Journals | Policy | Permission

Journal of Clinical Medicine Research

Original Article

Volume 13, Number 8, August 2021, pages 420-424

Perinatal Transmission and Clinical Outcomes of Neonates Born to SARS-CoV-2-Positive Mothers

Coronavirus disease 2019 (COVID-19) is an emerging disease that was detected for the first time among humans in December 2019. Its manifestations range from asymptomatic forms to death [1]. Due to the imposed restrictions and country lockdown, Jordan was not affected by the first wave of the pandemic [2]. However, starting on November 2021, the second wave devastated the country, with cumulative cases exceeding 600,000 cases [3].

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus causing COVID-19, is mainly transmitted via respiratory droplets or direct contact route [4]. However, vertical transmission from mothers to babies is controversial [5]. With regard to breastfeeding, it is unclear whether breast milk is a vector for virus transmission, although it was declared by the World Health Organization (WHO) and other worldwide organizations that mothers who wish to breastfeed can do so provided that they practice hygiene precautions [6].

Neonatal and pediatric patients infected with SARS-CoV-2 are mostly asymptomatic or present with mild illness [7]. In the neonatal period, the symptom presentation is quite variable, ranging from mild symptoms, such as nasal congestion, to fever, respiratory distress, hypoactivity, sepsis, and even death [8].

This prospective study aimed to compare the clinical outcomes, rates of virus detection, and presence of symptoms between SARS-CoV-2-positive and -negative neonates born to SARS-CoV-2-positive mothers.

This was a prospective observational study on neonates born to SARS-CoV-2-positive mothers at the Jordan University Hospital from March 2020 to April 2021.

This study was approved by the deanship of scientific research at the University of Jordan and by the ethical committee of the Jordan University Hospital (reference number 10-2020-8558). The study was performed in accordance with the Declaration of Helsinki. A structured data sheet was used to collect the demographic and clinical data of the included newborns.

Nasopharyngeal swabs were collected from the neonates according to the neonatal intensive care unit (ICU) protocol. At the beginning of the pandemic, the first swab was collected at delivery and after 48 h after delivery. A few months later, this protocol was modified, with the first swab collected at 24 h of age, followed by the second swab at 72 h of age. The SARS-CoV-2 reverse transcription-polymerase chain reaction (RT-PCR) test was used as the diagnostic test.

Neonates who did not require neonatal ICU admission were taken care of according to the international recommendation, adopting a room-in policy. The mothers were also counselled about breastfeeding and allowed to decide whether to breastfeed or to give formula. At discharge, the parents were instructed to return to the hospital if they developed symptoms. They were asked to contact health professionals at the neonatal unit via telephone if they had any concerns.

The data were analyzed using Excel 2010 (Microsoft; Redmond, Washington, USA). The frequency, mean, and standard deviation were calculated. Fisher’s exact test was used to compare the frequencies. A two-tailed t-test was used to compare the mean and standard deviation. Statistical significance was set at P < 0.05.

A total of 130 neonates born to 122 SARS-CoV-2-positive mothers were included. Only six of the included mothers were diagnosed before Jordan’s second wave of COVID-19 epidemic in November 2020. Sixteen mothers (13%) were symptomatic at the time of delivery. Among the neonates, 16 were SARS-CoV-2-positive based on results of RT-PCR tests using nasopharyngeal swabs. Eight (50%) neonates were positive on the first swab. Two (1.5%) had equivocal results. Most (62%) neonates were delivered via cesarean section, and 58 neonates were male (45%). The average gestational age was 36 weeks (range, 29 - 41 weeks), and the average birth weight was 2,900 g (range, 980 - 3,900 g). Only 38% neonates required admission to the neonatal ICU, mostly due to prematurity (Table 1).

Click to view

Table 1. Clinical and Demographic Data of Neonates Born to SARS-CoV-2-Positive Mothers

SARS-CoV-2-positive neonates were born at a significantly lower gestational age than SARS-CoV-2-negative neonates (35 vs. 37 weeks; P = 0.004). Further, SARS-CoV-2-positive neonates had significantly lower birth weight (2,400 vs. 2,790 g; P = 0.025). However, there was no significant difference in the number of premature neonates aged < 34 weeks in both groups. Moreover, SARS-CoV-2-positive neonates had significantly higher rates of neonatal ICU admission (68% vs. 34%, P = 0.014), surfactant therapy (25% vs. 0.9%, P = 0.000), C-reactive protein level elevation (18.8% vs. 3.6%, P = 0.041), and antibiotic therapy requirement (56% vs. 18.8%, P = 0.003) than SARS-CoV-2-negative neonates. They also had significantly higher rates of neonatal hyperbilirubinemia (37% vs. 10%, P = 0.011) and bradycardia (18.8% vs. 1.8%, P = 0.014) than SARS-CoV-2-negative neonates. However, there was no difference in the mortality rates between SARS-CoV-2-positive and -negative neonates (Table 1).

A multiple linear regression analysis was performed to examine whether the prematurity, neonatal SAR-CoV-2-positive status, or low birth weight variables significantly predicted admission. Low birth weight was found to be the most significant factor to predict admission to the neonatal unit with P value of 0.087, 0.085, and < 0.001, respectively.

Perinatal transmission of SARS-CoV-2 has been reported previously [9-11]. However, the exact route of transmission has not been documented. SARS-2-CoV-2 has been detected in the amniotic fluid, supporting its hematogenous spread through the placenta or through the aspiration and ingestion of maternal amniotic fluids [12]. Transmission can also occur later via breastfeeding [13] or from household contacts. However, evidence supporting vertical transmission has been increasing [14].

Transplacental transmission might have more severe outcomes if it occurs during the early stages of pregnancy, a gray zone that needs further investigation. In a study investigating the placental pathology in mothers with severe COVID-19, they found that the placentas showed an increased rate of decidual arteriopathy and other features of maternal vascular malperfusion, which reflect abnormalities in oxygenation within the intervillous space associated with adverse perinatal outcomes. The study further concluded that these changes were associated with hypertensive disorders of pregnancy and preeclampsia and may reflect a systemic inflammatory or hypercoagulable state influencing placental physiology [15]. Another study revealed an increased risk of miscarriages in the first trimester among pregnant SARS-CoV-2-positive women [16].

However, regarding perinatal SARS-CoV-2 infection, the route of transmission, whether transplacental or during birth, may be determined based on the duration before positive tests or whether clinical symptoms are observed. However, this will require a longer duration of isolation and outpatient follow-up and more serial testing in neonatal infants whose initial test results were negative. This places more strain on an already exhausted neonatal service.

The rate of transmission in our cohort was 12%, much higher than previously reported rates [10, 11, 16]. The National Registry for Surveillance and Epidemiology of Perinatal COVID-19 Infection reported a transmission rate of only 1.9% [10]. Similarly, in a large population-based cohort study in the UK, only 5% of the neonates born to SARS-CoV-2-infected mothers were infected [9]. In a Spanish cohort, the perinatal acquisition rate was 6.9% [16]. Various factors may explain the differences, but it may be mainly due to the differences in the COVID-19 illness stage among mothers at the time of delivery, which could potentially affect the rate of perinatal transmission due to the different intensities of viremia. Another theory that requires further investigation is the difference in the virus variant, as most of our cohort (n = 116) were recruited after November 2020, when Jordan started detecting cases of the UK variant [17], a more transmissible and potentially more lethal variant [18].

Our neonates were only tested during the first 72 h of life; hence, data on neonates who tested positive later could not be reviewed. One of our neonates was born at 30 weeks of gestation. His mother was SARS-CoV-2-positive before 6 weeks and 8 days prior to delivery. The neonate presented with respiratory distress syndrome, but his condition improved after administration of surfactant therapy. At the age of 9 days, he developed severe respiratory distress, requiring 100% oxygen. A thorough investigation was conducted. Septic workup and echocardiography revealed normal results, but he was tested positive for SARS-CoV-2 on the RT-PCT test using nasopharyngeal swab. This case might represent perinatal transmission or postnatal transmission from the visiting parent or the neonatal unit staff. However, none of the other babies in the unit was positive, and none of the staff who took care of him were positive. In another case, the mother was tested 2 days prior to delivery, and the neonate had negative nasopharyngeal swab results at 24 h of age. However, the parents did not return for the follow-up swab. The neonate presented at 19 days of age with mild respiratory symptoms and was later tested positive for SARS-CoV-2. Although these cases were more likely due to postnatal infection, perinatal transmission is a possibility.

The neonates born to SARS-CoV-2-positive mothers had good outcomes. One-third (38%) neonates required admission to the neonatal ICU, mostly (48%) due to prematurity (gestational age < 35 weeks). The second most common cause of admission was respiratory distress, seen in 30% neonates. There were three mortalities (2%), with one death due to respiratory failure and prematurity and another due to pulmonary hypertension. The third baby had intrauterine growth restriction and pancytopenia; bone marrow aspiration revealed hemophagocytic lymphohistiocytosis, a complication that can be attributed to the strong activation of the immune system after a severe infection (Table 1).

Neonates born to SARS-CoV-2-positive mothers can develop complications due to factors not directly related to the infection, such as maternal hypoxemia, preeclampsia, and placental hypoperfusion [11]. These complications might be due to the passage of inflammatory cytokines [19], which can be attributed to sepsis-like symptoms and elevated C-reactive protein levels (Table 1). Although these morbidities are relatively common during the neonatal period, affected newborns need long-term follow-up, especially for monitoring their neurodevelopmental status.

Among the SARS-CoV-2-positive newborns, 11 (68%) required admission to the neonatal ICU, mostly due to prematurity; the rate of neonatal ICU admission was significantly higher in SARS-CoV-2-positive newborns than in SARS-CoV-2-negative newborns (P = 0.014). This might be attributed to the fact that the positive newborns were more premature (35 vs. 37 weeks, P = 0.004) and had lower birth weights than the negative newborns (2,400 vs. 2,790, P = 0.025). This finding might also explain why the SARS-CoV-2-positive neonates required more surfactant therapy (P < 0.0007). However, there was no significant difference in the number of premature infants aged ≤ 34 weeks, which places them at higher risk of respiratory distress syndrome, between the two groups (31% vs. 17%, P = 0.18).

Bradycardia was reported in both groups, although there were significantly more cases among SARS-CoV-2-positive patients than in SARS-CoV-2-negative patients. The electrocardiogram showed sinus bradycardia, while the electrolyte and thyroid function tests showed normal findings. The echocardiogram was normal. Severe acute respiratory syndrome coronavirus from the 2002 outbreak was associated with sinus bradycardia in up to 15% patients [20]. Several studies have also linked the SARS-CoV-2 to bradycardia [21]. However, the exact mechanism is unknown. This may be due to direct SARS-CoV-2 infiltration into myocardial cells and the dedicated conduction system. It may also be due to the collateral damage from the activation of the inflammatory system and the resulting cytokine storm [22]. As such, the passage of maternal cytokines might explain the bradycardia in SARS-CoV-2-negative group. Another suggested mechanism for bradycardia is the activation of the angiotensin-converting enzyme 2 receptor, specifically in the sino-atrial nodal cells, leading to conduction disturbances [23]. However, this mechanism might not apply to newborns due to the lower expression and decreased affinity of the angiotensin-converting enzyme 2 receptor [24].

The milder disease observed in neonatal patients might be attributed to multiple factors, such as the following: lower intensity of exposure to SARS-CoV-2; weaker adaptive immunity, decreasing the severity of the inflammation responsible for most tissue damage; and relatively lower expression, affinity, and distribution of the angiotensin-converting enzyme 2 receptors, which facilitate SARS-CoV-2 entry into cells [25].

Our study limitation is its single center nature, and the lack of some of the maternal data. However, it provides evidence on the vertical transmission of the SARS-CoV-2. We also proved that the neonatal population is not at risk of severe illness, but long-term complications are unknown.

Acknowledgments

The authors acknowledge the efforts of the pediatric residents and neonatal nurses, the front-line workers at Jordan University hospital.

Financial Disclosure

This study did not receive any funding.

Conflict of Interest

The authors have no conflict of interest to declare.

Informed Consent

Patient consent was waived due to the observational nature of this study, in addition to the absence of patients’ identifiers.

Author Contributions

Conceptualization: Manar Al-Lawama. Data curation: Manar Al-Lawama, Noor Ghanim, Ayah Irsheid and Hiba Qtaishat. Formal analysis: Manar Al-Lawama, Noor Ghanim, Ayah Irsheid and Hiba Qtaishat. Methodology: Manar Al-Lawama and Eman Badran. Project administration: Manar Al-Lawama. Resources: Manar Al-Lawama, Eman Badran, Iyad Al-Ammouri and Ghada Massad. Supervision: Manar Al-Lawama. Writing original draft: Manar Al-Lawama, Noor Ghanim, Ayah Irsheid and Hiba Qtaishat. Writing review and editing: Iyad Al-Ammouri, Enas Al-Zyadneh, Montaha Al-Iede, Amira Daher and Fares Bakri.

Data Availability

The authors declare that data supporting the findings of this study are available within the article.

1. Zheng Z, Peng F, Xu B, Zhao J, Liu H, Peng J, Li Q, et al. Risk factors of critical & mortal COVID-19 cases: A systematic literature review and meta-analysis. J Infect. 2020;81(2):e16-e25.
   doi pubmed
2. Alqutob R, Al Nsour M, Tarawneh MR, Ajlouni M, Khader Y, Aqel I, Kharabsheh S, et al. COVID-19 crisis in Jordan: response, scenarios, strategies, and recommendations. JMIR Public Health Surveill. 2020;6(3):e19332.
   doi pubmed
3. https://covid19.who.int/region/emro/country/jo. Accessed Apr 9, 2021.
4. World Health Organization, 2020. Modes of transmission of virus causing COVID-19: Implications for IPC precaution recommendations [Internet]. Scientific Brief [online]. https://www.who.intr. Accessed Apr 6, 2021.
5. Tezer H, Bedir Demirdag T. Novel coronavirus disease (COVID-19) in children. Turk J Med Sci. 2020;50(SI-1):592-603.
   doi pubmed
6. Hethyshi R. Breast feeding in suspected or confirmed cases of COVID 19-a new perspective. J Obstet Gynaecol India. 2020;70(4):267-271.
   doi pubmed
7. Hong H, Wang Y, Chung HT, Chen CJ. Clinical characteristics of novel coronavirus disease 2019 (COVID-19) in newborns, infants and children. Pediatr Neonatol. 2020;61(2):131-132.
   doi pubmed
8. Rozycki HJ, Kotecha S. Covid-19 in pregnant women and babies: What pediatricians need to know. Paediatr Respir Rev. 2020;35:31-37.
   doi pubmed
9. Knight M, Bunch K, Vousden N, Morris E, Simpson N, Gale C, O'Brien P, et al. Characteristics and outcomes of pregnant women admitted to hospital with confirmed SARS-CoV-2 infection in UK: national population based cohort study. BMJ. 2020;369:m2107.
   doi pubmed
10. National registry for surveillance and epidemiology of perinatal COVID-19 infection: section on neonatal-perinatal medicine. American Academy of Pediatrics. https://services.aap.org/. Accessed on April 4, 2021.
11. Juan J, Gil MM, Rong Z, Zhang Y, Yang H, Poon LC. Effect of coronavirus disease 2019 (COVID-19) on maternal, perinatal and neonatal outcome: systematic review. Ultrasound Obstet Gynecol. 2020;56(1):15-27.
    doi pubmed
12. Dong L, Tian J, He S, Zhu C, Wang J, Liu C, Yang J. Possible vertical transmission of SARS-CoV-2 from an infected mother to her newborn. JAMA. 2020;323(18):1846-1848.
    doi pubmed
13. Costa S, Posteraro B, Marchetti S, Tamburrini E, Carducci B, Lanzone A, Valentini P, et al. Excretion of SARS-CoV-2 in human breast milk. Clin Microbiol Infect. 2020;26(10):1430-1432.
    doi pubmed
14. Vivanti AJ, Vauloup-Fellous C, Prevot S, Zupan V, Suffee C, Do Cao J, Benachi A, et al. Transplacental transmission of SARS-CoV-2 infection. Nat Commun. 2020;11(1):3572.
    doi pubmed
15. Shanes ED, Mithal LB, Otero S, Azad HA, Miller ES, Goldstein JA. Placental pathology in COVID-19. medRxiv. 2020.
    doi pubmed
16. Martinez-Perez O, Vouga M, Cruz Melguizo S, Forcen Acebal L, Panchaud A, Munoz-Chapuli M, Baud D. Association between mode of delivery among pregnant women with COVID-19 and maternal and neonatal outcomes in Spain. JAMA. 2020;324(3):296-299.
    doi pubmed
17. Sallam M, Mahafzah A. Molecular analysis of SARS-CoV-2 genetic lineages in Jordan: tracking the introduction and spread of COVID-19 UK variant of concern at a country level. Pathogens. 2021;10(3):302.
    doi pubmed
18. Challen R, Brooks-Pollock E, Read JM, Dyson L, Tsaneva-Atanasova K, Danon L. Risk of mortality in patients infected with SARS-CoV-2 variant of concern 202012/1: matched cohort study. BMJ. 2021;372:n579.
    doi pubmed
19. Dammann O, Leviton A. Maternal intrauterine infection, cytokines, and brain damage in the preterm newborn. Pediatr Res. 1997;42(1):1-8.
    doi pubmed
20. Yu CM, Wong RS, Wu EB, Kong SL, Wong J, Yip GW, Soo YO, et al. Cardiovascular complications of severe acute respiratory syndrome. Postgrad Med J. 2006;82(964):140-144.
    doi pubmed
21. Chinitz JS, Goyal R, Harding M, Veseli G, Gruberg L, Jadonath R, Maccaro P, et al. Bradyarrhythmias in patients with COVID-19: Marker of poor prognosis? Pacing Clin Electrophysiol. 2020;43(10):1199-1204.
    doi pubmed
22. Kochi AN, Tagliari AP, Forleo GB, Fassini GM, Tondo C. Cardiac and arrhythmic complications in patients with COVID-19. J Cardiovasc Electrophysiol. 2020;31(5):1003-1008.
    doi pubmed
23. Ferreira AJ, Moraes PL, Foureaux G, Andrade AB, Santos RA, Almeida AP. The angiotensin-(1-7)/Mas receptor axis is expressed in sinoatrial node cells of rats. J Histochem Cytochem. 2011;59(8):761-768.
    doi pubmed
24. Li Y, Zhou W, Yang L, You R. Physiological and pathological regulation of ACE2, the SARS-CoV-2 receptor. Pharmacol Res. 2020;157:104833.
    doi pubmed
25. Zimmermann P, Curtis N. Why is COVID-19 less severe in children? A review of the proposed mechanisms underlying the age-related difference in severity of SARS-CoV-2 infections. Arch Dis Child. 2020;106(5):429-439.
    doi pubmed

This article is distributed under the terms of the Creative Commons Attribution Non-Commercial 4.0 International License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Journal of Clinical Medicine Research is published by Elmer Press Inc.