Fetal brain biometry and cortical development after maternal SARS‐CoV‐2 infection in pregnancy: A prospective case–control study

Abstract

Objectives

To assess cerebral growth and the development of fetal cortex using neurosonography in fetuses from pregnancies experiencing severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) according to infection timing.

Methods

Pregnancies with by SARS‐CoV‐2 during first and second trimesters were prospectively studied and matched with unaffected controls. Enclosed women underwent neurosonography at 30–34 weeks of gestation and corpus callosum (CC) and cerebellar vermis (CV) lengths measured. Further Sylvian fissure (SF), insula. Parieto‐occipital fissure (POF), and calcarine sulci fissures (CSF) depths were obtained. The ultrasonographic variables considered were normalized with fetal head size.

Results

One hundred and seventy four consecutive pregnancies experiencing SARS COV 2 infection (81 before 14 weeks and 93 later) and 131 not affected pregnancies were considered. General and pregnancy characteristics were similar between the three groups of women. No significant differences existed in CC and CV lengths across groups. Similarly, insula, SF, POF And CSF depth did not result changed in fetuses of affected mothers.

Conclusions

SARS‐CoV‐2 infection does nor resulted associate with differential fetal cortical development or brain growth in mildly symptomatic pregnant women. This information may be useful to reassure infected mothers on the health of their fetuses.

Feat brain growth and cortical development were similar in infected mothers with mild symptoms compared to pregnancies not exposed to the virus. The knowledge of these findings may be clinically relevant and should be used to reassured and adequately counsel the mother of the low risk for their newborns to develop an abnormal neurodevelopment.

1. INTRODUCTION

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS‐CoV‐2) diffusion still is a leading worldwide issue of apprehension. ¹ Women with SARS‐CoV‐2 infection during their pregnancy have an independent and additional risk factor to develop adverse and maternal perinatal outcomes. ² , ³ , ⁴ , ⁵

Maternal viral infections like Zika virus or cytomegalovirus may extensively impair prenatal brain. ⁶ , ⁷ The role of maternal SARS‐CoV‐2 illness in the prenatal maturation and growth of the central nervous system (CNS) is mostly unknown at this time but there are evidences in newborns and infants of the existence of neurological complication induced by the infection. ⁸ , ⁹ Although this hypothesized association, there are no studies evaluated the impact of SARS‐CoV‐2 disease on prenatal brain development.

We speculated that this disease has the potential to induce detrimental effects on fetal brain by direct or undirect mechanism secondary to placenta dysfunction. ¹⁰ , ¹¹ , ¹²

The objective of this investigation was to assess fetal brain development and growth of fetuses from pregnancies with SARS‐CoV‐2 disease in comparison to unaffected subjects.

2. METHODS

2.1. Study population

Consecutive pregnancies affected by SARS‐CoV‐2 disease attending for prenatal care the Department of Obstetrics and Gynecology Università Tor Vergata Rome Italy from September 2020 to October 2021 were considered in a prospective casa‐control study. The criteria of inclusion were (a) certain gestational age assessed by crown‐ rump length at the 11–14 weeks scan, (b) confirmed SARS‐CoV‐2 infection during pregnancy, and (c) complete perinatal follow‐up. Exclusion were multiple pregnancies, the existence of fetal chromosomal anomalies or structural defects, maternal smoking, or pregnancy complications potentially that may affect brain development (i.e., pregestational or gestational diabetes, hypertensive, and autoimmune diseases). According to the timing of infection women were grouped as ≤ or >14 weeks of gestation. This cohort of women was matched to a control group of women not affected by SARS‐CoV‐2 during gestation and followed in our antenatal clinic during the same study interval. The same exclusion criteria of the study group were applied to construct the control group and they were paired with the former as regard as maternal and perinatal characteristics. Institutional Review Board (#Ost4‐2020 30/July 2020) was obtained and all participating women signed an informed consent,

The diagnosis of SARS‐CoV‐2 disease was confirmed by real‐time polymerase‐chain reaction (RT‐PCR) positive results obtained from nasopharyngeal swab specimens. All women with SARS‐CoV‐2 disease showed mild symptoms (fever, cough, sore throat, loss of smell and taste, diarrhea). Hospitalization was not necessary in any infected woman.

2.2. Ultrasonographic assessment

Fetal CNS evaluation was carried out at 30–34 weeks of gestation following our internal protocol. Examination were done using a Hera W10 Samsung equipment by transabdominal or transvaginal approach. The fetal head circumference (HC) was measured according ISUOG guidelines. ¹³ Corpus callosum (CC) and cerebellar vermis (CV) were visualized using techniques described elsewhere and their lengths measured. ¹⁴ , ¹⁵ Cortical evaluation was performed following a methodology previously developed. ¹⁶ Insula depth was obtained from the trans‐thalamic axial plane tracing a vertical line perpendicular to the midline starting from the distal portion of the cavum septum pellucidum to the proximal border of the cortex. To evaluate the Sylvian fissure (SF) the same line was continued from the border of the insula to the internal border of the parietal bone. Parieto‐occipital fissure (POF) depth was evaluated from the trans‐ventricular plane in its maximal size and when symmetrical with the contralateral fissure starting from the midline and taking care to avoid the cortex in the measurement. The calcarine sulcus fissure (CSF) depth was obtained from the coronal view of the trans‐cerebellar plane and the measurement was obtained perpendicularly from midline to the end of the fissure. CNS measurements were performed offline from images or videoclips by one of the authors (MEP) blind of the maternal condition.

2.3. Data analysis

Since the ultrasonographic measurements considered are affected by CNS size, were adjusted for HC values and transformed as measurement in mm /HC × 100.

A power analysis showed that a sample size of 65 patients in each gestational age interval for the study group and 130 controls is necessary to detect differences of 10% between the study groups, for a given 5% α error and 80% power.

Normality of data distribution was checked by applying the Shapiro Wilk normality test. Categorical variables were reported as numbers (n) and percentages (%) and analyzed using Fisher exact or Chi‐square tests while continuous variables were shown as median and interquartile range (IQR) or mean and standard deviation. Kruskal Wallis or ANOVA tests, followed by post‐hoc tests were used for comparing study groups.

Data were analyzed SPS version 28.0 (IBM Corp. Armonk. NY. USA) software. Differences were considered significant in presence of a p values <0.05.

3. RESULTS

The study population was of 305 women including 131 uncomplicated pregnancies, 81 with SARS‐CoV‐2 disease before 14 weeks of gestation and 93 with later infection. All women were asymptomatic with negative RT‐PCR swabs at neurosonographic scan. There were no differences in general and pregnancy characteristics between the study groups except, as expected by study entry criteria, for the timing of infection (Table 1).

TABLE 1.

General characteristics of study population stratified according to the exposure to SARS‐CoV‐2

Variables	Pregnancies complicated by SARS‐CoV‐2 infection ≤14 weeks (N = 81)	Pregnancies complicated by SARS‐CoV‐2 infection ≤14 weeks (N = 93)	Controls (N = 131)	p
Maternal age (years)	29.9 (28.0–32.2)	30.3 (27.9–32.2)	30.4 (28.2–32.3)	0.422
Maternal height (cm)	164 (157–171)	163 (156–170)	162 (155–168)	0.324
BMI (kg/m2)	27.1 (24.2–29.3)	26.6 (24.2–29.1)	26.5 (24.0–29.4)
Ethnicity (N %)				0.784
Caucasian	76 (93.85)	87 93.6%)	123 (93.9%)
Other	5 (6.2%)	6 (6.4%)	8 (6.2%)
Nulliparous	56 (69.1%)	63 (67.7%)	89 (67.0%)	0.327
Assisted conception (N %)	4 (4.9%)	5 (5.4%)	7 (5.3%)	0.668
Gestational age at COVID‐19 infection weeks	11.3 (8.3–13.7)	22.4 (17.1–27.3)		0.0001
Gestational age at delivery (weeks)	39.1 (38.3–40.7)	39.3 (37.9–40.7)	39.9 (38.1–40.9)	0.673
Birthweight (g)	3350 (2920–3810)	3390 (2950–3680)	3410 (2940–3790)	0.412
Male N (%)	42 (51.8%)	46 (49.5%)	65 (49.6%)	0.247

Note: Data are expressed as N and % or median and interquartile range.

Although there was a trend to lower values of CC (Figure 1) and cerebellar vermis length in fetuses of mothers infected before 14 weeks these differences did not reach the statistical significance (Table 2). A similar not significant trends were found for SF, POF and CFS depth while a tendency of higher values in insula depth in the earliest infection group despite it did not result in statistical significance (Table 2). There were no differences in all the absolute and HC corrected scissor depth when fetuses from women experiencing early or late infection were compared to control fetuses (Table 2).

FIGURE 1.

Box and wisker plots showing the differences among group of Corpus callosum length (panel A) and its normalized value for head circumference (panel B)

TABLE 2.

Fetal neurosonopraphic variables in fetuses from pregnancies complicated with SARS‐CoV2 before and after 14 weeks of gestation and in the control group

Variables	Control (N 131)	Infection ≤14 weeks (N 81)	Infection >14 weeks (N 93)	p
Gestational age at scan (weeks)	32.7 (31.8–33.7)	32.5 (30.3–33.7)	32.6 (31.7–33.3)	0.784
Head circumference (HC) (mm)	304 (292–312)	303 (290–310)	305 (288–312)	0.823
Corpus callosum length (mm)	40.4 (38.2–43.1)	39.1 (37.1–40.2)	39.9 (37.6–42.5)	0.073
Corpus callosum length/HC × 100	13.3 (10.8–15.3)	12.9 (10.2–14.6)	13.1 (10.9–15.2)	0.081
Cerebellar vermis length (mm)	20.5 (16.4–25.3)	18.7 (15.3–23.6)	20.3 (16.6–24.1)	0.092
Cerebellar vermis length/HC × 100	8.6 (7.0–9.2)	8.2 (6.6–9.1)	8.7 (6.9–9.4)	0.064
Insula depth (mm)	26.2 (24.1–28.3)	28.3(25.2–29.4)	26.2 (24.2–28.5)	0.069
Insula depth/HC × 100	8.7 (7.8–9.6)	8.9 (8.1–9.9)	8.8 (7.7–9.5)	0.073
Sylvian fissure (mm)	13.4 (11.2–15.3)	12.9 (11.1–14.7)	13.3 (11–3‐15.2)	0.743
Sylvian fissure depth/HC × 100	4.6 (3.9–4.4)	4.3 (3.8–4.5)	4.5 (3.7–4.6)	0.113
Parieto‐occipital fissure (mm)	11.5 (7.8–15.2)	11.3 (8.1–14.2)	11.4 (7.9–14.8)	0.212
Parieto‐occipital fissure /HC × 100	4.3 (3.8–4.9)	4.1 (3.7–4.8)	4.2 (3.7–4.8)	0.287
Calcarine sulcus (mm)	11.6 (7.3–15.4)	11.4 (8.4–15.5)	11.7 (8.1–15.3)	0.123
Calcarine sulcus/HC × 100	3.8 (3.2–4.9)	3.7 (3.3–5.0)	3.9 (3.1–5.2)	0.212

Note: Data are expressed as median and interquartile range.

4. DISCUSSION

4.1. Main findings

The data hereby reported evidence howSARS‐CoV‐2 disease in pregnancy did not significantly affect fetal growth and cortical development during the third trimester. The absence of differences among groups is present both when absolute values and corrected for fetal HC were considered. However, a not significant trend to have lower value of the variables considered in presence of first trimester infection is of interest and deserves a conformation on larger study population.

4.2. Strength and limitations

The main strength of our study was the prospective design, the relatively large population considered, and the comprehensive study protocol allowed to acquire a detailed fetal brain evaluation. Additionally, the study population was controlled as regard the maternal and fetal variables that may prenatally affect brain development.

A limitation of this study relies in considering only mildly symptomatic pregnancies, not excluding the possibility of different findings when a more severe disease is present. In fact, SARS‐CoV‐2 severe infections showed a higher prevalence of placental vasculopathy that may affect fetal CNS, ¹⁰ , ¹⁷ As a consequence we cannot ignore that the absence of association between the occurrence of the infection and the CNS indices considered may be secondary to the characteristics of our population that included pregnancies with a mild spectrum of the illness. Moreover, only the 3%–5% of pregnant women experience the severe form of the disease, ¹⁸ thus allowing to apply the findings resulting from this study to the large majority of women experiencing the infection in pregnancy.

A further limitation was that we do not perform a postnatal neurological follow up. As a consequence it is not possible to confirm that the absence of cortical and brain growth changes results in a normal postnatal neurological development.

4.3. Comparison with other studies

To the best of our knowledge, this is the first investigation evaluating the role of SARS‐CoV‐2 infection during pregnancy on prenatal cortical development.

Arculeta et al. ⁸ reported 2 case reports of newborns with ventriculomegaly on neuroimaging seizures and neurological dysfunction and attributed these findings to prenatal exposure to SARS‐CoV‐2 exposure during pregnancy. On the other hand, Ayed et al. ¹⁹ in a prospective study on 298 infants born by infected mothers found no differences with respect to the general population in neurodevelopment at 10–12 months after birth. Differently Edlow et al ²⁰ in a larger population evidenced a higher prevalence of neurodevelopment at 1 year in newborns of infected mothers. However in this study are mainly present in preterm infants and from Hispanic ethnicity factors that may act as confounding variables. Of interest Shuffrey et al. ⁹ evidenced at 6 months a difference in neurological development of infants born during pandemic but these differences were unrelated to prenatal exposure to maternal infection. These findings may explain how irrespectively of the absence of any neurological changes in utero as found in this study may explain how some infants born during pandemic may show a neurodevelopmental delay. Further the higher incidence of depression, anxiety, and grief during pandemic particularly in infected women has been associated with reduced levels of maternal–infant bonding that may results an impaired neurodevelopment. ²¹

4.4. Implications for clinical practice

On this basis women experiencing mild SARS‐CoV‐2 illness can be reassured and adequately counseled on the low risk for their newborns to develop an abnormal neurodevelopment. This is of paramount important since pregnant women with SARS‐CoV‐2 disease shows raised levels of anxiety mainly generated by the concern about potential detrimental effect of the infection on their fetus ²² , ²³ and this kind of reassuring information may help in improving maternal infant dyad. ²¹

5. CONCLUSION

SARS‐CoV‐2 disease during pregnancy is not characterized by differential prenatal brain growth patterns and cortical development at least in women in with mild symptoms. These information may be useful to reassure infected mothers on the health of their fetuses.

CONFLICT OF INTEREST

The authors declare no conflict of interest.

Mappa I, Pietrolucci ME, Pavjola M, Maruotti G, D'Antonio F, Rizzo G. Fetal brain biometry and cortical development after maternal SARS‐CoV‐2 infection in pregnancy: A prospective case–control study. J Clin Ultrasound. 2022;1‐5. doi: 10.1002/jcu.23382

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author upon reasonable request.