Anticonvulsants for preventing mortality and morbidity in full term newborns with perinatal asphyxia.

BACKGROUND: Seizures are common following perinatal asphyxia and may exacerbate secondary neuronal injury by increasing cerebral metabolic demand, causing fluctuations in oxygenation and perfusion, and triggering the release of excitatory neurotransmitters. Anticonvulsant therapy has been used in infants with perinatal asphyxia in order to prevent seizures. However, long term anticonvulsant therapy may lead to inhibition of brain development. Therefore, the routine use of anticonvulsant therapy to prevent seizures following perinatal asphyxia needs to be evaluated. OBJECTIVES: To assess the effect of administering anticonvulsants to infants of 37 weeks gestation or more following perinatal asphyxia on death or subsequent severe neurodevelopmental disability and/or the prevention of seizures. SEARCH STRATEGY: Relevant randomised controlled trials were identified using a combination of electronic database searches, hand searches and a search of the Cochrane Controlled Trials Registry. SELECTION CRITERIA: All randomised or quasi-randomised controlled clinical trials that reported data comparing the following outcomes: mortality, neurodevelopmental disability, neonatal seizures and adverse events, following anticonvulsant therapy in term infants (37 weeks or more) compared to controls (with or without placebo) following perinatal asphyxia. DATA COLLECTION AND ANALYSIS: Methodological quality and validity of studies were assessed without consideration of the results. Data relevant to the outcome were extracted and analysed. MAIN RESULTS: Seven randomised or quasi-randomised controlled trials that met the selection criteria were included. No studies were of sufficient methodological quality and size to demonstrate a valid, clinically significant change in the risk of mortality or severe neurodevelopmental disability. A meta-analysis combining five studies comparing barbiturates with conventional therapy following perinatal asphyxia demonstrated no difference in risks of death, severe neurodevelopmental disability, or the combined outcome of death or severe neurodevelopmental disability. AUTHORS' CONCLUSIONS: At the present time, anticonvulsant therapy to term infants in the immediate period following perinatal asphyxia cannot be recommended for routine clinical practice, other than in the treatment of prolonged or frequent clinical seizures. Any future studies should be of sufficient size to have the power to detect clinically important reductions in mortality and severe neurodevelopmental disability.

An ethically justified, clinically comprehensive approach to peri-viability: gynaecological, obstetric, perinatal and neonatal dimensions.

Peri-viability, 22-26 completed weeks' gestational age, has generated ongoing clinical ethical controversies concerning the roles of abortion, caesarean delivery for fetal indication, neonatal resuscitation and limits on life-sustaining treatment of neonates. This paper provides a comprehensive, ethically justified approach to the clinical management of peri-viable fetuses and infants. We reviewed available data about the outcomes of peri-viable fetuses and developed an outcomes-based ethical framework that appeals to the ethical principles of beneficence, autonomy and justice. We identified beneficence-based, autonomy-based and justice-based considerations that should guide clinical judgement, the informed consent process, and decisions about termination of pregnancy, caesarean delivery and setting justified limits on life-sustaining treatment of neonatal patients. Ethics is an essential component of perinatal medicine because it provides physicians with an evidence-based, ethically justified, comprehensive approach to the gynaecological, obstetric, perinatal and neonatal dimensions of peri-viability.

Cerebral perfusion in infants and neonates: preliminary results obtained using dynamic susceptibility contrast enhanced magnetic resonance imaging.

BACKGROUND: Previous studies have used the dynamic susceptibility contrast enhanced (DSCE) magnetic resonance (MR) imaging technique to measure cerebral perfusion in adults. OBJECTIVE: To assess the feasibility of the technique in a heterogeneous cohort of sick human infants and identify cerebral perfusion abnormalities. METHODS: Perfusion measurements were made by characterising the changing concentration of an injected bolus of contrast agent using a series of MR images acquired during the first pass of the contrast bolus. Qualitative values of relative cerebral blood flow (rCBF) were then calculated from these data on a pixel by pixel basis to generate parametric maps of perfusion. RESULTS: Images of perfusion were successfully calculated from 12 out of 27 neonates and infants, all with established cerebral pathology. Normal vascular anatomical structures such as the circle of Willis were identified within all calculated images. Values of rCBF were generally larger in grey matter than in white matter. In several patients, perfusion abnormalities resulted in structural abnormalities which were detected in conventional MR imaging at follow up. The acquisition of perfusion data was most difficult when the least mature brains were examined because of motion artefacts and a smaller head size with a lower level of rCBF than adults. CONCLUSIONS: This preliminary study shows that: (a) maps of rCBF can be acquired from neonates and infants; (b) characterisation of the bolus passage becomes progressively easier as the brain matures; (c) early abnormalities in cerebral perfusion may have negative prognostic implications; (d) the main difficulty when using the DSCE technique to study neonates relates to image artefacts resulting from bulk head motion.

Cerebral venous thrombosis, intraventricular haemorrhage and white matter lesions in a preterm newborn with factor V (Leiden) mutation.

We report a preterm newborn who presented extensive cerebral vein thrombosis on MRI but no abnormal neurological signs. The baby underwent MRI as germinal-matrix intraventricular haemorrhage was revealed by a routine ultrasound brain scan performed on day 16; earlier ultrasound scans (day 2, 7, 12) were all normal. Cerebral vein thrombosis was diagnosed at the first MRI scan together with abnormal restriction in diffusion weighted imaging in the frontal white matter parenchyma. Bilateral microcavitations with a linear pattern of distribution reflecting the distribution of medullary veins developed a week later in the same white matter areas where abnormal diffusion weighted imaging was formerly noted. The baby was later found to be heterozygous for factor V Leiden.

Magnetic resonance imaging of the infant brain: anatomical characteristics and clinical significance of punctate lesions.

OBJECTIVE: To describe the magnetic resonance imaging (MRI) characteristics of punctate brain lesions in neonates (number, appearance, distribution, and association with other brain abnormalities) and to relate them to neurodevelopmental outcome. METHODS: A retrospective analysis was performed of 110 MRI brain scans from 92 infants admitted in 1998 to the neonatal intensive care unit. Results of routine neurodevelopmental follow up (1998-2001) in those infants with punctate brain lesions were analysed. RESULTS: Punctate lesions were observed in 15/50 preterm and 2/42 term infants. In the preterm group, the number of lesions was < 3 in 20%, 3-10 in 27%, and > 10 in 53%. In 14/15 the lesions were linearly organised and located in the centrum semiovale. Other brain abnormalities were absent or minor--that is, "isolated" punctate lesions--in 8/15 and major in 7/15. In the term group, punctate lesions were organised in clusters and no other brain abnormalities were observed. Isolated punctate lesions were observed in 10/17 infants, and a normal neurodevelopmental outcome was seen in 9/10 (mean follow up 29.5 months). One infant showed a slight delay in language development. In the infants with associated brain lesions (7/17, mean follow up 27.5 months), outcome was normal in only two subjects. CONCLUSIONS: Punctate lesions are predominantly seen in preterm infants, are usually linearly organised, and border the lateral ventricles. Isolated punctate lesions may imply a good prognosis, because most of these subjects have a normal neurodevelopmental outcome so far.

Anticonvulsants for preventing mortality and morbidity in full term newborns with perinatal asphyxia.

OBJECTIVES: To assess the benefits and harm of administering anticonvulsants to infants of 37 weeks gestation or more following perinatal asphyxia with the primary aims of prevention of death or subsequent severe neurodevelopmental disability and/or the prevention of seizures. SEARCH STRATEGY: Relevant randomised controlled trials were identified using a combination of electronic database searches (MEDLINE and EMBASE), hand searches and a search of the Cochrane Controlled Trials Registry. SELECTION CRITERIA: All randomised, or quasi-randomised, controlled clinical trials with reported data comparing the following outcomes: mortality, neurodevelopmental disability, neonatal seizures and adverse events, following anticonvulsant therapy in term infants (37 weeks or more), compared to controls with or without placebo, following perinatal asphyxia. DATA COLLECTION AND ANALYSIS: Methodological quality and validity of studies were assessed without consideration of the results. Data relevant to the outcome were extracted and analysed. MAIN RESULTS: Five randomised or quasi-randomised controlled trials which met the selection criteria were identified. No studies were of sufficient methodological quality and size to demonstrate a valid, clinically significant change in the risk of mortality or severe neurodevelopmental disability. A meta-analysis combining three studies comparing barbiturates with conventional therapy following perinatal asphyxia demonstrated no difference in risks of death, severe neurodevelopmental disability, or death or severe neurodevelopmental disability. REVIEWER'S CONCLUSIONS: At the present time, anticonvulsant therapy to term infants in the immediate period following perinatal asphyxia cannot be recommended for routine clinical practice, other than in the treatment of prolonged or frequent clinical seizures. Any future studies should be of high quality: randomised control trials with allocation concealment, performance and outcome assessment blinding. Such studies should be of sufficient size, with minimal attrition, to have the power to detect clinically important reductions in mortality and severe neurodevelopmental disability, as the primary outcome measures.

Cerebral maturation in premature infants: quantitative assessment using MR imaging.

BACKGROUND AND PURPOSE: The assessment of whether brain development is at an appropriate level for age has become an integral part of clinical MR reporting, although few studies have quantitatively defined the developmental changes occurring in premature infants. We have developed a simple scoring system to assess four parameters of cerebral maturation--myelination, cortical folding, glial cell migration, and germinal matrix distribution--to determine the total maturation score (TMS). The aim of this study was to validate this scoring system in a large population of preterm infants across a range of gestational ages. METHODS: A retrospective analysis was conducted of MR images acquired over a 3-year period with an identical imaging protocol. Infants born more than 14 days before the imaging examination and those with a clinical or radiologic history suggestive of neuroabnormality were excluded from the study. The TMS was derived by consensus. Interobserver agreement was evaluated by using the Bland-Altman plot. RESULTS: Images from 134 infants (23-41 weeks' gestational age) were evaluated. The TMS was significantly related to the postmenstrual age of the infant, with the mean TMS for each age group increasing with advancing postmenstrual age. Interobserver agreement was found to be high (mean difference in score = 0.07, SD = 0.56). CONCLUSION: This scoring system provides a standardized method for assessing cerebral maturation in the premature infant. The TMS is easy to calculate from standard MR images, is reproducible, and can help detect changes occurring within a postnatal age of a few weeks.

Post-resuscitative management of the asphyxiated term and preterm infant.

Up until the recent past, the treatment for perinatal asphyxia included only supportive measures. Babies were resuscitated and then observed for signs of multi-organ system dysfunction. Apart from standard supportive management, a new arsenal of potential neuroprotective strategies have emerged over the past years, in order to decrease the severity of brain injury following asphyxia. Today, several neuroprotective therapies are being evaluated in human infants.

Magnetic resonance and cranial ultrasound characteristics of periventricular white matter abnormalities in newborn infants.

OBJECTIVE: To characterize the range of abnormalities within the periventricular white matter (PVWM) in a cohort of newborns using magnetic resonance (MR) brain imaging and to compare the focal MR abnormalities with the cranial ultrasound (CUS) findings. METHODS: Retrospective study of MR brain and CUS findings of infants born in the 18-month period 1998-1999. PVWM abnormalities were identified by MR and focal lesions were characterized by size, number and distribution using a grading scale. Correspondence with CUS findings was assessed. RESULTS: 175 MR examinations corresponding to n = 105 preterm infants, (median GA 28, range 23-36 weeks) and n = 25 term infants (median GA 39, range 37-42 weeks) were analysed for PVWM abnormalities. In the preterm group, MR demonstrated a normal PVWM in n = 76, focal areas of altered signal intensity (SI) in PVWM in n = 26 and venous infarction in n = 3. In the term group, MR demonstrated a normal PVWM in n = 15, focal areas of altered SI in PVWM in n = 4, oedematous PVWM in n = 2 and a middle cerebral artery infarction in n = 4. All infants with normal MR had normal CUS findings. A focal PVWM SI abnormality detectable on MR corresponded with an abnormality on CUS in only n = 10/30. CONCLUSIONS: MR appears considerably more sensitive than CUS in demonstrating the existence and extent of focal PVWM lesions in newborn infants. Satisfactory correspondence between the two imaging investigations is obtained only for cystic PVWM lesions.

Evidence of selection bias in preterm survival studies: a systematic review.

OBJECTIVE: To determine by how much selection bias in preterm infant cohort studies results in an overestimate of survival. DESIGN: Systematic review of studies reporting survival in infants less than 28 weeks of gestation published 1978-1998. Studies were graded according to cohort definition: A, stillbirths and live births; B, live births; C, neonatal unit admissions. Proportions of infants surviving to discharge were calculated for each week of gestation. RESULTS: Sixty seven studies report data on 55 cohorts (16 grade A, 23 grade B, 16 grade C). Studies that are more selective report significantly higher survival between 23 and 26 weeks of gestation (grade C > grade B > grade A, p < 0.01), exaggerating survival by 100% and 56% at 23 and 24 weeks respectively. CONCLUSION: To minimise the potential for overestimating survival around the limits of viability, future studies should endeavour to report the outcome of all pregnancies for each week of gestation (terminations, miscarriages, stillbirths, and all live births).

Neonatal catecholamine levels and neurodevelopmental outcome: a cohort study.

AIMS: To determine whether neonatal plasma catecholamine concentrations can be used to predict (a) death plus disability and (b) motor and cognitive impairment at 5 years of age. METHODS: A cohort comprised 136 preterm infants from two randomised controlled trials of neonatal sedation (1989-1992). Adrenaline (epinephrine) and noradrenaline (norepinephrine) were measured at baseline (first day) and 24 hours later. Intelligence and motor ability were assessed at 5-6 years. RESULTS: Infants who died or sustained disability had significantly higher plasma noradrenaline levels on the second day of life. Noradrenaline levels above 9.0 nmol/l were most predictive of death (likelihood ratio 3.27; 95% confidence interval 1.48 to 7.23) and death plus disability (likelihood ratio 3. 55; 95% confidence interval 1.77 to 7.10). There was no correlation between neonatal catecholamine levels and cognitive or motor impairment at 5-6 years. CONCLUSIONS: Elevated noradrenaline levels are associated with adverse outcome in preterm infants; however, the power to predict death or disability is limited and they are not predictive of later motor or cognitive impairment.

A gene for ataxic cerebral palsy maps to chromosome 9p12-q12.

Cerebral palsy (CP) has an incidence of approximately 1 in 750 births, although this varies between ethnic groups. Genetic forms of the disease account for about 2% of cases in most countries, but contribute a larger proportion in certain sub-types of the condition and in populations with a large proportion of consanguineous marriages. Ataxic cerebral palsy accounts for 5-10% of all forms of CP and it is estimated that approximately 50% of ataxic cerebral palsy is inherited as an autosomal recessive trait. We have identified a complex consanguineous Asian pedigree with four children in two sibships affected with ataxic cerebral palsy and have used homozygosity mapping to map the disorder in this family. A genome-wide search was performed using 343 fluorescently labelled polymorphic markers and linkage to chromosome 9p12-q12 was demonstrated. A maximum Lod score of 3.4 was observed between the markers D9S50 and D9S167 using multipoint analysis, a region of approximately 23cM. We have identified a family that segregates both ataxic CP and ataxic diplegia and have mapped the genetic locus responsible in this family to chromosome 9p12-q12. The identification of gene(s) involved in the aetiology of CP will offer the possibility of prenatal/premarital testing to some families with children affected with the disorder and will greatly increase our understanding of the development of the control of motor function.

Quantitative comparison of intrabrain diffusion in adults and preterm and term neonates and infants.

OBJECTIVE: Quantitative measurements of mean water diffusivity (D(av)) were made in human neonates, infants, and adults to assess changes in brain tissue that occur with maturation. SUBJECTS AND METHODS: Values of D(av) were obtained by calculating the average of the diffusion measurements made with diffusion-sensitizing gradients placed along three orthogonal directions. The mean diffusivity, a rotationally invariant determination of apparent diffusion coefficient, was measured in five healthy prematurely born neonates and infants, in 10 healthy term neonates and infants, and in five adults. RESULTS: Values of D(av) were found to decrease with maturation in most parts of the brain. In prematurely born neonates and infants with a postmenstrual age (postgestastional age + postnatal age) under 36 weeks, the average value of D(av) in frontal white matter was 1.90 x 10(-3) mm2 sec(-1). The corresponding value was measured as 1.62 x 10(-3) mm2 sec(-1) in neonates and infants born at term with a postnatal age of no more than 43 days and 0.79 x 10(-3) mm2 sec(-1) in the adult brain. CONCLUSION: Values of D(av) are known to decrease in neonates and young infants in the period immediately after ischemic insult. This decrease and the associated increase in signal intensity seen on diffusion-weighted imaging have been used to monitor ischemic brain injury in neonates and infants. Therefore, the decrease in D(av) that occurs with maturation, which we report in this study, must be considered if quantitative diffusion measurements are used to assess ischemic neonatal brain injury.

Anticonvulsants for preventing mortality and morbidity in full term newborns with perinatal asphyxia.

OBJECTIVES: To assess the benefits and harm of administering anticonvulsants to infants of 37 weeks gestation or more following perinatal asphyxia with the primary aims of prevention of death or subsequent severe neurodevelopmental disability and/or the prevention of seizures. SEARCH STRATEGY: Relevant randomised controlled trials were identified using a combination of electronic database searches (MEDLINE), hand searches and a search of the Neonatal Review Group trials register. SELECTION CRITERIA: All randomised, or quasi-randomised, controlled clinical trials with reported data comparing the following outcomes: mortality, neurodevelopmental disability, neonatal seizures and adverse events, following anticonvulsant therapy in term infants (37 weeks or more), compared to controls with or without placebo, following perinatal asphyxia. DATA COLLECTION AND ANALYSIS: Methodological quality and validity of studies were assessed without consideration of the results. Data relevant to the outcome were extracted and analysed. MAIN RESULTS: Five randomised or quasi-randomised controlled trials which met the selection criteria were identified. No studies were of sufficient methodological quality and size to demonstrate a valid, clinically significant change in the risk of mortality or severe neurodevelopmental disability. A meta-analysis combining three studies comparing barbiturates with conventional therapy following perinatal asphyxia demonstrated no difference in risks of death, severe neurodevelopmental disability, or death or severe neurodevelopmental disability. REVIEWER'S CONCLUSIONS: At the present time, anticonvulsant therapy to term infants in the immediate period following perinatal asphyxia cannot be recommended for routine clinical practice, other than in the treatment of prolonged or frequent clinical seizures. Any future studies should be of high quality: randomised control trials with allocation concealment, performance and outcome assessment blinding. Such studies should be of sufficient size, with minimal attrition, to have the power to detect clinically important reductions in mortality and severe neurodevelopmental disability, as the primary outcome measures.

An international network for evaluating neuroprotective therapy after severe birth asphyxia.

Animal studies have shown great promise in their applicability to potentially neuroprotective therapies for severe birth asphyxia in human babies. It is now necessary to consider a strategy to evaluate some or all of these techniques within the context of human neonatal randomized control trials (RCT). We have set up a pilot study for an international RCT of mature babies with severe asphyxia (defined by an Apgar score of 5 or less at 10 minutes) and have shown that we can recruit from 120 centers in 17 countries an average of three babies a week, which is the required number to undertake a study over a 2-year period with sufficient power to show a significant improvement in outcome. Particular attention must be given in future studies to the size of improvement in outcome required, generalizability of entry criteria, and the appropriate measure of functional outcome in treated babies.

"Sucrose analgesia": absorptive mechanism or taste perception?

It remains unclear whether "sucrose analgesia" is related to a pre- or postabsorptive mechanism. In a double blind cross over study sucrose reduced the pain response of preterm infants exposed to heel prick blood samples only when it was administered into the mouth. It was ineffective when administered intragastrically.

Folate-homocysteine interrelations: potential new markers of folate status.

We report a transient drop in plasma Hcy and Cys following a single oral dose of PteGlu. The thiol change was concomitant with both the peak plasma 5CH3H4PteGlu1 level (by HPLC) and the maximum plasma Lactobacillus casei activity which reflects absorption of unmodified PteGlu. The significant reciprocal association of Hcy with radioassay RBC folate (r = -0.28, 99% CI -0.48, -0.05, P = 0.0016), serum folate (r = -0.37, 99% CI -0.56, -16, P = 0.0001), and vitamin B12 (r = -0.42, 99% CI -0.59, -21, P = 0.0001) is shown and reflects the long-term nutritional effect of B vitamins on this important, potentially atherogenic thiol. These are now well-established associations. We extend the potential for investigation of folate metabolism in health and disease by evaluating a range of new folate indices which are based on erythrocyte coenzymes. These have been looked at independently and in association with established parameters. Erythrocyte methylfolates (mono- to hexaglutamate-5CH3H4PteGlu1-6), formylfolates (tri- to pentaglutamate-5CHOH4PteGlu3-5),formiminotetrahydrofolate (formiminoH4PteGlu1), unsubstituted tetrahydrofolate (H4PteGlu1), andpara-aminobenzoylglutamate (P-ABG) have been measured by HPLC with fluorescence detection. A positive linear association exists between (i) H4PteGlu1 and radioassay RBC folate (r = 0.50, 99% CI 0. 07, 0.77, P = 0.0036), and (ii) H4PteGlu1 and tetraglutamates of both formyl- and methylfolate (r = 0.52, 99% CI 0.10, 0.78, P = 0. 0022, and r = 0.56, 99% CI 0.15, 0.80, P = 0.0009, respectively). Since, in addition, a reciprocal linear association exists between Hcy and tetraglutamyl formylfolate (r = -0.41, 99% CI -0.73, 0.05, P = 0.0206), erythrocyte tetraglutamates may be a good reflection of the bodies' active coenzyme pools. Pentaglutamyl formylfolate, the longest oligo-gamma-glutamyl chain form of this coenzyme may be a good indicator of folate depletion. The abundance of this coenzyme both increases with increasing Hcy (r = 0.55, 99% CI 0.13, 0.80, P = 0.0014) and increases as H4PteGlu1, the principle folate congener, decreases (r = -0.59, 99% CI -0.82, -0.20, P = 0.0004). Furthermore, the apparent equilibrium between substrate (5CH3H4PteGlu1) and product (H4PteGlu1) of methionine synthase is significantly associated with the abundance of 5CHOH4PteGlu5 (r = -0.53, 99% CI -0. 79, -0.11, P = 0.0018). This suggests that low methionine synthase activity for whatever reason (metabolic or dietary) may lead to an increase in the relative abundance of 5CHOH4PteGlu5. Like 5CHOH4PteGlu5, evidence is given that 5CH3H4PteGlu6, the longest oligo-gamma-glutamyl chain form of this particular coenzyme pool, may also be a good indicator of folate depletion. This is shown by a change in the relative proportion of erythrocyte methylfolate polyglutamates following supplementation with 400 microg/day PteGlu. Short-chain polyglutamates of methylfolate (5CH3H4PteGlu1--> 5CH3H4PteGlu4) increase in proportion to the total methylfolate pool, while long-chain polyglutamates of methylfolate (5CH3H4PteGlu5 and particularly 5CH3H4PteGlu6) decrease in their relative abundance.

Randomised double blind trial of morphine versus diamorphine for sedation of preterm neonates.

AIMS: To compare the safety and effectiveness of morphine and diamorphine for the sedation of ventilated preterm neonates in a double blind, randomised trial. METHODS: Eighty eight babies were allocated to receive either morphine (n = 44) or diamorphine (n = 44) by bolus infusion (200 or 120 mcg/kg, respectively, over two hours), followed by maintenance infusion (25 or 15 mcg/kg/h, respectively) during the initial phase of their respiratory disease. Serial monitoring of physiological, behavioural, and biochemical variables over the first 24 hours of the infusions was performed. Longer term outcomes were also monitored. RESULTS: Morphine, but not diamorphine, was associated with a mean (SEM) decrease in mean arterial blood pressure of 2.2 (1.0) mm Hg (p = 0.05) over the initial loading infusion. Physiological (blood pressure variability) and behavioural measures of sedation (clinical assessment and sedation scoring) indicated that the two drug regimens were equally effective after 24 hours, but the sedative effects of diamorphine were evident more quickly than those of morphine. Both regimens significantly reduced plasma adrenaline concentrations over the first 24 hours of the infusions. No significant differences in mortality, ventilator days, chronic lung disease or intracranial lesions were noted. CONCLUSIONS: Both drug regimens reduce the stress response to ventilation in preterm neonates. However, diamorphine's more rapid onset of sedation and morphine's hypotensive tendency suggest that diamorphine is preferable for the sedation of mechanically ventilated preterm neonates.

Impaired regeneration of monoglutamyl tetrahydrofolate leads to cellular folate depletion in mothers affected by a spina bifida pregnancy.

Periconceptional folate prevents neural tube defects (NTD) by a mechanism which is unclear. The present study found significant changes in the equilibrium of the homocysteine remethylation cycle in NTD affected mothers, possibly involving B12-dependent methionine synthase or 5,10-methylenetetrahydrofolate reductase. Data were consistent with impaired Hcy remethylation leading to poor regeneration of H4PteGlu1, the main intracellular precursor of all folates. This lesion leads to cellular folate deficiency indicated by a significantly lower radioassay RBC folate and 5CH3H4PteGlu4 in affected mothers. The drop in this tetraglutamate is associated with an increase in the abundance of longer chain oligo-gamma-glutamyl folate, again reflecting the underlying folate deficiency. This effect may compromise purine, DNA-thymine, and methionine production, particularly during embryogenesis when folate demand is high. At this time serine hydroxymethyltransferase may play a critical role in conserving H4PteGlu1 for purine synthesis. Many of these depletion effects were corrected with folate supplementation for 1 month.