POTENTIAL RISK OF BRAIN DAMAGE AND POOR DEVELOPMENTAL OUTCOMES IN CHILDREN PRENATALLY EXPOSED TO SARS-COV-2: A SYSTEMATIC REVIEW

Leyser, Marcio; Marques, Fernanda Jordão Pinto; Nascimento, Osvaldo José Moreira do

doi:10.1590/1984-0462/2022/40/2020415

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Brasil

Revista Paulista de Pediatria

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REVIEW ARTICLE • Rev. paul. pediatr. 40 • 2022 • https://doi.org/10.1590/1984-0462/2022/40/2020415 copy

POTENTIAL RISK OF BRAIN DAMAGE AND POOR DEVELOPMENTAL OUTCOMES IN CHILDREN PRENATALLY EXPOSED TO SARS-COV-2: A SYSTEMATIC REVIEW

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

Objective:

To perform a systematic literature review to analyze existing data on the neurological effects of coronavirus on newborns.

Data

sources: We followed the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P), and searched the PubMed and Embase platforms for the keywords [brain damage OR pregnancy OR developmental outcomes] and [coronavirus OR SARS-CoV-2 OR SARS-CoV OR MERS-CoV] between January 1, 2000 and June 1, 2020.

Data

synthesis: Twenty-three reports described the course of pregnant women exposed to SARS-CoV-2, SARS-CoV, or MERS-CoV during the gestational period, eight to SARS-CoV-2, eight to SARS-CoV, and seven to MERS-CoV. No data were found on abnormalities in brain development or on a direct link between the virus and neurological abnormalities in the human embryo, fetus, or children. Spontaneous miscarriage, stillbirth, and termination of pregnancy were some complications connected with SARS/MERS-CoV infection. SARS-CoV-2 is not currently associated with complications in the gestational period.

Conclusions:

The literature has no data associating exposure to coronavirus during pregnancy with brain malformations and neurodevelopmental disorders. However, despite the lack of reports, monitoring the development of children exposed to SARS-CoV-2 is essential given the risk of complications in pregnant women and the potential neuroinvasive and neurotropic properties found in previous strains.

Keywords:
SARS-CoV-2; SARS-CoV; MERS-CoV; Pregnancy; Brain injuries; Coronavirus

Author/year	Study population	Study design and intervention	Outcome measures	Conclusions
Ng et al., 2004⁸8. Ng PC, Leung CW, Chiu WK, Wong SF, Hon EK. SARS in newborns and children. Biol Neonate. 2004;85:293-8. https://doi.org/10.1159/000078174 https://doi.org/https://doi.org/10.1159/...	n=12 pregnant women infected with SARS-CoV.	Review	Four pregnant women died; two had a spontaneous miscarriage and termination of pregnancy; no newborn had SARS-CoV infection.	Coronavirus is unlikely to be transmitted via the intrauterine route.
Lau et al., 2004⁹9. Lau KK, Yu WC, Chu CM, Lau ST, Sheng B, Yuen KY. Possible central nervous system infection by SARS coronavirus. Emerg Infect Dis. 2004;10:342-4. https://doi.org/10.3201/eid1002.030638 https://doi.org/https://doi.org/10.3201/...	n=1 32-year-old woman.	Case report	Incidence of generalized seizures with a positive RT-PCR for SARS-CoV in the cerebrospinal fluid.	SARS-CoV can infect multiple organ systems, and CNS can possibly be affected.
Yudin et al., 2005¹⁰10. Yudin MH, Steele DM, Sgro MD, Read SE, Kopplin P, Gough KA. Severe acute respiratory syndrome in pregnancy. Obstet Gynecol. 2005;105:124-7. https://doi.org/10.1097/01.AOG.0000151598.49129.de https://doi.org/https://doi.org/10.1097/...	n=1 33-year-old pregnant woman.	Case report	Labor occurred spontaneously at term, and a healthy female newborn was delivered.	No evidence of perinatal transmission.
Stockman et al., 2004¹¹11. Stockman LJ, Lowther SA, Coy K, Saw J, Parashar UD. SARS during pregnancy, United States. Emerg Infect Dis. 2004;10:1689-90. https://doi.org/10.3201/eid1009.040244 https://doi.org/https://doi.org/10.3201/...	n=2 pregnant SARS case-patients.	Letter	Neither of the two pregnant women had severe negative outcomes.	Few cases have been studied to define clearly the risks of pregnant women infected with SARS-CoV.
Robertson et al., 2004¹²12. Robertson CA, Lowther SA, Birch T, Tan C, Sorhage F, Stockman L, et al. SARS and pregnancy: a case report. Emerg Infect Dis. 2004;10:345-8. https://doi.org/10.3201/eid1002.030736 https://doi.org/https://doi.org/10.3201/...	n=1 36-year-old pregnant woman.	Case report	Healthy female infant was delivered without complications.	Long-term follow-up of infants is needed to characterize the pregnancy-related risks.
Lam et al., 2004¹³13. Lam CM, Wong SF, Leung TN, Chow KM, Yu WC, Wong TY, et al. A case-controlled study comparing clinical course and outcomes of pregnant and non-pregnant women with severe acute respiratory syndrome. BJOG. 2004;111:771-4. https://doi.org/10.1111/j.1471-0528.2004.00199.x https://doi.org/https://doi.org/10.1111/...	n=10 pregnant and 40 non-pregnant female patients.	Case-control	Four required endotracheal intubations, and six were admitted to the intensive care unit (ICU). Three deaths in the pregnant group.	Pregnant women with SARS experience a worse clinical course and poorer outcomes compared with non-pregnant women.
Shek et al., 2003¹⁴14. Shek CC, Ng PC, Fung GP, Cheng FW, Chan PK, Peiris MJ, et al. Infants born to mothers with severe acute respiratory syndrome. Pediatrics. 2003;112:e254. https://doi.org/10.1542/peds.112.4.e254 https://doi.org/https://doi.org/10.1542/...	n=5 liveborn infants.	Case series	No manifestations or radiological, hematologic, or biochemical evidence suggestive of SARS.	Newborns of mothers with SARS did not develop the disease.
Li et al., 2005¹⁵15. Li AM, Ng PC. Severe acute respiratory syndrome (SARS) in neonates and children. Arch Dis Child Fetal Neonatal Ed. 2005;90:F461-5. https://doi.org/10.1136/adc.2005.075309 https://doi.org/https://doi.org/10.1136/...	n=12 pregnant women infected with SARS-CoV included in this review	Review	No evidence suggests that the virus is transmitted transplacentally.	Vertical transmission of SARS-CoV from infected mothers to their newborns has not been observed.

Author/year	Study population	Study design and intervention	Outcome measures	Conclusions
Assiri et al., 2016¹⁶16. Assiri A, Abedi GR, Al Masri M, Bin Saeed A, Gerber SI, Watson JT. Middle East respiratory syndrome coronavirus infection during pregnancy: a report of 5 cases from Saudi Arabia. Clin Infect Dis. 2016;63:951-3. https://doi.org/10.1093/cid/ciw412 https://doi.org/https://doi.org/10.1093/...	n=5 pregnant women.	Case report	Two patients died, two cases resulted in perinatal death, one pregnancy led to intrauterine fetal demise, and one infant died after an emergency cesarean section.	MERS-CoV may pose serious health risks to both mothers and infants during pregnancy.
Alfaraj et al., 2019¹⁷17. Alfaraj SH, Al-Tawfiq JA, Memish ZA. Middle East respiratory syndrome coronavirus (MERS-CoV) infection during pregnancy: report of two cases & review of the literature. J Microbiol Immunol Infec. 2019;52:501-3. https://doi.org/10.1016/j.jmii.2018.04.005 https://doi.org/https://doi.org/10.1016/...	n=2 pregnant women.	Case report	Both patients did not deliver during hospitalization and subsequently delivered a healthy infant at term.	The outcome was favorable in most pregnancies associated with MERS-CoV cases.
Jeong et al., 2017¹⁸18. Jeong SY, Sung SI, Sung JH, Ahn SY, Kang ES, Chang YS, et al. MERS-CoV infection in a pregnant woman in Korea. J Korean Med Sci. 2017;32:1717-20. https://doi.org/10.3346/jkms.2017.32.10.1717 https://doi.org/https://doi.org/10.3346/...	n=1 39-year-old pregnant woman.	Case report	Benign maternal course that resulted in full recovery with subsequent healthy full-term delivery.	Further studies with a larger sample size will expand the knowledge of pathophysiology and perinatal outcome.
Alserehi et al., 2016¹⁹19. Alserehi H, Wali G, Alshukairi A, Alraddadi B. Impact of Middle East Respiratory Syndrome coronavirus (MERS-CoV) on pregnancy and perinatal outcome. BMC Infect Dis. 2016;16:105. https://doi.org/10.1186/s12879-016-1437-y https://doi.org/https://doi.org/10.1186/...	n=1 33-year-old pregnant woman.	Case report	Preterm delivery of a male infant without complications.	The pregnancy had a favorable outcome for the newborn.
Malik et al., 2016²⁰20. Malik A, El Masry KM, Ravi M, Sayed F. Middle east respiratory syndrome coronavirus during pregnancy, Abu Dhabi, United Arab Emirates, 2013. Emerg Infect Dis . 2016;22:515-7. https://doi.org/10.3201/eid2203.151049 https://doi.org/https://doi.org/10.3201/...	n=1 32-year-old woman.	Case report	Preterm delivery of a male infant without complications. The mother presented a progressive worsening of clinical status, leading to death.	MERS-CoV infection and pregnancy were a fatal combination in this case.
Park et al., 2016²¹21. Park MH, Kim HR, Choi DH, Sung JH, Kim JH. Emergency cesarean section in an epidemic of the middle east respiratory syndrome: a case report. Korean J Anesthesiol. 2016;69:287-91. https://doi.org/10.4097/kjae.2016.69.3.287 https://doi.org/https://doi.org/10.4097/...	n=1 39-year-old woman.	Case report	Placental abruption; urgent C-section.	The pregnancy had a favorable outcome for both mother and newborn.
Payne, 2014²²22. Payne DC, Iblan I, Alqasrawi S, Al Nsour M, Rha B, Tohme RA, et al. Stillbirth during infection with Middle East respiratory syndrome coronavirus. J Infect Dis. 2014;209:1870-2. https://doi.org/10.1093/infdis/jiu068 https://doi.org/https://doi.org/10.1093/...	n=1 39-year-old pregnant woman.	Case report	Second-trimester stillbirth in a pregnant woman with MERS-CoV infection.	MERS-CoV infection during pregnancy may pose serious health risks to both mother and fetus.

Author/year	Study population	Study design and intervention	Outcome measures	Conclusions
Juan et al., 2020²³23. Juan J, Gil MM, Rong Z, Zhang Y, Yang H, Poon LC. Effects of Coronavirus Disease 2019 (COVID-19) on maternal, perinatal and neonatal outcomes: a systematic review of 266 pregnancies. medRxiv. 2020;2020.05.02.20088484. https://doi.org/10.1101/2020.05.02.20088484 https://doi.org/https://doi.org/10.1101/...	n=266 pregnant women.	Systematic review	One case of neonatal asphyxia and one of neonatal death. The case reports described two maternal deaths among pregnant women with COVID-19.	Clinical characteristics of pregnant women with COVID-19 are similar to those of non-pregnant adults with COVID-19.
Egloff et al., 2020²⁴24. Egloff C, Vauloup-Fellous C, Picone O, Mandelbrot L, Roques P. Evidence and possible mechanisms of rare maternal-fetal transmission of SARS-CoV-2. J Clin Virol. 2020;128:104447. https://doi.org/10.1016/j.jcv.2020.104447 https://doi.org/https://doi.org/10.1016/...	n=179 newbornstested for SARS-CoV-2 at birth.	Review	Transmission was suspected in eight cases, five with positive nasopharyngeal SARS-CoV-2 RT-PCR and three with SARS-CoV-2 IgM.	Current data indicate very rare maternal-fetal transmission but are largely incomplete.
Lamouroux et al., 2020²⁵25. Lamouroux A, Attie-Bitach T, Martinovic J, Leruez-Ville M, Ville Y. Evidence for and against vertical transmission for SARS-CoV-2 (COVID-19). Am J Obstet Gynecol. 2020;223:91.e1-91.e4. https://doi.org/10.1016/j.ajog.2020.04.039 https://doi.org/https://doi.org/10.1016/... Alzamora et al., 2020²⁶26. Alzamora MC, Paredes T, Caceres D, Webb CM, Valdez LM, La Rosa M. Severe COVID-19 during pregnancy and possible vertical transmission. Am J Perinatol. 2020;37:861-5. https://doi.org/10.1055/s-0040-1710050 https://doi.org/https://doi.org/10.1055/...	n=68 deliveries and 71 neonates with maternal infection.n=1 41-year-old pregnant woman with COVID-19.	Case report	Neonatal infection was diagnosed within 48 hours of life in four cases.Neonatal nasopharyngeal swab was positive for SARS-CoV-2.	More definitive evidence is needed for counseling pregnant women on the risk of congenital infection.Vertical transmission remains controversial.
Karimi-Zarchi et al., 2020²⁷27. Karimi-Zarchi M, Neamatzadeh H, Dastgheib SA, Abbasi H, Mirjalili SR, Behforouz A, et al. Vertical transmission of coronavirus disease 19 (COVID-19) from infected pregnant mothers to neonates: a review. Fetal Pediatr Pathol. 2020;39:246-50. https://doi.org/10.1080/15513815.2020.1747120 https://doi.org/https://doi.org/10.1080/...	n=31 infected pregnant mothers.	Review	No COVID-19 infection was detected in their neonates or placentas. Two mothers died from COVID-19-related respiratory complications after delivery.	There is no evidence of intrauterine transmission. Mothers may be at increased risk for severe respiratory complications.
Schwartz et al., 2020²⁸28. Schwartz DA. An analysis of 38 pregnant women with COVID-19, their newborn infants, and maternal-fetal transmission of SARS-CoV-2: maternal coronavirus infections and pregnancy outcomes. Arch Pathol Lab Med. 2020;144:799-805. https://doi.org/10.5858/arpa.2020-0901-SA https://doi.org/https://doi.org/10.5858/...	n=38 pregnant women.	Review	No deaths among the 38 pregnant women. No confirmed cases of intrauterine transmission of SARS-CoV-2.	There is no evidence of intrauterine or transplacental transmission.
Chen et al., 2020²⁹29. Chen H, Guo J, Wang C, Luo F, Yu X, Zhang W, et al. Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records. Lancet. 2020;395:809-15. https://doi.org/10.1016/S0140-6736(20)30360-3 https://doi.org/https://doi.org/10.1016/...	n=9 pregnant women.	Retrospective review	No patient developed severe COVID-19 pneumonia or died. No neonatal asphyxia was observed in the newborns.	The clinical characteristics of pneumonia in pregnant women were similar to those reported for non-pregnant adult patients.
Lu et al., 2020³⁰30. Lu D, Sang L, Du S, Li T, Chang Y, Yang XA. Asymptomatic COVID-19 infection in late pregnancy indicated no vertical transmission. J Med Virol. 2020;92:1660-4. https://doi.org/10.1002/jmv.25927 https://doi.org/https://doi.org/10.1002/...	n=1 22-year-old pregnant woman.	Case report	COVID-19 nucleic acid test was three times negative in the newborn.	There might be no intrauterine infection caused by vertical transmission.

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[1] *Corresponding author. E-mail: marcio-leyser@uiowa.edu (M. Leyser).