Clinical findings in our study population indicate a very low risk of severe COVID-19 in children and adolescents. More than half of the individuals below 18 years of age remained asymptomatic (Table 1). In 80% of the families investigated, an adult was the first household member with COVID-19 symptoms. Specific antibodies were detected in 69% of children and adolescents and in 88% of adults exposed to SARS-CoV-2 (Table 1). Apart from a 15-year-old girl who was hospitalized because of a coincidence of COVID-19 with manifestation of type 1 diabetes mellitus, no subject below 18 years had to be hospitalized.
In our cohort of pregnant woman, nine maternal SARS-CoV-2 infections occurred in the first trimester of pregnancy. One of these mothers who had shown typical COVID-19 symptoms from day 54 after the last menstrual period (day 40 after conception) for one week, followed by an otherwise uneventful pregnancy, delivered a boy with unilateral microphthalmia, microcornea, and hypoplasia of both the optic nerve and the neurosensory retina (Figs. 1 A-C). Similar eye abnormalities, uni- or bilaterally, are seen in neonates with rubella embryopathy. The patient’s second eye and visually evoked potentials under flash stimulation (Fig. 1 D) were found to be normal. Any relevant family history as well as rubella, toxoplasmosis, herpes or cytomegalovirus infection have been excluded; vaccination of the mother against rubella before becoming pregnant and protective levels of rubella-specific IgG were evident. As the father had contracted COVID-19 five days before his wife, SARS-CoV-2 replication in the mother most likely happened in weeks 5 and 6 of embryonic development, during oculogenesis [8]. Maternal PCR testing for SARS-CoV-2 (nasopharyngeal swab) three days after symptom onset was positive. Both parents developed specific antibodies against the SARS-CoV-2 spike protein. At birth in gestational week 41 + 1, the infant weighed 4,000 grams; SARS-CoV-2 PCR tests were negative, while IgG against the nucleocapsid of SARS-CoV-2 (most likely of maternal origin) were still detectable in the cord blood. Ultrasonography of brain and abdomen did not reveal additional malformations.
We attempted to rule out genetic causes of optic nerve hypoplasia in this patient by whole exome sequencing and careful analysis of 54 genes possibly involved in developmental anomalies of the eye (complete CeGaT panels for microphthalmia/coloboma and optic nerve atrophy, includingABCB6, BMP4, MCAT, OPA1, OPA3, PAX2, PAX6, RAX, THEM126A, andWFS1). We detected a total of three gene variants with an allele frequency below 1%: The first of them, heterozygousABCB6variant c.649C > A (p.Q217K; transcript CCDS2436.1; ENST00000265316; NM_005689.4), was classified as benign by each of the mutation prediction tools used. It affects an exon in one of the two transcripts produced but an intron in the other transcript. The second possible mutation, heterozygousRAXvariant c.311G > A (p.G104D; transcript ENST00000256852.7) which is identical with c.565G > A (p.A189T) in anotherRAXtranscript (CCDS11972.1; ENST00000334889; NM_013435.3), does not, in our opinion, explain the phenotype, becauseRAXvariants have been considered as pathogenic in the literature only when present homozygously or compound-heterozygously. The third finding of potential significance, heterozygousMCATvariant c.235C > G (p.R79G; transcript CCDS14045.1; ENST00000327555; NM_014507.3), was classified as benign based on the SIFT and PolyPhen-2 scores and has been detected more frequently in a Swedish subpopulation.
Known teratogenic factors that may influence optic nerve development, such as maternal alcohol consumption during early gestation, smoking, drug abuse, and maternal diabetes mellitus, were also excluded. As the patient’s mother did not take any potentially teratogenic drugs, our findings suggest the eye abnormalities of the infant to be due either to materno-fetal transmission of SARS-CoV-2 or to an indirect effect of the maternal SARS-CoV-2 infection at the time of optic tract development. This conclusion must be taken with caution, because the only link that connects the association is the fact that the patient’s mother contracted COVID-19 during the relevant stage of embryogenesis. Given the high incidence of SARS-CoV-2 infection, the link may be entirely coincidental. On the other hand, this finding has to be reported to the scientific community to allow further investigation and to raise awareness of rare complications associated with COVID-19.
In order to identify the pathogenetic mechanisms underlying a link between SARS-CoV-2 infection and ocular developmental anomalies, further studies involving animal experiments would be required. Even if a direct impact of the virus on neurodevelopment was considered unlikely, cytokine storm and hyperinflammatory processes in a pregnant woman with SARS-CoV-2 infection could still increase the risk of neurodevelopmental disorders in early stages of pregnancy [9]. Based on the biological properties of SARS-CoV-2, Leyser and colleagues speculate that the virus might neutralize the maternal immune response by affecting interferon type 1 expression, similar to Zika virus, thereby facilitating virus spread and increasing the risk of damage to progenitor cells of the fetal brain [9].
The other 8 newborns of mothers with SARS-CoV-2 infection during early gestation did not show any clinical or ultrasonographic abnormality.
In 23 of the 27 neonates investigated in this study, no morbidity related to preceding SARS-CoV-2 infection of their mothers was observed, whereas maternal infection at the very end of pregnancy (n = 5), before sufficient passive immunity could be conferred to the baby, led to positive SARS-CoV-2 PCR results and mild COVID-19 symptoms in two newborns (40%; one male, one female), including a generalized postinfectious exanthema (Supplementary Fig. 1 A) that lasted for up to 14 days. An almost identical skin rash was observed with three days delay also in the otherwise healthy, postnatally SARS-CoV-2 PCR-negative twin of the affected girl. Knowledge about such cutaneous manifestations of COVID-19 is still limited and will improve differential diagnosis. In one of the two symptomatic newborns, clearly elevated but continuously decreasing D-dimers were recorded (Supplementary Fig. 1 B), explainable by an obvious cephalohematoma rather than by COVID-19-related thrombophilia.
Sonography of the brain and adrenal glands of the 5 perinatally exposed infants did not reveal any additional abnormalities.
The comparatively mild course of disease in our pediatric subpopulation confirms what has been observed by others [10], although current studies have not yet taken issues such as long COVID or myalgic encephalomyelitis/chronic fatigue syndrome [11] sufficiently into account. In addition, the data were obtained prior to the occurrence of SARS-CoV-2 variants of concern which appear to be transmitted more easily [12]. Perinatal SARS-CoV-2 infections of the infant leading to a mild course of disease have been reported elsewhere, too [1, 10], although their frequency in our study was higher than expected. An embryopathy associated with maternal COVID-19 is described here for the first time. Both should sensitize researchers and stimulate more systematic studies. If further cases of potentially SARS-CoV-2-induced malformations become known, COVID-19 vaccination recommendations for pregnant women may need to be reconsidered.