ACADEMIA Letters SARS-COV-2 and maternal/ neonatal implications. A narrative review Suzan Sirak, Paediatric Department, General Hospital of Xanthi, Xanthi, Greece Panagiota Kalamata, Faculty of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece Georgios N. Katsaras, Paediatric Department, General Hospital of Pella - Hospital Unit of Edessa, Edessa, Greece Fani Akritidou, Opthalmology Department, General Hospital of Pella – Hospital Unit of Edessa, Edessa, Greece Theodora Papamitsou, Department of Histology-Embryology, Aristotle University of Thessaloniki, Thessaloniki, Greece Introduction Since the first coronavirus disease-2019 (COVID-19) patient was diagnosed in China in November 2019 more and more people have become infected worldwide.(1) This rapid spread of the severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) soon led to a pandemic outbreak. Pregnant women positive for COVID-19 have been confirmed and this raised questions on how this virus can affect them and their infants. Epidemiology Villar et al (2) in a multinational cohort study, COVID-19 in pregnancy was associated with consistent and substantial increases in severe maternal morbidity and mortality and neonatal complications when pregnant women with and without COVID-19 diagnosis were comAcademia Letters, August 2021 ©2021 by the authors — Open Access — Distributed under CC BY 4.0 Corresponding Author: Georgios N. Katsaras, gkatsaras84@gmail.com Citation: Sirak, S., Kalamata, P., Katsaras, G.N., Akritidou, F., Papamitsou, T. (2021). SARS-COV-2 and maternal/ neonatal implications. A narrative review. Academia Letters, Article 3135. https://doi.org/10.20935/AL3135. 1 pared. Epidemiological data have revealed an increased number of preterm births reaching 47% on positive COVID-19 pregnant women. While, not many maternal deaths have yet been reported, Hantoushzadeh S et al. (3) reported that among 9 pregnant women with severe COVID-19 disease, at the time of reporting, 7 of 9 died, 1 of 9 remained critically ill and ventilator dependent, and 1 of 9 recovered after prolonged hospitalization. No changes in embryo’s growth or the placenta were observed, although on SARS positive pregnant women placental fibrosis and impairment in fetal development have been reported. What is more, Zhu et al. in their study found 6/9 cases with abnormal condition on the fetus. So raising awareness on the fetus health monitoring becomes a necessity.(4) Approximately 3% of neonates born from mothers with COVID-19 acquired infection through suspected vertical transmission (5). Regarding the baby’s nutrition, breast milk still seems to be the best option either extracted or breastfed, but taking into account all safety measures during this process.(6) Finally, recent data suggest that children born from healthy mothers during the pandemic have reduced verbal, motor, and overall cognitive performance compared to children born pre-pandemic (7). Maternal outcomes According to the literature, pregnant women are considered immunosuppressed. As a result, a pregnant woman is more prone to infection than a woman of the same age but not impregnated would have been. A recent study concerning 9 pregnant women with confirmed COVID19 found that nearly all of them presented with fever no higher than 39°C, 40% of them also presented with cough, additionally, 30% had myalgia and only 22% had a sore throat. It was shown that the onset of COVID-19 is very much like that in the general population. Pregnant women with COVID-19 are possible to have lymphopenia, elevated C-reactive protein (CRP) levels as well as aspartate transaminase (AST) and alanine transaminase (ALT) levels.(8) Lactate dehydrogenase (LDH) can as well be found elevated.(9) CT scans indicate an infected lung with ground glass nodules. All patients were able to deliver without developing severe pneumonia. It is feasible that some patients with COVID-19 have a negative nasopharyngeal swab although the rt-PCR test confirmed COVID-19 diagnosis. However there have been data of a pregnant individual who didn’t have any symptoms but were positive for SARS-COV 2 in a nasopharyngeal specimen, a test she underwent due to contact with another COVID-19 confirmed patient.(10) Pregnant patients were reported who got treated and discharged before labor and others who were admitted at the hospital and gave birth before full recovery to a patient who developed acute respiratory distress syndrome (ARDS) and had to be moved to the Intensive Care Unit (ICU) needing mechanical ventilation and later developed multiple Academia Letters, August 2021 ©2021 by the authors — Open Access — Distributed under CC BY 4.0 Corresponding Author: Georgios N. Katsaras, gkatsaras84@gmail.com Citation: Sirak, S., Kalamata, P., Katsaras, G.N., Akritidou, F., Papamitsou, T. (2021). SARS-COV-2 and maternal/ neonatal implications. A narrative review. Academia Letters, Article 3135. https://doi.org/10.20935/AL3135. 2 organ dysfunction syndrome (MODS). Evidence suggests that the vast majority of pregnant women with COVID-19 and no history of chronic disease were able to deliver an uninfected infant and remain in good health themselves past the infection.(11) Early pregnancy and first trimester It appears that miscarriage at this stage of pregnancy is quite common even reaching percentages around 60% based on a previously published case report. Such an incident usually happens from the second until the fifth week after the onset of symptoms. Most of the pregnant women infected with SARS in the first trimester had preterm delivery. All patients were provided with oxygen while hospitalized when oxygen saturation dropped.(12) Another study concluded that individuals infected with MERS-CoV MERS during first weeks of gestation, had a more serious course of illness than those infected with SARS-CoV-2, with a few pregnant patients in need of admission to an ICU and even fatal transmission in 30%.(13) Second and third trimester Pregnant individuals infected with the COVID-19 in the second or third trimester tend to have milder clinical symptoms rather than non-pregnant women. Maternal mortality is still minor. Liu Y et al. reported only two women that needed admission to ICU and one of them needed extracorporeal membrane oxygenation (ECMO).(10) Increased rates of preterm birth were noticed and the majority was delivered by cesarean section. In a study conducted by Chen et al. in 9 pregnant women positive for COVID-19, the difficulties encountered during pregnancy were pre-eclampsia, fetal distress, and premature rupture of the membrane. However all babies were born healthy with some being small for gestational age (SGA).(8) Although there is no clear evidence that COVID-19 affects the outcome in both mother and infant in the second or third trimester of pregnancy we should be alert because SARS-COV-2 and SARS-COV have genome resemblance up to 85%.(4) Prematurity So far, case series have shown increased rates of prematurity in hospitalized women positive with COVID-19. In a study by Chen et al. almost 50% of the patients delivered preterm babies. Αll women gave birth by caesarian section and the gestational age was approximately 36 weeks. However the infection with SARS-COV-2 was not statistically associated with preterm Academia Letters, August 2021 ©2021 by the authors — Open Access — Distributed under CC BY 4.0 Corresponding Author: Georgios N. Katsaras, gkatsaras84@gmail.com Citation: Sirak, S., Kalamata, P., Katsaras, G.N., Akritidou, F., Papamitsou, T. (2021). SARS-COV-2 and maternal/ neonatal implications. A narrative review. Academia Letters, Article 3135. https://doi.org/10.20935/AL3135. 3 delivery. Severe pre-eclampsia, history of stillbirth and caesarian section, irregular contractions, and premature rupture of the membranes were the causes that led to this decision.(8) On the other hand Liu et al. related prenatal complications with SARS-COV-2 as well as with normal changes that occur during pregnancy.(10) Pregnant women have a reduced inflammatory immune response and are more prone to hypoxia. Women with hypoxemia are more likely to have fetal distress or give birth to premature babies. In clinical cases of ten newborn infants delivered of positive mothers with SARS-COV-2, six were premature. All neonates presented clinical symptoms although the nasopharyngeal swabs specimens were tested negative. The main symptom was shortness of breath followed by increased heart rate and gastrointestinal hemorrhage and fever. Two infants were in a critical situation, one of them died due to multiple organ failure and disseminated intravascular coagulation (DIC) and the other one was cured with intravenous infusion of IVIG.(11) Fetal growth and placental effect It is possible that a pregnant individual’s SARS-COV2 infection can affect the fetus. Reports suggest that intrauterine fetal distress can be a consequence of a pregnant patient with confirmed COVID-19. By fetal distress we describe hypoxia of the embryo, either mild or severe, that can lead to premature birth, birth asphyxia, and even death.(11) Given that a pregnant patient with COVID-19 is closely monitored both regarding herself and the fetus, most deviations from the standard healthy status can usually be reversed before permanent damage is caused. Fetal growth seems not to be seriously affected in the vast majority of the reported cases up to date.(8) Nevertheless, recently published literature reports on a case of a 28-year-old COVID19 positive pregnant patient who, while hospitalized, developed pneumonia and soon after abnormal fetal heart rate and elimination of fetal movement were detected. An emergency caesarian section was performed, and the infant was born during the 30th week of gestation, although it being premature, it was healthy and COVID-19 negative. Both the patient and the neonate were eventually discharged in good health.(9) To our knowledge, placental tissue had been tested for COVID-19 and the result was negative for all pregnant patients in the entire published literature. There had also not been any signs of viral inflammation according to histopathology examination.(4) Neonatal outcomes There is a controversy regarding this matter. According to Chen (2020), newborns appear to be unaffected by the SARS-COV-2 infection of the mother.(8) However, another published cliniAcademia Letters, August 2021 ©2021 by the authors — Open Access — Distributed under CC BY 4.0 Corresponding Author: Georgios N. Katsaras, gkatsaras84@gmail.com Citation: Sirak, S., Kalamata, P., Katsaras, G.N., Akritidou, F., Papamitsou, T. (2021). SARS-COV-2 and maternal/ neonatal implications. A narrative review. Academia Letters, Article 3135. https://doi.org/10.20935/AL3135. 4 cal analysis suggested that the majority of infants born to mothers infected with SARS-COV-2 had shortness of breath (6 of 9), 2 of 9 presented with fever, 2 of 9 with thrombocytopenia and abnormal liver function, 1 with elevated heart rate, 1 suffered from pneumothorax and 1 was vomiting.(11) The nasopharyngeal swab of the neonates in both studies tested negative for COVID-19.(8,11) Vertical transmission seems to be unlikely based on the evidence thus far. Nonetheless, it cannot be denied that newborns can be presented with symptoms that can correlate with the mother’s infection. In any case, it is of benefit that a resuscitation team is present during labor of a COVID-19 confirmed pregnant individual.(1) Breastfeeding Breastfeeding is the ideal alimentary source for infants. Infants who breastfeed exclusively have more advanced visual acuity and speech, along with optimal cognitive development. Moreover, breastfeeding protects against infections of the respiratory system, gastroenteritis, otitis media, necrotizing enterocolitis, acute lymphocytic leukemia, and sudden infant death syndrome (SIDS). Finally, it has long-term benefits, such as lower likelihood of SIDS, postneonatal death, obesity, asthma, certain childhood cancers and diabetes.(14–18) The vertical transmission of SARS-COV-2 has not been confirmed. Chen et al. have reported that all the milk samples of positive mothers with pneumonia were negative.(8) The precautional abstinence of breastfeeding from mothers with COVID-19 infection that Favre et al. suggested is not evidence-based.(19) We can assume that, as with MERS, SARS, or other viruses, antibodies pass from the breast milk to the infant with a possible modulation of the clinical expression of the infant’s infection.(20) WHO recommends that mothers with any symptoms who are breastfeeding or practicing skin-to-skin contact should take all the necessary precautions, such as practicing respiratory hygiene, washing their hands, cleaning, and disinfecting any surfaces they touch. If they are severely ill, they can express their milk, and if they are so unwell that they cannot even express milk, they should think relactation as soon as they become better.(21) Conclusions The presented information is according to the current literature but subjected to changes as more emerging evidence becomes available. SARS-COV-2 seems less severe than MERS and SARS as far as the health of pregnant women is concerned. Miscarriage, intrauterine growth restriction, and preterm delivery are some possible outcomes regarding the pregnancy and the fetuses. Thus, the specialized personnel should be alerted to take all the precautions as Academia Letters, August 2021 ©2021 by the authors — Open Access — Distributed under CC BY 4.0 Corresponding Author: Georgios N. Katsaras, gkatsaras84@gmail.com Citation: Sirak, S., Kalamata, P., Katsaras, G.N., Akritidou, F., Papamitsou, T. (2021). SARS-COV-2 and maternal/ neonatal implications. A narrative review. Academia Letters, Article 3135. https://doi.org/10.20935/AL3135. 5 well as to intervene accordingly. Breastfeeding remains the best option when coming to the well-being of the babies but under all the necessary hygiene measures. Finally, medication treatment of COVID-19 positive patients was announced as being under consideration and trial during the outbreak includes Kaletra (Lopinavir and Ritonavir), Remdesivir and Chloroquine, but not yet including pregnant women. References 1. Chandrasekharan P, Vento M, Trevisanuto D, Partridge E, Underwood MA, Wiedeman J, et al. Neonatal Resuscitation and Postresuscitation Care of Infants Born to Mothers with Suspected or Confirmed SARS-CoV-2 Infection. Am J Perinatol. 2020 Apr 8;14203. 2. Villar J, Ariff S, Gunier RB, Thiruvengadam R, Rauch S, Kholin A, et al. Maternal and Neonatal Morbidity and Mortality Among Pregnant Women With and Without COVID-19 Infection. JAMA Pediatr. 2021 Aug 1;175(8):817. 3. 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Academia Letters, Article 3135. https://doi.org/10.20935/AL3135. 7 21. WHO. Breastfeeding advice during the COVID-19 outbreak. 2020 [assessed 2020 May 21]. Academia Letters, August 2021 ©2021 by the authors — Open Access — Distributed under CC BY 4.0 Corresponding Author: Georgios N. Katsaras, gkatsaras84@gmail.com Citation: Sirak, S., Kalamata, P., Katsaras, G.N., Akritidou, F., Papamitsou, T. (2021). SARS-COV-2 and maternal/ neonatal implications. A narrative review. Academia Letters, Article 3135. https://doi.org/10.20935/AL3135. 8