pregnancy does not need to be managed as per chronic histiocytic intervillositis/massive perivillous fibrin(oid) deposition.
In a future wave: • If there is a link between a variant of concern and poor fetal outcomes, consideration must be given to rapid diagnosis of the SARS-CoV-2 variant a woman has contracted to stratify her risk.

Future research
• A clear international system needs to be developed to record pregnancy-related COVID-19 cases, to characterise their clinical and pathophysiological course and to identify variants of concern which may cause SARS-CoV-2 placentitis.• Vaccine hesitancy should be addressed, as SARS-CoV-2 placentitis does not seem to occur in vaccinated women.• A multidisciplinary approach is needed to provide women with tailored evidence-based advice for their future pregnancies.systematic reviews. 19At this time many pregnant women were self-isolating, so COVID-19 cases may have been rare.However, at a similar time, a living systematic review was suggesting that although the number of events were few, there was an increase in stillbirth with SARS-CoV-2 infection (OR 2.84, 95% CI 1.25-6.45). 6ubsequently, we have established that there were increased stillbirth rates during the pandemic.A UK cohort study including pregnancies prior to the Delta variant, and prior to vaccines being routinely recommended showed that there was an increase in fetal death in those women with confirmed SARS-CoV-2 (aOR 2.21, 95% CI 1.58-3.31). 20In the USA a Centers for Disease Control and Prevention (CDC) study also showed that risk of stillbirth was increased both before the Delta variant (adjusted relative risk [aRR] 1.47 [95% CI 1.27-1.71)and during Delta predominance (aRR 4.04, 95% CI 3.28-4.97). 21This is supported by a Scottishbased registry study, incorporating Alpha and Delta waves, which reports an extended perinatal mortality rate of 22.6 per 1000 births (95% CI 12.9-38.5)in the population who had COVID-19 within 28 days of birth compared with a pandemic background rate of 5.6 per 1000 births (95% CI 5.1-6.2).In that study none of the women affected by fetal death was vaccinated. 10The uncertainty around the impact of SARS-CoV-2 infection on the fetus may have been compounded by the fact that many case series did not look at placentas, as the focus of the reports/audit was on admitted sick women.
As evidence emerged for the link between SARS-CoV-2 and stillbirth there was a clear need to understand the mechanisms contributing to the increased rates.The rise could be due to direct SARS-CoV-2 reasons (mother becoming unwell or placenta being affected by SARS-CoV-2) or to indirect effects (health system, COVID-19 restrictions, mental health disorders). 4We will now focus on the placental pathology associated with stillbirth with a particular focus on SARS-CoV-2 placentitis, which is the proposed pathology behind stillbirth directly related to SARS-CoV-2.

| Non-placentitis-related histopathological findings
The link between placental pathological findings and stillbirth is well documented. 22However, the story of placental pathology and SARS-CoV-2 is still emerging.First we will focus on non-placentitis-related pathological findings in SARS-CoV-2, before considering the special case of SARS-CoV-2 placentitis.
In late 2021 a systematic review of histopathological findings related to SARS-CoV-2 included 56 studies of 1008 pregnancies complicated by SARS-CoV-2. 23The observed histopathological findings included maternal vascular malperfusion (MVM), fetal vascular malperfusion (FVM), acute and chronic inflammatory pathology, increased perivillous fibrin, intervillous thrombosis and other findings. 23There were only 11 studies which had a control group, and for some outcomes this decreased to nine or ten studies. 23At this time, there was no difference in the development of MVM, but women who had SARS-CoV-2 were more likely to have FVM (OR 1.9, 95% CI 1.3-2.6),chronic inflammatory pathology (OR, 1.94, 95% CI 1.3-2.8),increased perivillous fibrin (OR, 6.8, 95% CI 2.7-17.0),intervillous thrombosis (OR 3.2, 95% CI, 2.0-5.2) and other histopathological anomalies (OR 2.0, 95% CI 1.4-2.7). 23A more recent review, which focused on larger case series, examined 1452 cases and concluded that there is no particular pattern of pathological changes associated with SARS-CoV-2 infection. 24This is at odds with the previously mentioned review, which found some placental pathological findings were more frequent in women following SARS-CoV-2. 23However, these histopathology findings do not necessarily correlate with poor clinical outcome.
In response to this lack of certainty, which they believed may be due to a lack of control populations, a case series reported 870 placentas (673 wild-type, 90 Alpha/Gamma era, 60 Delta era and 56 Omicron era) with an additional 185 controls.They found that SARS-CoV-2 infection is linked to increased MVM and that these changes were most common during the Delta variant, followed by the Alpha/ Gamma and, finally, the Omicron variant. 25Interestingly, another group from the USA examined 67 placentas of women who had recovered from COVID-19 and found that there was increased MVM and a trend towards increased FVM compared with controls; 26 a more recent study of 49 women who had recovered from COVID-19 and 50 controls showed similar findings. 27Neither group reported links to poor perinatal outcomes.However, in the larger cohort study there was an increase in MVM and decidual arteriopathy in women with moderate/severe disease compared with asymptomatic women. 25Again, the common feature of these studies is that any placental changes were not necessarily linked to poor fetal outcomes; furthermore, depending on their timing, these studies may not have identified the most at-risk population in the Alpha and Delta waves.
Determining histopathological causality can be challenging, 22 as histopathological findings can overlap in frequency between the placentas of healthy babies and those stillborn. 28Thus it is important to investigate individual cases thoroughly and to combine the results of the various investigations including fetal autopsy and placental pathology in a coherent manner.This is best achieved when performed by pathologists with specialist expertise in perinatal pathology.

| SARS-CoV-2 placentitis
In the third wave (Alpha variant) of the pandemic in Ireland a new association between stillbirth due to placental insufficiency and SARS-CoV-2 was noticed which did not seem to occur in the first wave. 29This led to a report on six stillbirths and one second-trimester miscarriage and documented the link between pregnancy loss and the deleterious histopathological changes of SARS-CoV-2 placentitis due to direct placental infection. 30,31Thus, active placental infection became an important histopathological focus.
The histopathological diagnostic entity that is SARS-CoV-2 placentitis has been described as a triad of histiocytic intervillositis, perivillous fibrin deposition and trophoblast necrosis (Figure 1A-D) 32 and has been associated with poor perinatal outcomes, including stillbirth, second-trimester miscarriage and impending fetal demise. 31,33However, to be truly defined as SARS-CoV-2 placentitis, it is ideally necessary to identify the virus in the placental tissue using in situ hybridisation or immunohistochemistry techniques. 34efore discussing SARS-CoV-2 placentitis in detail, it is useful to comment on the different elements of the proposed triad of histopathological findings associated with SARS-CoV-2 placentitis. 32This is necessary, as some terms used as pathological descriptors in the cases of SARS-CoV-2 placentitis (histiocytic intervillositis, perivillous fibrin deposition) may be confused with distinct pathological entities that are aetiologically unrelated, i.e. chronic histolytic intervillositis and massive perivillous fibrin(oid) deposition, as described below.
The intervillositis seen in SARS-CoV-2 placentitis has features similar to the entity known as chronic histiocytic intervillositis (CHI). 32,33CHI is a rare entity characterised by a histiocyte-predominant inflammatory infiltration of the intervillous space. 35,36It is found in 0.6% of second-and third-trimester placentas. 379][40] This variation may relate to different extents of placental parenchymal involvement and lack of any consistently used grading scheme.CHI is associated with fetal growth restriction. 40,41ecurrence rates are between 25% and 100%. 36,39,41,42CHI is favoured to represent an abnormal maternal immune reaction to the affected pregnancy. 41,43This differs from the situation where histiocytic intervillositis is a finding in a setting of documented infection where it has been described following infections in the TORCH group (e.g.toxoplasma, rubella, cytomegalovirus and Herpes), 38 although some feel this relation is unreliable.It is often accompanied by fibrin deposits and trophoblast necrosis.In this situation, as in the situation with SARS-CoV-2 placentitis, it is a descriptor of F I G U R E 1 Histopathological features of diffuse/focal and active/resolved SARS-CoV-2 placentitis.(A) Gross appearance of a placenta with extensive SARS-CoV-2 placentitis causing stillbirth; there are abnormal, coalescing cream nodules and streaks occupying more than 90% of the parenchyma.(B) In a less severe case resulting in live birth following an abnormal CTG and fetal bradycardia, there are similar nodules and streaks involving approximately 20% of the placenta.(C) In this case of active SARS-CoV-2 placentitis there is a mixed inflammatory infiltrate in the intervillous space that is rich in histiocytes (haematoxylin & eosin [H&E], 400× original magnification).(D) In other areas of the case there is prominent villous trophoblast injury with occlusion of the intervillous space by a combination of degenerating trophoblast fragments, degenerating inflammatory cells and eosinophilic fibrin-like material (H&E, 400× original magnification).(E) In these images there are two examples of resolved SARS-CoV-2 placentitis; in (i) there are dense cream deposits largely along the basal plate (arrowheads), an arrow highlights an incidental intervillous thrombus; in total there was less than 20% parenchymal involvement in this case; in (ii) the placenta was normal grossly apart from focal areas as shown, resembling old infarcts, resulting in less than 10% gross involvement.(F) In this resolved case of SARS-CoV-2 placentitis the low-power view of the affected area shows ghost outlines of villi without significant inflammation or active degeneration of trophoblast in much of the view; arrowheads show areas with some residual viable cells and debris at the lesion edge (H&E, 50× original magnification).(G) A high-power view of a resolved case shows eosinophilic material around the ghost outline of a villus (arrow) and no significant inflammation or active trophoblast necrosis (H&E, 400× original magnification).Deposition of small amounts of fibrinoid material in the placenta is a normal phenomenon but in certain pathological processes it can become so abundant it becomes known as massive perivillous fibrin(oid) deposition (MPFD).5][46] The aetiology of MPFD is not well understood.In SARS-CoV-2 the gross appearance of severely affected cases may resemble that of MPFD; the microscopic appearance shares some similarities.We should be careful not to cause confusion between MPFD as a clinicopathological entity and SARS-CoV-2 placentitis which is clearly infective in origin.
Trophoblast necrosis is not specific to SARS-CoV-2 placentitis and will be seen even in common lesions such as infarction and other forms of placental injury.Each of the three components of the 'triad' are thus not specific on their own but, when seen in combination, provide morphological clues that would prompt a pathologist to confirm the diagnosis with a technique that would confirm involvement of the placenta in COVID-19 (such as confirming the presence of the virus in the placenta with immunohistochemistry).
In our audit below we present data that suggests the trophoblast necrosis and inflammatory infiltrate are features of active infection and may not be seen in old 'resolved' or 'healed' lesions following SARS-CoV-2 placentitis (Figure 1E-G); thus they are not specific for SARS-CoV-2 placentitis, nor are they always necessary.Given the absence of ongoing trophoblast necrosis and inflammation, it may be that the finding of focal immunohistochemical positivity for SARS-Co-V2, 2-3 months after infection represents persistence of viral antigen after viral replication has ceased, but SARS-CoV2-RNA has been identified up to 230 days post-infection in non-respiratory tissues with little evidence of inflammation or cytopathic effect. 47With this in mind, we cannot necessarily assume the virus is truly inactive in these cases but we suggest the placental disease seems inactive and that descriptions such as 'inactive' or 'burnt-out' seem appropriate at this point in time.
SARS-CoV-2 placentitis was first used to describe the pathological changes in the placenta of a neonate whose mother had presented with reduced fetal movements after testing positive for SARS-CoV-2 10 days earlier.They were delivered via caesarean due to fetal heart rate abnormalities.Subsequent placental examination revealed 25% gross placental involvement with lace-like arrangements of nodules and streaks of abnormal parenchyma.Microscopically there was clumping of villi, loss of intervillous space and histiocytic intervillositis with prominent necrotic villous trophoblast and accumulation of necrotic debris in the intervillous space. 30Subsequently, these findings have been repeatedly identified in placentas infected with SARS-CoV-2 (see Table 3) and have been shown to be the predominant specific pathology associated with SARS-CoV-2-associated stillbirth. 31,33,48he syncytiotrophoblast is the cellular defence mechanism at the fetal-maternal interface, it contains the ACE2 receptor, which is a receptor for SARS-CoV-2, and the protease TMPRSS which cleaves the SARS-CoV-2 spike protein to facilitate infection. 37Other proposed receptors for SARS-CoV-2 in the placenta include DPP4 (CD26) and CD147. 49he syncytiotrophoblast is the most common placental cell type to be infected with SARS-CoV-2. 50It is one cell thick and it contains multiple mechanisms to avoid microbial or viral invasion.However, once it is destroyed, it may be possible for a virus to reach the fetal vessels, resulting in vertical transmission. 37It is not yet clear whether the necrosis described in SARS-CoV-2 placentitis is caused by SARS-CoV-2 infectivity, ischaemia due to histiocytic intervillositis and increased fibrin, a mechanism of programmed cell death to avoid viral infection, or is a mixture of all of these elements. 37Morphological interpretation has suggested that direct viral-cytopathic effects and immune-mediated mechanisms are responsible for the tissue necrosis. 31Any time that extensive trophoblast injury occurs, there is likely to be a breakdown of intraplacental anti-thrombotic mechanisms, resulting in fibrin and platelet deposition, obstruction of intervillous blood flow, intervillous thrombosis and likely secondary ischaemia.
The extent to which placentas develop these abnormalities is likely to account for fetal demise or hypoxic effects on the fetus/neonate; in many of the cases resulting in fetal death, the majority of the placenta is involved. 31Furthermore, the speed at which the virus exerts its effects on the placenta is remarkable, with many of the placental changes occurring within 21 days. 31,33These findings are consistent across most reports of SARS-CoV-2 placentitis (see Table 2).

| TH E POST U L ATE D M ECH A N ISM FOR POOR PER I NATA L OU TCOM E R E L ATE D TO SA R S -C oV-2 PL ACE N TA L I N FEC TION
The studies discussed in this review show that the development of placental infection can in a small number of cases lead to extensive placentitis and subsequently placental insufficiency. 50he mechanisms for the development of SARS-CoV-2 placentitis are being investigated.The working theory is that SARS-CoV-2 infects the syncytiotrophoblast because, like lung tissue, it contains the ACE2 receptor, which is a receptor for SARS-CoV-2, and the protease TMPRSS, which cleaves the SARS-CoV-2 spike protein to facilitate infection. 37,51,52nce infected, direct viral cytopathic effects or antiviral immune-mediated mechanisms (causing histiocyte recruitment and complement activation) may cause trophoblast necrosis. 30The breakdown in the protective, antithrombotic syncytiotrophoblast layer together with shedding of necrotic debris into the intervillous space is likely to explain the villous aggregation, fibrin deposition and thrombosis which results in clogging of the intervillous circulation that reduces placental functional capacity. 32,53hat is not understood is why a small minority of pregnancies are complicated by this process when the majority are not.The extent of parenchymal involvement determines outcome (Table 3).Most cases of fetal demise occurred within 21 days of maternal infection (Table 3).In many cases there was no evidence of growth restriction. 31,33This suggests a rapid course of placental infection and injury which can be easily explained by widespread evidence of infection in the Incidence of placentitis likely to be influenced by the timing of the study (not reported during wild-type variants) or vaccination status of the mother.
T A B L E 3 Clinical and histopathological summary of placentas testing positive for SARS-CoV-2.

Gestation at delivery
Vivanti 20 87 March 20 organ, as evidenced by immunohistochemical stains. 31,50It is easy to imagine a situation where a highly perfused organ such as the placenta becomes infected in a setting of maternal viraemia.

| PL ACE N TA L I N FEC TION A N D V IR A E MI A
SARS-CoV-2 can be detected in the blood so, like other respiratory viruses, 54 it is likely to reach the placenta and multiple other organs in which SARS-CoV-2 has been found, via that route. 54,55High levels of SARS-CoV-2 in plasma are associated with tissue damage, inflammation and coagulopathies and it is possible that this could predict disease severity. 56,57The viraemia may cause the complement activation and elevated cytokines, 32,54 which could explain the origins of SARS-CoV-2 placentitis. 32However, which person experiences the viraemia is likely to depend on multiple individual factors including co-morbidities, previous COVID-19, immunocompetency, genetics and vaccination status. 13,54iraemia has been difficult to capture in pregnant patients, with some finding it in unwell pregnant women 58 and others not, 59 although there are reports of SARS-CoV-2 viraemia occurring alongside SARS-CoV-2 placentitis. 60,61nterestingly, the incidence of viremia in the non-pregnant population is approximately 1-2% 62,63 and this rate is akin to the rate of SARS-CoV-2 placentitis we propose below.

| SA R S -C oV-2 PL ACE N TITIS CASE SER IE S
The infection of the placenta, especially the syncytiotrophoblast, with SARS-CoV-2 seems to play the key role in mediating the deleterious effects on the placenta which ultimately lead to fetal demise.Therefore, for this review, we have brought together reports of cases where placentas have been tested for SARS-CoV-2 whether by immunohistochemistry, in situ hybridisation techniques or polymerase chain reaction (PCR), and placental histopathology is reported with a clear description and support for their findings, along with clinical outcomes.In Table 3 we summarise the findings across nearly 40 studies with more than 200 placentas testing positive for SARS-CoV-2.More in-depth information is provided in Table S1.There are important common themes, although not all can be fully explored, as we are reliant on what is reported in the literature.From a clinical perspective the most important message from this collection of reported cases is that if women are vaccinated, they do not seem to contract SARS-CoV-2 placentitis.Furthermore, if placentas are not infected with SARS-CoV-2, then they are not associated with poor clinical fetal outcomes that can be attributed to the placental effects of SARS-CoV-2.Many women who contract SARS-CoV-2 placentitis are at most mildly symptomatic.The deleterious fetal effects of SARS-CoV-2 are generally quick, with as few as 3 days from symptoms/positive test (if any) to fetal effects, although in some cases serious effects can take several weeks.The earliest clinically obvious fetal sign of SARS-CoV-2 placentitis seems to be reduced fetal movements, with many women presenting, being reassured via observations, examination, fetal heart rate monitoring and ultrasound parameters and then returning with either stillbirth, fetal distress or bleeding (with or without contractions).The general pattern of fetal hypoxia has been decreased variability followed by evolving decelerations on fetal heart rate monitoring.A further useful area to consider may be that in some (but not all) cases, affected women have been thrombocytopenic prior to delivery.
From a histopathological perspective, if the placentas do not test positive for SARS-CoV-2, they do not on the whole have widespread changes of SARS-CoV-2 placentitis.Furthermore, it seems to be the diffuse SARS-CoV-2 placentitis which results in rapid fetal demise.Focal disease seems to provide a greater chance of a live birth and ongoing pregnancy.This seems particularly linked to weaker positivity in the placenta.These changes may be in placentas of women who have had the virus earlier in pregnancy. 64Table 3 and Table S1 includes information on the diffuse/focal nature of the placental involvement.However, this series of cases has shown, again, that the severity of COVID-19 symptoms does not correlate with severity of the histopathological lesion.

| Cork University Maternity Hospital case series
SARS-CoV-2 placentitis seems to be uncommon and its frequency affected by the SARS-CoV-2 variant circulating in the population.When the initial cluster of stillbirths was identified in Ireland during the Alpha wave it was clear to those T A B L E 3 (Continued)  assessing the situation that an unexpected change in disease pattern had occurred and a decision was taken in many Irish hospitals to start to examine all placentas from pregnancies affected by COVID-19.Here we report an audit of SARS-CoV-2 placentitis frequency in Cork University Maternity Hospital from 350 consecutive pregnancies affected by maternal COVID-19 through a time period covering the end of the Alpha wave, the Delta wave and the beginning of the Omicron wave (from May 2021 to February 2022).This time period largely spans the introduction of vaccination in pregnancy in Ireland.Six of these 350 placentas (1.7%) showed evidence of SARS-CoV-2 placentitis and all cases were in unvaccinated women (Figure 1).There was one stillbirth (with near 100% parenchymal involvement), one presentation with reduced movements and an abnormal CTG (with 30% parenchymal involvement), two clinically silent cases with unexpected active placental disease (with 20-25% involvement of the parenchyma) and two clinically silent cases with focal inactive 'resolved' disease (with respectively less than 20% and 10% parenchymal involvement) (Figure 1).The latter two cases showed immunohistochemical positivity for the SARS-CoV-2 virus 2 and 3 months, respectively, after the maternal infection.These two cases perhaps represent persistence of identifiable viral components after replication and the infection cycle as stopped, evidenced by a lack of ongoing trophoblast necrosis or inflammation.In all cases, parenchymal lesions were visible on initial gross placental examination.Due to limitations on laboratory resourcing, the audit led to a triage system whereby placentas from pregnancies with a history of maternal COVID-19 that were otherwise uncomplicated were, from March 2022, only examined microscopically if a gross abnormality was seen.These audit findings resonate with those from another similar-sized cohort from the USA. 65his current lack of predictability of who will be affected, evidenced by the cases summarised in Table 3, has led to significant uncertainties in the clinical management of women in relation to trying to avoid fetal demise when variants of concern are circulating.

| SA R S -C oV-2 VAC CI NAT ION
Vaccination reduces SARS-CoV-2 placentitis 50 and stillbirth, improves maternal outcomes 12 and is the mainstay of prevention.This is particularly important when there are variants of concern. 12mproved maternal outcomes with vaccination are a consistent finding, and evidence is building.A UK cohort study of the Omicron variant has reinforced this message and shown that although there is benefit from receiving any vaccine, being fully vaccinated reduces a mother's chance of admission to the intensive care unit.In their nationwide registry study (UKOSS), 19 women were admitted to the ICU: 14 were unvaccinated, three had one dose, one had two doses and one had unknown vaccination status. 66An earlier Scottish registry study showed that 98.9% of critical care admissions between December 2020 and September 2021 were unvaccinated and 93% of pregnant women admitted to hospital were unvaccinated. 10A national report of Ireland's ICU showed similar findings, with 89% of admissions not being fully vaccinated; 67 however, since Omicron became predominant, there have been no ICU admissions. 68accination improves fetal outcomes, with a recent systematic review showing a reduction in stillbirths of between 1% and 27% in a vaccinated compared with an unvaccinated population (OR 0.85, 95% CI 0.73-0.99).The reviews show a clear pattern of (when vaccination status is reported) no fetal deaths with SARS-CoV-2 placentitis (i.e.attributable directly to SARS-CoV-2) in a vaccinated population. 12accine safety is a concern for many women, perhaps fuelled by a lack of clear messaging at the start of the pandemic, with pregnant women not included in clinical trials, 12 followed by a relative delay in the national recommendations for vaccination. 10,13This has been further fuelled by opinions on social media, within social networks 69 and poor vaccine literacy among healthcare professionals. 70However, what is clear is that COVID-19 vaccination in pregnancy is safe. 71hen considering maternal and fetal adverse outcomes, several studies have investigated vaccines in pregnant women.These include a Scottish registry study of 2364 births to women with COVID-19 with no maternal deaths in women who had received the COVID-19 vaccination; the perinatal mortality rate was similar, if not less than, the pre-existing background rate.The perinatal deaths in that study (11 stillbirths and eight neonatal deaths) were in unvaccinated women. 10A Norwegian registry study showed that early pregnancy loss is not increased with vaccination. 72 Canadian cohort study of 97 590 pregnant women, compared based on vaccination status, found no increase in adverse pregnancy outcomes (including postpartum haemorrhage, chorioamnionitis, caesarean section, low APGAR scores, NICU admission).73 In Switzerland, a study of 1012 vaccinated women showed comparable rates of adverse outcomes compared with historical rates.74 The message is clear, there is no increase in adverse events for mother, fetus or neonate with the vaccine.Several studies have investigated placental histopathology comparisons of vaccinated versus unvaccinated groups and showed no difference; 75 in some cases, there are more histopathological abnormalities in the control group.76 This evidence suggests that COVID-19 vaccine is safe in pregnancy and can improve outcomes for the mother and fetus.
The fact that the vaccine is beneficial to women and their fetuses, means the concerning trend of vaccine hesitancy should be at the forefront of COVID-19 research.In a large cohort study in Scotland, women of reproductive age had the lowest vaccine uptake; this was worst in the youngest women and in the most deprived areas. 10This finding is emulated in the USA, where the disparities in vaccine uptake by race and ethnicity are likely to further widen disparities. 77,78

| AVOIDI NG STI L L BIRT H A N D H Y POX IC BR A I N I N J U RY I N SA R S -C oV-2 I N FEC TE D PR EGNA N T WOM E N
SARS-CoV-2 placentitis is an uncommon but serious complication of infection with a SARS-CoV-2 variant of concern.It is most likely to affect a pregnancy in days to weeks following SARS-CoV-2 infection, generally around 2 weeks post-infection, and it is not related to whether a woman is symptomatic or not. 13,31,33e would suggest treating women as follows: first, according to whether the currently predominant SARS-CoV-2 variant is a variant of concern for poor fetal outcomes (Omicron is not) or the specific variant as sequenced following a positive PCR test.If this suggests risk of SARS-CoV-2 placentitis, serial monitoring by CTG should be put in place, with close attention paid to fetal movements, as a trigger for additional monitoring.Vaccination seems to be a protective factor, and therefore resources should focus on unvaccinated women.A senior clinician should consider the appropriateness of antenatal corticosteroids.It may be valuable to perform a coagulation screen, particularly considering thrombocytopenia as a possible indicator of the pregnancy being at risk of SARS-CoV-2 placentitis.Furthermore, when a variant of concern for the fetus is prevalent, women reporting reduced movements should routinely have a SARS-CoV-2 PCR as part of their assessment to help stratify their risk and ongoing plan for monitoring.Ultrasound assessment is not useful in SARS-CoV-2 placentitis.

| HOW TO M A NAGE SU BSEQU E N T PR EGNA NCIE S OF WOM E N W HO H AV E H A D SA R S -C oV-2 PL ACE N TITIS
The challenge now lies in those women becoming pregnant again who have had a stillbirth, miscarriage or poor neonatal outcome alongside a SARS-CoV-2 infection.Placental histopathology reports may report CHI with or without MPFD.
Both independent yet linked conditions have an incidence well below 1%; 37,44 however, their recurrence risk is high, with that of CHI being 25-100%, 36,39,42 and similar levels of recurrence have been reported for massive perivillous fibrin deposition. 44The mainstay for management in subsequent pregnancies for these women has been aspirin and low molecular weight heparin, 44,79 but it has now evolved also to include hydroxychloroquine and prednisolone. 79As previously explained, in SARS-CoV-2, placentitis, terms such as histolytic intervillositis and massive fibrin deposition may be used as pathological descriptors and do not equate with the conditions 'chronic histolytic intervillositis' or 'massive perivillous fibrin(oid) deposition' as diagnostic entities.
We would agree with Schwartz et al. 33 that the term chronic histiocytic intervilliositis is not congruous with the speed at which pathological changes develop.In SARS-CoV-2 placentitis the pathological basis of the histiocytic intervilliositis/massive perivillous fibrin(oid) deposition is known, particularly when the virus is directly identified in the placenta.Therefore, if we recognise and diagnose SARS-CoV-2 placentitis properly, we can recognise that it is unlikely to require the management usually instigated in subsequent pregnancies for CHI/MPFD.

| FU T U R E R E SE A RCH
There remain some clear research priorities for SARS-CoV-2 placentitis.First, we need to optimise early identification of any SARS-CoV-2 variant of concern which may constitute a risk for placentitis and develop mechanisms to instigate a national/global obstetric response.If a new variant of concern becomes prevalent, a coordinated international effort to record pregnancy-related SARS-CoV-2 cases, along with their clinical and pathophysiological course, is needed for identification of ways to ensure good fetal outcome.
Secondly, a concerted effort to address vaccine hesitancy is needed, as current evidence suggests that vaccination protects against SARS-CoV-2 placentitis; however, we acknowledge that this is based on previous, not emerging variants, and future strains need to be monitored.This is likely to require detailed multidisciplinary research.This may require interventions to target staff alongside vulnerable populations.
Thirdly, there is a substantial international bank of placental tissue derived from uninfected, infected but uncomplicated and infected and complicated pregnancies spanning the pandemic.The research questions that try to explain why small percentages of infected pregnant women develop severe placental infection, whereas others have unaffected placentas, are not dissimilar to those concerning severe pulmonary disease.There is no access to lung tissue from healthy/less severe populations and probably limited banks of tissue from those with severe disease.The repositories of placental tissue may therefore provide information to benefit the broader population.There is an opportunity for obstetricians and placental pathologists to cooperate with a wider group of COVID-19 researchers.
Finally, it is imperative that both obstetricians and histopathologists work together across countries to monitor the clinical course, treatments and outcomes of pregnancies following SARS-CoV-2 placentitis so that we can provide women with tailored, evidence-based advice for their subsequent pregnancies.

AU T HOR C ON T R I BU T ION S
AM, BF and KD conceived the paper, carried out the review and drafted the article.

AC K NO W L E D GE M E N T S
We thank Dr Jessica White, Consultant Histopathologist at Cork University Hospital, and the perinatal medical scientists who processed the 350 placentas and took the macroscopic images, Susan Dineen and Therese Brosnan.

DATA AVA I L A BI L I T Y S TAT E M E N T
Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

E T H IC S A PPROVA L
None.

R E F E R E NC E S
(H) In (i) a diffuse active example of SARS-CoV-2 placentitis shows extensive immunohistochemical positivity for the virus in villous trophoblast; in (ii) a case of resolved placentitis with focal placental involvement still shows focal positivity for SARS-CoV-2; one of the examples shown in panel (E) showed such staining 3 months after maternal COVID-19 (SARS-CoV-2 immunohistochemistry, ([i] 50× original magnification, [ii] 200× original magnification).
the inflammatory reaction caused by the infection and does not equate with a diagnosis of CHI.

T A B L E 2
Prevalence of SARS-CoV-2 placentitis.

F
U N DI NG I N FOR M AT ION AM, NIHR Advanced Fellow (NIHR302530) is funded by the NIHR for this research project.The views expressed in this publication are those of the author(s) and not necessarily those of the NIHR, NHS or the UK Department of Health and Social Care.

Author Dates No. placentas examined Covid day at delivery Asymptomatic/ mild Vaccinated Thrombo- cytopenia Gestation at delivery
At least five cases reported in this case series are included elsewhere in this table. a