Severe acute respiratory syndrome coronavirus 2 infections are uncommon in newborn infants. This report describes possible in utero transmission of the B.1.1.7 (alpha) variant in a preterm infant born at 31 weeks’ gestational age who presented with severe respiratory disease. The infant was treated with high-frequency oscillatory ventilation, antiviral medications, and corticosteroids and transitioned to noninvasive respiratory support on day 33. By day 63, she was off positive pressure support and breathing room air and she was discharged from the hospital on day 70. She demonstrated normal growth and development at a 6-month follow-up visit. Placental histopathology revealed placentitis characterized by loss of intervillous spaces resulting from fibrin deposition and inflammatory cell infiltration. Optimum management strategies for treating infants with severe acute respiratory syndrome coronavirus 2 infection have yet to be determined.
A female infant was born at 31 + 5 weeks’ gestational age weighing 1950 g (75th-91st percentile) to a multiparous woman with preterm prolonged rupture of the membranes and pyrexia. The mother tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 1 week before delivery and underwent an emergency cesarean delivery under general anesthesia for placental abruption and pathologic cardiotocogram. She received intravenous antibiotics, steroids, and magnesium sulfate. After delivery, the mother developed disseminated intravascular coagulation, received multiple blood products, and was ventilated for 10 hours. She subsequently made a full recovery.
All staff who cared for the mother and baby had donned full personal protective equipment during the delivery. The infant was intubated and ventilated at 8 minutes of age because of ongoing respiratory distress and high oxygen requirements; she received endotracheal surfactant per local protocol. Apgar scores were 41, 65, and 810. She was stabilized and transferred to an isolation room on the neonatal unit. The baby’s mother could not visit until she had completed 14 days of isolation and had resolved symptoms of her disease. Ongoing care in the NICU was provided in an isolation room by staff wearing full personal protective equipment until day 49 after delivery.
The infant received a second dose of surfactant within the first 24 hours after delivery and remained ventilated because of increased oxygen requirements. A chest radiograph on day 1 showed florid air space shadowing (Fig 1A). On day 9, her condition deteriorated further and respiratory support was escalated to high-frequency oscillatory ventilation because of suboptimal blood gases and hypoxia (saturations 85%) despite maximum oxygen delivery. A trial of inhaled nitric oxide was discontinued in the absence of clinical improvement or evidence of pulmonary hypertension on echocardiogram.
Reverse transcription polymerase chain reaction (PCR) testing of endotracheal secretions for SARS-CoV-2 from the infant was positive at 49 hours (cycle threshold [Ct] value, 17.5 for the E gene and 19.5 for the N2 gene), day 3 (Ct value, 15.7 for the E gene and 17.4 for the N2 gene), and day 5 (Ct value, 15.1 for the E gene and 16.5 for the N2 gene) after birth. We discussed her management with a regional multidisciplinary SARS-CoV-2 expert team because of oxygen and ventilation requirements that were unexpected given her gestational age. Per consensus of the team, we prescribed a 10-day course of hydrocortisone (0.5 mg/kg twice daily intravenously for 7 days followed by once daily for 3 days) on day 10 (per the Early Prevention of Broncho-pulmonary Dysplasia and Neonatal Mortality in Very Preterm Infants Using Low Dose of Hydrocortisone [PREMILOC] protocol1 ) and intravenous remdesivir (loading dose of 2.5 mg/kg followed by 1.25 mg/kg once daily for 10 days, for which urgent compassionate access was provided by Gilead Pharmaceuticals). Because the infant continued to have high ventilation and oxygen requirements, we started a course of dexamethasone (initially intravenously) on day 22 consistent with the Dexamethasone: A Randomized Trial (DART) protocol2 and antifungal prophylaxis. Significant clinical improvement ensued after dexamethasone therapy and allowed extubation to noninvasive respiratory support on day 33 and discontinuation of positive pressure support on day 63. A timeline of her respiratory course and response to treatments, together with relevant inflammatory markers, is presented in Fig 1B.
PCR of blood for herpes simplex virus and varicella-zoster virus, urine for cytomegalovirus, and endotracheal secretions for respiratory syncytial virus, influenza A and B, parainfluenza 1, 2, and 3, enterovirus, adenovirus, rhinovirus, and human metapneumovirus were negative. Basic lymphocyte subsets, naïve and memory T-cell subsets, and T-cell receptor excision circles were normal. Multiple blood cultures were sterile. Serial cranial ultrasound scans showed resolving bilateral germinal matrix hemorrhages.
Endotracheal secretions and nasopharyngeal aspirates tested positive for SARS-CoV-2 through day 36. The viral genome sequence was confirmed as the B.1.1.7 lineage (alpha) variant. Placental immunohistochemical staining for SARS-CoV-2 spike protein was diffusely positive in syncytiotrophoblasts and histopathology revealed massive perivillous fibrin deposition (Fig 2 A–D). PCR (Cepheid) confirmed the presence of SARS-CoV-2 in placental tissue (Ct value, 19.7 for the E gene and 19.1 for the N2 gene) and sequencing also revealed the B.1.1.7 variant. The maternal sample was taken in a community clinic before admission to the hospital and was not sequenced; however, pairwise sequence alignment of samples from the baby and placenta showed 99.7% similarity.
The baby was discharged from the hospital on day 70. Her growth and development were normal at her 6-month follow-up visit.
This case report describes possible in utero transmission of SARS-CoV-2 caused by the B.1.1.7 (alpha) variant, resulting in severe respiratory disease in a preterm infant. In utero transmission of SARS-CoV-2 infection is rare.3,4 If the infant in this case report did acquire SARS-CoV-2 infection in utero, it is unknown whether transmission was due to hematogenous spread or from fetal ingestion of maternal blood secondary to the abruption. Although children are less severely affected by SARS-CoV-2 infections,5 the virulence of different variants requires close surveillance to conduct ongoing assessment of how different variants influence disease severity in specific patient groups.6
Population-based surveillance data have shown that confirmed SARS-CoV-2 infection is rare in newborn infants. In the United Kingdom, there were 5.6 cases per 10 000 live births recorded during the first UK SARS-CoV-2 peak in March and April 2020.7 Despite the low incidence in children, neonates appear to have more severe disease with 36% requiring critical care or respiratory support compared with 14% of older children in a European case series.8
When SARS-CoV-2 first emerged, there were no known treatments for this condition. Large, adaptive, randomized controlled trials have subsequently found evidence of benefit for both corticosteroids9 and tocilizumab10 in significantly reducing mortality in adult patients. Trials of potential treatment interventions in children with severe SARS-CoV-2 infection are less well represented in the literature.11
There are no definitive treatment strategies for babies who develop severe SARS-CoV-2 respiratory phenotype. The infant in this case report received both antiviral and corticosteroid therapies. Remdesivir was administered based on a previous report of its use in an ex-preterm baby12 with severe disease. Administration of high-dose postnatal steroids to preterm infants is controversial because of an association with adverse neurodevelopmental outcomes.13 Studies evaluating the safety and efficacy of reduced-dose dexamethasone use in preterm infants suggest less severe adverse neurodevelopmental outcomes.2,14 More recently, a trial evaluating postnatal hydrocortisone to reduce chronic lung disease in preterm infants did not find increased rates of neuro-disability among survivors allocated to the steroid arm.1,15 The corticosteroid choice and dosing regimens reported here were based on the regimens used in both the PREMILOC1 and DART2 studies to minimize the potential adverse neurodevelopmental effects of corticosteroid use in preterm babies. However, these dosing strategies were originally evaluated for the prevention and/or treatment of preterm babies with bronchopulmonary dysplasia, and we acknowledge that neither regimen may be effective for the management of severe SARS-CoV-2 respiratory phenotype. The infant described in this report made a significant improvement after dexamethasone was started (Fig 1B).
Viral genome sequencing in this case revealed SARS-CoV-2 B.1.1.7 variant in samples from the placenta and the baby. Updated consensus definitions for confirmed, possible, and unlikely in utero SARS-CoV-2 transmission from mother to child are now available from the World Health Organization.16 Proof of confirmed in utero mother-to-child transmission requires viral detection from a sterile site (in addition to other parameters) within 48 hours of birth and viral detection from placental tissue. Based on the World Health Organization criteria, the case presented here represents possible in utero mother-to-child transmission.
Although severe disease with SARS-CoV-2 is rare in babies, ongoing surveillance of disease severity with new variants is essential. This case report describes possible in utero mother-to-child transmission of SARS-CoV-2 B.1.1.7 variant in an infant born at 31 weeks’ gestational age and whose respiratory disease was more severe than the typical course of respiratory distress syndrome at that gestational age. Clinical improvement occurred after a 10-day course of remdesivir with hydrocortisone and a subsequent 9-day course of dexamethasone. Optimum regimens for treating severe SAR-CoV-2 respiratory infection in newborns have yet to be determined, and the inclusion of this patient group in research trials is essential. Case definitions for in utero transmission will require regular revision as improved diagnostic modalities become available. Future research toward reducing and/or preventing in utero transmission is critical to mitigate the potential disease burden in the neonatal population.
The authors thank Dr Victoria Bryant for advice and for providing placental photomicrographs and thank the Virology Department at Barts Health National Health Service Trust, London, United Kingdom, for performing sequencing and pairwise sequence alignment of samples. We would also like to thank the family for granting permission to write this case report.
Dr Fleming conceptualized the work, drafted the initial manuscript, and reviewed and revised the manuscript; Dr Pereira conceptualized the work, acquired the data, drafted the initial manuscript, and reviewed, revised, and submitted the manuscript; Drs Kapellou, Claxton, and Bamford conceptualized the work and reviewed and revised the manuscript; Prof Aladangady conceptualized the work, reviewed and revised the manuscript, and coordinated the work; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
Parents provided written consent to publish this case report.
FUNDING: No external funding.
CONFLICT OF INTEREST DISCLOSURES: Dr Bamford has received consultancy fees from Gilead in relation to treatment of coronavirus disease in children; the other authors have indicated they have no potential conflicts of interest to disclose.