Using event-related potentials to study perinatal nutrition and brain development in infants of diabetic mothers

Proper prenatal and postnatal nutrition is essential for optimal brain development and function. The early use of event-related potentials enables neuroscientists to study the development of cognitive function from birth and to evaluate the role of specific nutrients in development. Perinatal iron deficiency occurs in severely affected infants of diabetic mothers. In animal models, severe perinatal iron deficiency targets the explicit memory system of the brain. Cross-sectional ERP studies have shown that infants of diabetic mothers have impairments in recognition memory from birth through 8 months of age. The purpose of this study was to evaluate longitudinal development of recognition memory using ERPs in infants of diabetic mothers compared with control infants. Infants of diabetic mothers were divided into high and low risk status based upon their birth weights and iron status and compared with healthy control infants. Infants were tested in the newborn period for auditory recognition memory, at 6 months for visual recognition memory and at 8 months for cross modal memory. ERPs were evaluated for developmental changes in the slow waves that are thought to reflect memory and the Nc component that is thought to reflect attention. The results of the study showed differences in development between the IDMs and control infants in the development of the slow waves over the left anterior temporal leads and age-related patterns of development in the NC component. These results are consistent with animal models showing that perinatal iron deficiency affects the development of the memory networks of the brain. This study highlights the value of using ERPs to translate basic science information obtained from animal models to the development of the human infant.     

Neonates of diabetic mothers: The starting point for developing novel therapeutic approaches to ischemic heart and brain?

Diabetes mellitus represents the most common medical condition causing complications during pregnancy. However, there is still some controversy surrounding complications. Maternal hyperglycemia leads to fetal hyperglycemia. Offspring of diabetic mothers compensate excess glucose concentrations by producing higher levels of insulin causing transient hyperinsulinemia. Infants of diabetic mothers are at risk for congenital cardiac malformations, of which 40% are with hypertrophic cardiomyopathy. However, regardless of severity, cardiac hypertrophy is transient with echocardiographic resolution within the first months after birth. Neonates of diabetic mothers are more likely to suffer from macrosomia that predisposes the infant to birth asphyxia brain damage. However, there is no evidence for an increase in the incidence of brain injury from perinatal asphyxia in macrosomic babies of diabetic mothers in comparison to macrosomic newborns of non-diabetic mothers. We hypothesize that infants of diabetic mother may represent the starting point for developing novel approaches to the treatment and prevention of obstructive hypertrophic cardiomyopathy, AMI and stroke at every age.     

Neurocognitive sequelae of infants of diabetic mothers

On the basis of animal models, it was hypothesized that infants of diabetic mothers (IDMs) would be at risk for suffering damage to the hippocampus primarily because of fetal iron deficiency, chronic hypoxia, and hypoglycemia. This, in turn, may result in impairments in recognition memory at a young age. To test this model, the memory of 6-month-old IDMs and control infants was evaluated with electrophysiological (event-related potential [ERP]) and behavioral (looking time) measures. At 12 months, the Bayley Scales of Infant Development was administered. Our ERP measures showed robust evidence consistent with memory deficits in the IDMs. In contrast, the looking time measures and the Bayley exam failed to distinguish between the groups. From these results it was concluded that the ERP, but not the behavioral, measures are able to detect, in an at-risk population, deficits in recognition memory that are thought to be mediated by damage to the hippocampus.     

Neural Correlates of Emotion Processing in Typically Developing Children and Children of Diabetic Mothers

To examine the neurocognitive sequelae of children born to diabetic mothers (CDMs), event-related potentials (ERPs) in response to three facial expressions (happy, fear, anger) were collected from 42 children (18 CDMs, 24 controls), aged 36 and/or 48 months. A linear mixed models approach was used to model individual variation in amplitude and latency. As infants, CDMs in the present study displayed subtle impairments in attention and memory processing, including face recognition, as indexed by ERPs. Findings indicate that these same children, now ages 3–4 years, continue to display ERP patterns that differ from controls in amplitude, latency, and hemispheric asymmetry.     

Low-Level Prenatal Lead Exposure Alters Auditory Recognition Memory in 2-Month-Old Infants: An Event-Related Potentials (ERPs) Study

This study used event-related potentials (ERPs) to assess effects of low-level prenatal lead exposure on auditory recognition memory in 2-month-old infants. Infants were divided into four groups according to cord-blood lead concentration: (1) <2.00 μg/dL, (2) 2.00–2.99 μg/dL, (3) 3.0–3.7 μg/dL, and (4) ≥3.7 μg/dL. The first group showed the normally expected differences in P2, P750, and late slow wave (LSW) amplitudes elicited by mothers’ and strangers’ voices. These differences were not observed for one or more ERP components in the other groups. Thus, there was electrophysiological evidence of poorer auditory recognition memory at 2 months with cord-blood lead ≥2.00 μg/dL.     

Effect of the interval between pregnancies on perinatal outcomes

BACKGROUND: A short interval between pregnancies has been associated with adverse perinatal outcomes. Whether that association is due to confounding by other risk factors, such as maternal age, socioeconomic status, and reproductive history, is unknown. METHODS: We evaluated the interpregnancy interval in relation to low birth weight, preterm birth, and small size for gestational age by analyzing data from the birth certificates of 173,205 singleton infants born alive to multiparous mothers in Utah from 1989 to 1996. RESULTS: Infants conceived 18 to 23 months after a previous live birth had the lowest risks of adverse perinatal outcomes; shorter and longer interpregnancy intervals were associated with higher risks. These associations persisted when the data were stratified according to and controlled for 16 biologic, sociodemographic, and behavioral risk factors. As compared with infants conceived 18 to 23 months after a live birth, infants conceived less than 6 months after a live birth had odds ratios of 1.4 (95 percent confidence interval, 1.3 to 1.6) for low birth weight, 1.4 (95 percent confidence interval, 1.3 to 1.5) for preterm birth, and 1.3 (95 percent confidence interval, 1.2 to 1.4) for small size for gestational age; infants conceived 120 months or more after a live birth had odds ratios of 2.0 (95 percent confidence interval, 1.7 to 2.4);1.5 (95 percent confidence interval, 1.3 to 1.7), and 1.8 (95 percent confidence interval, 1.6 to 2.0) for these three adverse outcomes, respectively, when we controlled for all 16 risk factors with logistic regression. CONCLUSIONS: The optimal interpregnancy interval for preventing adverse perinatal outcomes is 18 to 23 months.     

Auditory recognition memory in 2-month-old infants as assessed by event-related potentials

Previous studies of auditory recognition memory in sleeping newborns reported 2 event-related potential (ERP) components, P2 and negative slow wave (NSW), reflecting voice discrimination and detection of novelty, respectively. In the present study, using high-density recording arrays, ERPs were acquired from 26 2-month-old awake infants as they were presented with a familiar and unfamiliar voice (i.e., mother and stranger) with equal probability. In addition to P2 and NSW, we observed a positive slow wave (PSW) over the right temporo-parietal scalp, indicating memory updating. Our study suggests that infants appear to have the capacity to encode novel stimuli as early as 2 months of age.     

Auditory Recognition Memory in 2-Month-Old Infants as Assessed by Event-Related Potentials

Previous studies of auditory recognition memory in sleeping newborns reported 2 event-related potential (ERP) components, P2 and negative slow wave (NSW), reflecting voice discrimination and detection of novelty, respectively. In the present study, using high-density recording arrays, ERPs were acquired from 26 2-month-old awake infants as they were presented with a familiar and unfamiliar voice (i.e., mother and stranger) with equal probability. In addition to P2 and NSW, we observed a positive slow wave (PSW) over the right temporo-parietal scalp, indicating memory updating. Our study suggests that infants appear to have the capacity to encode novel stimuli as early as 2 months of age.     

The effect of adverse intrauterine and newborn environments on cognitive development: the experiences of premature delivery and diabetes during pregnancy

The prenatal and early postnatal periods constitute a time of rapid development when the brain is in a state of both heightened plasticity and vulnerability. Premature infants and infants of diabetic mothers represent two experiments of nature that allow researchers to observe how the developing brain responds to early biological challenge of either a global or regionally specific nature. We outline a set of organizing principles for conceptualizing the mechanisms by which early adverse experience may be encoded in the brain and subsequently expressed in behavior. We then review the available literature on developmental outcomes for infants born premature and infants of diabetic mothers. Research examining the relative influence of experience and maturation in the development of preterm infants indicates that advance experience does not accelerate the advent of specific cognitive capacities, but may enhance performance once the particular ability has emerged. Long-term follow-up of preterm infants also reveals evidence for plasticity and cognitive improvement into early adolescence for later maturing executive functions. Finally we offer an integrated model for investigating cognitive outcomes in infants of diabetic mothers that incorporates data from animal, electrophysiological, and behavioral measures.     

Visual event-related brain potentials in 4-month-old infants at risk for neurodevelopmental impairments

The recording of event-related potentials (ERPs) is an electrophysiologic technique that has been used to evaluate the functional maturation of neural pathways responsible for recognition memory systems in infants and children. The purpose of this study was to evaluate ERP correlates of visual recognition memory in 4-month-old infants at risk for later cognitive impairments. We compared ERPs using a test of shape recognition at 4 months of age (adjusted for prematurity) in 16 high-risk, neonatal intensive care unit (NICU) survivors and 16 healthy full-term infants. ERPs were recorded while infants were familiarized with one stimulus (a red cross, 15 trials), then tested with 60 trials of this familiar stimulus and a novel stimulus (a red corkscrew). Both the NICU and control groups' ERPs demonstrated evidence of differential processing of the two stimuli, but the NICU groups' ERP patterns were distinctly different from those of the control group. In the NICU group, the novel stimulus elicited parietal positivity at 1000–1700 ms poststimulus, whereas in the control group the novel stimulus elicited occipital and frontal negativity at 500–1700 ms poststimulus. The ERP pattern demonstrated by the NICU group was atypical as it has not been previously described in healthy infants. The results of the study indicate that the ERP technique can be used to demonstrate altered patterns of neural activity during tasks of visual recognition memory in high-risk infants. We speculate that the atypical ERP patterns described in this study may indicate that patterns of synaptic organization were altered by neonatal events. © 1997 John Wiley & Sons, Inc. Dev Psychobiol 30 : 11–28, 1997     

The infant of the diabetic mother: correlation of increased cord C-peptide levels with macrosomia and hypoglycemia.

C peptide is secreted by pancreatic beta cells in amounts equimolar with insulin, and its levels provide a direct indication of endogenous fetal levels of insulin despite the presence of maternal insulin antibodies. To determine the presence of hyperinsulinemia and its relation to the development of complications in infants of diabetic mothers, we measured cord serum levels of C peptide in 79 infants of diabetic mothers and 62 infants of nondiabetic mothers. Infants of diabetic mothers had higher cord levels of C peptide, which were significantly associated with neonatal hypoglycemia and macrosomia (P less than 0.001) but not with hyaline-membrane disease. Cord levels of C peptide in infants of diabetic mothers were elevated at the earliest gestational age studied (less than 34 weeks) and were directly related to the severity of maternal diabetes, as assessed by the White classification. We conclude that hyperinsulinemia is present in infants of diabetic mothers and that it is related to some major complications in such infants.     

Obstetric and perinatal outcome and preliminary results of development of children born after in vitro maturation of oocytes

BACKGROUND: Careful follow-up of children born after in vitro maturation (IVM) of human oocytes is essential because the technique is still very new. METHODS: Obstetric and perinatal data were collected from all deliveries after IVM treatment during 1999-2004. The growth and development of IVM children was assessed at 6, 12 and 24 months using Muenchener Funktionelle Entwicklungs Diagnostik and Bayley Scales of Infants. RESULTS: In total, 43 women [age 31.2 +/- 3.9 (mean +/- SD) years] gave birth to 40 singleton infants and three sets of twins (multiple rate 7.0%). Obstetric complications occurred in 15 pregnancies (35%). The mean birthweight of singleton infants was 3550 +/- 441 g and that of twins 2622 +/- 194 g. The rate of preterm birth infants was 5% in singletons. No perinatal deaths occurred. At the age of 12 months, eight children (19%) expressed minor developmental problems and one girl was found to have optical glioma. At 2 years of age, neuropsychological development was within the normal range. CONCLUSIONS: The obstetric and perinatal outcome was good, and the mean birthweight of the infants was normal. Minor developmental delay was overexpressed at 12 months, but the development of the children was normal at 2 years.     

Mother-to-infant transmission of hepatitis B virus: a Chinese experience

Over 90% of infants infected with hepatitis B virus (HBV) caused by mother-to-infant transmission will evolve to carrier status, and this cannot be prevented until widespread administration of the HB vaccine and hepatitis B immune globulin (HBIG) is implemented. This prospective study of 214 infants born to HBsAg-positive mothers was carried out to determine if either perinatal or intrauterine HBV transmission could be effectively prevented with HBIG and the HB vaccine. Peripheral blood was collected from mothers and from newborns before they received HBIG and the HB vaccine, as well as at 0, 1, 7, 24, and 36 months after birth. Infants born with an ratio of signal to noise(S/N) value of >5 for HBsAg (ABBOTT Diagnostic Kit) were defined as mother-to-infant transmission cases, those with an S/N between 5 and 50 were classified as perinatal transmission cases, and those with an S/N >50 were considered intrauterine transmission cases. Mother-to-infant transmission occurred in approximately 4.7% (10/214) of the infants; the perinatal transmission and intrauterine transmission rates were 3.7% (8/214) and 0.9% (2/214), respectively. The risk of mother-to-infant transmission increased along with maternal HBeAg or HBVDNA levels. After 36 months of follow-up, all perinatal cases became HBsAg-negative, whereas all intrauterine transmission cases evolved into carrier status. These results indicate that infants infected via intrauterine transmission cannot be effectively protected by HBIG and HB vaccine.     

Deficiency of a naturally occurring protein inhibitor in brain of clinically ‘brain damaged’ newborn human infants — A possible cause of mental retardation?

The presence of an inhibitor of guanine deaminase in the ‘heavy’ mito-chondrial fractions of rat brain homogenates has been reported. The results of the present study, using brain homogenates from normal infants who died between ages 1–6 months, low birth weight infants who were brain damaged and died between ages 2 days–4 months and premature (7–8 months pregnancy) infants, who were considered clinical cases with acute brain damage and died 1–3 days after birth, indicate that while normal human brain contains the inhibitory material, it is conspicuously absent from the particulate fractions of brain damaged low birth weight and premature infants. Since brain damage at birth in an infant could result in mental retardation of some kind on development, a possible relationship between deficiency or absence of the inhibitory material of guanine deaminase in human brain and mental retardation is suggested.     

Consequences of Low Neonatal Iron Status Due to Maternal Diabetes Mellitus on Explicit Memory Performance in Childhood

Diabetic pregnancies are characterized by chronic metabolic insults, including iron deficiency, that place the developing brain at risk for memory impairment later in life. A behavioral recall paradigm coupled with electrophysiological measures was used to assess the longevity of these effects in 40 3½-year-old children. When memory demands were high, recall was significantly impaired in the at-risk group and correlated with perinatal measures of iron. Electrophysiological results suggested both encoding and retrieval processes were compromised. These findings support the hypothesis that prenatal iron deficiency leads to alterations in neural development that have a lasting impact on memory ability.     

Mother-to-child transmission of TT virus: sequence analysis of non-coding region of TT virus in infected mother-infant pairs

Summary.  To investigate vertical transmission of TT virus, TTV-DNA was looked for in serum samples taken from 22 mothers and their 22 infants at birth and during nine months of follow-up. Sixteen mothers at delivery and six infants within nine months of age had TTV-DNA detected by the amplification of the non coding (NC) region. Two of these newborns had positive viremia at birth. Sequence analysis of the NC region of five mother-infant pairs revealed that the TTV strains detected at three and six months of age in two of the infants were closely related to that of their mothers, whereas two that became TTV-DNA positive at three moths had a different nucleotide sequence from that of their mothers. One of the two infants with detectable viremia at birth also had a different nucleotide sequence from her mother. These findings suggest that both in utero and perinatal transmission of TT virus may occur, and that the strain detected in the infants was not invariably dominant in the mothers at delivery. Received June 20, 2001 Accepted August 30, 2001     

Mother-to-infant transmission of multiple blood-borne viral infections from multi-infected mothers

Infants born from mothers with multiple blood-borne viral infections are at risk of multiple transmissions. Whether the risk of transmission of multiple infections increases with the number of viruses infecting the mother is still unknown. The aim of this study was to describe the risk of mother-to-infant transmission of multiple infections from multi-infected mothers. Sixty-four pregnant women infected by at least two viruses among human immunodeficiency virus-type 1 (HIV-1), hepatitis C virus, TT virus, and GB virus type C, together with their 64 infants, were studied. Maternal blood samples were collected in the third trimester of pregnancy and all infants were prospectively followed for evaluation of transmission within 3 months after birth and two times in the subsequent 24 months. Transmission of single and of dual infection from mothers infected by two viruses was, respectively, 10/40 (25%) and 5/40 (12.5%) and from mothers infected by three viruses 9/20 (45%) and 2/20 (10%). One (25%) infant infected by one virus was born from the four mothers infected by four viruses. Transmission of single or dual infection was not significantly associated with the number of viruses infecting the mother (P = 0.9) in the linear regression analysis. Present study suggests the absence of a synergistic effect from viral interactions toward mother-to-infant transmission of multiple infections and supports the hypothesis that transmission from multi-infected mothers is the result of the specific interaction between each virus and the host. These observations may be of clinical relevance in perinatal counseling.     

Field evaluation of the efficacy and immunogenicity of recombinant hepatitis B vaccine without HBIG in newborn Vietnamese infants

A study involving more than 2,000 infants was conducted in Vietnam to assess the field effectiveness and immunogenicity of recombinant hepatitis B vaccine given at birth, 1 month, 2 months, without concomitant hepatitis B immune globulin (HBIG). All received a 5 microg dose of H-B-VAX II at birth. Infants born to non-carrier mothers (Group 1; N = 1798) then received 2.5 microg doses at 1 and 2 months of age, while infants of HBeAg-negative (Group 2; N = 125) or HBeAg-positive (Group 3; N = 88) carrier mothers received 5 microg doses. No Group 1 or 2 vaccinees were infected. In Group 3, 12 (14.6%) of 82 infants did become infected (estimated efficacy 84%). 98.0-98.6% of uninfected infants who were tested for anti-HBs developed a seroprotective concentration > or = 10 IU/L. In hyperendemic Vietnam, where routine maternal screening and passive-active prophylaxis of high-risk infants with vaccine plus HBIG is not feasible, administration of vaccine alone to all newborns may control effectively HBV infection.     

Early diagnosis of HIV-1-infected infants in Thailand using RNA and DNA PCR assays sensitive to non-B subtypes

OBJECTIVES: To evaluate the sensitivity and specificity of RNA and DNA polymerase chain reaction (PCR) for early diagnosis of perinatal HIV-1 infection and to investigate early viral dynamics in infected infants. DESIGN: A cohort study of 395 non-breastfed infants born to HIV-infected mothers in a randomized clinical trial of short-course antenatal zidovudine. METHODS: Infant venous blood specimens collected at birth, 2 months, and 6 months of age were tested by qualitative DNA and quantitative RNA PCR (Roche Amplicor). To determine sensitivity and specificity of DNA and RNA PCR, results were compared with later DNA PCR results and to antibody results at 18 months. The HIV-1 subtype of the mother's infection was determined by peptide serotyping. RESULTS: In the study, 92% of mothers were infected with subtype E. DNA PCR sensitivity was 38% (20 of 53) at birth, and 100% at 2 months (53 of 53) and 6 months (47 of 47). RNA PCR sensitivity was 47% (25 of 53) at birth and 100% (53 of 53) at 2 months. All samples that tested DNA-positive tested RNA-positive. Specificity was 100% for both DNA and RNA testing at all timepoints. For infected infants, the median viral load of RNA-positive specimens was 407,000 copies/ml (5.6 log10) at birth, 3, 700,000 copies/ml (6.6 log10) at 2 months, and 1,700,000 copies/ml (6.2 log10) at 6 months. Infant RNA levels at 2 and 6 months did not differ by maternal zidovudine exposure, or RNA level at birth. CONCLUSION: This RNA PCR assay performed well for diagnosing perinatal HIV subtype E infection, detecting nearly half of infected infants at birth, and 100% at 2 and 6 months, with 100% specificity. Infected infant viral RNA levels were very high at 2 and 6 months, and were unaffected by maternal zidovudine treatment.     

Perinatal transmission of hepatitis B virus in Thailand

Perinatal transmission of hepatitis B virus (HBV) from asymptomatic HBsAg carrier mothers to their infants was studied in 78 mother-infant pairs by determination of HBsAg, HBeAg and anti-HBe both in the mothers and in their infants at regular intervals for those children up to the time when they reached at least one year of age. Twenty-five out of the 78 (32.1%) infants born to these mothers were HBsAg-positive 2-6 months after birth and they remained so throughout the observation period of at least one year or more. Perinatal HBV transmission occurred only in infants born to HBsAg carrier mothers who were HBeAg-positive (92.6%) but not in those born to HBsAg carrier mothers who had no detectable HBeAg. This study suggests that preventive measures against HBV transmission during the perinatal period should be taken only for infants born to HBsAg carrier mothers who are HBeAg-positive. In addition, the active immune response to HBV was studied in 75 non-HBsAg carrier infants born to HBsAg carrier mothers by determination of anti-HBs at one year of age or older. Forty-three of these infants were treated with HBIG at birth and 32 infants received no treatment. It was found that infants born to HBsAg carrier mothers who were HBeAg-positive had a better active immune response (84.2% positive for anti-HBs) than infants born to HBsAg carrier mothers who had no detectable HBeAg or anti-HBe (14.3% and 20.4% positive for anti-HBs respectively).