Impact of Covid-19 on risk of severe maternal morbidity

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 [3‐5]. 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 [6‐9]. Studies have successfully shown that infections with wildtype, alpha, beta, gamma, and delta are all more harmful than omicron [6‐9]. As the attention was on comparing variants, efforts at identifying the specific life-threatening 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.

Among 162,576 deliveries between March 2020 and March 2022, 3,415 patients (2.1%) had a SARS-CoV-2 infection during pregnancy (Additional file 1: eTable 2). Patients with SARS-CoV-2 infections had higher rates of severe maternal morbidity than uninfected patients (6.1% vs. 3.0%). Covid-19 infection was more frequent in women aged ≥ 35 years and women who were multiparous or socioeconomically disadvantaged.

Covid-19 was associated with an increased risk of severe maternal morbidity (Table 1). Any Covid-19 infection during pregnancy was associated with 2.02 times the risk of severe maternal morbidity compared with no infection (95% CI 1.76–2.31). Associations were most prominent for acute renal failure (RR 3.01, 95% CI 1.79–5.06), assisted ventilation (RR 12.78, 95% CI 8.32–19.62), and intensive care unit admission (RR 6.16, 95% CI 5.04–7.54). Covid-19 was strongly associated with severe maternal morbidity during antepartum admissions (RR 5.25, 95% CI 3.94–7.01), although an elevated risk was also present with severe maternal morbidity during the delivery admission (RR 1.78, 95% CI 1.52–2.10) and during postpartum readmissions (RR 1.43, 95% CI 0.98–2.07).

The timing of infection during pregnancy influenced the risk of severe maternal morbidity (Table 2). Severe Covid-19 during antepartum (RR 13.60, 95% CI 10.72–17.26) and delivery admissions (RR 20.93, 95% CI 17.11–25.60) was associated with 13 to 20 times the risk of severe maternal morbidity compared with no infection. Mild Covid-19 during antepartum (RR 3.43, 95% CI 2.42–4.86) and delivery admissions (RR 1.34, 95% CI 1.06–1.70) was less strongly associated with severe maternal morbidity. In contrast, antepartum infections that never required hospitalization were not associated with severe maternal morbidity (RR 0.92, 95% CI 0.66–1.28).

Patients with severe Covid-19 infection during the delivery admission were at risk of most types of severe maternal morbidity (Table 3). Risks of assisted ventilation (RR 490.17, 95% CI 297.54–807.50), intensive care admission (RR 104.43, 95% CI 82.00–133.01), acute renal failure (RR 41.26, 95% CI 13.76–123.72), embolism, shock, sepsis, or disseminated intravascular coagulation (RR 6.83, 95% CI 1.74–26.87), and severe hemorrhage (RR 11.25, 95% CI 4.33–29.27) were elevated. Mild Covid-19 infections at delivery were nevertheless associated with renal failure and intensive care unit admission, although at lower magnitudes.

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.

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.

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, care providers should remain vigilant and continue promoting vaccination during pregnancy.