Severe Acute Respiratory Syndrome Coronavirus 2 Infection Versus Vaccination in Pregnancy: Implications for Maternal and Infant Immunity.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been associated with adverse maternal and neonatal outcomes, yet uptake of SARS-CoV-2 vaccines during pregnancy and lactation has been slow. As a result, millions of pregnant and lactating women and their infants remain susceptible to the virus. METHODS: We measured spike-specific immunoglobulin G (anti-S IgG) and immunoglobulin A (anti-S IgA) in serum and breastmilk (BM) samples from 3 prospective mother-infant cohorts recruited in 2 academic medical centers. The primary aim was to determine the impact of maternal SARS-CoV-2 immunization vs infection and their timing on systemic and mucosal immunity. RESULTS: The study included 28 mothers infected with SARS-CoV-2 in late pregnancy (INF), 11 uninfected mothers who received 2 doses of the BNT162b2 vaccine in the latter half of pregnancy (VAX-P), and 12 uninfected mothers who received 2 doses of BNT162b2 during lactation. VAX dyads had significantly higher serum anti-S IgG compared to INF dyads (P < .0001), whereas INF mothers had higher BM:serum anti-S IgA ratios compared to VAX mothers (P = .0001). Median IgG placental transfer ratios were significantly higher in VAX-P compared to INF mothers (P < .0001). There was a significant positive correlation between maternal and neonatal serum anti-S IgG after vaccination (r = 0.68, P = .013), but not infection. CONCLUSIONS: BNT161b2 vaccination in late pregnancy or lactation enhances systemic immunity through serum anti-S immunoglobulin, while SARS-CoV-2 infection induces mucosal over systemic immunity more efficiently through BM immunoglobulin production. Next-generation vaccines boosting mucosal immunity could provide additional protection to the mother-infant dyad. Future studies should focus on identifying the optimal timing of primary and/or booster maternal vaccination for maximal benefit.

Humoral response to anti-SARS-CoV-2 vaccine in breastfeeding mothers and mother-to-infant antibody transfer through breast milk.

The magnitude of mother-to-infant transfer of anti-SARS-CoV-2 antibodies through breast milk (BM) after maternal vaccination during breastfeeding, in the absence of transplacental transfer of IgG, remains unclear. Here, we quantified anti-S and anti-RBD IgG, IgA, IgA1, and IgA2 in maternal serum, maternal saliva, BM, infant buccal swabs, and infant feces up to 90 days after the second maternal vaccine dose. BNT162b2 vaccine induced long-lasting IgG in maternal serum, but weaker mucosal antibody production, with anti-SARS-CoV-2 IgG and IgA amounts in BM between 10- and 150-fold lower compared to serum. BM IgA were exclusively of the IgA1 isotype, with no production of the mucosal-specific and protease-resistant IgA2. Accordingly, only traces of antibodies were retrieved from the feces of breastfed infants, and no IgG nor IgA were retrieved from infants' buccal swabs. Newly engineered anti-SARS-CoV-2 vaccines may be needed to stimulate the antibody production at mucosal sites such as breast milk.

Coronavirus Disease 2019 Vaccination During Pregnancy and Breastfeeding: A Review of Evidence and Current Recommendations in Europe, North America, and Australasia.

In the late 2020s, less than 1 year into the coronavirus disease 2019 (COVID-19) pandemic, several anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines were introduced on a worldwide scale, with a significant positive impact on the consequences of the disease for several high-risk population groups. In the case of most bacterial or viral respiratory infections, pregnant women are at increased risk of complications, however, neither pregnant nor breastfeeding women were included in the first round of randomized clinical trials evaluating the safety and effectiveness of COVID-19 vaccines, because of safety and ethical concerns. Nevertheless, most anti-SARS-CoV-2 vaccines have not been expressly contraindicated during pregnancy or breastfeeding, and observational data on immune response, adverse effects, and clinical efficacy in pregnant and breastfeeding women have been progressively gathered during 2021. The vast majority of these data is reassuring for what concerns side effects for women and infants and points out the efficacy of vaccines in protecting women against COVID-19-related complications. Despite this, the hesitancy of pregnant and breastfeeding women at being vaccinated is still real. In this mini-review, we resume the available data on the clinical consequences of COVID-19 in pregnant women, as well as adverse effects, systemic and mucosal immune response, and clinical effectiveness of COVID-19 vaccines in pregnant and breastfeeding women. Moreover, we offer an updated overview of European, North American, and Australasian recommendations concerning COVID-19 vaccination in pregnant and breastfeeding women, in order to safely ensure the highest protection of women and their infants.

SARS-CoV-2 infection and neonates: Evidence-based data after 18 months of the pandemic.

After 18 months of the COVID-19 pandemic, data concerning SARS-CoV-2 infection in pregnant women and their neonates are progressively taking the place of complete uncertainty. Here, we summarize updated evidence regarding several critical aspects of perinatal SARS-CoV-2 infection, including 1) vertical transmission of the virus in utero, which is possible but seems rare according to current epidemiological data; 2) how COVID-19 during pregnancy can shape maternal and neonatal outcomes, either directly or indirectly; 3) how recommendations regarding the management of infected dyads have been progressively modified in light of new scientific evidence; and 4) how maternal infection or vaccination can induce the passive protection of fetuses and neonates against the infection, through the transfer of specific antibodies before and after birth.

Clinical relevance of SARS-CoV-2 infection in late pregnancy.

BACKGROUND: Evidence on the outcome of SARS-CoV-2 infection in pregnancy is generally reassuring but yet not definitive. METHODS: To specifically assess the impact of SARS-CoV-2 infection in late pregnancy, we prospectively recruited 315 consecutive women delivering in a referral hospital located in Lombardy, Italy in the early phase of the epidemic. Restriction of the recruitment to this peculiar historical time period allowed to exclude infections occurring early in pregnancy and to limit the recall bias. All recruited subjects underwent a nasopharyngeal swab to assess the presence of Sars-Cov-2 using Real-time PCR. In addition, two different types of antibodies for the virus were evaluated in peripheral blood, those against the spike proteins S1 and S2 of the envelope and those against the nucleoprotein of the nucleocapsid. Women were considered to have had SARS-CoV-2 infection in pregnancy if at least one of the three assessments was positive. RESULTS: Overall, 28 women had a diagnosis of SARS-CoV-2 infection in pregnancy (8.9%). Women diagnosed with the infection were more likely to report one or more episodes of symptoms suggestive for Covid-19 (n = 11, 39.3%) compared to unaffected women (n = 39, 13.6%). The corresponding OR was 4.11 (95%CI: 1.79-9.44). Symptoms significantly associated with Covid-19 in pregnancy included fever, cough, dyspnea and anosmia. Only one woman necessitated intensive care. Pregnancy outcome in women with and without SARS-CoV-2 infection did not also differ. CONCLUSIONS: SARS-CoV-2 infection is asymptomatic in three out of five women in late pregnancy and is rarely severe. In addition, pregnancy outcome may not be markedly affected.

Severe SARS-CoV-2 placenta infection can impact neonatal outcome in the absence of vertical transmission.

The effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on the pathophysiology of the placenta and its impact on pregnancy outcome has not yet been fully elucidated. Here, we present a comprehensive clinical, morphological, and molecular analysis of placental tissues from pregnant women with and without SARS-CoV-2 infection. SARS-CoV-2 could be detected in half of placental tissues from SARS-CoV-2-positive women. The presence of the virus was not associated with any distinctive pathological, maternal, or neonatal outcome features. SARS-CoV-2 tissue load was low in all but one patient who exhibited severe placental damage leading to neonatal neurological manifestations. The placental transcriptional response induced by high viral load of SARS-CoV-2 showed an immunopathology phenotype similar to autopsy lung tissues from patients with severe coronavirus disease 2019. This finding contrasted with the lack of inflammatory response in placental tissues from SARS-CoV-2-positive women with low viral tissue load and from SARS-CoV-2-negative women. Importantly, no evidence of vertical transmission of SARS-CoV-2 was found in any newborns, suggesting that the placenta may be an effective maternal-neonatal barrier against the virus even in the presence of severe infection. Our observations suggest that severe placental damage induced by the virus may be detrimental for the neonate independently of vertical transmission.

Case Report: Late-Onset Congenital Adrenal Hyperplasia and Acute Covid-19 Infection in a Pregnant Woman: Multidisciplinary Management.

Background: The impact of the Covid-19 infection on patients with chronic endocrine disease is not fully known. We describe here the first case of a pregnant woman with Covid-19 acute infection and non-classical congenital adrenal hyperplasia (NCAH). Case description: A woman at 36 weeks of gestation was referred to our Maternity Hospital for premature rupture of membranes (PROM). Her medical history was positive for NCAH on chronic steroid replacement till the age of 17 years (cortisone acetate and dexamethasone, both in the morning). At admission, her naso-oro-pharyngeal swab resulted positive for SARS-CoV-2. Due to hyperpyrexia and late preterm PROM, cesarean section was planned, and she was started on a 100 mg-bolus of hydrocortisone, followed by continuous infusion of 200 mg/24 h. A female neonate in good clinical condition and with a negative nasopharyngeal Covid-19 swab was delivered. On second postpartum day, the mother was in good condition and was switched to oral steroid therapy. On third postpartum day she worsened, with radiological signs of acute pulmonary embolism. Oro-tracheal intubation and mechanical ventilation were started, and she was switched back to intravenous steroid therapy. On April 30, pulmonary embolism was resolved, and on May 13th she was discharged in good condition. Conclusions: We report the first case of Covid-19 acute infection that occurred in late-pregnancy in a woman with NCAH on chronic steroid replacement. The management of the patient in a reference center with early involvement of a multidisciplinary team granted prompt care and adequate protection for all the involved sanitary operators.

Evaluation of Rooming-in Practice for Neonates Born to Mothers With Severe Acute Respiratory Syndrome Coronavirus 2 Infection in Italy.

Importance: The management of mother-infant dyads during the ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic constitutes a major issue for neonatologists. In mothers with SARS-CoV-2 infection, current recommendations suggest either to separate the dyad or encourage protected rooming-in under appropriate precautions. No data are available regarding the risk of mother-to-infant transmission of SARS-CoV-2 during rooming-in. Objective: To evaluate the risk of postnatal transmission of SARS-CoV-2 from infected mothers to their neonates following rooming-in and breastfeeding. Design, Setting, and Participants: A prospective, multicenter study enrolling mother-infant dyads from March 19 to May 2, 2020, followed up for 20 days of life (range, 18-22 days), was performed. The study was conducted at 6 coronavirus disease 2019 maternity centers in Lombardy, Northern Italy. Participants included 62 neonates born to 61 mothers with SARS-CoV-2 infection who were eligible for rooming-in practice based on the clinical condition of the mother and infants whose results of nasopharyngeal swabs were negative at birth. Exposures: Mothers with SARS-CoV-2 infection were encouraged to practice rooming-in and breastfeeding under a standardized protocol to minimize the risk of viral transmission. Main Outcomes and Measures: Clinical characteristics and real-time reverse transcriptase-polymerase chain reaction for SARS-CoV-2 on neonatal nasopharyngeal swabs at 0, 7, and 20 days of life. Results: Of the 62 neonates enrolled (25 boys), born to 61 mothers (median age, 32 years; interquartile range, 28-36 years), only 1 infant (1.6%; 95% CI, 0%-8.7%) was diagnosed as having SARS-CoV-2 infection at postbirth checks. In that case, rooming-in was interrupted on day 5 of life because of severe worsening of the mother's clinical condition. The neonate became positive for the virus on day 7 of life and developed transient mild dyspnea. Ninety-five percent of the neonates enrolled were breastfed. Conclusions and Relevance: The findings of this cohort study provide evidence-based information on the management of mother-infant dyads in case of SARS-CoV-2 maternal infection suggesting that rooming-in and breastfeeding can be practiced in women who are able to care for their infants.

SARS-CoV-2 infection and neonates: a review of evidence and unresolved questions.

SARS-CoV-2 infection in the neonatal period poses previously unmet challenges to obstetricians and neonatologists, but several key questions are yet to be answered. Few cases of presumed in utero vertical transmission of the virus from infected mothers to fetuses have been reported, but stronger evidence is needed, from larger datasets with multiple biospecimens rigorously analyzed. Whether acquired before or after birth, SARS-CoV-2 infection in neonates can be symptomatic, but our comprehension of neonatal immune response and the subsequent clinical characteristics of COVID-19 in early life are incomplete. Finally, the pandemic challenged several dogmas regarding the management of mother-infant dyads, and again more robust data are needed to support the formulation of evidence-based guidelines. Here, we briefly summarize existing evidence and key unresolved questions about SARS-CoV-2 infection and COVID-19 in the neonatal period.