Clinical outcomes and antibody transfer in a cohort of infants born to mothers with SARS-COV-2 infection during pregnancy (Coronascope Study)

doi:10.21203/rs.3.rs-2724546/v1

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Research Article

Clinical outcomes and antibody transfer in a cohort of infants born to mothers with SARS-COV-2 infection during pregnancy (Coronascope Study)

https://doi.org/10.21203/rs.3.rs-2724546/v1

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Journal Publication

published 10 Aug, 2023

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Purpose: We aimed to describe the outcomes, focusing on the hearing and neurological development, of children born to mothers with SARS-CoV-2 infection during pregnancy, and to evaluate the persistence of maternal antibodies in the first months of life.

Methods:An observational, prospective study at a tertiary hospital in Madrid (Spain) on infants born to mothers infected with SARS CoV-2 during pregnancy between March and September 2020. A follow-up visit at 1-3 months of age with a physical and neurological examination, cranial ultrasound (cUS), SARS-CoV-2 RT-PCR on NPS and SARS-CoV-2 serology were performed. Hearing was evaluated at birth through the automated auditory brainstem response and at six months of age through the auditory steady-state response. A neurodevelopmental examination using the Bayley-III scale was performed at 12 months of age.

Results:Of 95 infants studied, neurological examination was normal in all of them at the follow-up visit, as was the cUS in 81/85 (95%) infants, with only mild abnormalities in four of them. Serology was positive in 47/95 (50%) infants, which was not associated with symptoms or severity of maternal infection. No hearing loss was detected and neurodevelopment was normal in 96% of the children (median Z score: 0).

Conclusions: In this cohort, the majority of infants born to mothers with SARS-CoV-2 infection during pregnancy were healthy children with a normal cUS, no hearing loss and normal neurodevelopment in the first year of life. Only half of the infants had a positive serological result during the follow-up.

SARS-CoV-2

maternal infection

neurological outcomes

hearing outcomes

antibody transfer.

Hearing loss and neurodevelopmental delay in infants born to mothers with SARS-CoV-2 infection during pregnancy has been suggested, although data is inconsistent. Maternal antibody transfer seems to be high, with a rapid decrease during the first weeks of life.

What is new: Most infants born to mothers with SARS-CoV-2 infection during pregnancy had normal hearing screening, cranial ultrasound and neurodevelopmental status at 12 months of life. Antibodies against SARS-CoV-2 were only detected in 50% of the infants at two months of life.

Although pregnant women and newborns have been a major concern regarding the SARS-CoV-2 pandemics, the effect of maternal infection during pregnancy on the developing fetus remains unclear. It is well known that some maternal viruses can potentially provoke neurological damage or other long-term sequelae in infants[1], and SARS-CoV-2 causes neurological symptoms and radiological findings on newborns and children[2]. SARS-CoV-2 vertical transmission seems to be low[3–7] and vertically infected newborns mainly asymptomatic[4, 7], although there are some reports of neurological impairment[9]. The short-term clinical outcomes of infants born to mothers with SARS-CoV-2 infection during pregnancy seem to be good, yet most studies have focused on COVID-19 related symptoms at birth and their follow-up has been limited to the first weeks of neonatal life[3, 4, 9, 10]. As such, data on the neurological outcomes of these infants are still scarce, and while two studies showed good short-term outcomes[11, 12], hearing[13, 14] and neurological[15, 16] impairments have also been suggested.

Transplacental passage of maternal SARS-CoV-2 antibodies has been confirmed by analyzing the cord blood of neonates born to mothers infected with SARS-CoV-2 during pregnancy[18–21], although there is some evidence that they may have a short half-life[19, 21, 22].

Here we set out to describe the clinical outcomes of children born to mothers who were infected with SARS-CoV-2 during pregnancy, focusing particularly on the hearing and neurological development of the infants, and evaluating the persistence of maternal antibodies in these children in the first months of life.

We carried out an observational prospective study at the Hospital Universitario 12 de Octubre, a tertiary-care center located in southern Madrid (Spain). This hospital covers an estimated population of 400,000 inhabitants and attends around 4,000 deliveries each year. Infants born from March to September 2020 to mothers with SARS-CoV-2 infection during pregnancy were included in this study.

Mothers were considered to have had a SARS-CoV-2 infection during pregnancy if they had either a positive result in a SARS-CoV-2 Reverse-Transcription Polymerase Chain Reaction (RT-PCR) on a nasopharyngeal swab (NPS) sample and/or a positive SARS-CoV-2 serology test during pregnancy (no vaccine was available). During the whole study period, SARS-CoV-2 NPS RT-PCR was performed on pregnant women if they referred to any COVID-19 related symptom during their antenatal visits or at any other healthcare visit during their pregnancy. From April 2020, SARS-CoV-2 RT-PCR was performed on all pregnant women admitted to hospital, and from February 28th to May 10th 2020, SARS-CoV-2 serology was performed on all pregnant women as part of a seroprevalence study conducted by the Microbiology Department at our center[24]. All the serological samples from the pregnant women stored at the Microbiology Department biobank were evaluated for SARS-CoV-2 antibodies. The specific IgG against SARS-CoV-2 Receptor Binding Domain and S proteins were studied, and SARS-CoV-2 seropositivity was defined as the presence of anti-SARS-CoV-2 IgG antibodies in the serum (titer > 1:100).

Pregnant women

The clinical and microbiological data from pregnant women were recorded retrospectively from their electronic medical records. The date of maternal infection was defined as the day of the first positive RT-PCR, if available. If the mother’s diagnosis was based only on a positive serology result, the date of maternal infection was established as the first day of COVID-19 related symptoms, if indicated. In mothers with no positive RT-PCR result and no related symptoms, we were unable to establish the date of infection. The management of pregnant women documented with acute COVID-19 included a complete physical examination, blood tests and a chest X-ray if SpO₂ on pulse oximetry was below 96% or if they had tachypnea, defined as a respiratory rate > 30 breaths per minute.

The preferred route of delivery was vaginal in the absence of any contraindications. At delivery, a positive NPS RT-PCR with a negative serology result was considered acute maternal infection.

Newborns

An experienced neonatologist performed a complete examination of all the infants in the first 24 hours of life as standard practice. Infants were considered preterm if they were born at < 37 weeks of gestational age (WGA). An automated auditory brainstem response (A-ABR) examination was performed on all newborns in the first 48 hours of life. In newborns born to mothers with an acute infection at delivery, NPS RT-PCR was also performed within the first 24 hours of life. If this test was positive, it was repeated in the next 24 hours and if it was still positive, the newborn was considered to have a vertical SARS-CoV-2 transmission as defined previously[25]. Newborns with documented SARS-CoV-2 infection at birth were subjected to a full physical examination, blood tests and a chest X-ray if hypoxemia or respiratory distress was evident. In the absence of clinical signs that required hospital admission, out-patient management was proposed. Infants born to mothers with acute SARS-CoV-2 infection and negative SARS-CoV-2 NPS RT-PCR at birth were followed by their primary-care pediatrician and with a follow-up phone call by a Pediatric Infectious Diseases Specialist during the first two weeks of life.

A first follow-up visit was performed between the 1st and 3rd month of life to all infants, at which their head circumference, weight and length were measured, and a complete physical and neurological examination was carried out by an experienced pediatrician. The neurological examination at this visit was defined as normal if posture, tone, movement and interaction were consistent with their age. SARS-CoV-2 NPS RT-PCR and serology were also performed. SARS-CoV-2 related symptoms, hospitalizations post-delivery and any RT-PCR performed outside of the study visits were recorded.

A cranial ultrasound (cUS) was performed by a pediatric radiologist at three months of age, and an auditory steady-state response (ASSR) exam was performed at six months by an ENT specialist. A neurodevelopment evaluation was assessed at 12 months of age using the Bayley-III scale of Cognitive, Language and Motor indexes. Z-scores were calculated from composite scores considering a mean of 100 and a standard deviation of 15. A Z-score ≤ -1 was considered mild developmental deficit and a Z-score ≤ -2 a developmental disorder.

The serological test performed on the children was a commercial SARS-CoV-2 anti-Nucleocapsid IgG assay (Abbott) and a positive result was defined as the presence of anti-SARS-CoV-2 IgG antibodies in serum with an index value > 0.5. The weight, length and head circumference percentiles at birth and during the follow-up visits were calculated using Carrascosa et al. Spanish charts adjusted for sex and gestational age at birth. Infants were considered small for their gestational age (SGA) when their weight was below the 10th percentile, and when the head circumference was less than the 3rd percentile the infant was attributed microcephaly.

Statistical analysis

The categorical variables are presented as frequencies (n) and percentages (%), and the continuous variables as the mean and standard deviation (SD) or median and interquartile range (IQR), depending on the distribution of the variable. The χ2 test or Fisher’s exact test was applied to assess differences between the groups of categorical variables, and a Mann-Whitney U-test was used for the continuous variables. A p value < 0.05 was considered statistically significant and the analyses were carried out using R software (R Core Team, 2015).

Ethical considerations

This study was approved by the Ethics Committee of the Hospital Universitario 12 de Octubre (nº 20/241) and informed consent was obtained from the parents of all the infants that participated in the study.

This study was carried out on 95 newborns to 94 pregnant women. The mean gestational age at the time of SARS-CoV-2 infection was 29 (± 4, IQR 21–35) WGA. In 79 (84%) women, maternal infection occurred in the third trimester. SARS-CoV-2 related symptoms, their microbiology results and the outcomes of pregnancy can be seen in Table 1.

Table 1

Clinical and microbiological data of pregnant women.
	N = 94
Age (years)	34 (29–38)
SARS-CoV-2 RT-PCR on NPS	93 (98.9)
- Negative	40 (43.0)
- Positive	53 (57.0)
Serology performed	60 (63.8)
- Negative	5 (8.3)
- Positive	55 (91.7)
Date of infection available	83 (87.3)
Gestational age at time infection	29 + 4 (21–35)
- 1st trimester	4 (4.3)
- 2nd trimester	0
- 3rd trimester	79 (84.0)
Asymptomatic	21(22.3)
COVID-19 related symptoms	73(77.7)
- Fever	39 (46.4)
- Respiratory symptoms	58 (69.1)
- Pneumonia	22 (23.7)
Hospital admission due to SARS-CoV-2 infection	21 (22.3)
ICU admission due to SARS-CoV-2 infection	1 (1.1)
Mode of delivery
- Vaginal delivery	65 (69.1)
- Cesarean section	29 (30.9)
ICU, intensive care unit; RT-PCR, Reverse-Transcription Polymerase Chain Reaction; NPS, nasopharyngeal swab. Qualitative data are expressed as the total number (n) and the percentage (%), and quantitative data as the median and the interquartile range (IQR).

Of the 95 newborns, 50 (53%) were females and the median gestational age was 39 + 3, (IQR 38–40) WGA, with ten (10%) infants born preterm (see Table 2 for the perinatal outcomes of the infants). Of these newborns, 13 (14%) required hospital admission. RT-PCR was performed at birth on eight of these admitted newborns and the results were negative in all cases. The most frequent cause of admission at birth was transient tachypnea of the newborn (TTN: n = 6, 46%), followed by maternal disease after birth (n = 2, 15%). The other causes were: prematurity, spontaneous pneumothorax, meconium aspiration, neonatal shock due to TTN and pneumothorax, and a diagnosis of left renal agenesis and type III esophageal atresia (one case of each cause, 8%). In this latter infant, renal agenesis was diagnosed in the 19th week of pregnancy and type III esophageal atresia was detected postnatally on the third day of life. The mother of this infant had a symptomatic COVID-19 infection, with a positive NPS RT-PCR in the 24th week of pregnancy. During the follow-up, no genetic causes or other anomalies were identified in this child. Of these hospitalized newborns, six (6% of the total cohort) were admitted to the NICU and 11 (12%) required respiratory support. None of these admissions was associated with COVID-19 and none of them died (for additional information see Table 3). All 95 infants were subjected to an A-ABR in the first 48 hours of life and 89 (94%) passed this test.

Table 2. Perinatal characteristics of the infants.

	N=95
Sex
- Female	50 (52.6)
- Male	45 (47.4)
WGA	39+3 (38-40)
Preterm infants (<37 WGA)	10 (10.5)
- Moderately preterm (32-37 WGA)	9 (9.5)
- Very preterm (28-32 WGA)	0
- Extremely preterm (<28 WGA)	1 (1.1)
1-minute APGAR score	9 (9-9)
- <7	6 (6.3)
- <3	0
5-minute APGAR score	10 (10-10)
- <7	6 (6.3)
- <3	0
Cord blood pH	7.2 (7.2-7.3)
Skin to skin	77 (82.0)
Breastfeeding	86 (91.5)
Birth weight (g)	3340 (2940-3530)
- SGA	18 (16.7)
Birth length (cm)	50.0 (49.0-51.0)
Birth head circumference (cm)	35.0 (34.0-35.9)
- Microcephaly	7 (6.1)
Admission	13 (13.7)
- Days of admission	5.0 (2.2-7.7)
NICU admission	6 (6.3)
- Days of NICU admission	7.5 (6.2-12.5)
Need for respiratory support	11 (11.6)
- Nasal prongs	1 (9.1)
- CPAP therapy	6 (54.5)
- Mechanical ventilation	4 (36.4)
Thoracic X-ray	9 (9.6)
- Normal	2 (22.2)
- Abnormal	7 (77.8)
WGA, Weeks of Gestational Age; SGA, Small for Gestational Age; NICU, Neonatal Intensive Care Unit. Qualitative data are expressed as the total number (n) and the percentage (%), and quantitative data as the median and the interquartile range (IQR).

Table 3. Follow-up visit.

	N=95
Age (days)	56 (35 - 88)
Hospital admission since hospital discharge	4 (4.2)
COVID-19 related admissions	0 (0)
COVID-19 related symptoms	8 (8.5)
- Respiratory symptoms	3 (37.5)
- Diarrhea	1 (12.5)
- Fever	2 (25)
- Others	2 (25)
SARS-CoV-2 NPS RT-PCR at non-study medical visits	8 (8.5)
- Negative	8 (100)
- Positive	0 (0)
Physical examination	95 (100)
- Normal	87 (91.6)
- Abnormal	5 (5.3)
· Systolic murmur without heart abnormalities in echocardiography	2 (40)
· Cutaneous hemangioma	1 (20)
· Umbilical hernia	1 (20)
· Stridor	1 (20)
Neurological evaluation	95 (100)
- Normal	95 (100)
Weight (g)	5200 (4350-6100)
- Weight < P10	8 (7.4)
Length (cm)	58.2 (54.5-61.0)
Head circumference (cm)	39.0 (38.0-40.0)
- Microcephaly	2 (2.7)
SARS-CoV-2 NPS RT-PCR	93 (97.9)
- Positive	1 (1.1)
- Negative	92 (98.9)
SARS-CoV-2 serology	94 (98.9)
- Positive	47 (50)
- Negative	47 (50)
RT-PCR, Reverse-Transcription Polymerase Chain Reaction; NPS, Nasopharyngeal swab. Qualitative data are expressed as the total number (n) and the percentage (%), and quantitative data as the median and the interquartile range (IQR).

SARS-CoV-2 NPS RT-PCR was performed at birth on 28 neonates born to mothers with acute infection at delivery. Of these, only one (4%) returned a positive RT-PCR in the first 24 hours of life, a result that was repeated 24 hours later confirming vertical transmission. This newborn was asymptomatic and did not require hospital admission or any additional medical visits. Moreover, this infant had normal perinatal and follow up outcomes, including cUS and auditory screening (for additional information on this infant see ref. [26]).

All the infants received a follow-up visit at a median age of 56 (IQR 35–88) days. Eight (8%) had developed COVID-19 related symptoms after hospital discharge. SARS-CoV-2 NPS RT-PCR was performed on all these infants at non-study medical visits and all were negative. There were four (4%) infants admitted to hospital (Supplementary Table 1) and none of them had a positive SARS-CoV-2 RT-PCR at admission. Physical examination at the first follow-up visit was normal in all but five (5%) infants. Systolic murmur was detected in two infants, without any associated heart abnormalities in echocardiography. Other abnormalities were a cutaneous hemangioma, an umbilical hernia, and stridor after type III esophageal atresia surgery in individual children (n = 1 each category). Neurological evaluation was normal according to age in all infants. SARS-CoV-2 NPS RT-PCR was performed on 93 infants and was positive in only one case (1%). This infant had mild rhinorrhea and hospital admission was not required. SARS-CoV-2 antibody detection was also assessed in 94 infants and was positive in 47 cases (50%). Additional information of the follow up visit can be seen in table 4. Serology results were not associated with the presence of symptoms or the severity of maternal infection, skin-to-skin care, or breastfeeding (Table 5). A cUS was performed on 85 (89%) infants at a median age of 97 (IQR 74–123) days, with a normal result in 81 (95%), and an abnormal one in four. One preterm baby had grade 1–2 intraventricular hemorrhage that resolved during the follow-up. The other three findings were a mild increase in the extra-axial space, lenticulostriated vasculopathy and mild white matter edema. There were 43 infants, including the six who failed the newborn hearing screening, who were evaluated by a pediatric ENT specialist at a median age of 210 (IQR 125–295) days, all returning normal ASSR hearing results.

Table 4. Comparative results of infants with positive/negative serology at the follow-up visit (1-3 months)

	All N=94	Negative IgG N=47	Positive IgG N=47	P value
Mother’s symptoms	73 (77.7)	33 (70.2)	40 (85.1)	0.137
Fever	39 (46.4)	15 (37.5)	24 (54.5)	0.178
Respiratory symptoms	57 (67.9)	25 (62.5)	32 (72.7)	0.442
Pneumonia	21 (22.6)	7 (15.2)	14 (29.8)	0.152
Mother’s need for admission	21 (23.9)	8 (17.8)	13 (30.2)	0.263
Mother’s need for ICU admission	1 (5.0)	1 (12.5)	0	0.398
Mode of delivery				0.901
Cesarean section	30 (31.9)	16 (34.0)	14 (29.8)
Operative	10 (10.6)	5 (10.6)	5 (10.6)
Vaginal	54 (57.4)	26 (55.3)	28 (59.6)
Sex				1.000
Female	49 (53.3)	25 (54.3)	24 (52.2)
Male	43 (46.7)	21 (45.7)	22 (47.8)
Weight (g)	3335 [2935;3515]	3340 [2775;3510]	3330 [2960;3510]	0.520
Length (cm)	50.0 [49.0;51.0]	50.0 [48.5;51.0]	50.0 [49.0;51.0]	0.405
Head circumference (cm)	34.9 (1.28)	34.8 (1.29)	34.9 (1.27)	0.845
Skin to skin	76 (81.7)	35 (76.1)	41 (87.2)	0.262
Breastfeeding	85 (91.4)	44 (95.7)	41 (87.2)	0.267
SARS-CoV-2 RT-PCR on NPS at birth				0.370
Negative	26 (96.3)	17 (100)	9 (90.0)
Positive	1 (3.70)	0 (0.00)	1 (10.0)
A-ABR at birth				0.677
Failed (1 ear)	5 (5.32)	3 (6.38)	2 (4.26)
Failed (both ears)	1 (1.06)	1 (2.13)	0 (0.00)
Pass	88 (93.6)	43 (91.5)	45 (95.7)
Need for neonatal admission	14 (14.9)	6 (12.8)	8 (17.0)	0.772
Need for respiratory support	11 (11.7)	3 (6.38)	8 (17.0)	0.199
Hospital admission to discharge	5 (5.32)	3 (6.38)	2 (4.26)	1.000
COVID-19 related symptoms at discharge	8 (8.60)	4 (8.51)	4 (8.70)	1.000
Cough	3 (37.5)	2 (50.0)	1 (25.0)
Diarrhea	1 (12.5)	0 (0.00)	1 (25.0)
Fever	2 (25.0)	1 (25.0)	1 (25.0)
Others	1 (12.5)	1 (25.0)	1 (25.0)
Weight at follow-up (g)	5311 (1187)	5317 (1271)	5304 (1108)	0.958
Length at follow-up (cm)	58.1 (4.42)	57.9 (4.80)	58.4 (4.04)	0.602
Head circumference at follow-up (cm)	39.1 (1.99)	39.2 (2.13)	38.9 (1.85)	0.503
SARS-CoV-2 RT-PCR on NPS at the follow-up visit				1.000
Negative	91 (98.9)	45 (97.8)	46 (100)
Positive	1 (1.09)	1 (2.17)	0 (0.00)
WGA at infection	29.3 [21.5;34.7]	33.3 [19.1;37.2]	27.9 [22.5;32.4]	0.145
Days of life	53.0 [35.0;88.0]	62.0 [42.0;89.5]	49.0 [34.0;87.5]	0.197
ICU: Intensive Care Unit. WGA: weeks of gestational age. A-ABR: automated auditory brainstem response. RT-PCR: Reverse-Transcription Polymerase Chain Reaction. NPS: nasopharyngeal swab. Qualitative data are expressed as the total number (n) and the percentage (%), and quantitative data as the mean and standard deviation (SD) or median and interquartile range [IQR] according to the normality of the data.

The Bayley-III tests were performed on 55 children at 12 months of age (median age 12 [IQR 12–13] months). The median Z scores were 0 (IQR 0–0) for the cognitive and motor, and 0 (IQR − 0.5-0) for the language scales. Thus, 53 (96%) were considered to have a normal neurodevelopment, while one child showed a mild development deficit (Z scores − 1) and another, a developmental disorder (Z scores − 2).

To our knowledge, this is the first study to use cUS during the follow-up of infants born to mothers with SARS-CoV-2 infection during pregnancy. Mild abnormalities in cUS were found in only four infants, and in one case (intraventricular hemorrhage) it could be explained due to prematurity and it resolved in the follow-up. The infant with white matter edema was evaluated at six months of life by the pediatric neurologist with normal findings, and no neurodevelopmental abnormalities were found in the follow-up of the other two infants. These mild findings have been described in up to 17% in otherwise healthy children[27].

Neurological examination at first visit was normal in all cases and only one child had a neurodevelopmental disorder according to the Bayley-III scale at 12 months. Although previous data suggested a higher rate of neurodevelopmental disorders[16, 17], results supporting our findings have also been published[11, 12] and neurological examination was seen to be normal in an Italian cohort[12]. In another study, birth during the pandemic but not in utero exposure to SARS-CoV-2 was associated with poorer neurodevelopmental status at six months of age[13]. Although limited interactions with other children and the restrictions in social life implemented during the pandemic period could have affected the neurodevelopment of children, we did not find a high proportion of children with neurodevelopmental delay.

The results in our cohort support that SARS-CoV-2 infection during pregnancy does not affect hearing outcomes in infants. In a previous study, 18.8% of exposed newborns failed hearing screening at birth (otoacoustic emissions), yet all had normal hearing when they were retested (A-ABR) at three months of age[12]. Another study also showed that a higher proportion of children born to mothers with SARS-CoV-2 infection during pregnancy failed hearing screening (A-ABR) at birth compared with a control group (40% vs 25%)[14]. Moreover, an insufficiency in the medial olivocochlear efferent system was suggested in such infants elsewhere[15].

The high rate of SGA (17%) and microcephaly (6%) at birth was notable, although it decreased to normal rates at the follow-up visit (7% and 3%). High rates of SGA in newborns have been reported previously[28] and placental damage caused by SARS-CoV-2, even in the absence of vertical transmission, has been proposed as a possible explanation[19]. Regarding the perinatal outcomes, despite the high rate of preterm infants previously reported[3, 4, 6, 27], we report a rate of preterm births (10%) similar to that in our hospital in 2020 (10.4%). Concerns about severe COVID-19 in pregnant mothers could have influenced the higher rate of preterm delivery[5]. Moreover, severe maternal COVID-19 cases are more likely to be diagnosed and preterm delivery rate could be overestimated in studies without serological screening. Regarding neonatal admissions, infants born to mothers with COVID-19 infection during pregnancy have been seen to have a higher risk of respiratory distress and hospital admission[3, 6, 27]. Here, the rate of admission to our neonatal unit was 14%, lower than the overall neonatal admission during 2020 (21.7%). NICU admission was also lower in neonates born to mothers with SARS-CoV-2 infection than in non-exposed newborns in 2020 (6% vs 10.2%).

The only newborn with a positive SARS-CoV-2 NPS RT-PCR at birth in our sample had a vertical transmission, according to the definition in Blumberg et al.[25]. Thus, the rate of vertical transmission in our cohort was low (4%), similar to the published rates below 5%[3–5, 10]. Moreover, our findings support the low morbidity associated with vertical transmission[7, 9], as this infants was asymptomatic. During the study period, RT-PCR tests were performed routinely on all infants with COVID-19 related symptoms during the follow-up and on all infants at the first follow-up visit, where only one returned a positive test result. This infant had mild symptoms with no need for admission or any additional medical visits. Similarly low rates of horizontal transmission after birth have been published[4, 9, 10]. This low incidence of early postnatal infection among this group could be due to maternal antibody transfer during pregnancy[29]. A large number of infants were breastfed and given skin-to-skin care in our sample. Given the low rates of horizontal transmission and the mild symptoms in most infants infected here, health professionals should encourage women infected with SARS-CoV-2 during pregnancy to maintain skin-to-skin care and breastfeeding as good practices.

Only 50% of infants gave a positive result in serology tests at the follow-up visit. The number of children with SARS-CoV-2 antibodies in cord blood born to mothers with SARS-CoV-2 infection during pregnancy has been reported to be higher[17, 19, 20]. By contrast, the rate of children with a positive serology at birth is low in pregnant women with acute infection at delivery[30]. Our cohort included mothers with past and acute infection at the time of delivery, and serological testing was not carried out routinely at birth. It is possible that SARS-CoV-2 antibodies decrease rapidly in non-infected infants during the first weeks of life, as previously suggested[19, 21, 22].

The main limitation of our study is that the serological analysis employed on mothers and infants differed. Maternal serology was part of a research protocol and IgG against SARS-CoV-2 Receptor Binding Domain and S proteins were evaluated[24] but subsequently, only tests with anti-Nucleocapsid IgG antibodies were available at our hospital and thus, this technique was used during the infant’s follow-up. Not all the women included had a positive SARS-CoV-2 RT-PCR during pregnancy as their diagnosis was also based on a positive serology result. However, as the first case of COVID-19 in Spain is not thought to have occurred before January 2020[31], we can be sure that all of them had the SARS-CoV-2 infection during pregnancy. The mother’s data were also collected retrospectively, with the inherent limitations that this implies. By contrast, all the data from children were collected prospectively with a close follow-up. Unfortunately, not all the infants were able to complete the follow-up due to unavailability to attend the visits or contact the families.

To conclude, in this study most of the infants born to mothers with SARS-CoV-2 infection during pregnancy were healthy infants with no hearing loss, normal neuroimaging, normal neurological examination, and normal neurodevelopment at 12 months of age. Maternal antibodies seem to decrease fast in theses infants. Long-term outcomes should be evaluated, although neurological and hearing impairment as a result of maternal infection seem to be unlikely.

A-ABR

automated auditory brainstem response

ASSR

auditory steady-state response

COVID-19

coronavirus disease 2019

cUS

cranial ultrasound

IQR

interquartile range

NICU

neonatal intensive care unit

NPS

nasopharyngeal swab

RT-PCR

reverse-transcription polymerase chain reaction

SARS-CoV-2

severe acute respiratory syndrome coronavirus 2

standard deviation

SGA

small for gestational age

WGA

weeks of gestational age

TTN

transient tachypnea of the newborn

Ethics approval and consent to participate: This study was approved by the Ethics Committee of the Hospital Universitario 12 de Octubre (nº 20/241) and informed consent was obtained from the parents of all the infants that participated in the study.

Consent for publication: not applicable.

Availability of data and materials: After de-identification all the individual data collected for the study is available from the correspondent author under reasonable request.

Competing interests: The authors have no conflicts of interest relevant to this article to disclose.

Funding/support: This study was not specifically founded by any source. DBG (INT20/00086) and IHG (PI19/01005) hold “Intensification of Research Activity in the National Health System” contracts from the Instituto de Salud Carlos III, co-funded by the European Social Fund. SV was funded by the Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III and Fondos FEDER (Contrato Río Hortega CM20/00173).

Author’s contributions: Daniel Blázquez-Gamero conceived the study, designed the work, analyzed the data, interpretated the data and drafted the manuscript. Jaime Carrasco Colom conceived the study, designed the work, contributed to the acquisition of the data and revised and made valuable contributions to the manuscript. Ángela Manzanares conceived the study, contributed to the acquisition of the data, analyzed and interpretate the data and drafted the manuscript. Estrella Esquivel analyzed and interpretate the data, and made valuable contributions to the manuscript. Alfredo Pérez-Rivilla, Rafael Delgado, María Dolores Folgueira, Alberto Galindo and María Teresa Moral-Pumarega designed the work and revised and made valuable intellectual contributions to the manuscript. Alicia Álvaro Gómez, Isabel Serrano Escribano, Elisa Aguirre Pascual, Joaquín de Vergas, Sara Reda del Barrio, Cinta Moraleda, Cristina Epalza, Elisa Fernández-Cooke, Luis Prieto, Berta Zamora, Serena Villaverde and Ignacio Herraiz contributed to the acquisition of the data and revised and made valuable contributions to the final version of the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

Acknowledgments: The authors would like to thank Mark Sefton (BiomedRed SL) for his valuable assistance in the author editing of this manuscript.

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No competing interests reported.

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Clinical outcomes and antibody transfer in a cohort of infants born to mothers with SARS-COV-2 infection during pregnancy (Coronascope Study)

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Pregnant women

Newborns

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