key: cord-0871688-9fz9zei5
authors: Bajpai, Divya; Shah, Silvi
title: COVID-19 pandemic and pregnancy in kidney disease
date: 2020-08-07
journal: Adv Chronic Kidney Dis
DOI: 10.1053/j.ackd.2020.08.005
sha: 9d01edc73efb22905f896bb00bc60c7a518e958a
doc_id: 871688
cord_uid: 9fz9zei5

Abstract Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a rapidly spreading pandemic. Due to changes in the immune system and respiratory physiology, pregnant women are vulnerable to severe viral pneumonia. We review the clinical course, pregnancy outcomes, and management of women with COVID-19 in pregnancy with a focus on those with kidney involvement. Current evidence does not show an increased risk of acquiring SARS-CoV-2 during pregnancy and the maternal course appears to be similar to non-pregnant patients. However, severe maternal disease can lead to complex management challenges and has shown to be associated with higher incidence of preterm and caesarean births. The risk of congenital infection with SARS-CoV-2 is not known. All neonates must be considered as high-risk contacts and should be screened at birth and isolated. Pregnant women should follow all measures to prevent SARS-CoV-2 exposure and this fear should not compromise antenatal care. Use of telemedicine, videoconferencing, and non-invasive fetal and maternal home monitoring devices should be encouraged. High- risk pregnant patients with comorbidities and COVID-19 require hospitalization and close monitoring. Pregnant women with COVID-19 and kidney disease are a high-risk group and should be managed by a multidisciplinary team approach including a nephrologist and neonatologist.

As of June 17 2020, the Coronavirus disease 2019 (COVID- 19) , has affected 8,184,331 individuals from 213 countries and resulted in 443,959deaths (https://coronavirus.jhu.edu/).

Severe acute respiratory syndrome coronavirus -2 (SARS-CoV-2) causes COVID- 19 . It belongs to the same family as previous SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV)which causes significant morbidity and mortality in pregnant women 1 .Here we discuss the practical aspects of COVID-19 in pregnancy, on the premise that evidence in this field is rapidly evolving and that currently available is limited mostly to retrospective case series.

Changes in the immune system and the respiratory physiology make pregnant women vulnerable to severe viral infections. To "tolerate" the developing fetus, there is an attenuation of cellular immunity (T Helper cell 1 to T Helper cell 2 shift). This, along with alteration in the hormonal milieu (prostaglandins and progesterone) is known to worsen the risk of influenza in pregnancy 2 . Pregnancy is also associated with a decrease in lung volume and hampered capability to clear airway secretions, predisposing the woman to severe hypoxia in cases of pneumonia. Pregnant women who acquire respiratory infections in the third trimester are more likely to have a severe disease course 3 . Physiological rhinitis, shortness of breath, and dry cough related to laryngeal acid reflux are common in pregnancy and can lead to delay in diagnosis of COVID-19. To enter the cell, SARS-C0V-2 binds to angiotensin-converting enzyme 2 (ACE2) receptors via its spike-like protein 5 .In pregnancy, there is a significant increase in the ACE2 mRNA in the kidney, placenta, and uterus which can impact the vulnerability of the pregnant woman for COVID-19 4 .

Experts agree that social distancing decreases the chances of acquiring COVID-19 5 .

However, pregnancy mandates several health center visits for examination, ultrasonography, fetal viability tests like nonstress test, and biophysical profile, which might increase their exposure. Thus, pregnant women face a double whammy of increased exposure and susceptibility due to physiological changes as discussed above. As per the available evidence, pregnancy has not shown to increase the risk of acquiring COVID-19 1,6-8 . Nonetheless, we need more evidence from the prospective cohort studies to ascertain the true susceptibility of pregnant women to COVID-19.

At the beginning of the pandemic, it was hypothesized that a relatively younger age of this population may favour milder disease. Also, increased anti-inflammatory cytokines (interleukin-4 and interleukin-10) associated with pregnancy might attenuate the cytokine release syndrome which is associated with severe disease 9 . Comorbidities (hypertension, diabetes, severe heart or lung disease, severe obesity, and immunocompromised state) increase the risk of severe disease as in the nonpregnant population. Early reports suggested that the course of COVID-19 in pregnant women is not worse than in non-pregnant population [10] [11] [12] [13] However, a recent report of 91,412 pregnant women from the Centers for Disease Control noted that pregnant women were more likely to receive intensive care (1.5% versus 0.9%) and mechanical ventilation (0.5% versus 0.3%) as compared to the nonpregnant patients even after adjusting for age, comorbidities, and ethnicity 14 . This is in contrast with previously published literature from across the globe. In a cohort of 147 pregnant women in the WHO-China Joint Mission Report with COVID-19, 8% of women had severe disease, and 1% percent of the study cohort was critical 15 . In a systematic review J o u r n a l P r e -p r o o f including 538 pregnancies with COVID-19, 15% had severe disease and 1.4% were critical 16 .In comparison, 80% of the non-pregnant population with COVID-19 from China had mild disease, 15% had severe disease and 5% were critical 17 . In a study from New York where all obstetric admissions were screened for SARS-CoV-2 infection, 14 out of 43 (32.6%) women were found to be asymptomatic at presentation, of which, 10 (71%) women developed symptoms during delivery admission or post-partum (8 women developed mild disease and 2 women developed severe/critical disease) 18 . As of 11 June 2020, published literature has 13 maternal deaths [19] [20] [21] . It is important to note that most of these women did not have any comorbidities. They were diagnosed to have COVID-19 late in pregnancy which might have contributed to the adverse outcome. There are additional deaths reported in media which were also in premorbid healthy women diagnosed to have COVID-19 late in pregnancy 22-24 . As the evidence in evolving on the maternal course in COVID-19, it is imperative that pregnant women must be considered a high risk group and should be closely monitored for the worsening of the disease.

In two systematic reviews 25, 16 of 252 and 538 pregnant women each with COVID-19, 15% -20% had preterm births, and 70% -85% were caesarean deliveries. It is important to note that these studies predominantly report symptomatic women (up to 75%). Various factors can contribute to increased preterm and caesarean births in women with COVID-19 including fever, hypoxia, shock, and deteriorating maternal condition. In a study from France reporting 21 deliveries of women with COVID-19, 5 were preterm births and they were medically indicated for a severe maternal condition related to COVID-19 26 . Also, 7 out of 9 caesarean sections were done due to COVID-19.Thus, severe COVID-19 in late pregnancy can J o u r n a l P r e -p r o o f indirectly affect pregnancy outcomes by increasing the chances of elective preterm deliveries.

Laboured breathing during vaginal delivery along with the difficulty to wear a face mask might increase the chances of aerosolization. However, there is no conclusive evidence to date to alter the route of delivery due to COVID-19 and it should be guided by standard obstetric indications. Although reports from first trimester infections are scarce, miscarriages are seen in only 2% of patients 15 . Maternal hyperthermia during organogenesis increases the risk of congenital anomalies 27 like neural tube defects and childhood inattention disorders 28 .

These have not been reported yet in COVID-19.

Angiotensin-converting enzyme 2 (ACE2) receptors which function as the "doorway" for SARS-CoV-2 to enter the cell, are widely expressed in the placenta. Nonetheless, the maternal viremia rate is low making placental seeding less likely 29 .In two systematic reviews of 538 and 51 pregnancies each, there was no evidence of vertical transmission 16, 30 . However, few reports have documented positive early nasopharyngeal swabs 31,32 from the neonates and/or presence of neonatal IgM antibodies 33, 34 . None of these cases were positive for amniotic fluid, placenta, or fetal blood. As IgM antibodies do not normally cross the placenta, their presence can either be due to injured placenta allowing passage or production by neonate if the virus crosses the placenta. False positive tests and cross-reactivity can occur.

To date, the virus has not been detected in the cord blood and amniotic fluid specimens.

Positive vaginal swab has been reported in one patient 35 . This neonate was delivered at 35 weeks and 5 days by planned caesarean section, had no contact with vaginal fluid, membranes were intact before birth and there was no skin to skin contact with the mother after birth. Neonatal nasopharyngeal swabs were positive at birth, on day 2 and day 7.

Placenta showed multiple areas of inflammation and infarction, suggestive of primary SARS-CoV-2 infection. There was no respiratory involvement in the neonate 35 . As of June 10 2020, the risk of congenital infection with SARS-CoV-2 is not clearly known. However, the neonate is at a definite risk of acquiring the infection postnatally, hence she/he should be considered a high-risk contact and managed accordingly (see below).

Adequate antenatal care is associated with improved maternal and fetal outcomes, and it should be maintained at ≥95% and partial pressure of oxygen should be ≥70 mmHg. This is to maintain an oxygen diffusion gradient from the mother to the fetal side of the placenta. As prone positioning will be difficult later in pregnancy, a semi-prone position can be tried to J o u r n a l P r e -p r o o f improve oxygenation. Chest radiograph and computed tomography can be done if clinically indicated with an abdominal shield as they carry a low fetal radiation dose. Admission Ddimer levels > 1 µg/mL are known to predict increased mortality in COVID-19 41 , but these levels are normally elevated in pregnancy hence difficult to interpret 42 

Emerging evidence suggests that hypercoagulability adversely impacts prognosis in COVID-19 44 and routine pharmacologic prophylaxis is recommended in hospitalized patients with COVID-19 unless contraindicated 45 . Pregnancy itself is a hypercoagulable state and is associated with an increased risk of venous thromboembolism 46 . Low molecular weight heparin should be given to hospitalized pregnant patients with COIVD-19 . They can be later transitioned to unfractionated heparin in the peripartum period.

Several drugs are currently being evaluated for the treatment of COVID-19. Remdesivir is a nucleotide analogue that has activity against SARS-CoV-2 in vitro. It has been safely used in pregnant women with Ebola and Marburg disease 47 . Currently, it is being used on a compassionate -use basis in pregnant patients with COVID-19, but most of the randomized trials have excluded pregnant women. Chloroquine and its metabolites have also been used safely in pregnancy in the past, however, due to a large volume of distribution higher doses will be needed in pregnancy (1000mg /day) 48 . Hydroxychloroquine with or without azithromycin can cause arrythmias due to QT prolongation and should be used cautiously withcardiacmonitoring 49 . Protease inhibitor, Lopinavir-Ritonavir is known to be safe in pregnancy. Although they cross the placenta, no adverse effect is seen on the fetus.

Baricitinib, a Janus kinase inhibitor, is a potential drug for COVID-19, however, it has shown embryotoxicity in animal studies 50 and is thus to be avoided in pregnancy. Tocilizumab, a humanized monoclonal antibody against interleukin-6, crosses the placenta and is secreted in breast milk. Caution should be exercised with its use in pregnancy. Steroids have been evaluated for patients with severe COVID-19 including acute respiratory distress syndrome and shock. Both dexamethasone and methylprednisolone cross the placenta. There is some association with their use in the first trimester and increased abortions and birth defects like oral clefts 51, 52 . However, the evidence is not conclusive and the risk depends on the dose and duration of use. The use of antenatal steroids for the standard obstetric indication is discussed above.

J o u r n a l P r e -p r o o f Babies born to positive mothers are to be considered as high risk contacts. They should be tested within 24 hours with nasopharyngeal/throat swabs and also for the presence of IgG and IgM antibodies. Irrespective of the result of this testing, they should be kept in isolation from other healthy infants and should be cared for with all the precautions used for positive patients. According to the Centres for Disease Control and Prevention, the decision on whether to separate the positive mother and her baby should be individualized based on the clinical condition of the mother and the baby, the mother's desire to breastfeed, facilities, and additional caregivers available for separation at the hospital and home. It should be a shared decision of the mother, the caregivers, and the clinician. If separation is indicated but could not be implemented, physical distancing (≥ 6 feet) from the mother can be practiced. Mother can wear a face mask and practice hand hygiene when in close contact.

There is minimal data on the transmission of SARS-CoV-2 through breast milk. Out of 29 samples tested in two studies, one tested positive for SARS-CoV-2 by nucleic acid testing 25, 53 . Close contact while breastfeeding can lead to droplet infection. Nonetheless, the benefits of breastfeeding to the baby and the mother outweigh the risk known up till now. If the mother chooses to breastfeed, she should wear a mask, and clean her hands and breasts before each feeding. Breastmilk can also be expressed using all personal hygiene precautions and can be fed to the baby by an uninfected caregiver.

During pregnancy, the mother can experience several psychological changes and is vulnerable to develop anxiety and depression 54 provide more stress to mothers and their families. In the quarantine, there is a potential for increased rates of domestic violence and gender-based discrimination 55, 56 . In a populationbased study from China, more than half of the respondents experienced moderate to severe psychological impact 57 .Given the current concern of acquiring COVID-19, there may be a decrease in seeking preventive health care for both mother and the baby. Telehealth and group video sessions can be useful tools to provide women with quality care and support during this time. Whether women attend visits in-person or virtually, all pregnant women should be screened for mood and anxiety disorders.

Acute kidney injury in a pregnant woman with COVID-19 25% to 29% of nonpregnant patients who are critically ill with COVID-19 can develop acute kidney injury (AKI) 58, 59 . Pregnancy related hemodynamic changes involving the kidney makes the woman vulnerable to develop AKI 60 .In healthy pregnant women, increased kidney blood flow and glomerular hyperfiltration result in lower serum creatinine levels. Thus, creatinine values considered normal in the non-pregnant state will be high in pregnancy 61 .

Hence cut-off for serum creatinine defining AKI is lower than the non-pregnant population (>0.8mg/dl or >70.72 µmol/l) 62 Diarrhea which is a common symptom of COVID-19 can cause increased tacrolimus trough levels. Thus, close monitoring of calcineurin inhibitors trough levels, kidney function and fetal parameters is needed.

In conclusion, pregnant patients constitute a vulnerable population that requires multidisciplinary care during the COVID-19 pandemic. We are still unaware of the exact risk and the long term consequences of COVID-19 to the mother and the baby. There is an urgent need for large prospective studies with international collaboration. The surveillance data collected during antenatal and delivery visits can also be extrapolated to asymptomatic J o u r n a l P r e -p r o o f nonpregnant populations strengthening the knowledge base. Finally, patients with chronic kidney disease who conceive during the COVID-19 pandemic require dedicated specialized care for a successful pregnancy course.

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