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COVID-19 in Pregnancy

Synopsis COVID-19 infection during pregnancy is associated with severe complications and adverse effects for the mother, the fetus, and the neonate. The frequency of these outcomes varies according to the region, the gestational age, and the presence of comorbidities. Many COVID-19 interventions, including oxygen therapy, high flow nasal cannula, and invasive mechanical ventilation, are challenging and require understanding physiological adaptations of pregnancy. Vaccination is safe during pregnancy and lactation and constitutes the most important intervention to reduce severe disease and complications.


INTRODUCTION
Coronavirus disease 2019 (COVID-19) infection during pregnancy is associated with severe complications and adverse effects for the mother, fetus, and neonate. 1,2 Pregnancy constitutes a risk factor for hospitalization, intensive care admission, and death among COVID-19 women of reproductive age. 3 The physiological adaptations in the respiratory system during pregnancy impose a significant challenge in managing pregnant women who develop acute respiratory distress syndrome (ARDS) in the context of COVID-19 infection. 4 Additionally, the thromboembolic risk of pregnancy increases the likelihood of thrombosis, including pulmonary embolism. 5 Even though this situation was identified during the pandemic, many pregnant women died without access to intensive care units. 6 COVID-19 infection might increase the risk of preterm delivery and stillbirth. 7 Conversely, inconsistent evidence suggests that vertical transmission is probable but infrequent. 8 Despite all pregnancy-related complications during the COVID-19 pandemic, many pregnant patients decline to be vaccinated, assuming uncertainty regarding the safety and protection against current variants. This review summarizes the lessons learned in assessing, managing, and caring for pregnant patients with COVID-19 infection.
A systematic review and meta-analysis focused on the relationship between comorbidities and COVID-19 severity, including thirteen studies and 154 deceased patients. The presence of at least one severe comorbidity showed a twofold increased risk of death. Overall, overweight (BMI > 25 kg/m 2 ) and obesity doubled the risk of death, with no differences in gestational diabetes or asthma.
ICU admission was related to five-fold increased risk of death, with no difference in respiratory support or mechanical ventilation. 15 Another study showed the main predictors of mortality (increase in the odds of maternal mortality (OR: 1.15, [95% CI: 1.05-1.26]) were the need for invasive mechanical ventilation and a more prolonged ICU stay. 16

Pathophysiology of COVID-19 complications in pregnancy
During the pandemic, pregnant women were at significant risk of presenting with more severe forms of COVID-19 infection and a high risk of pregnancy complications. 17 COVID-19 causes a severe systemic inflammatory response associated with vascular alterations that could be of particular interest considering the physiological changes in the immune, respiratory, cardiovascular, coagulation, and renal systems during pregnancy. 18 Alterations of the respiratory system include mucosal edema, capillary engorgement of nasal and oropharyngeal mucosa, and laryngeal tissues. In addition, the diaphragm is displaced 4 cm upward, decreasing functional residual capacity by 10-25% at term. In the cardiovascular system, there is a reduction in systemic vascular resistance that allows the homeostatic control of pregnancy-related hemodynamic changes, an increase in cardiac output, an expanded blood volume, and a decrease in blood pressure. Based on these changes, despite the low level of evidence and some debate raised by the difficulties in achieving improvements in oxygenation during COVID-19, many experts and clinical societies propose an O2 saturation (SpO2) at ≥ 95%. 19 J o u r n a l P r e -p r o o f SARS-CoV-2 causes severe alterations in the cardiovascular system, including the recruitment of inflammatory leukocytes in the vascular tissue, leading to tissue damage and cytokine release, followed by disseminated intravascular coagulation. To an extent, specific clinical responses of pregnant women to COVID-19 could be related to changes in the levels of ACE2 with reduced sensitivity to Ang II. 20 In terms of severity, thrombotic microangiopathy was invoked as one of the mechanisms in severe COVID-19 cases. The protease ADAMTS13 (A Disintegrin-like and Metalloprotease with thrombospondin type 1 motif no. 13) is a marker of microangiopathy responsible for controlling von Willebrand multimer size. Recent evidence shows an imbalance of the von Willebrand/ADAMTS13 axis in pregnant women with COVID-19, indicating that nulliparous women group O showed Willebrand/ADAMTS-13 ratios significantly lower than those in non-O. In this population, the Willebrand to ADAMTS13 ratio was associated with preterm delivery. 21

Obstetric complications associated with COVID-19 during pregnancy
Infection in pregnant women was associated with a higher risk of adverse pregnancy outcomes, such as fetal growth restriction, premature rupture of membranes, fetal distress, preterm birth (delivery before 37 weeks of gestation), spontaneous abortion, and stillbirth. 2 SARS-CoV-2 during pregnancy was associated with a higher risk of developing preeclampsia. 22,23 Table 1 describes accumulative evidence from a total of 706 pregnant women with COVID-19 in 18 countries, demonstrating that the risk of obstetric complications varies according to symptom status. 2 An observational cohort study from the USA involving 683,905 patients, including the pre-and post-pandemic periods (2019 -2021), demonstrated that women with COVID-19 were more likely to experience both early and late preterm birth, preeclampsia, disseminated J o u r n a l P r e -p r o o f intravascular coagulopathy, pulmonary edema, the need for invasive mechanical ventilation and in-hospital mortality than women without  In pregnant patients with COVID-19, the cesarean section rate was high, and iatrogenic preterm birth was reported to be as high as 25%. 25 A recent meta-analysis including 42 studies and 438,548 pregnant women reported that COVID-19 during pregnancy increased the risk of preeclampsia (OR: 2.11), preterm birth (OR: 1.82), and stillbirth (OR: 2.11). 26 Another metaanalysis including 790,754 pregnant women also described an increased risk of preeclampsia in patients infected with SARS-CoV-2. 23 A meta-analysis including forty-five studies with a low-tomoderate risk of bias reported 1,843,665 pregnancies during the pandemic (2020) and 23,564,552 pregnancies during a variable pre-pandemic period (from 2002 to 2019, depending on the studies included). This meta-analysis did not find a difference in the odds of stillbirth between the pandemic and pre-pandemic periods, with an increase in mean birth weight during the pandemic compared with the pre-pandemic period and a reduction in unadjusted but not adjusted estimates of preterm birth. 16

Fetal and neonatal disease
A link between fetal or neonatal disease and COVID-19 has not been well elucidated.
During the pandemic, some data support that being pregnant with COVID-19 increases the risk of adverse pregnancy and birth outcomes and a low risk of congenital transmission. 27 Pregnant women who test positive for COVID-19 seem to be at a higher risk of lower birth weight and premature birth. 28 In a recent publication, the overall miscarriage rate in pregnant women with

Clinical assessment and disease severity
Most pregnant women with COVID-19 present with mild to moderate symptoms (81-86% of cases) and are monitored as outpatients for 7 to 14 days after the onset of symptoms. 36 More than 70% of infected women were in their third trimester, with no evidence that supports an association between gestational age and COVID-19 mortality and morbidity. 37 However, SARS-CoV-2 was more severe in pregnant women than in the general population, with an increased risk of hospital admission, with 5% developing a severe form requiring ICU admission and J o u r n a l P r e -p r o o f approximately 35% requiring intubation, with a maternal mortality of close to 2.7%. 25 The most common symptoms were fever, cough, chest pain, dyspnea, and fatigue. 38 Pregnant patients appear to present more commonly with more advanced COVID-19 chest tomography findings than the general adult population, but characteristic laboratory abnormalities are similar to the general population. 38

Pharmacological interventions
Six studies involving a total of 599 women reported pharmacological treatment of COVID-19 in pregnancy that included antiviral therapy, systemic corticosteroids, antibiotics, and immunotherapy; however, the types and doses of the medications were not specified. 42 Antenatal corticosteroids may be used routinely for fetal lung maturation between 24 and 34 weeks.
However, clinicians should make decisions in those < 24 or > 34 weeks of gestation on a case-bycase basis. Magnesium sulfate may be used cautiously for seizure prevention in the context of severe preeclampsia and fetal neuroprotection to reduce the risk of cerebral palsy associated with prematurity in those with hypoxia and renal compromise. Thromboprophylaxis in pregnant J o u r n a l P r e -p r o o f patients with COVID-19 should consider disease severity, the timing of delivery to disease onset, inpatient vs. outpatient status, underlying comorbidities, and contraindications to the use of anticoagulation. 43 To date, corticosteroids, particularly dexamethasone, are the most proven and recommended treatment for pregnant patients with COVID-19 who are mechanically ventilated or require supplemental oxygen. 44 Although no subgroup analysis was performed on pregnant women, the RCOG and the WHO stated that no harm is expected from steroid use. Concerns about pregnancy safety led to recommending prednisolone as the first choice instead of dexamethasone because prednisolone is extensively metabolized in the placenta, with minimal transfer to the fetus.
Other options are methylprednisolone or hydrocortisone for pregnant women. 45 Antivirals with different mechanisms of action, such as protease inhibitors and nucleotide or nucleoside analogs, have been proposed for COVID-19 treatment. 46  Although some studies describe the effects of hydroxychloroquine and antibiotics, this has now been shown not to be beneficial and is not recommended for either nonpregnant patients or pregnant women. Adverse events with treatment were three-fold higher than placebo, but very few serious adverse events were found. 52 Case reports suggest that convalescent plasma administered to pregnant women with severe COVID-19 benefits both the mother and the fetus. However, these studies suffer from relevant reporting bias. 53 Clinical trials to investigate the use of convalescent plasma for COVID-19 during pregnancy are lacking. More recent evidence showed no benefit, including in pregnant and nonpregnant populations. 54 The use of convalescent plasma in patients who tested negative for anti-SARS-CoV-2 antibodies at baseline has not been associated with improved survival (RR 0.94, 95% CI 0.87-1.02). In patients with COVID-19, treatment with convalescent plasma, compared with control, was not associated with lower all-cause mortality or improved disease progression, irrespective of disease severity and baseline antibody status. 53 Immunomodulators (tacrolimus), interferon, and J o u r n a l P r e -p r o o f inhaled nitric oxide in pregnancy and lactation are not routinely recommended and need further evaluation. 55

Nonpharmacological interventions for COVID-19 in pregnancy
In the context of moderate to severe COVID-19 infection, the same treatment principles apply to pregnant women and nonpregnant patients regarding nonpharmacological interventions, such as oxygen supplementation or mechanical ventilation. However, invasive mechanical ventilation is arduous in pregnant patients. This is due to the increased demand for oxygen in pregnancy secondary to a higher metabolic rate and increased oxygen consumption. The gravid uterus contributes to ventilatory impairment, and achieving the required volumes during mechanical ventilation can be challenging. 56 Prone positioning has been proven to help ventilate patients in the presence of ARDS.
Although no trials include pregnant women, techniques describe how proning can be performed in this group of patients. For example, some authors describe how they place pillows in a specific way to put the pregnant woman in a comfortable position without compromising the pregnancy. 57 However, this should not be practiced in patients with a wound from a recent cesarean section (first two weeks) or when pregnancy is over 34 weeks pregnant; the heavily pregnant uterus can make this position more difficult. Furthermore, after 24-28 weeks, there is the risk of aortocaval compression when proning a pregnant woman.

Oxygen therapy, high flow nasal cannula, and ventilatory support
International guidelines recommend maintaining a SpO2 > 94% in pregnancy. Another recommendation focuses on supplemental oxygen modalities, including a face mask or high flow nasal cannula (HFNC). Using HFNC in patients with severe COVID-19 decreased the need for mechanical ventilation support and time for clinical recovery. Despite these benefits, pregnancy-J o u r n a l P r e -p r o o f specific or COVID-19-related interventions are poorly reported in the published literature. None of the randomized trials using HFNC reported outcomes in pregnant women or pregnancy was an exclusion criterion. 58 Comparative data for pregnant women for treatments proven effective in the general population lack clinically meaningful interpretation. Thus, despite a potential benefit, there is little evidence to support recommendations regarding using HFNC in obstetrics.
Eleven studies reported nonpharmacological interventions, of which mechanical ventilation was reported in six studies and oxygen administration in eight. In total, 1738 women were included in these studies; 240 were exposed to interventions, 28 patients had mechanical ventilation, and 212 had oxygen administration. 42 Prone positioning remains a well-proven intervention in ARDS and should be considered in pregnant women when indicated. We recognize that proning might not be effective in all cases. However, prone positioning is an option to improve oxygenation in patients with moderate to severe hypoxemia (PaFiO2 ≤ 150 mmHg) before considering delivering a premature infant or maternal cannulation for extracorporeal membrane oxygenation (ECMO). 57 The use of ECMO in pregnancy has increased, and evidence supports its use, feasibility, and favorable outcomes. A recent publication, including six ECMO centers from three different continents and 60 cases over ten years, describes a maternal survival rate of 87% with an acceptable neonatal outcome. 59