Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is a virus that causes neurological symptoms in a significant proportion of patients in addition to respiratory symptoms. Intrauterine exposure to the virus has been demonstrated to exert a detrimental effect on the developing nervous system. However, developmental disorders frequently remain undetected until late infancy or early childhood. Consequently, there is a paucity of published data on neurodevelopment in young children following SARS-CoV-2 infection of their pregnant mothers.

To this end, detailed data from children aged 36-60 months exposed to SARS-CoV-2 in utero will be compared with unexposed children of the same age on several clinical outcome parameters. Data in this cohort study will be adjusted for possible confounding variables, such as gestational age at birth, sex, or umbilical arterial pH, in order to investigate a relative risk of intrauterine SARS-CoV-2 infection on clinical outcomes, such as child development. Furthermore, the potential protective effect of SARS-CoV-2 vaccination during pregnancy will be investigated.

This study will provide significant data on the clinical outcomes of children exposed perinatally to SARS-CoV-2. The findings will enable healthcare providers to establish a risk score-adapted follow-up strategy for the general paediatric population of infants.

In Utero Exposure to SARS-CoV-2 - the CRONOS registry The "COVID-19 Related Obstetric and Neonatal Outcome Study" (CRONOS) investigated the short-term effects of SARS-CoV-2 infections on mothers and their newborns during pregnancy. From April 3rd, 2020, to February 10th, 2023, data on 8,540 women and their newborns were collected, with active participation from 130 out of 686 (19%) German obstetric hospitals. The study was approved by the ethics committees of the coordinating center (UKSH Kiel, AZ: D 451/20) and each participating hospital. Information about CRONOS has been published on the German Society of Perinatal Medicine´s website, www.dgpm-online.org, and the German Clinical Trials Registry (DRKS00021208). About 2,000 women agreed to be contacted again for further follow-up.

The CRONOS-Kids study focuses on child health and will study some of the intrauterine-exposed children longitudinally. As an increased rate of placentitis with a concomitant increased risk of stillbirth and preterm delivery has been seen in infections with the Alpha and Delta variants, women with an SARS-CoV-2 infection between January 2021 and December 2021, initially recruited in the five participating university hospitals, will be contacted.

Recruiting for CRONOS-Kids On each of the five research sites, women initially participating in CRONOS will be invited via email, letter, or by phone to participate in the CRONOS-Kids study.

Unexposed children and their parents will be invited to participate via their local pediatricians.

All women will be able to book appointments at their respective hospitals via a dedicated website (http://cronos-kids.de). The management of patient contact will be conducted exclusively by non-examiners. Pseudonymization will be used.

Study instruments All children will undergo examination by personnel specifically trained for this purpose. In order to assess potential motor and cognitive deficiencies, the M-ABC-2 and the ASQ-3 will be utilised. Furthermore, social-emotional aspects will be addressed using a specific SE-test.

Questions of a general nature will address the subjects of pregnancy, birth, and social circumstances, with a view to identifying potential sources of bias with regard to developmental delays.

Potential bias To circumvent any potential bias in the study, responsibility for patient contact and examinations will be allocated to different members of the research team. Personnel conducting neurodevelopmental testing will adhere to the principles of blinding, ensuring that they remain unaware of the subjects' exposure status.

We expect a bias in the participation of highly educated and German-speaking families. This is likely to affect both the exposed and non-exposed groups.

Statistical analysis The Marburg University research team will manage data refinement. Analysis will control for potential confounders such as children´s sex, weeks of gestational age at birth, asphyxia at birth and social circumstances.

To be able to measure a mean effect in an unpaired t-test with an alpha level of 0.05 and a power of 0.8 (Cohen's d = 0.5), 64 subjects per group are required, i.e

Inclusion Criteria:

• Toddlers (age 33 to 60 months), who were exposed (case) or not exposed (controll) with SARS-CoV-2 intrauterin.

Exclusion Criteria:

• No parental consent

In a pilot study intrauterine exposed toddlers are eligible for inclusion in the study if their mothers are registered in the CRONOS registry in the following five university hospitals: Marburg University Hospital, Jena University Hospital, Kiel University Hospital, Dresden University Hospital and Freiburg University Hospital.

Controls, i.e. infants who have not been exposed to SARS-CoV-2, are eligible for enrolment if they live in the proximity of the recruiting hospitals.

Participants did not agree in data sharing.