Prevention, Evaluation, and Management of Coronavirus (COVID-19) in Pregnancy and Puerperium

Etiology

The disease is caused by an encapsulated ribonucleic (RNA) virus – severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), which belongs to the family of viruses Coronaviridae.[8] This group of viruses also houses the SARS-CoV1 virus, the culprit for the previous ‘SARS’ pandemic in 2005 and the Middle East respiratory syndrome coronavirus (MERS-CoV).[9] 

The origin of the virus remains a hotly debated topic, but one of the propounded theories involves a complex lineage involving wild bats, pangolins, and/or seafood.[10][11][12] The droplet-borne virus enters the respiratory tract and attaches to the ACE2 receptors on the human cells, which allow further entry into the cells themselves.[13] Further replication within the cell and the initiation of an inflammation cascade results in the characteristic respiratory manifestations of the disease.

Epidemiology

As per the data published by the Centers for Disease Control and Prevention (CDC), about 150,000 pregnant women have contracted COVID-19 in the United States of America (USA) as of December 2021. The CDC publishes data related to the same on its website and a dedicated Morbidity and Mortality Weekly Report (MMWR). The last dedicated pregnancy-related documents published were in November 2021.[14][15] 

Among these, as per available data, about 25,000 women required hospitalizations, and about 600 needed intensive care admissions. About 250 women were reported to have succumbed to the disease. The largest number of women with reported infections belonged to the age group of 25 to 29 years, closely followed by the 30 to 34 years age group. White, non-Hispanic women and Hispanic women, in that order, were the largest ethnic sub-groups in the infected population.

From the available data of about 38000 live births, about 4000 were preterm births. Where data from testing infants born to women with COVID-19 was available, about 150 of nearly 3300 infants had tested positive for COVID-19 during their birth hospitalization.

Nearly 40% of the surveyed pregnant women were fully vaccinated with either the two-dose series of mRNA-1273 or BNT162b2 or the single-dose regime of the Ad26.COV2.S vaccine.

Results synthesized from international publications, which included some data from the USA, show that preterm birth was the commonest adverse outcome worldwide.[16] About 3.7% of more than 4000 neonates tested positive for COVID-19 worldwide, which is less than half of the fraction reported in the updated CDC data for the USA.[14]

History and Physical

A systematic review of the published data regarding COVID-19 in pregnancy reported that fever, dyspnea, and cough were the most common symptoms experienced by the patients.[17] Generally, in the first week, the patient is likely to exhibit symptoms suggestive of upper respiratory disease, and during the following week, lower respiratory symptoms develop if the disease progresses. Based on the other systems involved, the patients may present with extra-pulmonary symptoms such as palpitations, syncope, diarrhea, abdominal pain, and so on.[6]

Similarly, the patient may present with an obstetric complication of COVID-19 as a part of her presentation. However, given the non-specificity of the complications, a retrospective diagnosis of COVID-19 may not be easy.

A patient's travel history has become more relevant than before in the present pandemic times.[18] Policy decisions regarding diagnostic algorithms are likely to be influenced by the location.

Contact history is also extremely important. Decisions regarding quarantine, assessment of the risk of progression to severe disease, and exploring the option of post-exposure prophylaxis are all dependent on a good contact history.

While examining an obstetric patient, one should now remember to ask for a vaccination history and a history of being previously infected with COVID-19. Patients who are incompletely vaccinated or unvaccinated are at higher risk of progressing to severe COVID-19.[19]

Similarly, with waning immunity, it is relevant to know the date of the final dose in a vaccination series as well. Knowing the patient's COVID-19 illness history is vital for deciding when to vaccinate next.[20] The relevant treatment history if previously infected would include knowing whether a monoclonal antibody product was used or not, which may further influence the timing of vaccination.

History of comorbid illnesses helps risk stratification and influences management. Comorbid illnesses as classified by the CDC, which portend higher risk for severe illness, are patients with cancer, chronic kidney disease, chronic liver disease, chronic respiratory diseases, recipients of stem cell transplants on immunosuppression, obesity, diabetes, and hypertension. Women older than 25 years of age, those living in high transmission areas, those living in areas where appropriate social distancing is not feasible, those living in areas with low vaccination rates, and those belonging to certain racial minorities (Black, Hispanic, American Indian and Alaskan). The list continues to change per the evolving evidence.[21]

Physical examination of a patient with COVID-19 mimics the spectrum of the disease itself, with no abnormal findings in the asymptomatic, to signs of acute respiratory distress syndrome in severe cases.

Markers on physical examination of an additional risk factor for poor outcomes would include a high body mass index (BMI) (>30 kg/m2), signs of chronic steroid use, and stigmata of liver disease.

Tachycardia, tachypnea, hypoxia (on pulse-oximetry), use of accessory muscles of respiration, and crackles on lung auscultation are the likely findings of the respiratory examination. Chest pain, hemoptysis, and unilateral lower limb swelling could indicate venous thromboembolism. Arrhythmias, hypotension, and peripheral edema could instigate an evaluation for myocardial dysfunction.[22]

From the obstetric point-of-view, the patient may present with pain in the abdomen, regular progressive uterine contractions, leaking per vaginum, and a dilated cervix on examination: the classical presentation of preterm birth. A tender abdomen reduced fetal movements, and a non-reassuring cardiotocograph may all indicate placental abruption, which has also been seen with COVID-19. The association of abruption and COVID-19 has yet been unequivocally established, but literature in favor of the same has been published.[23]

Evaluation

The gold standard test for the evaluation of a COVID-19 suspect, presently, is an RT-PCR of the appropriate respiratory (nasopharyngeal or endotracheal or bronchoalveolar lavage) samples.[24] Placental tissue, cord blood, etc., have been tested, albeit with limited sensitivity compared to respiratory samples.[25] Antigen testing, though specific, is less sensitive.

A case with respiratory distress in pregnancy is likely to have several differential diagnoses.[26] The assessment must be a multidisciplinary effort, given the myriad of presentations and complications of COVID-19. For suspected COVID-19 pneumonia, a pregnant patient can undergo radiological investigations as necessitated by the condition. Essentially, if ionizing radiation is necessitated in the form of a CT scan or an X-ray, the same should not be denied because of the pregnancy.[27] 

COVID-19 is associated with an increased risk of pulmonary embolism.[28] The routine assessment for a patient with suspected embolism in pregnancy would continue as a non-COVID-19 afflicted pregnancy. Those with signs of venous thromboembolism may benefit from a bedside venous ultrasound of the lower extremities. A lung ultrasound, with the ‘BLUE’ (Bedside Lung Ultrasound in Emergency) protocol, may help further diagnose the cause for respiratory distress in a patient, which may include pulmonary edema (cardiogenic and non-cardiogenic), pulmonary embolism, pneumonia, and even identify pneumothoraces or pneumomediastinum early.[29] A modified protocol called M-BLUE has also been proposed.[30]

Blood investigations for the patients include routine blood investigations, including a complete blood count (CBC) with differential, liver, and renal function tests. The CBC may show signs of a typical viral disease with leukopenia or another cell line depression. Patients presenting late in the illness may show leukocytosis suggestive of a secondary bacterial infection. A neutrophil-lymphocyte ratio (NLR) may be of prognostic significance, with high ratios closely related to poor outcomes.[31]

Liver function tests may show raised transaminase levels in the patients at baseline.[32] Remdesivir and tocilizumab are both likely to raise the transaminase levels, and as per the label, a ten-times rise from baseline will require a dose reduction or omission. Renal function assessment may detect early onset acute kidney injury. A d-dimer level in the non-pregnant patients may help guide decision-making for imaging. However, in the pregnant patient, a D-dimer value may be of limited value in the evaluation. Predictive scores for thromboembolism are not validated for use in pregnancy.[33] 

IL-6 levels, CRP levels, and ferritin levels may help assess the level of inflammation.[34] Although none may be needed to initiate therapy in a rapidly progressing patient who will be given anti-inflammatory drugs like tocilizumab, based on a clinical decision.

An electrocardiogram, echocardiography, and cardiac enzymes may be relevant in individual cases with suspected myocarditis.[35]

From the obstetric point of view, a patient with COVID-19 pneumonia can undergo cardiotocography to assess fetal well-being. Depending on the presentation, ultrasonography or magnetic resonance imaging to assess for preterm birth (by cervical length measurement) and fetal parameters to estimate corresponding gestational age in a patient may be necessary.

Treatment / Management

Management of COVID-19 during pregnancy and the puerperium should be an interprofessional approach involving obstetricians, pulmonologists, and neonatologists at the very least. The decision to use investigational drugs and any drug under emergency-use authorization must be made as a team while explaining the risk-benefit ratio of the same to the patient.

Medical Management

• Oxygenation: Though it does not vary significantly in most aspects from non-pregnant individuals, one of the basic differences is the threshold for oxygen supplementation, which is at <95% in pregnant individuals. This is to ensure adequate oxygen delivery to the fetus.[36] Non-invasive and invasive ventilation initiation is guided further as per the patient's respiratory status.
• Remdesivir: Remdesivir is beneficial in both preventing disease progression from mild to severe and preventing worse outcomes in severe disease; however, the major studies for its use did not include pregnant or lactating mothers. A few case reports and series have seen its use on compassionate grounds. The NIH also advises physicians not to withhold it in pregnant women when there is an appropriate indication.[37][38] 
• Monoclonal antibody therapy: It is presently recommended for patients with mild COVID-19 and risk factors for progression to severe disease. The presently available monoclonal antibodies with EUA are bamlanivimab-etesivimab, casirivimab-imdevimab, and sotrovimab.[39] The National Institutes of Health (NIH) guidelines note pregnancy as an independent risk factor for severe disease. Though there is no large, direct pregnancy-related data, the risk-benefit ratio and the previous evidence for tolerance of other IgG antibodies suggest that one must consider their use even in pregnancy.[40] The American College of Obstetricians and Gynecologists (ACOG) notes that at times, a patient's pregnancy may be the only risk factor, and, in such cases, patients with an additional risk factor may be considered for monoclonal antibody therapy. An additional indication for monoclonal antibody therapy is for post-exposure prophylaxis in unvaccinated, incompletely vaccinated, and those with factors that would lead to poor immune response development.[41]
• Interleukin-6 (IL-6) inhibitors: Tocilizumab or sarilumab, which are presently indicated in patients with a rapidly increasing oxygen requirement, cross the placental barrier and may have an immunosuppressive effect on the fetus.[42] Hence, they are not recommended in pregnant patients presently. However, a discussion with the patient or the relatives of a rapidly deteriorating patient is essential before entirely ruling out the use of these medications.
• Janus Kinase (JAK) Inhibitors: Baricitinib and tofacitinib also are likely to cross the placental barrier.[43] However, retrospective analyses of patients who have been given tofacitinib for rheumatological diseases and ulcerative colitis have shown no additional adverse events.[44][45][46] However, as the drugs reach the fetus, embryopathy cannot be entirely refuted.
• Anticoagulation: Pregnant patients who require hospitalization for COVID-19 are eligible for prophylactic anticoagulation as in non-pregnant individuals.[47] Similarly, the regime must be discontinued on discharge. However, in the peripartum period or with per vaginal bleeding, the risk-benefit ratio of even prophylactic anticoagulation must be appropriately weighed. A patient who has been on anticoagulation, before the diagnosis of COVID-19, for other causes can continue the same. The choice of anticoagulants in pregnancy are heparins, and between unfractionated heparin and low-molecular-weight heparin (LMWH), the latter is preferred.[48] Unfractionated heparin provides the shortest off-anti-coagulation period (6 hours) and is thereby convenient for decision making. But monitoring of aPTT levels for adequacy of anticoagulation is necessitated. LMWH requires a longer period of anticoagulation (12 to 24 hours) before intervention may be performed but generally needs no further monitoring. Warfarin needs several days of washout and is as such avoidable in the antepartum period but may be considered postpartum given that it is not secreted in breastmilk.[49] However, warfarin also requires INR monitoring and has several dietary and genetic factors which influence its absorption and efficacy. Postpartum, anticoagulation if indicated, must be initiated after the epidural catheter has been removed with a minimum gap of 4 hours. However, factors like needle insertion trauma and the bleeding risk of the patient may influence the decision.[33] Novel oral anticoagulants are presently not recommended for pregnant or lactating mothers due to the lack of safety data and the possibility of transplacental passage, given the smaller molecular size.[50]
• Other drugs: Other experimental drugs inclusive of zinc, ivermectin, plasma therapy, nitazoxanide, etc., either have insufficient evidence for recommendations for use presently or are not recommended, and thereby any use in pregnancy must be approached on the merits of the individual drugs. An exhaustive list of the same is available in the NIH guidelines.
• Prone Positioning: Of the non-pharmacological approaches, one of the challenges is proning during pregnancy. Patients eligible for prone positioning for hypoxemia can undergo proning in early pregnancy like a non-pregnant individual. However, proning with the gravid uterus becomes a challenging prospect with advancing gestational age. Appropriate padding above and below the uterus to avoid aortocaval compression and thoracic compression must be ensured. If full proning is not feasible, left lateral decubitus may also be used for pregnant patients.[51]
(B3)

Obstetric Management

It is advisable that pregnant patients suspected of or diagnosed with COVID-19 who require hospitalization be hospitalized at a center with the capability for maternal and fetal monitoring as per need. Presently ACOG has not recommended additional visits or monitoring for pregnant patients with COVID-19. The mode of delivery should be determined as per routine obstetric indications for any mode.[52] 

COVID-19 pneumonia in pregnancy is not an independent indication for a Caesarean section per se. Steroids are not needed if the patient is not hypoxemic unless indicated for fetal maturity as per a routine obstetric indication. Conversely, if steroids are indicated for COVID-19 pneumonia, they must be given as would be for a non-pregnant individual.[53]

Management of Concomitant diseases and Vaccination Decisions

Patients who have been advised to take inhaled corticosteroids or systemic steroids for other systemic pathologies must continue their steroids irrespective of the COVID-19 infection.[54][55][56] However, patients who have been on long-term systemic steroids may be unable to mount an adequate immune response once vaccinated.[57] Hence these patients should receive an additional dose of vaccine for the mRNA schedule. Additionally, a booster dose is indicated as per routine for all patients who have completed a course of vaccination and have completed six months since the last dose. 

Post-natal Management

It is important to establish that a shared-decision-making approach is presently the best for post-natal management of the mother and child. The ACOG, NIH, and American Academy of Pediatricians (AAP) have released their statements and/or guidance documents regarding the same.

Separation of the mother and child is inevitable in the event either suffer from a severe illness, which requires further management, which will hamper breastfeeding and/or contact. Additionally, separation may be opted for in circumstances where the mother is suspected or confirmed to have COVID-19, and the child is at high risk for severe illness (e.g., a premature child).[58]

Mothers must be counseled regarding the possibility of the passage of any investigational drug that they may be prescribed through breast milk and the paucity of information regarding the effects on neonates. This will empower them to participate better in the shared decision-making process regarding breastfeeding.

If symptomatic, mothers may opt to stay away from their children for the period of infectivity, roughly ten days from symptom onset for mild or moderate illness and 20 days for severe illness or in immunocompromised conditions with prolonged viral shedding. However, a practical problem could exist in patients who are eligible for a discharge before the completion of the isolation period. In these cases, if the home isolation is such that it makes mother-child separation unfeasible, a policy of separation during the hospital stay may not change the risk of the child.

Additionally, if a child has been tested during the birth hospitalization and tests positive, there is no need to separate the pair unless necessitated for medical intervention.

Testing children of mothers with suspected or diagnosed COVID-19 is unlikely to influence therapy considerations for the neonates given the absence of approved specific therapy. Testing may be considered to identify the need for infection control practices while handling the children, as per availability and hospital policy. As per AAP, a 48-72 hourly testing regime to ensure mucosal clearance of the virus can be followed. For a child who tests positive for COVID-19 and remains asymptomatic, a follow-up for at least two weeks is recommended even if discharged.

For mothers who opt to stay away from their children during the infectious period, breast pumps may be provided to encourage breast milk expression. For pairs that are together, masking should be a policy for the mothers and NOT for the neonates. In the inter-feeding period, distancing by six feet to minimize exposure is advisable.

The risk of anxiety, depression, and several disorders in the anxiety disorders spectrum increases after COVID-19. Facilitating counseling and psychiatry consult as per the patient's need while actively observing for signs of these anxiety disorders is essential. This includes at least one postpartum screening attempt with a questionnaire. This effort must be taken irrespective of an antepartum assessment, given that the risk continues for a year postpartum.[59](B3)

Differential Diagnosis

Differentials for the case depend on the involved system and, at times, the gestational age at presentation. A few are discussed below:

Atypical Pneumonia Due to Other Viruses or Organisms

Influenza, mycoplasma pneumoniae, and pneumocystis carinii pneumonia (in immunocompromised hosts) may present similarly in a pregnant patient, either clinically or radiologically. An RT-PCR for COVID-19 and Influenza, induced sputum for pneumocystis, and cold agglutinin titers may help establish a diagnosis in times of doubt. Given that the host for pneumocystis is immunocompromised, co-occurrence of severe COVID-19 has also been reported. 

Venous Thromboembolism

A patient in severe respiratory distress may have a pulmonary embolism as the chief cause of the cardiorespiratory compromise rather than severe pneumonia alone. Assessment with a CTPA (with an abdominal shield) may help differentiate patients from those with severe COVID-19 or COVID-19 associated ARDS.[60] COVID-19 and pregnancy both being risk factors for thromboembolism. This differential needs to be considered carefully. Standard society guidelines may be followed to rule out an embolism. Amniotic fluid embolism (and other non-thrombotic embolism syndromes) are also differentials.

Peripartum Cardiomyopathy

In the last trimester and the immediate postpartum period, patients may present with symptoms of acute respiratory distress, which may be attributed to COVID-19 on the pre-test probability of the same in the times of pandemic. However, a vigilant physician will pick up cases with possible peripartum cardiomyopathy, where the patient may present with signs of left ventricular failure and breathlessness. Certain authors have also published cases suggesting COVID-19 as the cause of cardiomyopathy in their patients.[61]

Heart Failure of Various Etiologies

Myocarditis may be attributable to COVID-19, and a patient in distress must be evaluated with an electrocardiogram and cardiac enzymes at the very least. A transthoracic echocardiogram may help identify any ventricular dysfunction that may be present.[62] Stenotic heart disease and associated pulmonary edema may also present with respiratory distress and overlapping radiological features.

HELLP Syndrome

Several reports have suggested that COVID-19 could mimic, be associated with, or overlap with the catastrophic HELLP syndrome. Management of the same is similarly challenging and requires systematic efforts to avoid adverse maternal and fetal outcomes.[63]

Other extra-pulmonary symptoms will have their own set of differential diagnoses, as per the involved system. Similarly, several radiological differentials for a patient with COVID-19 are independent of the pregnancy status.[60]

Prognosis

Women who recover from COVID-19 during their pregnancy may have an uneventful pregnancy further. No alterations in the time for delivery need to be made for the same. Those in the later trimesters may be at risk of preterm births, stillbirths, pre-eclampsia, and placental abruption. However, the absolute risk of all of the outcomes is constantly being re-evaluated as more data is collected.[64] 

Persistent symptoms may be seen after an acute episode of COVID-19 in pregnant patients as well, the colloquial “long COVID.” One of the adopted definitions for long COVID or late sequelae of COVID is symptoms that last beyond four weeks or 28 days of the acute illness.[65]

Fatigue, joint pains, and chest pain are the common complaints of the patients suffering from the same. Patients who suffer from severe COVID or ARDS have higher chances of developing post-COVID fibrotic sequelae.

Complications

Complications of COVID-19 in pregnancy include the following:

• Maternal: Acute respiratory distress syndrome, pulmonary embolism, arrhythmias, placental abruption.
• Fetal: Preterm birth, stillbirth

Each of the complications, in principle, is to be managed, medically or surgically, similar to a non-COVID-19 case, and patients must be informed in advance regarding the possibility of such complications in the future.