Cerebro-placental and umbilico-cerebral ratios in uncomplicated monochorionic twins: Longitudinal references and comparison with singletons.

OBJECTIVES: Monochorionic twins (MC) are at high risk of adverse outcomes and Doppler investigation of umbilical and cerebral flows is mandatory for their surveillance. The cerebro-placental (CPR) and umbilico-cerebral (UCR) ratios are considered non-invasive measures of fetal adaptation to hypoxemia. We aimed to provide longitudinal references for CPR and UCR from 16 to 37 weeks of gestation that are specific for MC twins, and compare these with singleton charts. METHODS: Longitudinal study of a cohort of consecutive uncomplicated MC twin pregnancies monitored at our unit from 2010 to 2018. The estimated centile curves were obtained estimating the median with fractional polynomials by a multilevel model and the external centiles through the residuals. The comparison with singletons references was made through graphic evaluation. RESULTS: One-hundred-fifty-two MC pregnancies were included with a median of 10 longitudinal ultrasounds each. References for CPR and UCR in function of gestational age are presented. Compared to singletons, MC twins showed an earlier and greater circulatory redistribution with lower CPR and higher UCR median values. CONCLUSIONS: MC twin-specific references for CPR and UCR suitable for serial monitoring are presented. The comparison with singleton references demonstrates substantial differences in the hemodynamic balance that must be considered when interpreting findings in MC twins.

Epigenome Wide Association and Stochastic Epigenetic Mutation Analysis on Cord Blood of Preterm Birth.

Preterm birth (PTB) can be defined as the endpoint of a complex process that could be influenced by maternal and environmental factors. Epigenetics recently emerged as an interesting field of investigation since it represents an important mechanism of regulation. This study evaluates epigenetic impact of preterm birth on DNA methylation. Genome-wide DNAm was measured using the Illumina 450K array in cord blood samples obtained from 72 full term and 18 preterm newborns. Lymphocyte composition was calculated based on specific epigenetic markers that are present on the 450k array. Differential methylation analysis was performed both at site and region level; moreover, stochastic epigenetic mutations (SEMs) were also evaluated. The study showed significant differences in blood cell composition between the two groups. Moreover, after multiple testing correction, statistically significant differences in DNA methylation levels emerged between the two groups both at site and region levels. Results obtained were compared to those reported by previous EWAS, leading to a list of more consistent genes associated with PTB. Finally, the SEMs analysis revealed that the burden of SEMs resulted significantly higher in the preterm group. In conclusion, PTB resulted associated to specific epigenetic signatures that involve immune system. Moreover, SEMs analysis revealed an increased epigenetic drift at birth in the preterm group.

A Novel Donkey Milk-derived Human Milk Fortifier in Feeding Preterm Infants: A Randomized Controlled Trial.

OBJECTIVES: The purpose of the present randomized controlled clinical trial was to compare the use of donkey milk-derived fortifier (DF) with commercial bovine milk-derived fortifier (BF) in very preterm or very-low-birth-weight newborns, in terms of feeding tolerance. METHODS: This trial included 156 newborns born at <32 weeks of gestational age and/or with a birth weight ≤1500 g. Newborns were randomized 1:1 to receive enteral feeding with either a BF-arm, or a new, DF-arm for 21 days. The fortification protocol was the same for both study arms, and the 2 diets were designed to be isoproteic and isocaloric. Feeding tolerance was assessed by a standardized protocol. RESULTS: The risk of feeding intolerance tended to be lower in DF-arm than in BF-arm, with a relative risk reduction of 0.63 (95% confidence interval: -0.29, +0.90). The mean number of episodes per newborn of feeding intolerance and feeding interruptions (any duration) were consistently lower in the DF-arm than in the BF-arm. Episodes of bilious gastric residuals and vomiting were significantly lower in the DF-arm. Time needed to reach full enteral feeding (150 mL ·â€Škg ·â€Šday) and daily weight increase between the first day of exclusive enteral feeding (ie, without administering intravenous fluids) and discharge were similar in the BF- and DF-arms. CONCLUSIONS: These results suggest that DF improve feeding tolerance when compared with standard bovine-derived fortifiers, with a similar auxological outcome.

Nutritional adequacy of a novel human milk fortifier from donkey milk in feeding preterm infants: study protocol of a randomized controlled clinical trial.

BACKGROUND: Fortification of human milk is a standard practice for feeding very low birth weight infants. However, preterm infants often still experience suboptimal growth and feeding intolerance. New fortification strategies and different commercially available fortifiers have been developed. Commercially available fortifiers are constituted by a blend of ingredients from different sources, including plant oils and bovine milk proteins, thus presenting remarkable differences in the quality of macronutrients with respect to human milk. Based on the consideration that donkey milk has been suggested as a valid alternative for children allergic to cow's milk proteins, due to its biochemical similarity to human milk, we hypothesized that donkey milk could be a suitable ingredient for developing an innovative human milk fortifier. The aim of the study is to evaluate feeding tolerance, growth and clinical short and long-term outcomes in a population of preterm infants fed with a novel multi-component fortifier and a protein concentrate derived from donkey milk, in comparison to an analogous population fed with traditional fortifier and protein supplement containing bovine milk proteins. METHODS: The study has been designed as a randomized, controlled, single-blind clinical trial. Infants born <1500 g and <32 weeks of gestational age were randomized to receive for 21 days either a combination of control bovine milk-based multicomponent fortifier and protein supplement, or a combination of a novel multicomponent fortifier and protein supplement derived from donkey milk. The fortification protocol followed is the same for the two groups, and the two diets were designed to be isoproteic and isocaloric. Weight, length and head circumference are measured; feeding tolerance is assessed by a standardized protocol. The occurrence of sepsis, necrotizing enterocolitis and adverse effects are monitored. DISCUSSION: This is the first clinical study investigating the use of a human milk fortifier derived from donkey milk for the nutrition of preterm infants. If donkey milk derived products will be shown to improve the feeding tolerance or either of the clinical, metabolic, neurological or auxological outcomes of preterm infants, it would be an absolute innovation in the field of feeding practices for preterm infants. TRIAL REGISTRATION: ISRCTN - ISRCTN70022881 .

Effect of maternal age, height, BMI and ethnicity on birth weight: an Italian multicenter study.

AIM: To assess the effect of maternal age, height, early pregnancy body mass index (BMI) and ethnicity on birth weight. SUBJECTS AND METHODS: A cross-sectional study was conducted on more than 42,000 newborns. Ethnicity was defined by maternal country of birth or, when missing (<0.6% of records), by citizenship. The effect of maternal characteristics on birth weight was evaluated with general linear models. RESULTS: Maternal height and BMI, although not age, significantly affected birth weight. Among Italian babies, 4.7% of newborns were classified as appropriate-for-gestational age (AGA) (birth weight between the 10th and the 90th centile) according to the country-specific Italian Neonatal Study (INeS) charts and were re-classified as either large-(LGA) (birth weight >90th centile) or small-(SGA) (birth weight <10th centile) for gestational age (GA) after adjustment for maternal characteristics. On the contrary, 1.6% of Italian newborns were classified as SGA or LGA according to the INeS charts and re-classified as AGA after adjustment. Maternal ethnicity had a significant impact on birth weight. Specifically, babies born to Senegalese mothers were the lightest, whilst babies born to Chinese mothers were the heaviest. CONCLUSIONS: Maternal height and early pregnancy BMI, should be considered in the evaluation of birth weight. The effect of ethnicity suggests the appropriateness of ethnic-specific charts. Further studies are necessary to determine if changes in birth weight classification, may translate into improved detection of subjects at risk of adverse outcomes.

A mechanistic approach to tracing anthropometric charts: the extended mechanistic growth function method.

OBJECTIVES: The Extended Mechanistic Growth Function (EMGF) method (Clementi et al. [1999]: Am J Med Genet 87:317-323) is a possible alternative to the Cole and Green LMS method ([1992] Stat Med 11:1305-1319) to construct cross-sectional anthropometric charts. It differs from the technique used by Kuczmarski et al. ([2002]: Vital Health Stat 11:1-190) to trace the CDC growth charts in that all centiles are simultaneously fitted with a single function. The aim of this study is to show how an EMGF model can be designed. METHODS: To illustrate the structure and properties of the EMGF method, the data of the Italian Neonatal Study (Bertino et al. [2010]: J Pediatr Gastroenterol Nutr 51:353-361) were analyzed. The dataset included the birth weight of 45,272 single liveborn babies with gestational ages ranging from 23 to 42 weeks. The EMGF method consists of three steps. In the preliminary step, selected age-dependent raw centiles of the anthropometric trait are computed. In the smoothing step, all centiles are simultaneously fitted with a growth function extended with the inclusion of a few extra parameters. In the transformation step, estimates of the age-dependent L (skewness), M (median), and S (coefficient of variation) parameters are derived. RESULTS: A four-parameter generalized logistic function, extended with five parameters to model between-sex differences, distance between centiles and their slope, was found to fit the raw centiles of birth weight distribution with a residual standard deviation of 51.3 g. CONCLUSIONS: The EMGF method represents a bridge to link cross-sectional and longitudinal studies and allows us to identify milestones of the median growth in a population in the same way used for individual profiles.

Systematic review of the methodological quality of studies designed to create neonatal anthropometric charts.

UNLABELLED: Babies all over the world are assessed at birth using neonatal anthropometric charts as a matter of clinical routine. This systematic review evaluated the methodological quality of studies designed to create neonatal anthropometric charts and to highlight features in the charts that could affect clinical decision-making and comparisons between populations. The variety and quality of available charts could affect how newborns at risk are identified, together with the indications for treatment, especially nutritional interventions. CONCLUSION: The studies that generated the charts currently recommended for clinical use have major methodological limitations and international and regional comparisons are very difficult.

Evaluation of the galactogogue effect of silymarin on mothers of preterm newborns (<32 weeks).

Hypogalactia has a relative high frequency in women having delivered preterm infants, who often have difficulties in maintaining a sufficient production of milk for their infants' needs over prolonged periods of time. Recent studies have shown a potential galactogogue effect of silymarin on milk production in animal models (cows and rats) and in humans (mothers of term newborns); nonetheless, none of the studies conducted on humans consisted of double-blind randomized clinical trials and no data are available concerning mothers who delivered preterm infants. The aim of our study was to assess the efficacy of silymarin (BIO-C®) as galactogogue and its tolerability in mothers who delivered preterm infants. We enrolled 50 mothers at 10±1 days post-partum who had delivered infants at ® and placebo arms. No adverse events were observed in the 2 arms among mothers and infants, and silymarin and its metabolites were not detectable in the analyzed human milk samples. Further investigation on specific patient groups affected by hypogalactia, defined according to stricter criteria, should be planned to assess the efficacy of the product in increasing milk production.

Age-specific reference values for serum FSH and estradiol levels throughout the reproductive period.

High serum day 3 FSH levels are associated with poor ovarian reserve and reduced fertility, but the interpretation of FSH values according to age is still not univocal. The purpose of this study was to determine age-dependent reference values in women with regular menstrual cycles and FSH as a guide for specialists. The study was performed at the Department of Mother-Infant of a University-based tertiary care centre. One-hundred ninety-two healthy normal menstruating women were recruited for the study. All patients attended the department on menstrual cycle day 3 for a blood sample for FSH and estradiol determination. A linear relationship between FSH or estradiol serum levels and age was observed. The FSH level increased by 0.11 IU for every year of age (1 IU for every 9 years of age). The values of FSH and estradiol corresponding to the 5th, 25th, 50th, 75th, 95th centiles for any specific age have been calculated. Serum FSH levels need to be interpreted according to age-dependent reference values. Serum FSH levels on 95th centile for any age may represent a warning sign for reduced ovarian reserve.

Reference values in ovarian response to controlled ovarian stimulation throughout the reproductive period.

Abstract The age-related decline in ovarian response to gonadotropins has been well known since the beginning of ovarian stimulation in IVF cycles and has been considered secondary to the age-related decline in ovarian reserve. The objective of this study was to establish reference values and to construct nomograms of ovarian response for any specific age to gonadotropins in IVF/ICSI cycles. We analyzed our database containing information on IVF cycles. According to inclusion and exclusion criteria, a total of 703 patients were selected. Among inclusion criteria, there were regular menstrual cycle, treatment with a long GnRH agonist protocol and starting follicle-stimulating hormone (FSH) dose of at least 200 IU per day. To estimate the reference values of ovarian response, the CG-LMS method was used. A linear decline in the parameters of ovarian response with age was observed: the median number of oocytes decreases approximately by one every three years, and the median number of follicles >16 mm by one every eight years. The number of oocytes and growing follicles corresponding to the 5th, 25th, 50th, 75th and 95th centiles has been calculated. This study confirmed the well known negative relationship between ovarian response to FSH and female ageing and permitted the construction of nomograms of ovarian response.