Impact of Covid-19 on risk of severe maternal morbidity

Background We examined the risk of severe life-threatening morbidity in pregnant patients with Covid-19 infection. Methods We conducted a population-based study of 162,576 pregnancies between March 2020 and March 2022 in Quebec, Canada. The main exposure was Covid-19 infection, including the severity, period of infection (antepartum, peripartum), and circulating variant (wildtype, alpha, delta, omicron). The outcome was severe maternal morbidity during pregnancy up to 42 days postpartum. We estimated risk ratios (RR) and 95% confidence intervals (CI) for the association between Covid-19 infection and severe maternal morbidity using adjusted log-binomial regression models. Results Covid-19 infection was associated with twice the risk of severe maternal morbidity compared with no infection (RR 2.02, 95% CI 1.76–2.31). Risks were elevated for acute renal failure (RR 3.01, 95% CI 1.79–5.06), embolism, shock, sepsis, and disseminated intravascular coagulation (RR 1.35, 95% CI 0.95–1.93), and severe hemorrhage (RR 1.49, 95% CI 1.09–2.04). Severe antepartum (RR 13.60, 95% CI 10.72–17.26) and peripartum infections (RR 20.93, 95% CI 17.11–25.60) were strongly associated with severe maternal morbidity. Mild antepartum infections also increased the risk, but to a lesser magnitude (RR 3.43, 95% CI 2.42–4.86). Risk of severe maternal morbidity was around 3 times greater during circulation of wildtype and the alpha and delta variants, but only 1.2 times greater during omicron. Conclusions Covid-19 infection during pregnancy increases risk of life-threatening maternal morbidity, including renal, embolic, and hemorrhagic complications. Severe Covid-19 infection with any variant in the antepartum or peripartum periods all increase the risk of severe maternal morbidity. Supplementary Information The online version contains supplementary material available at 10.1186/s13054-023-04584-6.


Background
Covid-19 infection during pregnancy is associated with preterm birth and stillbirth [1,2], but less is known about the risk of severe maternal morbidity.Severe maternal morbidity comprises life-threatening events such as thromboembolism, severe hemorrhage, and sepsis, many of which may naturally complicate Covid-19 infection [3][4][5].A meta-analysis of 18 studies found that Covid-19 tripled the risk of intensive care unit admission, need for respiratory support, and use of mechanical ventilation in pregnant women [6].While these studies provide important information on the need for critical care, many cases may be due to respiratory complications that are not necessarily related to pregnancy or severe maternal morbidity.Very little is known about the types of life-threatening morbidities that women with Covid-19 may be at risk of during pregnancy.
The impact of Covid-19 on severe maternal morbidity is poorly understood because prior research has focused on demonstrating that newer SARS-CoV-2 variants are not as dangerous as earlier variants in pregnant women [6][7][8][9].Studies have successfully shown that infections with wildtype, alpha, beta, gamma, and delta are all more harmful than omicron [6][7][8][9].As the attention was on comparing variants, efforts at identifying the specific lifethreatening morbidities in SARS-CoV-2 infected women have been rare.Only two studies have addressed this issue, both suggesting that infected pregnant women who require critical care may be at risk of severe obstetrical hemorrhage, venous thromboembolism, and respiratory morbidity [10,11].However, other types of severe maternal morbidity were not examined, leaving the underlying effect of Covid-19 in pregnancy largely unknown.We examined how SARS-CoV-2 infection was associated with different types of severe maternal morbidity in a large cohort of pregnant women.

Study population
We performed a population-based cohort study of 162,576 deliveries in Quebec, Canada, between March 1, 2020 and March 31, 2022.We extracted data on the deliveries from the Maintenance and Use of Data for the Study of Hospital Clientele registry, which contains discharge summaries for hospitalizations before, during, and after pregnancy [12].The data include nearly all pregnancies that led to a live birth or stillbirth in Quebec, as 98% occur in hospital.
The data contain patient diagnoses and procedures during hospitalization, coded using the tenth revision of the International Classification of Diseases (ICD-10) and Canadian Classification of Health Interventions (CCI).We identified any diagnosis of severe maternal morbidity during hospitalizations between conception and 42 days following pregnancy.We also identified any diagnosis of a Covid-19 infection during antepartum and peripartum hospitalizations.We only considered Covid-19 infections that were present before or during admissions at which there was an occurrence of severe maternal morbidity, to ensure that the exposure preceded the outcome.We excluded women with invalid identifiers as we could not capture all clinical events in these patients.

SARS-CoV-2 infection
The main exposure measure was SARS-CoV-2 infection during antepartum admissions or at delivery.During the study period, hospitals in Quebec systematically screened pregnant women for SARS-CoV-2 infection at admission [13].In addition, at the time of delivery, hospitals collected data from outpatient charts on past infections that did not require admission [13].Thus, we were able to identify antepartum Covid-19 infections that required admission prior to delivery, antepartum infections that did not require admission, and peripartum infections at the delivery admission.Infection was confirmed by polymerase chain reaction and identified through ICD-10 codes (Additional file 1: eTable 1).
We further classified SARS-CoV-2 infection by severity, based on symptoms or comorbid conditions during admission (Additional file 1: eTable 1).To identify severe cases, we used the National Institutes of Health's Covid-19 severity guidelines [14,15].Women with moderate to severe Covid-19 symptoms, including pneumonia, bronchitis, lower respiratory tract complications, pulmonary embolism, and other related conditions were classified as having severe Covid-19.Patients with symptoms such as cough and sore throat, or who were asymptomatic, were classified as having mild Covid-19.

Severe maternal morbidity
The main outcome measure was severe maternal morbidity, following the definition of the Public Health Agency of Canada [3].Severe maternal morbidity was defined as life-threatening conditions during pregnancy or within 42 days postpartum, including severe preeclampsia or eclampsia; severe hemorrhage requiring transfusion or secondary to a coagulation defect; embolism, shock, sepsis, or disseminated intravascular coagulation; acute renal failure; hysterectomy and surgical complications; other rare life-threatening morbidity (cardiomyopathy, cardiac arrest and resuscitation, myocardial infarction, pulmonary edema and heart failure, cardiac complications of anesthesia, cerebrovascular accident, acute fatty liver requiring transfusion, hepatic failure, cerebral edema or coma, complications of anesthesia, status asthmaticus, adult respiratory distress syndrome, acute abdomen, uterine rupture, inverted uterus, sickle cell anemia with crisis, acute psychosis, status epilepticus); admission to an intensive care unit; and assisted ventilation [17].We identified the timing of severe maternal morbidity (during antepartum admissions, at the delivery hospitalization, during postpartum readmissions) and total number of severe maternal morbidities (1, 2 or more).

Covariates
We examined factors that could influence the association between Covid-19 infection and severe maternal morbidity, such as maternal age (< 25, 25-34, ≥ 35 years), parity (0, 1, ≥ 2 previous deliveries), comorbidity including preexisting diabetes, hypertension, obesity, dyslipidemia, and tobacco, alcohol, and substance use disorders (yes, no), socioeconomic disadvantage (advantaged, disadvantaged, unspecified), and place of residence (rural, urban, unspecified).Socioeconomic disadvantage was measured using a composite index of the proportion of individuals with low education, unemployment, and low income in the immediate neighborhood [18].

Statistical analysis
We calculated the rate of severe maternal morbidity per 1000 deliveries for women with and without Covid-19, and estimated risk ratios (RR) and 95% confidence intervals (CI) for the association of SARS-CoV-2 infection with risk of severe maternal morbidity using adjusted log-binomial regression models.Models were adjusted for maternal age, parity, comorbidity, socioeconomic disadvantage, and place of residence.We estimated associations for different types of severe morbidity, as well as according to timing and total number of morbidities.The reference group comprised women without Covid-19 infection during pregnancy.
In sensitivity analyses, we changed the reference group to patients who delivered before the pandemic (January 1, 2017 to February 29, 2020), to determine if the associations could have been attenuated by an effect of pandemic containment measures.
We analyzed the data in SAS v9.4 (SAS Institute Inc., Cary, NC) and used an alpha level of 0.05 with a twotailed test to determine statistical significance.As we used anonymized data, we obtained an ethics waiver from our research institution.
The timing of infection during pregnancy influenced the risk of severe maternal morbidity ( Patients with antepartum Covid-19 infections were also at risk of severe maternal morbidity (Table 4).Compared with no infection, severe antepartum infections were associated with use of assisted ventilation (RR 85.19, 95% CI 37.08-195.74),intensive care admission (RR 70.96, 95% CI 53.95-93.34),acute renal failure (RR 12.70, 95% CI 3.22-50.13),and embolism, shock, sepsis, or disseminated intravascular coagulation (RR 8.42, 95% CI 3.87-18.34).Mild infections during antepartum hospitalizations were also associated with most of these outcomes, but to a lesser extent.Antepartum infections that did not require hospitalization were not associated with most outcomes.
The alpha variant, followed by delta and wildtype, were associated with the greatest risk of severe maternal morbidity (Table 5).These strains were most strongly associated with acute renal failure and other life-threatening morbidity (4 to 6 times greater risk).Associations weakened during omicron, although Covid-19 remained associated with assisted ventilation (RR 7.41, 95% CI 3.75-14.64)and intensive care unit admission (RR 3.03, 95% 2.10-4.36).
We obtained similar results when we changed the reference group to patients who delivered before the pandemic.

Discussion
This population-based cohort study suggests that Covid-19 infection during pregnancy was associated with an increased risk of severe maternal morbidity that stayed relatively consistent over the course of the first two years of the pandemic, up until the arrival of the omicron variant.Risk of severe maternal morbidity was greatest during circulation of wildtype and the alpha and delta variants.The omicron variant remained associated with a greater risk of severe maternal morbidity, but at a lower magnitude.Severe antepartum or peripartum infections were associated with most types of severe maternal morbidity, particularly acute renal failure, severe hemorrhage, and embolism, shock, sepsis, and disseminated intravascular coagulation.Associations were weaker or absent for mild antepartum and peripartum infections.Our findings suggest that pregnant patients with Covid-19 are at risk of several types of severe maternal morbidity, with the dominant circulating variant and infection severity modifying the risk.Renal, hemorrhagic, and embolic complications seem to be the most prevalent.
Severe maternal morbidity includes serious complications during pregnancy, delivery, or within 42 days postpartum that are life-threatening [19].Although the exact definition varies from study to study, complications such as eclampsia, obstetric hemorrhage, and heart failure are generally included.Yet, studies of the impact of Covid-19 on severe pregnancy outcomes generally focus on measures of critical care, not the underlying morbidities requiring care [2].A meta-analysis of more than 30 studies found that pregnant women with Covid-19 were around 2.5 times more likely to require intensive care and assisted ventilation than infected nonpregnant women [2].Risks were 5.4 times greater when infected pregnant women were compared with uninfected pregnant women.However, the investigators could not identify the specific life-threatening conditions that led to critical care.As many indications for critical care may not relate to pregnancy, the extent to which Covid-19 affects serious maternal morbidity remains unclear [20].
Understanding the types of pregnancy complications that are more prevalent in patients with Covid-19 requires use of a validated measure of severe maternal morbidity [10].Yet, only a handful of studies have examined standardized measures of severe maternal morbidity meant to identify life-threatening outcomes of pregnancy [8,10,11,15].A multicenter study of 3 129 patients with SARS-CoV-2 found that infection at delivery was associated with twice the risk of any severe maternal morbidity measured as a composite indicator, compared with 12 504 uninfected patients in the U.S. [8].Early variants were associated with up to seven times the risk of severe respiratory, non-respiratory, and non-hemorrhagic maternal morbidity, while omicron was associated with severe respiratory morbidity only [8].Other studies have found that Covid-19 infection was associated with 1.5 to 2.5 times the risk of any life-threatening outcome, again measured using a composite score [10,11,15].Only two studies have assessed specific morbidities, finding that obstetrical hemorrhage and venous thromboembolism were the most common severe outcomes in women with Covid-19 [10,11].However, the number of morbidities examined was limited in both studies.Using a comprehensive measure of severe maternal morbidity, we were able to demonstrate that pregnant women were at risk of these and several other complications that have not previously been examined.In our data, some of the strongest associations were with acute renal failure, embolism, shock, sepsis, disseminated intravascular coagulation, and severe hemorrhage.Risk of renal failure was elevated even for mild peripartum Covid-19 infections.Renal injury has been widely reported in nonpregnant patients with Covid-19 [21].The kidney may be particularly sensitive to Covid-19 during pregnancy, as glomerular filtration rates increase up to 50% by the early second trimester [22].As a result, superimposed stress or shock due to SARS-CoV-2 infection could more readily lead to renal injury [23].A U.S. multicenter study found that the severe morbidities most prevalent among women with Covid-19 were renal failure, sepsis, and transfusion, although the relative risk of these outcomes was not measured [8].Embolic complications may also be prevalent.A study of 43 886 patients from California found that pregnant women with SARS-CoV-2 had three times the risk of venous thromboembolism and greater rates of sepsis [11].Some of these findings could be explained by placental malperfusion, thrombosis, or inflammation, as pregnant women with Covid-19 tend to be at risk of these disorders [15].Covid-19 is also associated with coagulopathy [10], which may increase the risk of hemorrhage or disseminated intravascular coagulation [11,24].
The severity of Covid-19 infection affected the magnitude of association with severe maternal morbidity.We found that severe infections had a greater impact, although mild infections increased the risk of some outcomes, such as renal failure.In the only other study that assessed severity of Covid-19, severe infections were also associated with a greater risk of maternal morbidity [15].However, the analysis was restricted to pregnancies before December 2020 and did not include a number of complications that are normally considered part of severe maternal morbidity [15].Disseminated intravascular coagulation has been reported in pregnant women with mild or asymptomatic Covid-19 [24].
Women with severe antepartum or peripartum Covid-19 infections were all at risk of severe maternal morbidity.Antepartum infections may impact outcomes at delivery through vascular malperfusion or other pathological changes in the placenta, as placental dysfunction is known to persist after infection resolves [25].Patients may also develop placental abnormalities associated with preeclampsia or coagulation defects that increase the risk of renal failure and severe hemorrhage at delivery [24,26,27].Yet, prior studies have paid less attention to antepartum infections.An analysis of seven hospitals from New York found that both antepartum and peripartum infections increased the risk of obstetrical hemorrhage at delivery [10].Underlying conditions such as obesity and diabetes may exacerbate the risk of Covid-19 complications and severe maternal morbidity [2,17].
This study has limitations.We used administrative data that may be affected by misclassification of exposures or outcomes that may have attenuated the strength of associations.We did not have information on potential confounders such as ethnicity and number of prenatal visits.However, it is unlikely that residual confounding explains the findings as associations were strong for most types of severe maternal morbidity.We did not have data on maternal vaccination status, although vaccination during pregnancy was not actively promoted in our population until the latter part of 2021 [28].Part of the reduced risk during omicron may be due to vaccination.It is possible some cases of severe preeclampsia were misdiagnosed owing to an overlap with Covid-19 symptoms.Patients with Covid-19 may also have had different levels of antenatal care.Results for intensive care should be interpreted with caution as women may have been admitted to intensive care units as a safeguard, especially early in the pandemic.We could not analyze self-reported Covid-19 infections.We likely did not capture all mild or asymptomatic antepartum cases, which may have affected results for infections not requiring hospitalization.We could not confirm the SARS-CoV-2 strain, however the dominant variant accounted for more than 50% of infections during each time period [8,16].Quebec provides universal healthcare, but future research is needed to determine if the findings are generalizable to areas with alternate healthcare systems.

Conclusions
This study of more than 160000 patients found that Covid-19 infection during pregnancy was associated with several types of severe maternal morbidity, including acute renal failure, severe hemorrhage, impaired coagulation, and embolism.Severe infections drove most of the excess risk, whether infections occurred antenatally or near the time of delivery.All dominant strains of SARS-CoV-2 were associated with severe maternal morbidity, although the risk was not as elevated during omicron.As there appears to be a continued risk of renal, embolic, and hemorrhagic severe maternal morbidity,

Table 1
Association of Covid-19 infection with severe maternal morbidity a Adjusted for maternal age, parity, comorbidity, socioeconomic disadvantage, and place of residence

Table 2
Association of severity of Covid-19 infection and circulating variant with risk of severe maternal morbidity a Adjusted for maternal age, parity, comorbidity, socioeconomic disadvantage, and place of residence

Table 3
Association of Covid-19 infection during delivery admission with risk of severe maternal morbidity a Association for severe or mild infection relative to no infection, adjusted for maternal age, parity, comorbidity, socioeconomic disadvantage, and place of residence Prevalence

Table 4
Association of antepartum Covid-19 infection with risk of severe maternal morbidity a Association for severe or mild infection relative to no infection, adjusted for maternal age, parity, comorbidity, socioeconomic disadvantage, and place of residence b 67% of patients hospitalized with mild antenatal Covid-19 were admitted for obstetric reasons.Associations persisted when we removed these potentially incidental cases

Table 5
Association of dominant circulating variant with risk of severe maternal morbidity a Association for dominant variant relative to no infection, adjusted for maternal age, parity, comorbidity, socioeconomic disadvantage, and place of residence