COVID-19 in pregnancy: Perinatal outcomes and complications

Abstract

BACKGROUND

The risk of severe coronavirus disease 2019 (COVID-19) in pregnant women is elevated.

AIM

To examine the outcomes of pregnant women with COVID-19 and report perinatal outcomes and complications, while providing a brief review of current literature.

METHODS

The study included pregnant women presenting from April 2020 to February 2022 to the emergency department (ED) of a tertiary hospital. We retrospectively recorded the maternal and perinatal files, including patient epidemiological and clinical characteristics, laboratory values, outcomes, treatment modalities and associations were explored.

RESULTS

Among the 60 pregnant women, 25% required hospitalization, all of whom were symptomatic. Preterm delivery occurred in 30% of cases. Ten percent of neonates required admission to the neonatal intensive care unit, and 5% were classified as small for their gestational age. All mothers survived COVID-19 and pregnancy, with 6.6% requiring invasive mechanical ventilation. Preterm delivery rates did not differ between hospitalized and non-hospitalized pregnant women; composite unfavorable perinatal outcomes, including stillbirth, small for gestational age, or neonatal intensive care unit (ICU) admission, did not significantly increase in the cases hospitalized for COVID-19 (P = 0.09). The odds of hospitalization increased 2.3-fold for each day of delayed ED presentation [adj. OR (95%CI: 1.46-3.624), P < 0.001]. Comorbidity status was an independent predictor of hospitalization, albeit with marginal significance [adj. OR = 16.13 (95%CI: 1.021-255.146), P = 0.048]. No independent predictors of adverse fetal outcome (composite) were identified, and eventual hospitalization failed to reach statistical significance by a slight margin (P = 0.054).

CONCLUSION

Delayed ED presentation and comorbidities increase hospitalization odds. This study highlights the importance of continuous and specific guidance for managing pregnant COVID-19 patients, including timely and appropriate interventions to minimize maternal and perinatal morbidity and mortality.

Key Words: SARS-CoV-2; COVID-19; Pregnancy; Maternal outcomes; Preterm delivery

Core Tip: Pregnant individuals' risk of contracting severe disease from severe acute respiratory syndrome coronavirus 2 infection is elevated. If hospitalization for coronavirus disease 2019 is indicated for expecting mothers, it is crucial the medical treatment to take place in a facility equipped to monitor both maternal and fetal health. Early detection and management of these cases are paramount for optimal results regarding motherhood and newborn care outcomes.

INTRODUCTION

Coronavirus disease 2019 (COVID-19) is a multisystem disease that has a variety of effects on pregnant women and their bearing[1]. Pregnant women with COVID-19 have experienced drastic rises in severe maternal illness and mortality, as well as neonatal complications[2,3]. Risk factors for severe maternal morbidity in pregnancy may also increase risk of COVID-19 illness in pregnancy[4].

Women with COVID-19 had higher rates of preterm birth and delivery, intrauterine growth restriction with low birth weight and higher incidences of fetal distress and maternal death than women without COVID-19[1,2,5,6]. Analysis of 1249634 delivery hospitalizations in the US from March 2020 to September 2021, revealed that pregnant women with COVID-19 are more likely to experience stillbirth than those without the virus. (Adjusted RR: 1.90; 95%CI: 1.69-2.15)[7]. Higher magnitude of association was observed during delta variant[7]. As far as complications are concerned, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is also implicated in the occurrence of severe complications, including acute kidney injury and disseminated intravascular coagulation, in pregnant populations. The penultimate complication of acute respiratory distress syndrome (ARDS) is also much more likely to occur in pregnant individuals, requiring use of positive pressure oxygenation or even invasive mechanical ventilation[8]. Women with COVID-19 had a greater risk of admission to intensive care unit (ICU)/high-dependency unit. Among all ICU admissions, women with COVID-19 diagnosis stayed longer than women without COVID-19[2,8].

Given the unique biological characteristics of the mother and fetus, therapeutic interventions during pregnancy necessitate distinct clinical management. Although recommendations for treatment plans are the same for both pregnant and non-pregnant individuals[9], a number of issues need to be considered. Vertical transmission, differences in pharmacokinetics and pharmacodynamics, drug toxicities, and post-natal care are only among the issues that physicians should consider when managing COVID-19 pregnant patients.

We aimed to report our center's experience with COVID-19 pregnant patients, exploring previously reported clinical, therapeutic correlations and outcomes, and set a basis for further discussion.

MATERIALS AND METHODS

We retrospectively recorded the maternal and perinatal outcomes of SARS-CoV-2 positive pregnant women presenting from April 2020 – February 2022 in the emergency obstetric department of a tertiary hospital. Our study was conducted in accordance with the declaration of Helsinki and principles of good clinical practice and was approved by our institution’s review and ethics board (477/24-11/2022).

The study included pregnant women of any gestational age who tested positive for SARS-CoV-2 using reverse transcription polymerase chain reaction and presented to our emergency obstetric department during the study period. Patient demographics, clinical characteristics, pertinent medical history, clinical manifestations, and laboratory values were documented upon presentation. Outcomes and treatment modalities were also recorded, and associations explored.

Preterm delivery is defined as birth occurring before 37 completed weeks of gestation. Gestational age refers to the length of pregnancy calculated from the first day of the last menstrual period. Small for gestational age (SGA) is defined as birth weight below the 10th percentile for the gestational age.

All quantitative variables are described as the median and interquartile range. All qualitative variables are described as absolute frequencies (n) and percentages. χ² test and Fischer’s exact test were used to evaluate the relationships between categorical variables. The Shapiro-Wilk test was used to assess the normality of observed values. Independent-samples t-test was performed for comparison of normally distributed continuous variables across groups. Mann-Whitney U test was used for the rest of the continuous variables. Logistic regression was utilized for constructing prediction models for the need for hospitalization.

RESULTS

Sixty pregnant women were included in our cohort. The median age of the sample was 30 years (IQR, 24-35). The median gestational age at the time of presentation was 36 weeks (IQR, 30-38). Almost half of the women were asymptomatic at presentation (45%). Symptomatic patients presented at a median time of 3 (IQR, 2-7) days following symptom onset, mostly complaining of fever (54.5%) and cough (57.6%), dyspnea while at rest (33.3%), while 33.3% experienced premature contractions. One (1.66%) of them was diagnosed with gestational hypertension (but not preeclampsia), 3 (5%) had gestational diabetes, and 3 (5%) were obese, with a body mass index (BMI) greater than 30. All the women were unvaccinated against SARS-CoV-2 during the study period.

Eventually, 15 participants (25%) were admitted to the hospital. Thirteen (21.6%) women received antiviral medication (remdesivir), whereas 25 (41.6%) received corticosteroids. At the time that this cohort study was carried out nirmatrelvir/ritonavir, monoclonal antibodies, tocilizumab, baricitinib had either not received approval or experience was absent in pregnant population, hence not utilized in our center.

With regard to the recorded pregnancy outcomes, 18 (30%) neonates were delivered preterm, and 4 (6.6%) pregnancies were complicated by obstetric implications (hydramnios, preeclampsia) resulting in fetal distress. Two (3.3%) cesarean sections (CS) due to maternal ARDS were performed. In total, two stillbirths (3.3%) were noted, and one pregnancy ended in miscarriage (1.6%). Six (10%) neonates eventually required admission to the neonatal intensive care unit (NICU), whereas three (5%) were classified as SGA. All mothers survived both COVID-19 and pregnancy, despite 4 (6.6%) requiring invasive mechanical ventilation during the course of their hospitalization. The clinical features of all pregnant women and the treatment modalities used, as well as their recorded hospitalization and pregnancy outcomes, are summarized in Table 1.

Table 1 Patient characteristics (n = 60).

Demographics
Age median (IQR)	30 (24-35)
Gestational week median (IQR)	36 (30-38)
Comorbidities (%)
Hypertension	1 (1.66)
Diabetes	3 (5)
Hypothyroidism	5 (8.5)
BMI > 30	3 (5)
Hematologic condition	4 (6.8)
Former OB/GYN pathology	3 (5)
Symptomatology
Days from onset median (IQR)	3 (2-7)
Asymptomatic (%)	27 (45)
Fever (%/symptomatic)	18 (54.5)
Dyspnea (%/symptomatic)	11 (33.3)
Cough (%/symptomatic)	19 (57.6)
Contractions (%/symptomatic)	11 (33.3)
Pregnancy outcomes (%)
Preterm delivery	18 (30)
Fetal clinical abnormalities	4 (6.6)
Neonatal ICU admission	6 (10)
Miscarriage	1 (1.66)
Still birth	2 (3.33)
SGA	3 (5)
CS due to ARDS	2 (3.33)
Maternal outcomes (%)
Hospitalization	15 (25)
Survival	60 (100)
IMV	4 (6.6)
Pharmacologic management (%)
Corticosteroids	25 (41.6)
Remdesivir	13 (21.6)

BMI: Body mass index; OB/GYN: Obstetric/gynecologic; ICU: Intensive care unit; SGA: Small for gestational age; CS: Cesarean section; ARDS: Acute respiratory distress syndrome; IMV: Invasive mechanical ventilation.

A subgroup analysis of the clinical characteristics and laboratory values of the women admitted to the hospital for the disease was performed. Adverse perinatal outcomes were collectively evaluated as a single composite endpoint, comprising all possible adverse events related to the fetus or neonate, that is, stillbirth, NICU admission, and SGA. Women in need of hospitalization presented with more severe conditions, as reflected in the significant difference in clinical manifestations including dyspnea, severity indices (World Health Organization Clinical Progression Scale, P/F < 400), and laboratory values including lymphopenia, white blood cells, lactate dehydrogenase, C-reactive protein, and ferritin, while presented later in the course of disease (6 vs 0 days since onset in hospitalized and non-hospitalized women, respectively, P < 0.001) (Table 2). All obese individuals, defined as those with a BMI > 30 kg/m², required hospitalization (P = 0.03). The remaining recorded comorbidities did not seem to play a role in the decision to admit, as reflected by the non-significant difference across groups in comorbidity status (P = 0.25). Cramer’s V for increased BMI was calculated to be 0.397, for a decreased P/F ratio of 0.631, whereas for dyspnea it was 0.821, suggesting a strong correlation of all three parameters with hospital admission.

Table 2 Hospitalized vs non-hospitalized pregnant women, n (%).

	Hospitalized (n = 15)	Not hospitalized (n = 45)	P value
Demographics
Age median (IQR)	34 (23-40)	29.67 (26-34)	0.36
Former smokers	2 (13.3)	6 (13.3)	0.584
BMI > 30	3 (20)	0 (0)	0.013
At least one co-morbidity	4 (26.6)	6 (13.3)	0.25
Gestational week median (IQR)	30 (26-36)	36 (34-38)	0.031
Clinical manifestations
Asymptomatic	0 (0)	27 (37.7)	< 0.001
Days from onset median (IQR)	7 (2-9)	2 (2-3)	0.006
Fever (symptomatic)	10 (66.6)	8 (17.7)	0.2
Dyspnoea (symptomatic)	11 (73.3)	0 (0)	< 0.001
Cough (symptomatic)	11 (73.3)	8 (17.7)	0.09
Contractions (symptomatic)	2 (13.3)	16 (35.5)	0.026
Disease severity
WHO CPS median (IQR)	5 (5-6)	2 (1-4)	< 0.001
P/F < 400	10 (66.6)	3 (20)	< 0.001
Need for NIV	6 (13.3)	0 (0)	< 0.001
Need for IMV	4 (8.8)	0 (0)	< 0.001
Pharmacological management
Corticosteroids	13 (86.6)	12 (26.6)	< 0.001
Remdesivir	8 (53.3)	5 (11.1)	0.02
Pregnancy outcomes
Preterm delivery	5 (33.3)	13 (28.8)	0.745
Composite adverse perinatal	5 (33.3)	6 (13.3)	0.09
Laboratory values median (IQR)
WBC (Κ/μL)	6980 (5580-8320)	9110 (7380-11150)	0.01
LYMPH (Κ/μL)	1.142 (0.785-1.570)	1.300 (1.020-1.880)	0.102
CPK (ng/mL)	69 (20-94)	65.5 (35-164)	0.179
LDH (IU/L)	318 (258-376)	210 (178-283)	0.001
CRP (mg/dL)	5.94 (2.09-9.81)	2.34 (1.02-4.47)	0.028
Ferritin (ng/mL)	149 (101-140)	74 (34.5-95.5)	0.001
D-Dimers (μg/mL)	1.470 (0.670-2.180)	1.492 (1.045-2.215)	0.303

WHO CPS: World Health Organization Clinical Progression Score for COVID-19; BMI: Body mass index; P/F: PaO2/FiO2 ratio; NIV: Non-invasive ventilation; IMV: Invasive mechanical ventilation; WBC: White blood cells; LYMPH: Lymphocyte count; CPK: Creatine phosphokinase; LDH: Lactate dehydrogenase; CRP: C-reactive protein.

The gestational age differed significantly between the two groups (30^thvs 36^th median week of presentation for hospitalized and non-hospitalized women, respectively), while the presence of contractions was significantly higher in the non-hospitalized subgroup of pregnant women (P = 0.026). None of the asymptomatic individuals were admitted to the hospital. Preterm delivery rates were not different among hospitalization sub-groups. The composite outcome of adverse perinatal events, including stillbirth, SGA, and NICU admission, did not significantly increase in women hospitalized for COVID-19 (P = 0.09).

Multiple logistic regression revealed that when accounting for a woman’s age, gestational age, and comorbidity status, defined as having at least one reported comorbid condition, days since symptom onset was an independent predictor of hospitalization. For each day of delayed ED presentation, the odds of hospitalization increased 2.3-fold [adj. OR (95%CI: 1.46-3.624), P < 0.001]. Comorbidity status proved to be an independent predictor of hospitalization with marginal significance [adj. OR = 16.13 (95%CI: 1.021-255.146), P = 0.048]. No independent predictors of adverse fetal outcome (composite) were identified, with eventual hospitalization failing to reach statistical significance only by a slight margin (P = 0.054).

DISCUSSION

In our cohort of patients, only a fourth of the unvaccinated pregnant individuals required hospitalization due to disease severity, as reflected in the severity indices. Delay in presentation and the presence of comorbidities seem to predict the need for hospitalization but not composite adverse perinatal events or pregnancy outcomes.

Our findings align with previous authors reporting that the majority of COVID-19 pregnant individuals present and remain asymptomatic through follow-up[5]. When symptoms appear, they do not seem to differ from non-pregnant individuals, although one report noted that pregnant individuals were less likely to present fever, myalgia, dyspnea or cough[1,5,10]. Also, in a subsequent study, fever and cough among pregnant women were reported to be even lower[11]. Delay in presentation was identified as a risk factor for severe disease, hence the need for hospitalization, similar to others[12]. This comes as no surprise since, as the disease progresses, viral toxicity is complicated by the presence of systemic inflammatory response[13].

The extent of vertical transmission (in utero, intrapartum, early postnatal period) remains inconclusive and fluctuates between 1.6% and 6.3%, while the overall rate of congenital infection has been reported to be 2.7%[14,15]. Severe COVID-19, ICU admission or death of the mother, and postnatal infection have all been recognized as risk factors for mother-to-child transmission[14]. To this end, specific strains of the SARS-COV-2 may theoretically increase the likelihood of vertical transmission by causing more severe maternal illness. This is proven for the delta, gamma, and alpha strains. On the other hand, omicron strain results in less placental injury and might be associated with a lower risk of vertical transmission[16]. The median gestational week at the time of presentation at our cohort was found to be 36 weeks (IQR, 24-35), meaning that most of the pregnant women presenting to our center were infected in the third semester of their pregnancy (n = 46, 76.7%); thus, no birth defects would be likely at least attributed to SARS-CoV-2 considering almost completion of organogenesis by the time of infection. Nonetheless, results from an international retrospective cohort study that compared obstetric and neonatal outcomes of SARS-CoV-2-positive patients according to gestational age at the time of infection, showed that maternal infection after 20 weeks of gestation increased the risk for a composite of adverse obstetric outcomes, and maternal infection after 26 weeks increased the risk for a composite of adverse neonatal outcomes, in contrast to earlier infection during pregnancy[17]. Global data have shown that the risk of miscarriage or congenital anomalies does not seem to be increased above baseline in COVID-19 pregnant women, with an overall miscarriage rate of 11%[18-24]. Pre-term delivery was observed in almost 30% of our patients, which could be partly attributed to higher stress during the pandemic and alterations in maternity services[25,26]. However, in general, increased pre-term and moderately increased cesarean section rates have been observed among pregnancies with COVID-19[27-29]. In addition, a study noted a decline in vaginal delivery rates which could be due to the perception that opting for cesarean deliveries could potentially reduce the likelihood of COVID-19 transmission[30]. Nonetheless, the limitation of inability to distinguish between spontaneous and iatrogenic preterm birth persists in many studies. As also noted by these authors, it seems that many third-trimester cases are delivered by planned cesarean, pre-emptively driven by the unproven belief that the management of severe maternal respiratory disease would be improved by delivery. Thus, although spontaneous pre-term deliveries do occur, the reason for the observed rise in pre-term and cesarean section rates seems to be multifactorial[31-33]. Similarly, rates of stillbirth, even though they remained low, cannot be detached from potential co-founders, including disruptions to maternal care and maternal supportive services[25,26,34].

The therapeutic management of the pregnant individuals with COVID-19 does not differ significantly compared to the usual management of the non-pregnant COVID-19 patients, according to the current guidelines. However, there are some exceptions regarding the pharmacological parameters of the treatment due to the differences in volume distribution, the potential toxicities for the fetus, the existence of the vertical transmission, and the lactation and the post-natal care in general. In total, only 21.6% of our cohort received remdesivir with favorable results and no adverse perinatal outcomes. Experience in therapy has mostly come from the compassionate use program and the Gilead Global Safety Database[35,36]. Compassionate use of remdesivir among 86 pregnant women hospitalized with COVID-19 between March 21, 2020, and June 16, 2020, was correlated with high rates of recovery, while rapid deployment valve (RDV) did not raise any new safety signals[35,37]. Early RDV administration was linked to better clinical outcomes, including lower rates of ICU admission and decreased progression to critical disease, prompt improvement, and recovery by day 7 in pregnant individuals hospitalized with COVID-19[38]. In a similar way, early RDV administration was linked to better pregnancy outcomes, such as significantly lower rates of preterm delivery and COVID-19-related maternal death in pregnant patients admitted to hospital[38,39]. A systematic review and a meta-analysis further supported RDV’s promising results in pregnant women with COVID-19 infection, with elevated transaminases as the only notable adverse event, requiring monitoring[40,41].

In our cohort of patients, 41.6% received corticosteroids, the majority of whom were in need of hospitalization. Dexamethasone was associated with a decrease mortality in COVID-19 patients requiring oxygen therapy, thus embedded in international guidelines since the beginning of the pandemic[9,42]. Nonetheless, from the trials that followed, pregnant patients were included only in REMAP-CAP (number of pregnant patients unknown)[43] and RECOVERY (0.06% of participants were pregnant)[42]. RECOVERY trial compared higher dose corticosteroids with standard dose and found that treatment with higher doses leads to increased mortality in COVID-19 patients with hypoxia, who do not require ventilatory support. However, only 3 of the participants were pregnant[44]. Τhe choice of corticosteroid during pregnancy has been based on whether the fetus or the mother was the intended recipient of the medication. In the former scenario, it is preferable for mothers to receive hydrocortisone, methylprednisolone, prednisolone, and prednisone, which are converted by placental enzymes into inactive metabolites and limit fetal exposure to 10%[45-47]. In the latter scenario, when the fetus is being treated, synthetic fluorinated corticosteroids, such dexamethasone, are chosen in order to stimulate fetal lung maturation[45-48]. Associations between corticosteroid administration and adverse pregnancy outcomes, including gestational diabetes, pre-eclampsia, intrauterine growth restriction, congenital malformations, and preterm birth, have been variably reported in the past[46-49]. Also, repeated courses of dexamethasone have been associated with long-term adverse outcomes, such as impaired neurodevelopment[50]. However, evaluating the safety of corticosteroids, and dexamethasone in particular, in this context is still difficult due to a number of confounders, including co-medications and the overrepresentation of high-risk pregnancies in these trials, which inevitably introduce bias[46].

At the time this cohort study was carried out, approval and experience with other agents including tocilizumab, anakinra, baricitinib, nirmatrelvir/ritonavir, tixagevimab/cilgavimab and molnupiravir was scarce or absent; hence we chose not to administer to our patients. Of note, to date, there are recommendations against the use of molnupiravir in pregnant patients due to reported fetal toxicity in animal studies unless there are no other options available and therapy is clearly indicated[9].

None of our patients was vaccinated even though recommendations clearly state that undergoing COVID-19 vaccination–preferably with a non-vector vaccine–should be carried out in all unvaccinated people planning pregnancy or those who are already pregnant[51]. The same applies to booster shots as well as to the updated COVID-19 vaccine[51]. Vaccination early in gestation appears to have higher benefit against maternal risk of COVID-19 related hospitalization, death, and pregnancy complications[52,53]. In a recent study, the effectiveness of mRNA vaccination against SARS-CoV-2 infection after the second dose was 89.5%, a lower risk of stillbirth was observed in the vaccinated cohort compared with the unvaccinated group, and there was no evidence of adverse maternal or neonatal outcomes[54]. Other authors reported that the stillbirth rate among vaccinated women was almost half compared to those who were unvaccinated[55]. In addition, a study noted that the increased pre-term birth risk, which was more pronounced during the early years of the pandemic, disappeared in regions with high vaccination rates[56]. Completing the COVID-19 immunization series by the mother during pregnancy was also linked to a lower incidence of COVID-19 hospitalization in infants less than six months of age[57]. A recent meta-analysis provided further evidence that COVID-19 vaccination is safe and highly effective in preventing maternal SARS-CoV-2 infection without increasing the risk of adverse maternal and neonatal outcomes[58]. Research conducted in Scotland revealed that an overwhelming majority of SARS-CoV-2 infections, hospital visits and critical care admissions were due to unvaccinated pregnant women. Furthermore, all baby deaths reported were attributed to the same demographic[59]. Even with the predominance of the omicron variant, which is typically associated with less severe maternal and neonatal manifestations, the importance of vaccine administration remains significant as demonstrated by a recent study[55,60].

Study limitations

This study cohort was conducted mostly in the absence of available vaccine against SARS-CoV-2. Even when first vaccine regimens were approved, hesitancy prevailed among pregnant population similar to other vaccines, as also highlighted in our study that no vaccinated pregnant patients were included. Similarly, no oral antivirals were available at the time this study took place[61]. Moreover, our data were produced while non-omicron variants were prevailing. It remains to be seen whether similar manifestations and outcomes would be observed in presence of new variants, even though presence of delta variant was associated with more severe outcomes even among pregnant patients[62]. However, reported data thus far regarding infection with the omicron variant during pregnancy indicate that it results in less severe disease and fewer adverse maternal and neonatal outcomes[55,63].

CONCLUSION

For pregnant individuals, the risk of contracting severe disease from SARS-CoV-2 infection is elevated: It is essential for these patients to consult with a healthcare professional at any sign of symptoms. If hospitalization for COVID-19 is indicated for expecting mothers, medical treatment should take place in a facility equipped to monitor both maternal and fetal health. Early detection and management are paramount for optimal results regarding motherhood and newborn care outcomes.