Saudi Society of Maternal-Fetal Medicine guidance on pregnancy and coronavirus disease 2019

1.1. Severity and progression during pregnancy

Pregnancy is a state of partial immunosuppression in which pregnant women are more vulnerable to viral infections, and morbidity is higher, even with seasonal influenza. Consequently, the COVID-19 pandemic may have serious effects in pregnant women. Furthermore, it is important that pregnant women and their families, as well as the general public and healthcare providers, receive the most accurate information available.

As has been observed with other related coronavirus infections (SARS-CoV and MERS-CoV) and with other viral respiratory infections, such as influenza, pregnant women might be at a greater risk for severe illness, morbidity, or mortality compared with the general population.8 A study of one series of hospitalized non-pregnant patients in China found that up to 32% of individuals developed severe pneumonia and 19% of all infected hospitalized patients progressed to acute respiratory distress syndrome (ARDS), with mortality ranging from 1.4% to 4.3% across all cases.^9,10 These figures varied according to regions and different testing strategies.

Signs and symptoms of COVID-19 during pregnancy are expected to be similar to those in the general population. The most common clinical features of COVID-19 in hospitalized patients are fever (99%), fatigue (70%), dry cough (59%), anorexia (40%), myalgia (35%), dyspnea (31%), and sputum production (27%). The most serious frequent presentation of COVID-19 is pneumonia.11 A systematic review of 108 pregnancies reported that most data were collected from women presenting in the third trimester. Fever was present in 68% of patients, 34% of patients had cough, and 91% of the 108 pregnancies involved cesarean section deliveries.12

1.2. Adverse pregnancy outcomes and congenital anomalies

The lack of evidence related to vertical transmission of SARS-CoV-2 in the first trimester is a limiting factor in determining the risks of teratogenicity related to the virus itself. The majority of severe cases of COVID-19 have been reported in the third trimester.13

Currently, there is a lack of evidence concerning the risk of miscarriage or early pregnancy loss in mothers infected with SARS-CoV-2. However, SARS has been reported to be associated with a high miscarriage rate of 57%.14 This finding should be taken into consideration, as the underlying pathology between SARS-CoV-2 and SARS appears to be similar.

At present, based on limited data, there is no evidence that the virus is teratogenic and there is no increased risk of fetal congenital anomalies in pregnant women with COVID-19. Furthermore, data in relation to SARS suggest no increase in fetal congenital anomalies.15

Adverse health outcomes, including respiratory distress, prematurity, and even fetal death, have been found in infants born to mothers affected with COVID-19. However, it is unclear whether these adverse outcomes are related to COVID-19 infection itself or to the mother’s condition.

1.3. Vertical transmission

Owing to the recent emergence of the COVID-19 pandemic, data are limited and vertical transmission of this virus is uncertain. Chen et al13 reported on 9 pregnant women with COVID-19 in their third trimester. In that study, samples were obtained from amniotic fluid, cord blood, and neonatal throat swabs, and 6 patients tested negative for COVID-19 for these samples. These results indicated that in women who had developed COVID-19 infection in the third trimester and had been tested, no evidence of intrauterine infection due to vertical transmission was found.

In March 2020, Schwartz reported an extensive analysis of 38 pregnant women with COVID-19, their newborn infants, and maternal-fetal transmission of SARS-CoV-2, maternal COVID-19 infections, and pregnancy outcomes.16 The analysis concluded that there were no confirmed cases of intrauterine transmission of SARS-CoV-2 from mothers with COVID-19 to their fetuses. All neonatal specimens tested using real-time polymerase chain reaction for SARS-CoV-2 were negative.

In a recent study involving 6 neonates born to mothers with COVID-19, no evidence of vertical transmission was reported.13 However, a recent report published on March 2020 by Dong et al17 described a case of a neonate born to a mother who tested positive for SARS-CoV-2 IgM, which may represent a neonatal immune response to maternal infection. In another report, Zeng et al18 reported test results concerning 3 neonates who tested positive for SARS-CoV-2 on nasopharyngeal and anal swabs. More recently, 2 additional cases involving newborns who tested positive for SARS-CoV-2 have been reported.^19,20

Considering the limited data, newborns of mothers with COVID-19 should be monitored carefully for evidence of transmission.

2.1. Antenatal care of women not suspected or confirmed to have COVID-19

Social distancing is the most important intervention during a pandemic.21 The first priority for physicians caring for pregnant women is to prevent disease spread; therefore, the standard antenatal appointment schedule may need to be modified to minimize direct contact while maintaining adequate maternal and fetal care.

In low-risk populations, reducing the number of in-person antenatal visits is encouraged to minimize exposure and support social distancing. In the inverted pyramid of antenatal care proposed by Sonek et al,22 an early visit is recommended between 11 and 13 gestation weeks to determine dates, undertake prenatal blood tests, and perform risk assessment. If a patient is deemed to be low-risk, subsequent antenatal visits can be arranged at the following gestational ages: 20, 37, and 41 weeks. This model might be used as an alternative to the traditional model of care. In-person visits can involve an office visit or a home visit, depending on each healthcare institution’s resources and available healthcare personnel.

Telehealth use has grown noticeably in the past few years globally and in the past few months in Saudi Arabia. Multiple successful examples have been reported from local healthcare institutions.23 One university hospital in Saudi Arabia has been communicating with patients through the WhatsApp application to address all non-urgent questions and relevant matters to minimize obstetric triage visits. Refill prescriptions are sent to patients’ homes via mail delivery to avoid patients arriving at hospitals to collect their medication. Another hospital has used a simple telehealth method of telephoning the patient prior to her clinic visit. If care can be provided over the phone, the in-person visit is rescheduled to a later date. These are individual and local attempts to adapt to the global COVID-19 pandemic. There is no robust evidence to support any approach over another in implementing social distancing while providing appropriate antenatal care.

Hospitals need to understand their patient populations and resources in devising a system that provides antenatal care while enhancing social distancing. A suggested care model that combines both telehealth and in-person visits is summarized in Table 1. For high-risk patients, care should be individualized and tailored to patients’ needs and fetal condition.

2.2. Antenatal care for women with suspected or confirmed COVID-19

Patients’ risk for COVID-19 should be assessed prior to their hospital visit for antenatal care. For suspected COVID-19-positive stable pregnant women, investigation and isolation should be implemented according to Saudi Ministry of Health (MOH) protocols, and any antenatal care appointment should be rescheduled after 14 days. The Royal College of Obstetricians & Gynaecologists (RCOG), London, United Kingdom recommend that all routine appointments (for example, growth scans and oral glucose tolerance tests) for women with suspected or confirmed COVID-19 should be delayed until after the recommended period of isolation.24

Antenatal care for high-risk pregnancies in women with suspected or confirmed COVID-19 should be individualized. In this population, when maternal or fetal monitoring cannot be delayed, appointments and fetal scans can be arranged preferably at the end of the working day.23 For hospitalized patients, a portable ultrasound machine for fetal surveillance can be assigned to these cases if hospital resources allow. Staff providing care should apply personal protective equipment (PPE) precautions, as the Saudi Center for Disease Prevention and Control guidelines have indicated.25 Clinical areas exposed to these patients should be appropriately sanitized and equipment properly disinfected.

However, concerning pregnant women with poorly controlled comorbidities who are suspected to have COVID-19, admission can be discussed by a multidisciplinary team and individualized depending on the patient’s status and the institution’s capacity and policies. Comorbidities include, but are not limited to, hypertension; diabetes mellitus; asthma; human immunodeficiency virus-positive; chronic heart, liver, lung, and kidney diseases; hemoglobinopathies; and patients on immunosuppressive agents.

All pregnant women confirmed as having COVID-19 should be admitted and managed as inpatients, in accordance with Saudi MOH guidelines.

2.3. Hospital care for patients with suspected or confirmed COVID-19 (Appendix 1)

Patients with suspected/confirmed COVID-19 who require admission should be isolated in a negative-pressure room, preferably in hospitals with adequate facilities and multidisciplinary expertise to manage critically ill obstetric patients. Based on clinical evaluation, they should be triaged and stratified into mild, moderate, severe, and critical categories (Table 2).24

Patients should be managed by a multidisciplinary team comprising specialists in maternal-fetal medicine, infectious diseases, anesthesiology, neonatology, and intensive care (Table 3). All medical staff caring for patients with COVID-19 should use PPE, including head covers, gowns, N95 masks, goggles, gloves, and shoe covers.

3.1. Chloroquine/hydroxychloroquine and azithromycin

Chloroquine and hydroxychloroquine are effective in inhibiting SARS-CoV-2 infection in vitro. Hydroxychloroquine is observed to have a more potent antiviral activity.26 The use of chloroquine has been included in treatment guidelines from China’s National Health Commission and has been claimed to be associated with reduced progression of disease and duration of symptoms.^27,28 However, there are no published primary data to support these claimed associations.

There are limited clinical data on either of these medications. In an open-label study of 36 patients with confirmed COVID-19, hydroxychloroquine administration (200 mg twice daily for 10 days) was associated with a 70% negative result of a nasopharyngeal PCR swab at day 6 compared with a 12.5% negative result in patients with no specific treatment.29 In this study, azithromycin was used in combination with hydroxychloroquine.

Despite the limited clinical data and given the relative safety of short-term use of hydroxychloroquine, the lack of known effective interventions and antiviral activity, some evidence (based on expert opinion) has shown that it is reasonable to use this agent in hospitalized patients with severe or risk for severe infection, particularly if they are not eligible for other clinical trials.30 Optimal dosing is uncertain; various regimens are being used, including 400 mg twice daily on day one then once daily for 5 days, 400 mg twice daily on day one then 200 mg twice daily for 4 days, and 600 mg twice daily on day one then 400 mg daily for 4 days.31 Considering the safety of hydroxychloroquine/chloroquine use in pregnancy, it is reasonable to apply the same regimen as that of non-pregnant patients (Table 3). Regarding concerns about the risk of death due to arrythmia from single or combined use of these medications, the absolute magnitude is smaller than the potential benefit from treatment of COVID-19. The use of high-dose chloroquine (600 mg twice daily for 10 days) and the combination of hydroxychloroquine and azithromycin is not recommended because of the potential for toxicities.^32,33

3.2. Antiviral treatment

Antiviral treatment has been routinely used to treat patients with COVID-19 infection in China and is also recommended for pregnant patients. Combination therapy with antiproteases, namely, lopinavir/ritonavir, is currently not recommended, as it has unfavorable pharmacodynamics, and there is lack of evidence on its effectiveness from clinical trials.31 A recent systematic review of 2 randomized trials and 21 observational studies concluded that it is uncertain whether lopinavir/ritonavir and other antiretroviral medication improve clinical outcomes in patients with severe symptomatic disease.34 A more recent randomized controlled trial, RECOVERY, showed no beneficial effect of lopinavir/ritonavir in patients hospitalized with COVID-19.35

Remdesivir is a novel nucleotide analog active against SARS-CoV-2 in vitro and related coronaviruses (including SARS and MERS-CoV) both in vitro and in animal studies.36 Several randomized trials are ongoing to evaluate the efficacy of remdesivir for moderate or severe COVID-19. Preliminary data have led expert panels to recommend remdesivir for the treatment of COVID-19 in patients with severe disease, but not in those with mild or moderate disease.37 It is unknown whether remdesivir is safe for use during pregnancy and lactation.

3.3. Statins

Statins are one of the proposed medications to treat patients with COVID-19. Generally, they are contraindicated in pregnancy. A risk-benefit analysis should be conducted before using investigational therapeutic agents in pregnant women outside of clinical trials.38

3.3. Convalescent plasma therapy

There is insufficient evidence in support of convalescent plasma, SARS-CoV-2-specific immune globulin, and non-SARS-CoV-2-specific intravenous immunoglobulin (IVIG), and these are currently not recommended for use except in the context of a clinical trial.39

3.4. Antibacterial treatment

Empiric antimicrobial treatment for bacterial pneumonia may be considered for patients with suspected or confirmed COVID-19. SARS-CoV-2 may also cause extensive lung damage, which increases the risk of secondary bacterial pneumonia. Prompt initiation of antibiotics is indicated if there is evidence of secondary bacterial infection or if bacterial sepsis is suspected.

3.5. Glucocorticoids

Glucocorticoids have been associated with an increased mortality risk in patients with influenza and delayed viral clearance in patients with MERS-CoV infection. There is no clear evidence of benefit in the management of SARS, while there is convincing evidence of adverse short- and long-term harm.40

The RECOVERY trial has recently showed reduced 28-day mortality in hospitalized patients with COVID-19 on respiratory support.41 The Saudi Ministry of Health recently updated their protocol for managing patients with suspected/confirmed COVID-19. Pregnant and breastfeeding patients with severe or critical disease are recommended to receive prednisolone 40 mg orally once daily or intravenous hydrocortisone 80 mg twice daily instead of dexamethasone.42

3.6. Supportive therapy

Adequate rest, hydration, nutritional support, antipyretics, and water and electrolyte balance are essential supportive measures for patients with COVID-19. Vital signs and oxygen saturation are needed to be closely monitored. Depending on disease severity and extent of hypoxemia, supplemental oxygen inhalation (60%-100% concentration at a rate of 40 L/min) should be given through a high-flow nasal cannula. Intubation and mechanical ventilation, or even extra-corporeal membrane oxygenation (ECMO), may be required to maintain oxygenation. Complications may include septic shock, acute kidney injury, and virus-induced cardiac injury. Consequently, it is important to check arterial blood gases, lactate levels, renal function, liver function, and cardiac enzymes, as indicated according to the clinical situation.

The use of non-steroidal anti-inflammatory drugs (NSAIDs) early in the course of the disease has been observed to have a negative effect on disease outcome.43 These findings are based on case reports of 4 young patients who received NSAIDs early in the course of infection and who experienced severe disease. Conversely, there are no clinical or population-based data to confirm the risks of using NSAIDs. The European Medicines Agency and the WHO do not recommend that NSAIDs be avoided when clinically indicated.^44,45 The Saudi Centers for Disease Control and Prevention has recommended the avoidance of ibuprofen.23 In light of these concerns, the SSMFM encourages the use of acetaminophen in place of NSAIDs for reduction of fever.

4.1. Tocolytics

Given the uncertainty regarding the effect of NSAIDs on COVID-19, indomethacin should be avoided currently. Therefore, nifedipine may be used as an alternative in patients presenting with preterm labor and requiring tocolysis. Other tocolytic agents may be contemplated with caution, and interaction with other medications should be considered.

4.2. Betamethasone/Dexamethasone

Steroids for fetal lung maturity should be used cautiously in pregnant women with severe COVID-19 disease who are at <34 weeks of gestation. Worsening morbidity of viral pneumonia has been associated with the administration of steroids.46 However, steroids for fetal lung maturity may be considered for patients with mild to moderate disease who are at <34 gestation weeks.

4.3. Progesterone

Given the lack of evidence on the effects of progesterone on COVID-19 and adverse pregnancy outcomes associated with early progesterone cessation, progesterone use may be continued in cases of mild disease.47 The use of progesterone in severe cases should be individualized.

4.4. Magnesium sulfate (MgSO4)

Magnesium sulfate is usually indicated in the obstetric setting for maternal eclampsia prophylaxis or fetal neuroprotection. There is a lack of evidence concerning the effects of MgSO4 on pregnant patients with COVID-19. This medication, excreted by the kidneys, may affect the respiratory status of the patient. Magnesium sulfate may be given to patients with mild disease. In patients with severe disease, administration needs to be individualized depending on the medical condition. Possible drug interactions also need to be considered.

4.5. Thromboprophylaxis

There is increasing evidence that patients with COVID-19 infection are at high risk of developing venous thromboembolism (VTE). In a study conducted in China, COVID-19 patients who received unfractionated heparin (UFH)/low-molecular-weight heparin (LMWH) had significantly better survival than those who did not. Pregnancy is also a well-known risk factor for VTE. Less mobilization of pregnant women due to the COVID-19 pandemic and hospitalization are likely to further increase the risk.

The recommended doses of UFH/LMWH were based on body weight and D-dimer measurements.48 D-dimer levels in pregnancy differ from those in a non-pregnant state. This should be considered when calculating the risk score assessment for VTE and prescribing LMWH for pregnant women. The SSMFM recommends that a thrombosis expert be included in the care of patients with suspected/confirmed COVID-19. The SSMFM also recommends commencement of LMWH thromboprophylaxis for all pregnant women with confirmed COVID-19 who are admitted to hospital and who are not expected to deliver within 12 hours. It is recommended to continue postpartum LMWH thromboprophylaxis for at least 10 days postpartum; however, this may be extended to 6 weeks, depending on the patient’s clinical status upon discharge and on the presence of other comorbidities.

4.6. Low-dose aspirin

Low-dose aspirin is widely used in obstetrics for pregnant women (example, prevention of pre-eclampsia, fetal growth restriction, and recurrent fetal loss). There is lack of evidence regarding risks associated with aspirin use in pregnant women with suspected/confirmed COVID-19. The SSMFM advises continuation of low-dose aspirin for pregnant women without COVID-19 infection.

Low-dose aspirin use in pregnant women with suspected/confirmed COVID-19 infection should be individualized based on the clinical indication, gestational age, and maternal condition.49 The SSMFM advises to withhold low-dose aspirin in patients with severe-critical COVID-19 infection.

Patients receiving immunomodulatory agents

Immunocompromised patients with COVID-19 are at an increased risk for severe disease and the decision to discontinue prednisone, biologics, or other immunosuppressive drugs in the setting of SARS-CoV-2 infection must be determined on a case-by-case basis. For individuals with underlying conditions who require treatment with these agents and are without COVID-19, there is no evidence that routinely discontinuing treatment is of any benefit. Furthermore, discontinuing these medications may result in a loss of response when the agent is reintroduced. This approach is supported in guidance from various dermatology, rheumatology, and gastroenterology societies.^50-52

A. Gestational age

A previable gestational age (<23-24 weeks) pregnancy may need to be terminated to improve the maternal condition if agreed upon by a panel of experts (obstetrician and intensivist/pulmonologist) who consider continuation of pregnancy life-threatening.

For early preterm fetuses (23-24 weeks to 33+6 weeks), although pregnancy can be terminated for maternal indications, counseling should include discussing the risks and benefits of administering steroids as well as MgSO4 for neuroprotection if the maternal condition allows.

Planning of delivery for a reasonably mature fetus (≥34 weeks) should be individualized according to the patient’s condition.

B. Maternal condition

The maternal medical condition should be evaluated by internal medicine and intensive care specialists, and should include an assessment of the medical and social risks of contracting SARS-CoV-2 and the presence of comorbidities. For diagnosis and evaluation of the disease progress, the use of computed tomography scanning and plain chest radiographs are permitted, if indicated, regardless of the fetal gestational age, with the use of abdominal shield protection. Based on a comprehensive evaluation, a decision should be made to determine whether expeditious delivery is needed to improve the maternal condition. If the maternal medical condition necessitates an urgent delivery, a cesarean section can be performed with epidural, spinal, or general anesthesia. Pediatricians should be involved if preterm delivery is decided.

C. Fetal assessment parameters

If the maternal medical condition allows trial of vaginal delivery, then continuous fetal monitoring is advised during labor. A cesarean section is only recommended for the standard obstetrical indications.

D. Risk of vertical transmission

If a decision is taken to expedite delivery, then delivery needs to be performed regardless of the risk of vertical transmission for patients in this category.

8.1. Postpartum maternal care

The location for postpartum care will be determined according to the condition and stability of the patient. Suspected/confirmed stable patients with mild symptoms can be nursed in the postpartum ward with appropriate isolation until the infection is cleared (Table 4). Patients who require respiratory support are likely to be treated and managed in an intensive care unit (ICU). A venous thromboprophylaxis risk assessment should be followed as per the patient’s medical condition and local institution policies.

Pain control should follow standard guidelines. It has recently been hypothesized that NSAIDs such as ibuprofen could aggravate COVID-19 symptoms;59 however, the United States FDA does not discourage the use of ibuprofen based on currently available information.60

Severe illness during pregnancy can increase the risk of mental health illnesses. Women who have experienced severe maternal morbidity have significantly greater odds of being treated for a psychiatric disorder.61 Maternal-neonatal separation in COVID-19 cases may cause anxiety to parents and lead to maternal depression.62 Emotional, psychological support, and counseling should be provided. Vigilant monitoring for postpartum depression is recommended. Women who have been critically ill may need post-traumatic stress syndrome support.

Standard contraceptive counseling should be provided as appropriate while the patient remains in hospital. No COVID-19-specific data are available concerning the choice of contraception regimen.

8.2. Neonatal care

Maternal health status is relevant in deciding the extent of mother/neonate contact. The issue of segregation should be discussed thoroughly with the patient and family, and individualized care is recommended (Table 5).

Neonates delivered by mothers with confirmed COVID-19 should be categorized as suspected cases and isolated, in line with Saudi MOH guidelines.63 There is a lack of consensus regarding mother/neonate contact. The RCOG has advised that neonates not otherwise requiring special care be kept together with their mothers in the immediate postpartum period.24 Qia64 and Liang et al65 recommended temporary separation of the mother and her neonate to prevent close contact, to avoid virus transmission. This separation period is recommended to continue for a minimum of 2 weeks.^64,65 The American College of Obstetricians and Gynecologists Clinical Advisory Board adopted a United States Centers for Disease Control and Prevention recommendation that facilities should consider temporary separation of confirmed or suspected patients with COVID-19 until the mother has been confirmed as being no longer infectious.^66,67

The SSMFM prefers to err on the side of caution in considering segregation, as the spread method and transmission from the mother to the neonate have not yet been well established. Temporary separation is likely to facilitate care for both a mother and a neonate, and minimize healthcare workers’ contact and exposure risks, especially given the current universal shortage of PPE.

Chen et al8 found no evidence that this virus was excreted in breast milk in a limited number of tested samples. However, direct breastfeeding is not recommended, as it requires long and close contact.66 There is conflicting limited evidence in the literature regarding breastfeeding. The SSMFM recommends a detailed discussion with the mother concerning risks and benefits of breastfeeding in patients with COVID-19, covering the limited available data concerning excretion of the virus in the breastmilk, the potential presence of antibodies, the risks of infection from the neonatal care provider, and the care needed while handling the neonate to avoid infection as well as alternative feeding options, such as expressed breast milk and formula. Ultimately, the family will have to make an informed choice between expressed breast milk and formula, regardless of which strict infection control criteria are applied.

Natural or medical methods for milk suppression may be considered if a patient chooses not to express breast milk or if medically indicated. Neonates born to mothers with suspected or confirmed COVID-19 are considered to be high risk and should have clear discharge criteria. The family should be educated appropriately and provided with information, as mentioned in Table 5.^68,69