PIGA Mutations Can Mimic Neonatal Hemochromatosis.

Neonatal hemochromatosis (NH), one of the most common causes of liver failure in the neonate, often causes fetal loss or death during the neonatal period. Most cases are thought to be due to gestational alloimmune disease; however, other rare causes have been reported. NH is generally considered congenital and familial but not heritable. We present an infant diagnosed with NH whose clinical course differed significantly from that of most NH cases: at 11 months of age he had normal levels of liver enzymes, ferritin, and bilirubin, and normal neurodevelopment. This term male infant was born with a history of intrauterine growth restriction, oligohydramnios, and pericardial effusion. On day of life 1, he had hyperbilirubinemia and transaminitis; on day of life 3, ferritin was elevated; and on day of life 9, an MRI revealed iron deposits in the liver and renal cortex. Phenotypic features prompted a genetics consult. Whole-exome sequencing revealed a variant in the phosphatidylinositol glycan biosynthesis class A protein (PIGA) gene. Germ-line PIGA mutations are generally thought to be lethal in utero; however, there are reports of infants with PIGA mutations associated with dysmorphic features, neurologic manifestations, biochemical perturbations, and systemic iron overload; development can be normal up to 6 months of age. Because of the differences between infants with NH versus PIGA germ-line mutations in inheritance, prognosis, and natural history of disease, we propose that PIGA gene testing should be considered when evaluating newborns who present with NH.

Milk protein-based infant formula containing rice starch and low lactose reduces common regurgitation in healthy term infants: a randomized, blinded, and prospective trial.

OBJECTIVE: Spit-up (regurgitation) reduction with prethickened milk protein-based infant formulas containing rice starch has been clinically demonstrated in infants with heavy spit-ups but not in otherwise healthy normal infants with common spit-ups. The objective of this study was to evaluate growth, gastrointestinal tolerance, and efficacy to reduce common spit-up in normal, healthy term infants fed an investigational rice starch prethickened lactose-free milk protein-based infant formula. METHODS: This double-blind, randomized, parallel study evaluated the investigational rice starch prethickened lactose-free (low lactose < 100 mg/L) milk protein-based infant formula compared to a standard, commercially available, iso-nutrient, lactose-containing (100% of carbohydrate) milk-based infant formula (control) for growth and gastrointestinal tolerance in healthy term infants (n = 132/group) fed from 14 ± 3 days to 112 days of age. Data were classified and analyzed as evaluable (EV; subjects completing study per protocol) or intent-to-treat data (ITT; all subjects with available data). RESULTS: Growth as indicated by weight gain (primary variable) and formula intake were not significantly different (p > 0.05) between feeding groups (EV or ITT). Though both formulas were well tolerated, spit-up frequency was significantly lower (p < 0.05) in the rice versus control group by 53% at 28 days of age, 54% at 56 days, 48% at 84 days, and 32% at 112 days (EV). Importantly, infants in the rice group were 1.6 to 1.8 times more likely to report zero spit-up than infants in the control group. The rice group also had higher percentages of soft and yellow stools. CONCLUSIONS: The rice starch prethickened lactose-free milk protein-based formula (rice) supported normal growth and safe use as the sole source of feeding for normal infants over the first 4 months of life. The rice formula was efficacious in providing a clinically relevant reduction of spit-up frequency in otherwise healthy term infants.

Factors that affect the postnatal increase in superior mesenteric artery blood flow velocity in very low birth weight preterm infants.

OBJECTIVE: To identify factors related to the postnatal increase in superior mesenteric artery blood flow velocity (SMA BFV). STUDY DESIGN: SMA BFV was measured in 35 infants (birth weight 1047±246 g) on day of life (DOL) 1, 3, 5, 7 10 and 14. Latent curve modeling (LCM) was used to measure the longitudinal change in BFV for each subject, and the correlation between changes in BFV and baseline values. Non-parametric correlations were calculated between BFV and variables previously reported to be related to SMA BFV. RESULTS: There was significant variability in SMA BFV on DOL 1, a significant increase from DOL 1-14, and significant variability in the postnatal increase. Infants with higher enteral feeding volumes had greater increases, while infants receiving positive pressure ventilation or hyperalimentation had lower increases. CONCLUSIONS: Several clinical factors affect the postnatal increase in SMA BFV. The use of LCM is useful in longitudinal studies of very low birth weight (VLBW) infants, who are clinically and demographically heterogeneous.

Effects of maternal magnesium sulfate administration on intestinal blood flow velocity in preterm neonates.

BACKGROUND: Antenatal MgSO4 administration is used extensively as a tocolytic agent and to treat preeclampsia. Various effects on the fetus and newborn have been reported, and MgSO4 has well-documented vasoactive effects. OBJECTIVE: To determine if antenatal MgSO4 administration affects intestinal blood flow velocity in newborn preterm infants. METHODS: Peak, mean and end-diastolic velocities in the superior mesenteric artery were measured on day 1 of life. Maternal medical records were reviewed to identify infants whose mothers had been administered MgSO4 for preterm labor or preeclampsia within 24 h of delivery. RESULT: Fifty-six infants were studied: 27 were exposed and 29 were not exposed to antenatal MgSO4. Mean birth weight (1,371 ± 349 and 1,401 ± 469 g, respectively), gestational age (29.7 ± 2.0 and 30.0 ± 2.9 weeks, respectively) and infant hemodynamic and clinical variables (other than clinical indication for antenatal MgSO4 administration) were similar between groups. There were no significant differences between the exposed and unexposed groups in intestinal blood flow velocities. For the exposed group, however, there was a significant negative correlation between mean velocity and the number of hours from birth to the time superior mesenteric artery blood flow velocity measurements were made (p = 0.002); there was no correlation for the unexposed group (p = 0.852). CONCLUSION: Group mean values indicate that antenatal exposure to MgSO4 does not significantly affect intestinal blood flow velocity in newborn preterm infants. However, the significant negative relationship between mean blood flow velocity and time from birth to blood flow velocity measurement in exposed infants suggests that there may be measurable effects of MgSO4 exposure within the hours immediately after birth. Trials that prospectively evaluate the development of intestinal blood flow velocities are needed to further clarify potential effects of antenatal MgSO4 on the gastrointestinal tract of preterm infants.

Maternal nativity as a risk factor for gastroschisis: a population-based study.

BACKGROUND: The prevalence of gastroschisis is increasing in many parts of the world, although the etiology is largely unexplained. Young maternal age has been the only consistently identified, strong risk factor. The objective of this study was to examine the role of maternal nativity in relation to other suspected risk factors for gastroschisis in Florida. METHODS: We conducted a retrospective cohort study of singleton infants born in Florida from 1998-2003. Gastroschisis cases were identified from the Florida Birth Defects Registry. Demographic and perinatal data were obtained from birth records. Multivariable Poisson regression was used to estimate adjusted prevalence ratios (PRs) and 95% confidence intervals (CIs) for each factor of interest. RESULTS: The 6-year birth prevalence of gastroschisis was 3.26 per 10,000 live births, and the annual rate increased 41% during the study period. In addition to maternal age and marital status, maternal race/ethnicity and nativity were significantly associated with the risk of delivering an infant with gastroschisis. Compared with non-Hispanic white women, non-Hispanic black women had the lowest risk of delivering an infant with gastroschisis (PR, 0.19; 95% CI, 0.13-0.26), followed by Hispanic women (PR, 0.60; 95% CI, 0.43-0.83). Women born outside the United States were significantly less likely than U.S.-born women to deliver an infant with gastroschisis (PR, 0.59; 95% CI, 0.41-0.86). CONCLUSIONS: Although young maternal age remains a strong significant risk factor for gastroschisis in Florida, other factors such as maternal race/ethnicity and nativity could be important in explaining the increasing prevalence of gastroschisis.

Right tracheal bronchus in an infant with congenital diaphragmatic hernia.

Neonates with congenital diaphragmatic hernia (CDH) often have other major malformations. Anatomic airway anomalies associated with CDH include congenital stenosis, pulmonary hypoplasia, and abnormal bronchial branching. We describe an infant with CDH who, after developing recurrent upper-lobe atelectasis, was found to have a right tracheal bronchus. This clinically significant anomaly can have important and potentially preventable adverse consequences.

Longitudinal measurements of bone status in preterm infants.

BACKGROUND: Quantitative ultrasound measurement of the speed of sound (SOS) through bone has been investigated as a means of assessing bone status in preterm infants. Few studies report longitudinal measurements. OBJECTIVE: To assess longitudinal changes in bone SOS in preterm infants. METHODS: Sixty preterm infants with gestational ages of < 33 weeks and with birth weight appropriate for gestational age (AGA), and 48 healthy, term AGA infants were enrolled. SOS measurements of the tibia were made within the first week of life in the preterm infants, and within the first 72 hours of life in the term infants. During their hospital stay, weekly measurements of tibial SOS were made in 29 of the preterm infants, who were divided into three gestational age groups: Group 1: 24-26 weeks (n = 8), Group 2: 27-29 weeks (n = 9), and Group 3: 30-32 weeks (n = 12). RESULTS: The median SOS value for the 60 newborn preterm infants was significantly lower than that for the 48 newborn term infants (2,924 versus 3,036 m/sec, p < 0.001). At each time point, SOS values for each of the preterm infant gestational age groups were significantly lower than the term newborn infant SOS values. SOS values decreased significantly over time for the entire cohort of 29 preterm infants (p < 0.001), and for Groups 1 (p = 0.015) and 2 (p = 0.003). At several time points, there was a significant negative correlation between serum alkaline phosphatase levels and SOS values, and a significant positive correlation between serum phosphorus levels and SOS values. CONCLUSION: SOS measurements of the tibia decline during hospitalization in preterm infants, suggesting a progressive loss of bone strength. Longitudinal measurements of bone SOS in combination with serum alkaline phosphatase and serum phosphorus levels may identify infants at risk of developing osteopenia of prematurity.

Nutrition for preterm infants after hospital discharge.

Preterm infants accrue significant nutrient deficits during hospitalization, and at the time of discharge most VLBW preterm infants have moderate to severe growth failure. Infants with significant morbidities and infants with ELBW have more severe growth failure since they regain birth weight at a later age, and they gain weight more slowly. Catch-up growth accelerates after hospital discharge. The rates of catch-up growth vary according to many factors including birth weight, gestational age, parental size, adequacy of intrauterine growth, neurologic impairment, clinical course, and nutrition. Most catch-up growth occurs within the first 2 to 3 years of life; however, compensatory catch-up growth may continue into adolescence and adulthood. Despite evidence of ongoing catch-up growth, the mean growth measurements of children and adults who were born preterm and with VLBW are lower than their term-born peers. Accelerated rates of catch-up growth are associated with better neurodevelopmental outcomes. Inadequate head circumference growth, in particular, may have long-term prognostic significance for later neurodevelopment in preterm infants. Nutrient-enriched formulas that provide 22 kcal/oz are often prescribed for VLBW preterm infants after hospital discharge. Several studies have reported that preterm infants fed the enriched versus standard term infant formulas have greater rates of catch-up growth during the first year of life, including greater increases in head circumference. The nutrient-enriched formulas appear to be of particular benefit for male infants. There is less information regarding the nutrient needs of breast-fed infants after hospital discharge. However, several studies have demonstrated that preterm infants fed unfortified human milk after discharge have growth rates and bone mass that are lower than formula-fed infants during infancy. The use of fortified human milk, or alternate feedings with a nutrient-enriched formula may be useful for breast-fed infants who have delays in catch-up growth. Additional studies are needed to determine whether enriched feedings might be of particular benefit for preterm infants who are at greater risk for postnatal growth failure, including infants born SGA, or with extremely low birth weights, intrauterine growth restriction, or chronic conditions such as bronchopulmonary dysplasia. The potential effect of nutritional programming on long-term outcomes of preterm infants also requires further investigation.

The hemodynamic effects of neonatal patent ductus arteriosus shunting on superior mesenteric artery blood flow.

OBJECTIVE: To determine if the ratio of the pulsatility index (PI) of the left pulmonary artery to the PI of the descending aorta, the Rp/Rs index, correlates with the degree of ductal steal from the intestine in neonates with a patent ductus arteriosus (PDA). STUDY DESIGN: Echocardiograms and Doppler studies of the superior mesenteric artery (SMA) were performed in 41 neonates less than 35 weeks gestational age with a hemodynamically significant PDA (hsPDA). RESULTS: There was a significant negative correlation between the Rp/Rs index and the SMA PI after controlling for ductal size (r=-0.476, p<0.008). CONCLUSIONS: The Rp/Rs index can be used as an indicator of ductal steal on intestinal blood flow. The Rp/Rs index may be a useful adjunct to existing and new techniques for improving early assessment and treatment of hsPDA, and for evaluating the effects of hsPDA on systemic organs.

Dietary nucleotides and intestinal blood flow velocity in term infants.

OBJECTIVES: Two previous studies have shown that the addition of nucleotides to single feedings of formula is associated with increased 90-minute postprandial superior mesenteric artery (SMA) blood flow velocity (BFV). To assess the effect of chronic feeding of nucleotide-supplemented formula, we measured pre- and postprandial SMA BFV in term infants fed formula with or without added nucleotides for 4 weeks. METHODS: At 1 week of age, healthy, term infants were randomized to receive formula with added nucleotides (NT+), or formula without added nucleotides (NT-) from age 1 to 5 weeks. When the infants were 5 weeks of age, SMA BFV was measured by Doppler ultrasound 15 minutes before the assigned feeding (baseline) and 30, 60, and 90 minutes after the start of feeding. A reference group of human milk-fed infants was studied before and after breast feeding. RESULTS: Thirty formula-fed (NT+ = 17; NT- = 13) and 10 human milk-fed infants were studied. Baseline BFV was similar among the three groups. BFV increased in each group from baseline to 30 minutes after initiation of feeding and progressively declined from 30 to 90 minutes in infants fed NT- formula or human milk. In infants fed NT+ formula, BFV decreased between 30 and 60 minutes. However, from 60 to 90 minutes, velocity was unchanged or increased. At 90 minutes, mean and peak systolic velocities were significantly greater in the NT+ group than the NT- group (P < 0.001). CONCLUSIONS: These data agree with those of previous studies showing increased 90-minute postprandial SMA BFV after a feeding with nucleotide-supplemented formula. The clinical significance of these findings is unknown.

The use of quantitative ultrasound in assessing bone status in newborn preterm infants.

OBJECTIVE: Quantitative ultrasound is increasingly used to assess bone status in adults and children; however, few studies have been carried out in neonates. Our objective was to determine if tibial bone speed of sound (SOS) correlates with gestational age and birth anthropometrics, and if bone SOS is related to maternal factors. STUDY DESIGN: We prospectively studied 95 preterm infants to assess factors related to bone status as measured by quantitative ultrasound. RESULTS: We found significant (p< or =0.001) positive correlations between SOS and gestational age, birth weight, length, head circumference and tibial length. There was no significant relationship between SOS and prenatal steroid use, gestational diabetes, pre-eclampsia, race or parity. CONCLUSIONS: Quantitative ultrasound is an easy to use and inexpensive tool for assessing bone status in preterm neonates. Tibial SOS correlated with gestational age and birth anthropometrics, and was not related by few maternal factors.

Advances in nutritional modifications of infant formulas.

Modifications to infant formulas are continually being made as the components of human milk are characterized and as the nutrient needs of diverse groups of infants are identified. Formulas with long-chain polyunsaturated fatty acids added in amounts similar to those in human milk have recently become available in the United States; infants fed these formulas or human milk have higher tissue concentrations of long-chain polyunsaturated fatty acids and reportedly have better visual acuity than do infants fed nonsupplemented formulas. Selenium, an important antioxidant, is present in higher concentrations in human milk than in non-fortified cow milk-based formula, and the selenium intakes of infants fed nonfortified formulas are reported to be at or below recommended levels. Blood selenium concentrations and plasma glutathione peroxidase activity are higher in infants fed selenium-supplemented formulas or human milk than in infants fed non-fortified formulas. Nucleotides and their related products play key roles in many biological processes. Although nucleotides can be synthesized endogenously, they are considered "conditionally essential." Nucleotide concentrations in human milk are higher than in unsupplemented cow milk-based formulas, and studies in animals and human infants suggest that dietary nucleotides play a role in the development of the gastrointestinal and immune systems. Formulas for preterm infants after hospital discharge are designed to meet the needs of a population in whom growth failure is common. Several studies have shown that preterm infants fed nutrient-enriched formulas after hospital discharge have higher rates of catch-up growth than do infants fed standard term-infant formulas.

The effects of dietary nucleotides on intestinal blood flow in preterm infants.

Nucleotides (NT) are reported to affect development of the immune and gastrointestinal systems, and they are currently added to most term infant formulas. In the present study, dietary NT effects on superior mesenteric artery blood flow were investigated. Formula-fed preterm infants were studied once with a 20 kcal/oz. term infant formula containing 80.6 mg/L of NT (NT+), and once with the same formula with no added NT (NT-) (n = 20, gestational age 28.0 +/- 2.2 wk). A reference group of preterm infants fed human milk was also studied (n = 20, gestational age 29.0 +/- 1.6 wk). Superior mesenteric artery blood flow velocities (BFV) were measured by Doppler ultrasound 15 min before and 30, 60, and 90 min after the start of the feed. BFV rose in all infants from baseline to 30 min after feed initiation, and progressively declined thereafter in infants fed NT- or human milk. However, NT+ feedings were associated with a minimal change in BFV between 60 and 90 min. As a result, the difference in blood flow velocities between baseline and 90 min was significantly greater with the NT+ versus the NT- feedings for the mean, peak systolic, and end diastolic velocities (p = 0.03, 0.05, and 0.03, respectively). BFV after the NT- and human milk feedings were similar. These data suggest that orally administered NT are associated with effects on the intestinal vasculature.

Maternal dietary docosahexanoic acid content affects the rat pup auditory system.

Previous studies of the effects of dietary docosahexanoic acid (DHA), 22:6n3, on neurodevelopment have focused mainly on visual-evoked potentials and indices of visual activity, measures that may be confounded by effects on the retina rather than on neural pathways. We investigated the effect of pre- and postnatal maternal dietary DHA content on auditory brainstem conduction times (ABCTs), the appearance of the auditory startle reflex (ASR), and 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) activity in brainstem homogenates. Timed pregnant dams were fed, beginning on day 2 of gestation and throughout lactation, a purified diet containing one of three levels of DHA (0, 1, or 3% of total fatty acids, or 0, 0.4 or 1.2% of total energy). On postnatal day (PND) 3, pups were randomly crossfostered within diet groups to minimize litter effects and culled to 10 per litter. Cerebrums and milk from culled pups stomachs were collected for lipid analysis. The timing of appearance of the ASR was determined between PND 10 through 14 and ABCTs were measured in pups on PND 24 and 31. Pups were sacrificed on PND 31 and cerebrums were removed. In each of two replicated studies, pups in the 1% DHA group weighed significantly less on PND 3 and they gained significantly less weight from PND 3 to 31 compared with pups in the 0 or 3% groups (p<0.01). The auditory studies were not conducted on the 1% DHA group since measures of auditory function are in part a function of somatic growth. The tissue fatty acid data for the 1% DHA group did not show unexpected findings. Higher dietary DHA was reflected in milk and pup cerebrums, and levels of arachidonic acid were inversely related to levels of DHA. In the pups of dams fed diets containing 3% versus 0% DHA, the ASR appeared significantly later (p<0.001) and the ABCTs were longer (p<0.05) on PND 31. CNPase activity levels were not different between the 0 and 3% DHA groups. This study demonstrated that the auditory brainstem response is sensitive for identifying effects of diet on neurodevelopment, and that diets supplemented with high levels of DHA may exert a negative influence on central nervous system development, potentially through effects on myelin. This study suggests the need for further studies of pre- and postnatal long chain polyunsaturated fatty acid dietary supplementation.