Medical and neurodevelopmental outcomes at 10 months of age in infants born at 34 weeks plus to mothers with COVID‐19

Abbreviation

SARS‐CoV‐2

severe acute respiratory syndrome coronavirus 2

COVID‐19 has affected pregnant women and their foetuses since the spring 2020. We previously studied 26 infants who were born at 34 plus weeks of gestation and not separated at birth from mothers with symptomatic severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infections in the last 2 weeks of pregnancy. The infants were born during the first pandemic wave in Alsace, France, and had favourable outcomes at 1 month of age. ¹ Short‐term favourable outcomes in such patients have also been confirmed by a large Swedish register‐based study. ²

Little is known about the mid‐term or long‐term outcomes of such infants, but prenatal exposure to SARS‐CoV‐2 may affect infants' neurodevelopmental trajectories. One study found that three of eight infants born to mothers with SARS‐CoV‐2 had abnormal magnetic resonance imaging findings at 44 weeks of corrected age, including delayed myelinisation and unusual white matter signals, but no clinical repercussions. ³

This observational study followed up the medical outcomes of our cohort ¹ when they reached 10 months of age and was carried out from 15 March to 24 April 2020 in the maternity wards of 2 level III public hospitals in Strasbourg and Mulhouse, France. It was approved by the local ethics committee of Strasbourg Medical Faculty (CE‐2020‐86), and the parents provided written informed consent.

The main investigator phoned the parents when the infants were 10 months old, told them about the study and requested consent to interview the infants' usual paediatricians about their medical history. The parents were then sent written study information, a consent form and the questionnaires. If they did not reply after 2 weeks, the questionnaires were completed over the phone and they returned the consent form. The paediatricians were mainly contacted by e‐mail.

Neurodevelopmental status was measured by the validated French‐Canadian version of the Ages and Stages Questionnaires (ASQ), Second Edition, for 10‐month‐old infants. The questionnaires were completed by at least one French native‐speaking parent and contained five main domains covering 30 questions. Abnormal neurodevelopmental was defined as a score of less than 25 in at least one domain.

Parental questionnaires were used to collect the infants' medical histories and cross‐checked with the data from their paediatricians. These included asthma, bronchiolitis, bacterial pneumonia, otitis, laryngitis, fever without obvious cause or weight gain difficulties.

The study comprised 24 of the original 26 mother–infant dyads and their main perinatal characteristics have previously been reported. ¹ The infants' mean gestational age was 39.0 ± 2.1 weeks, their mean birth weight was 3144 ± 599 grams, and 50% were male. Only one mother was not symptomatic before delivery. Three infants were born preterm, and two had respiratory distress syndrome that required a few hours of ventilation in the neonatal intensive care unit. One had self‐limiting hyperthermia in the maternity ward. Only one asymptomatic neonate tested positive for SARS‐CoV‐2 on Day 3. ¹

Table 1 summarises the main outcomes. One male showed abnormal neurological development at 10 months, with a ASQ gross motor subdomain score of 15. However, his other subdomain scores were normal and monthly examinations by his paediatrician showed no neurological concerns. He tested negative on Days 0 and 3 and was asymptomatic during the first month of life. A 7‐month‐old man was hospitalised with pyelonephritis, and his parents described a short febrile seizure. His electroencephalography findings and the paediatric neurologist team's findings were both normal, with no indication for a lumbar puncture or cerebral imaging. He did not relapse or need anti‐convulsant medication. This suggests that the seizures did not result from brain tissue damage due to a perinatal infection.

TABLE 1.

Main outcomes of 24 patients followed up at 10 months of age

Ages and Stages Questionnaire subdomain scores, mean (SD)
Communication	45 ± 9.3
Gross motor a	50 ± 11.5
Fine motor	52.5 ± 8.3
Problem‐solving	55 ± 8.6
Personal–social	40 ± 8.4
Hospital care (%)
Hospitalisation	1 (4.2)
Paediatric emergency room consultations	4 (16.7)
Infectious diseases (%)
Nasopharyngitis	11 (45.8)
Otitis	5 (20.8)
Bronchiolitis	3 (12.5)
Bacterial pneumonia	1 (4.2)
Pyelonephritis	1 (4.2)
Varicella	1 (4.2)
Fever of unknown origin	2 (8.3)
SARS‐CoV‐2 infection	0 (0)
Non‐infectious medical history (%)
Hyperthermia‐induce seizures	1 (4.2)
Asthma	1 (4.2)
Weight gain difficulties	2 (8.3)

Abbreviation: SD, standard deviation.

^a Only 1 abnormal score (<25) for gross motor subdomain.

No adverse neurological and medical outcomes were detected in our cohort at 10 months of age. Few studies have reported long‐term follow‐ups in such infants. Ayed et al. ⁴ followed 298 infants with in utero exposure to SARS‐CoV‐2 until 10–12 months and assessed their neurodevelopmental status with the ASQ, Third Edition. This showed that 10% had neurodevelopmental delay, defined as less than 2 standard deviations in at least 1 subdomain. Edlow et al. ⁵ reported an increased proportion of developmental disease in 1‐year‐old infants born to mothers with SARS‐CoV‐2 during pregnancy.

The small sample size and absence of a non‐SARS‐CoV‐2 control group were limitations as they prevented definitive conclusions about neurodevelopmental trajectories. Another limitation was the lack of data on breastfeeding‐induced immunisation. Finally, we only reported the neurological outcomes of infants exposed in the last 2 weeks of intrauterine life. Data on earlier exposure to the inflammatory stress associated with maternal SARS‐CoV‐2 infection would have been interesting. Ayed et al. ⁴ reported increased abnormal ASQ scores in infants exposed during the first or second trimester.

This 10‐month follow‐up reassuringly suggested that these infants had not experienced major neurodevelopmental delays after in utero exposure to SARS‐CoV‐2. Our zero‐separation strategy could have contributed to these favourable outcomes. However, long‐term follow‐up studies of larger population‐based cohorts are required to see whether minor difficulties appear later.

CONFLICT OF INTEREST

None.