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Background: Since human milk contents does not meet the high need of very low birth weight infants, fortification of breast milk is a standard practice for this population. As donkey milk has been long considered for children allergic to cow's milk proteins due to its low allergic properties, a new donkey milk-derived fortifier (DF) has been recently evaluated as a valid alternative to bovine milk-derived fortifier (BF). It seems to improve feeding tolerance when compared with standard BF, with similar neurodevelopmental and auxological outcome at 18 months of age. The aim of this study is to evaluate the development of allergic manifestations occurring in the population of the "Fortilat Trial" at 6-8 years of age. Methods: Allergic manifestations were assessed by an ad hoc questionnaire administered to families. The occurrence of asthma, allergic rhinitis and oculorhinitis, rashes and atopic dermatitis, food allergies, accesses to an emergency department for allergic reactions, and the need of antihistamine have been investigated. Results: In total, 113 infants were enrolled in the study (BF arm: n = 60, DF arm: n = 53). No difference in risk was observed between the two groups for all the considered outcomes. In conclusion, our data suggest that DF does not impact the development of allergic manifestations in the first years of life. Clinical Trial Registration number: ISRCT N70022881.
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Hipersensibilidad a los Alimentos , Hipersensibilidad a la Leche , Recién Nacido , Lactante , Niño , Animales , Femenino , Bovinos , Humanos , Leche Humana , Equidae , Estudios de Seguimiento , Lactancia Materna , Alimentos Fortificados , Hipersensibilidad a la Leche/epidemiologíaRESUMEN
BACKGROUND: Human cytomegalovirus (HCMV) is the leading cause of congenital infections resulting in severe morbidity and mortality among newborns worldwide. Although both the host's and the virus' genetic backgrounds contribute to the outcome of infections, significant gaps remain in our understanding of the exact mechanisms that determine disease severity. OBJECTIVES: In this study, we sought to identify a correlation between the virological features of different HCMV strains with the clinical and pathological features of congenitally infected newborns, therefore proposing new possible prognostic factors. STUDY DESIGN: This short communication presents five newborns with congenital cytomegalovirus infection, whose clinical phenotype during fetal, neonatal, and follow-up periods is correlated with in-vitro growth properties, immunomodulatory abilities and genome variability of HCMV strains isolated from organic samples (urine) of the patients. RESULTS: The five patients described in this short communication displayed a heterogeneous clinical phenotype and different virus replication properties, immunomodulatory abilities, and genetic polymorphisms. Interestingly, we observed that an attenuate viral replication in-vitro influences the immunomodulatory abilities of HCMV, leading to more severe congenital infections and long-term sequelae. Conversely, infection with viruses characterized by aggressive replicative behavior in-vitro resulted in asymptomatic patients' phenotypes. CONCLUSIONS: Overall, this case series suggests the hypothesis that genetic variability and differences in the replicative behavior of HCMV strains result in clinical phenotypes of different severity, most likely due to different immunomodulatory properties of the virus.
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Líquidos Corporales , Infecciones por Citomegalovirus , Recién Nacido , Humanos , Citomegalovirus/genética , Fenotipo , Polimorfismo GenéticoRESUMEN
BACKGROUND: In 2021, we showed an increased risk associated with COVID-19 in pregnancy. Since then, the SARS-CoV-2 virus has undergone genetic mutations. We aimed to examine the effects on maternal and perinatal outcomes of COVID-19 during pregnancy, and evaluate vaccine effectiveness, when omicron (B.1.1.529) was the variant of concern. METHODS: INTERCOVID-2022 is a large, prospective, observational study, involving 41 hospitals across 18 countries. Each woman with real-time PCR or rapid test, laboratory-confirmed COVID-19 in pregnancy was compared with two unmatched women without a COVID-19 diagnosis who were recruited concomitantly and consecutively in pregnancy or at delivery. Mother and neonate dyads were followed until hospital discharge. Primary outcomes were maternal morbidity and mortality index (MMMI), severe neonatal morbidity index (SNMI), and severe perinatal morbidity and mortality index (SPMMI). Vaccine effectiveness was estimated, adjusted by maternal risk profile. FINDINGS: We enrolled 4618 pregnant women from Nov 27, 2021 (the day after WHO declared omicron a variant of concern), to June 30, 2022: 1545 (33%) women had a COVID-19 diagnosis (median gestation 36·7 weeks [IQR 29·0-38·9]) and 3073 (67%) women, with similar demographic characteristics, did not have a COVID-19 diagnosis. Overall, women with a diagnosis had an increased risk for MMMI (relative risk [RR] 1·16 [95% CI 1·03-1·31]) and SPMMI (RR 1·21 [95% CI 1·00-1·46]). Women with a diagnosis, compared with those without a diagnosis, also had increased risks of SNMI (RR 1·23 [95% CI 0·88-1·71]), although the lower bounds of the 95% CI crossed unity. Unvaccinated women with a COVID-19 diagnosis had a greater risk of MMMI (RR 1·36 [95% CI 1·12-1·65]). Severe COVID-19 symptoms in the total sample increased the risk of severe maternal complications (RR 2·51 [95% CI 1·84-3·43]), perinatal complications (RR 1·84 [95% CI 1·02-3·34]), and referral, intensive care unit (ICU) admission, or death (RR 11·83 [95% CI 6·67-20·97]). Severe COVID-19 symptoms in unvaccinated women increased the risk of MMMI (RR 2·88 [95% CI 2·02-4·12]) and referral, ICU admission, or death (RR 20·82 [95% CI 10·44-41·54]). 2886 (63%) of 4618 total participants had at least a single dose of any vaccine, and 2476 (54%) of 4618 had either complete or booster doses. Vaccine effectiveness (all vaccines combined) for severe complications of COVID-19 for all women with a complete regimen was 48% (95% CI 22-65) and 76% (47-89) after a booster dose. For women with a COVID-19 diagnosis, vaccine effectiveness of all vaccines combined for women with a complete regimen was 74% (95% CI 48-87) and 91% (65-98) after a booster dose. INTERPRETATION: COVID-19 in pregnancy, during the first 6 months of omicron as the variant of concern, was associated with increased risk of severe maternal morbidity and mortality, especially among symptomatic and unvaccinated women. Women with complete or boosted vaccine doses had reduced risk for severe symptoms, complications, and death. Vaccination coverage among pregnant women remains a priority. FUNDING: None.
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COVID-19 , Resultado del Embarazo , Embarazo , Recién Nacido , Humanos , Femenino , Masculino , Eficacia de las Vacunas , COVID-19/diagnóstico , COVID-19/epidemiología , COVID-19/prevención & control , SARS-CoV-2 , Prueba de COVID-19 , Estudios Prospectivos , MadresRESUMEN
BACKGROUND: The effect of COVID-19 in pregnancy on maternal outcomes and its association with preeclampsia and gestational diabetes mellitus have been reported; however, a detailed understanding of the effects of maternal positivity, delivery mode, and perinatal practices on fetal and neonatal outcomes is urgently needed. OBJECTIVE: To evaluate the impact of COVID-19 on fetal and neonatal outcomes and the role of mode of delivery, breastfeeding, and early neonatal care practices on the risk of mother-to-child transmission. STUDY DESIGN: In this cohort study that took place from March 2020 to March 2021, involving 43 institutions in 18 countries, 2 unmatched, consecutive, unexposed women were concomitantly enrolled immediately after each infected woman was identified, at any stage of pregnancy or delivery, and at the same level of care to minimize bias. Women and neonates were followed up until hospital discharge. COVID-19 in pregnancy was determined by laboratory confirmation and/or radiological pulmonary findings or ≥2 predefined COVID-19 symptoms. The outcome measures were indices of neonatal and perinatal morbidity and mortality, neonatal positivity and its correlation with mode of delivery, breastfeeding, and hospital neonatal care practices. RESULTS: A total of 586 neonates born to women with COVID-19 diagnosis and 1535 neonates born to women without COVID-19 diagnosis were enrolled. Women with COVID-19 diagnosis had a higher rate of cesarean delivery (52.8% vs 38.5% for those without COVID-19 diagnosis, P<.01) and pregnancy-related complications, such as hypertensive disorders of pregnancy and fetal distress (all with P<.001), than women without COVID-19 diagnosis. Maternal diagnosis of COVID-19 carried an increased rate of preterm birth (P≤.001) and lower neonatal weight (P≤.001), length, and head circumference at birth. In mothers with COVID-19 diagnosis, the length of in utero exposure was significantly correlated to the risk of the neonate testing positive (odds ratio, 4.5; 95% confidence interval, 2.2-9.4 for length of in utero exposure >14 days). Among neonates born to mothers with COVID-19 diagnosis, birth via cesarean delivery was a risk factor for testing positive for COVID-19 (odds ratio, 2.4; 95% confidence interval, 1.2-4.7), even when severity of maternal conditions was considered and after multivariable logistic analysis. In the subgroup of neonates born to women with COVID-19 diagnosis, the outcomes worsened when the neonate also tested positive, with higher rates of neonatal intensive care unit admission, fever, gastrointestinal and respiratory symptoms, and death, even after adjusting for prematurity. Breastfeeding by mothers with COVID-19 diagnosis and hospital neonatal care practices, including immediate skin-to-skin contact and rooming-in, were not associated with an increased risk of newborn positivity. CONCLUSION: In this multinational cohort study, COVID-19 in pregnancy was associated with increased maternal and neonatal complications. Cesarean delivery was significantly associated with newborn COVID-19 diagnosis. Vaginal delivery should be considered the safest mode of delivery if obstetrical and health conditions allow it. Mother-to-child skin-to-skin contact, rooming-in, and direct breastfeeding were not risk factors for newborn COVID-19 diagnosis, thus well-established best practices can be continued among women with COVID-19 diagnosis.
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COVID-19 , Complicaciones Infecciosas del Embarazo , Complicaciones del Embarazo , Nacimiento Prematuro , Efectos Tardíos de la Exposición Prenatal , COVID-19/epidemiología , Prueba de COVID-19 , Niño , Estudios de Cohortes , Femenino , Humanos , Recién Nacido , Transmisión Vertical de Enfermedad Infecciosa , Atención Perinatal , Embarazo , Complicaciones Infecciosas del Embarazo/diagnóstico , Complicaciones Infecciosas del Embarazo/epidemiología , Resultado del Embarazo , Nacimiento Prematuro/epidemiologíaRESUMEN
BACKGROUND: Among nonpregnant individuals, diabetes mellitus and high body mass index increase the risk of COVID-19 and its severity. OBJECTIVE: This study aimed to determine whether diabetes mellitus and high body mass index are risk factors for COVID-19 in pregnancy and whether gestational diabetes mellitus is associated with COVID-19 diagnosis. STUDY DESIGN: INTERCOVID was a multinational study conducted between March 2020 and February 2021 in 43 institutions from 18 countries, enrolling 2184 pregnant women aged ≥18 years; a total of 2071 women were included in the analyses. For each woman diagnosed with COVID-19, 2 nondiagnosed women delivering or initiating antenatal care at the same institution were also enrolled. The main exposures were preexisting diabetes mellitus, high body mass index (overweight or obesity was defined as a body mass index ≥25 kg/m2), and gestational diabetes mellitus in pregnancy. The main outcome was a confirmed diagnosis of COVID-19 based on a real-time polymerase chain reaction test, antigen test, antibody test, radiological pulmonary findings, or ≥2 predefined COVID-19 symptoms at any time during pregnancy or delivery. Relationships of exposures and COVID-19 diagnosis were assessed using generalized linear models with a Poisson distribution and log link function, with robust standard errors to account for model misspecification. Furthermore, we conducted sensitivity analyses: (1) restricted to those with a real-time polymerase chain reaction test or an antigen test in the last week of pregnancy, (2) restricted to those with a real-time polymerase chain reaction test or an antigen test during the entire pregnancy, (3) generating values for missing data using multiple imputation, and (4) analyses controlling for month of enrollment. In addition, among women who were diagnosed with COVID-19, we examined whether having gestational diabetes mellitus, diabetes mellitus, or high body mass index increased the risk of having symptomatic vs asymptomatic COVID-19. RESULTS: COVID-19 was associated with preexisting diabetes mellitus (risk ratio, 1.94; 95% confidence interval, 1.55-2.42), overweight or obesity (risk ratio, 1.20; 95% confidence interval, 1.06-1.37), and gestational diabetes mellitus (risk ratio, 1.21; 95% confidence interval, 0.99-1.46). The gestational diabetes mellitus association was specifically among women requiring insulin, whether they were of normal weight (risk ratio, 1.79; 95% confidence interval, 1.06-3.01) or overweight or obese (risk ratio, 1.77; 95% confidence interval, 1.28-2.45). A somewhat stronger association with COVID-19 diagnosis was observed among women with preexisting diabetes mellitus, whether they were of normal weight (risk ratio, 1.93; 95% confidence interval, 1.18-3.17) or overweight or obese (risk ratio, 2.32; 95% confidence interval, 1.82-2.97). When the sample was restricted to those with a real-time polymerase chain reaction test or an antigen test in the week before delivery or during the entire pregnancy, including missing variables using imputation or controlling for month of enrollment, the observed associations were comparable. CONCLUSION: Diabetes mellitus and overweight or obesity were risk factors for COVID-19 diagnosis in pregnancy, and insulin-dependent gestational diabetes mellitus was associated with the disease. Therefore, it is essential that women with these comorbidities are vaccinated.
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COVID-19 , Diabetes Mellitus Tipo 1 , Diabetes Gestacional , Obesidad Materna , Adiposidad , Adolescente , Adulto , Índice de Masa Corporal , COVID-19/diagnóstico , COVID-19/epidemiología , Prueba de COVID-19 , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Gestacional/prevención & control , Femenino , Humanos , Insulina/uso terapéutico , Obesidad/complicaciones , Sobrepeso/complicaciones , Embarazo , Resultado del EmbarazoRESUMEN
BACKGROUND: It is unclear whether the suggested link between COVID-19 during pregnancy and preeclampsia is an independent association or if these are caused by common risk factors. OBJECTIVE: This study aimed to quantify any independent association between COVID-19 during pregnancy and preeclampsia and to determine the effect of these variables on maternal and neonatal morbidity and mortality. STUDY DESIGN: This was a large, longitudinal, prospective, unmatched diagnosed and not-diagnosed observational study assessing the effect of COVID-19 during pregnancy on mothers and neonates. Two consecutive not-diagnosed women were concomitantly enrolled immediately after each diagnosed woman was identified, at any stage during pregnancy or delivery, and at the same level of care to minimize bias. Women and neonates were followed until hospital discharge using the standardized INTERGROWTH-21st protocols and electronic data management system. A total of 43 institutions in 18 countries contributed to the study sample. The independent association between the 2 entities was quantified with the risk factors known to be associated with preeclampsia analyzed in each group. The outcomes were compared among women with COVID-19 alone, preeclampsia alone, both conditions, and those without either of the 2 conditions. RESULTS: We enrolled 2184 pregnant women; of these, 725 (33.2%) were enrolled in the COVID-19 diagnosed and 1459 (66.8%) in the COVID-19 not-diagnosed groups. Of these women, 123 had preeclampsia of which 59 of 725 (8.1%) were in the COVID-19 diagnosed group and 64 of 1459 (4.4%) were in the not-diagnosed group (risk ratio, 1.86; 95% confidence interval, 1.32-2.61). After adjustment for sociodemographic factors and conditions associated with both COVID-19 and preeclampsia, the risk ratio for preeclampsia remained significant among all women (risk ratio, 1.77; 95% confidence interval, 1.25-2.52) and nulliparous women specifically (risk ratio, 1.89; 95% confidence interval, 1.17-3.05). There was a trend but no statistical significance among parous women (risk ratio, 1.64; 95% confidence interval, 0.99-2.73). The risk ratio for preterm birth for all women diagnosed with COVID-19 and preeclampsia was 4.05 (95% confidence interval, 2.99-5.49) and 6.26 (95% confidence interval, 4.35-9.00) for nulliparous women. Compared with women with neither condition diagnosed, the composite adverse perinatal outcome showed a stepwise increase in the risk ratio for COVID-19 without preeclampsia, preeclampsia without COVID-19, and COVID-19 with preeclampsia (risk ratio, 2.16; 95% confidence interval, 1.63-2.86; risk ratio, 2.53; 95% confidence interval, 1.44-4.45; and risk ratio, 2.84; 95% confidence interval, 1.67-4.82, respectively). Similar findings were found for the composite adverse maternal outcome with risk ratios of 1.76 (95% confidence interval, 1.32-2.35), 2.07 (95% confidence interval, 1.20-3.57), and 2.77 (95% confidence interval, 1.66-4.63). The association between COVID-19 and gestational hypertension and the direction of the effects on preterm birth and adverse perinatal and maternal outcomes, were similar to preeclampsia, but confined to nulliparous women with lower risk ratios. CONCLUSION: COVID-19 during pregnancy is strongly associated with preeclampsia, especially among nulliparous women. This association is independent of any risk factors and preexisting conditions. COVID-19 severity does not seem to be a factor in this association. Both conditions are associated independently of and in an additive fashion with preterm birth, severe perinatal morbidity and mortality, and adverse maternal outcomes. Women with preeclampsia should be considered a particularly vulnerable group with regard to the risks posed by COVID-19.
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COVID-19/complicaciones , Preeclampsia/virología , Complicaciones del Embarazo/virología , SARS-CoV-2 , Adulto , COVID-19/epidemiología , Femenino , Humanos , Hipertensión Inducida en el Embarazo/virología , Estudios Longitudinales , Preeclampsia/epidemiología , Embarazo , Resultado del Embarazo , Nacimiento Prematuro/epidemiología , Estudios Prospectivos , Factores de RiesgoRESUMEN
Background: ExtraUterine Growth Restriction (EUGR) is a common definition for in-hospital growth failure of very preterm infants. Wide heterogeneity is found in definitions and anthropometric charts used to describe EUGR. Aim: We aim to compare two traditional definitions of EUGR with a newly proposed one, based on a longitudinal evaluation, that takes into account the physiological period of fluid loss after birth. We also wish to detect which definition could better predict neurodevelopmental impairment at 24 months of corrected age (CA). Methods: A total of 195 infants with GA < 30 were included. EUGR was calculated both for weight and head circumference (HC). Cross-sectional EUGR was defined as measurements < 10th percentile at discharge; longitudinal EUGR was defined as Δz-score < -1 between birth and discharge measurements. The new longitudinal "post-loss" EUGR definition was proposed as Δz-score < -1 between measurements taken at 14-21 days of life and at discharge. Longitudinal postnatal Intergrowth-21st charts specifically built on preterm infants were used. Association with major and minor neurodevelopmental impairment at 24-month CA was assessed for each definition. K coefficient and ROC curve were evaluated. Results: Longitudinal "post-loss" definition of EUGR for HC is the one predicting minor neurodevelopmental impairment at the multivariate analysis (OR = 3.94), and it is also associated with a worse General Quotient. The chosen cut-off (Δz-score < -1) is the proper one. Conclusion: HC in-hospital growth could be a more accurate tool than weight to predict neurodevelopmental outcomes and especially minor neurological impairment. Longitudinal "post-loss" definition of EUGR assessed on longitudinal charts for preterm infants could be the most appropriate definition from the methodological, clinical, and prognostic point of view.
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Adequate nutrition is fundamental to neonatal survival and short-term outcomes, but it also has long-term consequences on quality of life and neurologic development of preterm infants. Donkey milk has been suggested as a valid alternative for children allergic to cows' milk proteins, due to its biochemical similarity to human milk; we, hence, hypothesized that donkey milk could be a suitable basis for developing an innovative human milk fortifier for feeding preterm infants. The aim of the current study was to extend the findings and to evaluate the neurodevelopmental outcomes at 18 months of corrected age of the infants enrolled in the clinical trial named "Fortilat". Infants born ≤1500 g and <32 weeks of gestational age were randomized to receive either a combination of bovine milk-based multicomponent fortifier and protein supplement or a combination of a novel multicomponent fortifier and protein supplement derived from donkey milk. The followed fortification protocol was the same for the two groups and the two diets were designed to be isoproteic and isocaloric. All infants enrolled were included in a developmental assessment program. The neurodevelopmental assessment was performed at 18 ± 6 months of corrected age. Minor and major neurodevelopmental impairment and General Quotient (GQ) at the Griffiths-II Mental Development Scale were considered. The GQ was considered both in continuous and as two classes: lower than and higher than (or equal to) a defined cutoff (GQcl). The difference in GQ and GQcl between the two arms was estimated using Mann-Whitney-Wilcoxon test or Fischer exact test, respectively, on the assumption of casual loss at follow-up. A further analysis was performed using generalized linear models. There were 103 children (bovine milk-derived fortifier arm = 54, donkey milk-derived fortifier arm = 49) included for the neurodevelopmental follow-up. All observations were included in the interval of 18 ± 6 months of corrected age. No significant difference was observed between the two arms in the incidence of neurologic sequelae and the GQs were similar in the two arms. Our results demonstrated no difference for the donkey milk-derived fortifier compared to standard bovine-derived fortifier regarding long-term neurodevelopmental outcomes.
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Alimentos Fortificados , Recien Nacido Prematuro/crecimiento & desarrollo , Recién Nacido de muy Bajo Peso/crecimiento & desarrollo , Leche , Trastornos del Neurodesarrollo/epidemiología , Animales , Bovinos , Equidae , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Lactante , Recién Nacido , Modelos Lineales , Masculino , Pruebas de Estado Mental y Demencia , Trastornos del Neurodesarrollo/prevención & control , Resultado del TratamientoRESUMEN
Human milk fortification is a routine clinical practice for feeding preterm infants. We hypothesized that donkey milk can be a suitable basis for developing an innovative human milk fortifier. Our randomized controlled single-blind clinical trial, named "Fortilat", evaluated the feeding tolerance, growth and clinical short-term outcomes in a population of preterm infants fed with a novel multi-component fortifier and a protein concentrate derived from donkey milk. The aim of the current study is to extend the previous findings and to evaluate the auxological outcomes of the infants enrolled in the "Fortilat" trial at 18 months of age. In the previous trial "Fortilat", the fortification protocol followed was the same for the two groups, and the two diets were designed to be isoproteic and isocaloric. All infants enrolled in the trial were included in a premature infant developmental evaluation program consisting of hospital visits at 40 ± 1 weeks of postmenstrual age, and at 6, 12 and 18 months of corrected age. Weight, head circumference and length were expressed in z-score using neonatal Intergrowth21st and INeS charts at birth, and WHO 0-5 years growth charts at 18 months. 122 children (Bovine-arm = 62, Donkey-arm = 60) were included in this study. All the observations were recorded in the interval of 18 ± 3 months of the correct age. The two groups did not differ for head circumference, length or weight at 18 months of age. Our data show that fortifiers derived from donkey milk had not different long term auxological outcomes of standard bovine-derived fortifier, but the new donkey milk fortifier was well tolerated in our population.