Impact of maternal SARS-CoV-2 booster vaccination on blood and breastmilk antibodies.

Maternal COVID-19 vaccination could protect infants who are ineligible for vaccine through antibody transfer during pregnancy and lactation. We measured the quantity and durability of SARS-CoV-2 antibodies in human milk and infant blood before and after maternal booster vaccination. Prospective cohort of lactating women immunized with primary and booster COVID-19 vaccines during pregnancy or lactation and their infants. Milk and blood samples from October 2021 to April 2022 were included. Anti-nucleoprotein (NP) and anti-receptor binding domain (RBD) IgG and IgA in maternal milk and maternal and infant blood were measured and compared longitudinally after maternal booster vaccine. Forty-five lactating women and their infants provided samples. 58% of women were anti-NP negative and 42% were positive on their first blood sample prior to booster vaccine. Anti-RBD IgG and IgA in milk remained significantly increased through 120-170 days after booster vaccine and did not differ by maternal NP status. Anti-RBD IgG and IgA did not increase in infant blood after maternal booster. Of infants born to women vaccinated in pregnancy, 74% still had positive serum anti-RBD IgG measured on average 5 months after delivery. Infant to maternal IgG ratio was highest for infants exposed to maternal primary vaccine during the second trimester compared to third trimester (0.85 versus 0.29; p<0.001). Maternal COVID-19 primary and booster vaccine resulted in robust and long-lasting transplacental and milk antibodies. These antibodies may provide important protection against SARS-CoV-2 during the first six months of life.

The contributions of parental lactation on offspring development: It's not udder nonsense!

The Developmental Origins of Health and Disease (DOHaD) hypothesis describes how maternal stress exposures experienced during critical periods of perinatal life are linked to altered developmental trajectories in offspring. Perinatal stress also induces changes in lactogenesis, milk volume, maternal care, and the nutritive and non-nutritive components of milk, affecting short and long-term developmental outcomes in offspring. For instance, selective early life stressors shape the contents of milk, including macro/micronutrients, immune components, microbiota, enzymes, hormones, milk-derived extracellular vesicles, and milk microRNAs. In this review, we highlight the contributions of parental lactation to offspring development by examining changes in the composition of breast milk in response to three well-characterized maternal stressors: nutritive stress, immune stress, and psychological stress. We discuss recent findings in human, animal, and in vitro models, their clinical relevance, study limitations, and potential therapeutic significance to improving human health and infant survival. We also discuss the benefits of enrichment methods and support tools that can be used to improve milk quality and volume as well as related developmental outcomes in offspring. Lastly, we use evidence-based primary literature to convey that even though select maternal stressors may modulate lactation biology (by influencing milk composition) depending on the severity and length of exposure, exclusive and/or prolonged milk feeding may attenuate the negative in utero effects of early life stressors and promote healthy developmental trajectories. Overall, scientific evidence supports lactation to be protective against nutritive and immune stressors, but the benefits of lactation in response to psychological stressors need further investigation.

Assessment of the scope, completeness, and consistency of various drug information resources related to COVID-19 medications in pregnancy and lactation.

BACKGROUND: Drug use in pregnancy and lactation is challenging. It becomes more challenging in pregnant and lactating women with certain critical clinical conditions such as COVID-19, because of inconsistent drug safety data. Therefore, we aimed to evaluate the various drug information resources for the scope, completeness, and consistency of the information related to COVID-19 medications in pregnancy and lactation. METHODS: Data related to COVID-19 medications from various drug information resources such as text references, subscription databases, and free online tools were used for the comparison. The congregated data were analyzed for scope, completeness, and consistency. RESULTS: Scope scores were highest for Portable Electronic Physician Information Database (PEPID), Up-to-date, and drugs.com compared to other resources. The overall completeness scores were higher for Micromedex and drugs.com (p < 0.05 compared to all other resources). The inter-reliability analysis for overall components by Fleiss kappa among all the resources was found to be 'slight' (k < 0.20, p < 0.0001). The information related to the older drugs in most of the resources, provides in-depth details on various components such as pregnancy safety, clinical data related to lactation, the effect of the drug distribution into breast milk, reproductive potential/infertility risk and the pregnancy category/recommendations. However, the information related to these components for newer drugs was superficial and incomplete, with insufficient data and inconclusive evidence, which is a statistically significant observation. The strength of observer agreement for the various COVID-19 medications ranged from poor to fair and moderate for the various recommendation categories studied. CONCLUSION: This study reports discrepancies in the information related to pregnancy, lactation, drug level, reproductive risk, and pregnancy recommendations among the resources directing to refer to more than one resource for information about the safe and quality use of medications in this special population.The present study also emphasizes the need for development of comprehensive, evidence-based, and precise information guide that can promote safe and effective drug use in this special population.

Anti-SARS-CoV-2 Immunoglobulins in Human Milk after Coronavirus Disease or Vaccination-Time Frame and Duration of Detection in Human Milk and Factors That Affect Their Titers: A Systematic Review.

Human milk (HM) of mothers infected with or vaccinated against SARS-CoV-2 contains specific immunoglobulins, which may protect their offspring against infection or severe disease. The time frame and duration after infection or vaccination, during which these immunoglobulins are detected in HM, as well as the major factors that influence their levels, have not been fully elucidated. This systematic review aimed to collect the existing literature and describe the immune response, specifically regarding the immunoglobulins in HM after COVID-19 disease or vaccination in non-immune women. We conducted a systematic search of PubMed and Scopus databases to identify studies published up until 19 March 2023. In total, 975 articles were screened, and out of which 75 were identified as being relevant and were finally included in this review. Infection by SARS-CoV-2 virus primarily induces an IgA immune response in HM, while vaccination predominantly elevates IgG levels. These immunoglobulins give HM a neutralizing capacity against SARS-CoV-2, highlighting the importance of breastfeeding during the pandemic. The mode of immune acquisition (infection or vaccination) and immunoglobulin levels in maternal serum are factors that seem to influence immunoglobulin levels in HM. Further studies are required to determine the impact of other factors, such as infection severity, lactation period, parity, maternal age and BMI on immunoglobulin level in HM.

Detection of IgA and IgG Antibodies against the Structural Proteins of SARS-CoV-2 in Breast Milk and Serum Samples Derived from Breastfeeding Mothers.

Background: COVID-19 vaccination or natural infection is associated with the development of immunity. The search of IgA and IgG antibodies against all the structural proteins (spike, nucleocapsid, membrane, and envelope) of SARS-CoV-2 in breastfeeding mothers is associated with immunity that can help the newborn avoid development of the infection. Methods: In this study, we analyzed 30 breastfeeding women that provided samples of breast milk and serum and evaluated the presence of IgA, total IgG, and subclasses against the structural proteins of SARS-CoV-2. Results: We reported a high seroprevalence to IgA (76.67-100%) and negativity to IgG against all analyzed proteins in breast milk. Seroprevalence in serum samples was around 10-36.67% to IgA and 23.3-60% to IgG. Finally, we detected the presence of the subclasses IgG1, IgG2, and IgG4 against all the structural proteins of SARS-CoV-2. Conclusions: This work provides evidence of the presence of IgA and IgG antibodies against the four structural proteins of SARS-CoV-2 in breast milk and serum samples derived from breastfeeding women, which can confer immunity to the newborn.

Smell and taste of milk during tube feeding of preterm infants: neurodevelopmental follow-up of the randomized TASTE trial, study protocol.

BACKGROUND: The Taste And Smell To Enhance nutrition (TASTE) trial investigated the effects of smell and taste of milk with tube feeding compared to routine care on the growth of preterm infants. There was no difference between groups in growth (weight, head circumference, length) z-scores at discharge from the hospital. Infants in the intervention group had higher head circumference and length z-scores at 36 weeks postmenstrual age, both secondary outcomes. The objective of this follow-up study is to assess 2-year neurodevelopmental and growth outcomes after exposure of preterm infants to the smell and taste of milk with tube feeding compared to routine care. METHODS: This is a neurodevelopmental follow-up study of a two-center, placebo-controlled randomized trial. Infants born before 29 weeks postmenstrual age and/or with a birth weight of less than 1250 g were randomized to smell and taste of milk with each tube feed or routine care. The current follow-up assessed the 2-year neurodevelopmental and growth outcomes of participants of the TASTE trial discharged from the hospital (n = 334). The primary outcome is survival free of any major neurodevelopmental impairment comprising any moderate/severe cerebral palsy (Gross Motor Function Classification System score II-V), Bayley Scales of Infant and Toddler Development, Third/Fourth Edition (Bayley-III/Bayley-4) motor, cognitive, or language scores < -2SD, blindness, or deafness at 2 years of age. Other outcomes include death, breastfeeding within the first year, and respiratory support, oral feeding, and anthropometric parameters at 2 years of age. The Human Research Ethics Committees of Mater Misericordiae Limited and the Royal Women's Hospital approved the TASTE trial including the neurodevelopmental follow-up described in this protocol. DISCUSSION: For patients and their families, the neurodevelopmental outcomes of preterm infants are of utmost importance. Consequently, they should be investigated following any interventional study performed during the newborn period. Furthermore, improved weight gain and head growth in the hospital are associated with better long-term neurodevelopmental outcomes. Smelling and tasting of milk is an uncomplicated and cost-effective intervention that may improve the growth and neurodevelopmental outcomes of preterm infants. Potential limitations affecting this follow-up study, caused by the COVID-19 pandemic, are anticipated and discussed in this protocol. TRIAL REGISTRATION: Name of the registry: Australian and New Zealand Clinical Trials Registry; Registration number: ACTRN12617000583347 ; Registration date: 26 April 2017.

Impact of Type of Enteral Feeds on Early Postoperative Outcomes After Congenital Heart Surgery in Neonates and Young Infants: A Single Center Experience in a Limited Resource Environment.

Background: Breast milk is known to prevent infections and is recommended for enteral feeding of infants after congenital heart surgery (CHS). During the Covid-19 pandemic, expressed breast milk (EBM) was not always available; hence, feeding after CHS was maintained with EBM or infant formula (IF) or both; we evaluated the impact of enteral feed type on early postoperative outcomes after CHS. Methods: In a prospective observational study, consecutive neonates and infants <4 months undergoing CHS were divided into EBM, IF, or EBM+IF groups; incidences of postoperative infections, ventilation duration, intensive care unit (ICU) stay, and mortality were studied. Results: Among 270 patients; 90 (33.3%) received EBM, 89 (32.9%) received IF, and 91 (33.7%) received EBM+IF. IF group had more neonates (78.7%[IF] vs 42.2%[EBM] and 52.7%[EBM+IF], P < 0.001) and greater surgical complexity. Postoperative infections were 9 (10.0%) in EBM; 23 (25.8%) in IF; and 14 (15.4%) in EBM+IF (P = .016). IF group (OR 2.58 [1.05-6.38], P = .040), absence of preoperative feeding (OR 6.97 [1.06-45.97], P = .040), and increase in cardiopulmonary bypass time (OR 1.005 [1.001-1.010], P = .027) were associated with postoperative infection. Ventilation duration in hours was 26 (18-47.5) in EBM; 47 (28-54.5) in IF; and 40 (17.5-67) in EBM+IF (P = .004). ICU stay in days was 4 (3-7) in EBM; 6 (5-9) in IF; and 5 (3-9) in EBM+IF (P = .001). Mortality did not differ (P = .556). Conclusion: IF group had a greater proportion of neonates with higher surgical complexity. Patients who received EBM after CHS had fewer postoperative infections and better postoperative outcomes compared to those receiving IF or EBM+IF.

Maternal transfer of IgA and IgG SARS-CoV-2 specific antibodies transplacentally and via breast milk feeding.

BACKGROUND: Although there have been many studies on antibody responses to SARS-CoV-2 in breast milk, very few have looked at the fate of these in the infant, and whether they are delivered to immunologically relevant sites in infants. METHODS: Mother/infant pairs (mothers who breast milk fed and who were SARS-CoV-2 vaccinated before or after delivery) were recruited for this cross-sectional study. Mother blood, mother breast milk, infant blood, infant nasal specimen, and infant stool was tested for IgA and IgG antibodies against SARS-CoV-2 spike trimer. RESULTS: Thirty-one mother/infant pairs were recruited. Breast milk fed infants acquired systemic anti-spike IgG antibodies only if their mothers were vaccinated antepartum (100% Antepartum; 0% Postpartum; P<0.0001). Breast milk fed infants acquired mucosal anti-spike IgG antibodies (in the nose) only if their mothers were vaccinated antepartum (89% Antepartum; 0% Postpartum; P<0.0001). None of the infants in either group had anti-spike IgA in the blood. Surprisingly, 33% of the infants whose mothers were vaccinated antepartum had high titer anti-spike IgA in the nose (33% Antepartum; 0% Postpartum; P = 0.03). Half-life of maternally transferred plasma IgG antibodies in the Antepartum infant cohort was ~70 days. CONCLUSION: Vaccination antepartum followed by breast milk feeding appears to be the best way to provide systemic and local anti-SARS-CoV-2 antibodies for infants. The presence of high titer SARS-CoV-2-specific IgA in the nose of infants points to the potential importance of breast milk feeding early in life for maternal transfer of mucosal IgA antibodies. Expectant mothers should consider becoming vaccinated antepartum and consider breast milk feeding for optimal transfer of systemic and mucosal antibodies to their infants.

Breastfeeding provides a protective hug and the benefits have outweighed the risks during the COVID-19 pandemic.

Mothers have been very hesitant about breastfeeding when they have COVID-19 infection or vaccinations. Maternal milk protects neonates through its high biological value, immune factors and anti-infectious molecules and this review shows that the virus that causes COVID-19 is not transmitted through breast milk. COVID-19 vaccines induce anti-spike antibodies with neutralising capacity, and phagocytosis, and no vaccine particles or messenger ribonucleic acid have been detected in breast milk. Most drugs used for maternal COVID-19 infections are safe for breastfed infants. CONCLUSION: The clear benefits of breastfeeding by far outweigh the very low risk of infant infections from COVID-19.

SARS-CoV-2 detection in human milk: a systematic review.

PURPOSE: To synthesize the current evidence for the presence of SARS-CoV-2 RNA in the human milk of mothers with confirmed COVID-19 and its potential role in neonatal SARS-CoV-2 infection. MATERIALS AND METHODS: Using terms related to novel coronavirus 2019 and human milk, a systematic search was performed in three electronic databases (PubMed, EMBASE, and Web of Science) for studies published between December 2019 and 15 October 2020. Published peer-reviewed studies reporting the results of RT-PCR for SARS-CoV-2 RNA in human milk in mothers with confirmed COVID-19 were included. Proportion meta-analysis of case series and prospective cohort studies was performed using STATA version 14.2 (StataCorp, College Station, TX) and pooled estimate (with 95% confidence interval) of overall incidence of SARS-CoV-2 transmission was calculated. RESULTS: We identified 936 records, of which 34 studies (24 case-reports, 10 cohort studies) were eligible for this systematic review. A total of 116 confirmed COVID-19 lactating women (88 in cohort and 28 in case-reports) underwent RT-PCR testing in human milk, and 10 (six in case reports) were detected to have SARS-CoV-2 RNA. The overall pooled proportion (from cohort studies) for SARS-CoV-2 RNA detection in human milk was 2.16% (95% CI: 0.0-8.81%, I2: 0%). Four studies (six patients) also reported the presence of SARS-CoV-2 specific antibodies (along with RT-PCR) in human milk. CONCLUSIONS: The limited low-quality evidence suggests that SARS-CoV-2 RNA is detected in human milk in an extremely low proportion, however, based on current evidence no conclusion can be drawn about its infectivity and impact on the infants. In concordance with World Health Organization recommendations, exclusive breastfeeding should be considered in all cases unless any other contraindication exists.

Early human milk lactoferrin during SARS-CoV-2 infection.

BACKGROUND/AIM: Early human milk provides protection against viral infections due to its high nutritional value, abundance of maternal antibodies and the specific role of lactoferrin (Lf). Lf blocks the early interaction between SARS-CoV-2 and host cells by binding to specific cell receptors and has been proposed as a preventative and adjunct treatment for COVID-19. This preliminary report aimed to investigate concentrations of Lf in early milk of SARS-CoV-2 positive mothers versus non-infected controls. MATERIAL AND METHODS: In a cohort of 13 SARS-CoV-2 positive mothers and 15 controls, breast milk concentrations of Lf were determined by ELISA on day 3 postpartum. Additionally, colostrum samples of infected mothers were analyzed for SARS-CoV-2 RNA detection and anti-SARS-CoV-2 IgA and IgG determination using RT-qPCR and ELISA, respectively. RESULTS: No differences were found in breast milk Lf concentrations between SARS-CoV-2 positive mothers and controls. In a subgroup analysis, however, symptomatic mothers (n = 7) presented with lower breast milk Lf concentrations, as compared to asymptomatic mothers (p = .041) and healthy controls (p = .029). All milk samples tested negative for SARS-CoV-2 RNA. Early human milk of infected mothers displayed IgA and IgG SARS-CoV-2 specific reactivity. CONCLUSIONS: Our data showed a different early breast milk Lf "profile" between COVID-19 symptomatic and asymptomatic mothers with the latter being at non-COVID levels (control group). SARS-CoV-2 RNA was not detected in any breast milk sample. Early human milk Lf levels are potentially influenced by the severity of maternal COVID-19 infection during pregnancy.

Maternal, Infant, and Breast Milk Antibody Response Following COVID-19 Infection in Early Versus Late Gestation.

BACKGROUND: Coronavirus disease 2019 [severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)] infection at varying time points during the pregnancy can influence antibody levels after delivery. We aimed to examine SARS-CoV-2 IgG, IgM and IgA receptor binding domain of the spike protein and nucleocapsid protein (N-protein) reactive antibody concentrations in maternal blood, infant blood and breastmilk at birth and 6 weeks after SARS-CoV-2 infection in early versus late gestation. METHODS: Mothers with SARS-CoV-2 infection during pregnancy were enrolled between July 2020 and May 2021. Maternal blood, infant blood and breast milk samples were collected at delivery and 6 weeks postpartum. Samples were analyzed for SARS-CoV-2 spike and N-protein reactive IgG, IgM and IgA antibodies. Antibody concentrations were compared at the 2 time points and based on trimester of infection ("early" 1st/2nd vs. "late" 3rd). RESULTS: Dyads from 20 early and 11 late trimester infections were analyzed. For the entire cohort, there were no significant differences in antibody levels at delivery versus 6 weeks with the exception of breast milk levels which declined over time. Early gestation infections were associated with higher levels of breastmilk IgA to spike protein ( P = 0.04). Infant IgG levels to spike protein were higher at 6 weeks after late infections ( P = 0.04). There were strong correlations between maternal and infant IgG levels at delivery ( P < 0.01), and between breastmilk and infant IgG levels. CONCLUSIONS: SARS-CoV-2 infection in early versus late gestation leads to a persistent antibody response in maternal blood, infant blood and breast milk over the first 6 weeks after delivery.

Anti-Spike Antibodies Present in the Milk of SARS-CoV-2 Vaccinated Mothers Are Complement-Activating.

Although only 0.8-1% of SARS-CoV-2 infections are in the 0-9 age-group, pneumonia is still the leading cause of infant mortality globally. Antibodies specifically directed against SARS-CoV-2 spike protein (S) are produced during severe COVID-19 manifestations. Following vaccination, specific antibodies are also detected in the milk of breastfeeding mothers. Since antibody binding to viral antigens can trigger activation of the complement classical - pathway, we investigated antibody-dependent complement activation by anti-S immunoglobulins (Igs) present in breast milk following SARS-CoV-2 vaccination. This was in view of the fact that complement could play a fundamentally protective role against SARS-CoV-2 infection in newborns. Thus, 22 vaccinated, lactating healthcare and school workers were enrolled, and a sample of serum and milk was collected from each woman. We first tested for the presence of anti-S IgG and IgA in serum and milk of breastfeeding women by ELISA. We then measured the concentration of the first subcomponents of the three complement pathways (i.e., C1q, MBL, and C3) and the ability of anti-S Igs detected in milk to activate the complement in vitro. The current study demonstrated that vaccinated mothers have anti-S IgG in serum as well as in breast milk, which is capable of activating complement and may confer a protective benefit to breastfed newborns.

Detection of SARS-CoV-2 in Human Breast Milk.

Certain viral pathogens can be shed into the human breast milk and cause infections in the infant upon breastfeeding. Thus, it is important to clarify whether viral RNA as well as infectious virus can be found in breast milk. The complexity of this body fluid poses several challenges for viral RNA isolation and detection of infectious virus. We here provide a protocol that allowed the identification of SARS-CoV-2 RNA in breast milk and the isolation of infectious virus after the virus has been artificially spiked into milk samples.