Early human milk feeding is associated with a lower risk of necrotizing enterocolitis in very low birth weight infants.

BACKGROUND: Necrotizing enterocolitis (NEC) is a frequent cause of mortality and morbidity in very low birth weight (VLBW) infants. Human milk (HM) feeding has been associated with lower risk of NEC. However, mothers of VLBW infants often experience insufficient milk production, resulting in mixed feedings of HM and formula. Moreover, medical complications often limit the volume of feeding they can be given. OBJECTIVE: To determine if high proportions of (50% or greater) HM enteral feeding within the first 14 days of life are protective against NEC. METHOD: This was a prospective cohort study of VLBW infants who were grouped according to the HM proportion of enteral feeding in the first 14 days: <50% (low human milk, LHM, n=46) and > or =50% (high human milk, HHM, n=156). The outcome of interest was development of NEC (Bell stage 2 or 3). Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) and to assess potential confounding due to perinatal risk factors. RESULT: Two hundred and two infants were studied. Confirmed NEC occurred in 5/46 (10.6%) of the LHM group, as compared with 5/156 (3.2%) of the HHM. Gestational age was the only perinatal factor associated with risk of NEC. After adjustment for gestational age, HHM was associated with a lower risk of NEC ((OR=0.17, 95% CI: 0.04 to 0.68), P=0.01). CONCLUSION: Enteral feeding containing at least 50% HM in the first 14 days of life was associated with a sixfold decrease in the odds of NEC.

Gastroesophageal reflux in very low birth weight infants: association with chronic lung disease and outcomes through 1 year of age.

OBJECTIVE: To analyze the association between chronic lung disease (CLD) and clinically diagnosed gastroesophageal reflux (GER) in very low birth weight (VLBW) infants, and between GER and outcomes at 1 year adjusted age. METHODS: A total of 375 consecutively born VLBW infants with CLD and 345 gestational age-matched controls were studied. Records were reviewed to ascertain which infants were diagnosed with GER (based on clinical suspicion or confirmatory tests) and which infants had delayed growth or development at 1 year adjusted age. RESULTS: Infants with CLD were treated for GER more frequently than controls (CLD: 27% versus controls: 9%; p < 0.0001). Among infants with CLD, those with and without GER were comparable in terms of the days on supplemental oxygen [124 (64 to 93) vs 121 (47 to 394)] and the proportion with cystic changes on chest radiograph (44% vs 47%). Comparing outcomes at 1 year for infants with and without GER, no differences were found in the rates of Bayley Mental Developmental and Psychomotor Developmental Indices of < 70, cerebral palsy, and measurements below the 10th percentile. CONCLUSION: Among VLBW infants, an association exists between CLD and GER, although this association might be due to greater diagnostic suspicion in infants with CLD. In VLBW infants, GER does not appear to increase the risk of delayed growth or development.

A linear regression model to predict the pH of neonatal parenteral nutrition solution.

INTRODUCTION: Providing the high calcium intake necessary for normal bone mineralization in rapidly growing very low birth weight infants is difficult because calcium and phosphorus solubility is limited in the range of parenteral nutrition pH. A major determinant of calcium and phosphorus solubility in vitro is solution pH. The objective of this study was to develop and assess the accuracy of a method to predict the final parenteral solution pH as a linear function of the individual parenteral component concentrations. METHODS: pH values were measured for 205 neonatal parenteral nutrition solutions prepared during a 5-week period. Concentrations of the 13 components used to synthesize parenteral nutrition were determined for each solution. Data from 135 samples were used to develop a linear regression coefficient model with pH as the dependent variable. From the regression model the pH was predicted for the remaining 70 samples using the seven significant solution component concentrations, and the predicted and measured solution pH values were compared. RESULTS: The mean measured parenteral nutrition pH for all solutions was 5.364 +/- 0.110 (mean +/- SD, range 5.03-5.73). The absolute mean pH difference between the predicted and measured value for the 70 test samples was 0.04 +/- 0.04. pH estimated with the model correlated highly with measured pH (r2 = 0.77). The seven components in the regression model accounted for 81% of the pH variance. CONCLUSION: The pH of neonatal parenteral nutrition solutions can be predicted accurately as a linear function of the solution concentrations of the following seven components: sodium acetate, sodium phosphate, potassium phosphate, potassium acetate, magnesium sulphate, amino acid solution and dextrose. The absolute mean difference between measured pH and predicted pH was 0.04. Applying this method to estimate pH with the interactive properties of computer-based ordering systems could enhance calcium and phosphorus administration to very low birth weight infants.

Randomized placebo-controlled trial of a 42-day tapering course of dexamethasone to reduce the duration of ventilator dependency in very low birth weight infants: outcome of study participants at 1-year adjusted age.

OBJECTIVE: Ventilator-dependent preterm infants are often treated with a prolonged tapering course of dexamethasone to decrease the risk and severity of chronic lung disease. The objective of this study was to assess the effect of this therapy on developmental outcome at 1 year of age. METHODS: Study participants were 118 very low birth weight infants who, at 15 to 25 days of life, were not weaning from assisted ventilation and were then enrolled in a randomized, placebo-controlled, double-blind trial of a 42-day tapering course of dexamethasone. Infants were examined at 1 year of age, adjusted for prematurity, by a pediatrician and a child psychologist. A physical and neurologic examination was performed, and the Bayley Scales of Infant Development were administered. All examiners were blind to treatment group. RESULTS: Groups were similar in terms of birth weight, gestational age, gender, and race. A higher percentage of dexamethasone recipients had major intracranial abnormalities diagnosed by ultrasonography (21% vs 11%). Group differences were not found for Bayley Mental Development Index (median [range] for dexamethasone-treated group, 94 [50-123]; for placebo group, 90 [28-117]) or Psychomotor Development Index Index (median [range]) for dexamethasone-treated group, 78 (50-109); for placebo-treated group, 81 [28-117]). More dexamethasone-treated infants had cerebral palsy (25% vs 7%) and abnormal neurologic examination findings (45% vs 16%). In stratified analyses, adjusted for major cranial ultrasound abnormalities, these associations persisted (OR values for cerebral palsy, 5.3; 95% CI: 1.3-21.4; OR values for neurologic abnormality 3.6; 95% CI: 1.2-11.0). CONCLUSIONS: A 42-day tapering course of dexamethasone was associated with an increased risk of cerebral palsy. Possible explanations include an adverse effect of this therapy on brain development and/or improved survival of infants who either already have neurologic injury or who are at increased risk for such injury.

Randomized placebo-controlled trial of a 42-Day tapering course of dexamethasone to reduce the duration of ventilator dependency in very low birth weight infants.

OBJECTIVE: To assess the effect on duration of ventilator dependency of a 42-day tapering course of dexamethasone in very low birth weight neonates. METHODS: Infants (N = 118) were assigned randomly, within birth weight/gender strata, to treatment with either a 42-day tapering course of dexamethasone or an equal volume of saline as placebo. Entry criteria were 1) birth weight <1501 g; 2) age between 15 and 25 days; 3) <10% decrease in ventilator settings for 24 hours and FIO2 >/=0.3; 4) absence of patent ductus arteriosus, sepsis, major congenital malformation, congenital heart disease; and 5) no evidence of maternal HIV or hepatitis B infection. The dosage schedule was 0.25 mg/kg bid for 3 days, then 0.15 mg/kg bid for 3 days, then a 10% reduction in the dose every 3 days until a dose of 0.1 mg/kg had been given for 3 days, from which time a dose of 0.1 mg/kg qod was continued until 42 days after entry. The primary endpoint was the number of days on assisted ventilation after study entry. Secondary outcomes of interest included days on supplemental oxygen, days of hospitalization, and potential adverse effects, such as infection, gastrointestinal bleeding, left ventricular hypertrophy, and severe retinopathy of prematurity. RESULTS: Infants in the dexamethasone- and placebo-treated groups were similar in terms of baseline attributes, including birth weight, gestational age, gender, race, and ventilator settings at entry. Infants treated with dexamethasone were on assisted ventilation and supplemental oxygen for fewer days after study entry (median days on ventilator, 5th and 95th percentiles, 13 [1-64] vs 25 [6-104]; days on oxygen, 59 [6-247] vs 100 [11-346]). No differences were found in risk of death, infection, or severe retinopathy. In subgroup analyses, the association of dexamethasone with more rapid weaning from the ventilator was weaker among infants enrolled before the 16th day of life, infants with chest radiographs showing cystic changes and/or hyperinflation, and infants requiring an FIO2 >/=0.7 or a peak inspiratory pressure >/=19 at study entry. CONCLUSIONS: A 42-day tapering course of dexamethasone decreases the duration of ventilator and oxygen dependency in very low birth weight infants and is not associated with an increased risk of short-term adverse effects.

Perinatal events and the risk of intraparenchymal echodensity in very-low-birthweight neonates.

A case-control study was performed to identify perinatal events associated with intraparenchymal echodensity on cranial ultrasonography--an important antecedent of cerebral palsy in very-low-birthweight infants. Forty-eight infants with birthweight < 1500 g and intraparenchymal echodensity on cranial ultrasound examination and 90 controls with normal cranial ultrasounds were identified within a cohort of 1791 consecutive very-low-birthweight infants born at a regional obstetric referral centre. Data about potential risk factors were obtained from medical records of cases and controls. Among prenatal factors, chorioamnionitis (odds ratio[OR]: 3.2; 95% confidence interval: 1.3, 8.1) and placental abruption (OR 2.6 [1.0, 6.6]) were associated most strongly with an increased risk of intraparenchymal echodensity and pre-eclampsia (OR 0.3 [0.1, 0.8]) was associated most strongly with a decreased risk. When controlling for gestational age, multiple gestation was also associated with an increased risk (OR 2.7 [1.0, 7.5]). Neonatal factors independently associated with an increased risk included low systolic blood pressure (< 33 mmHg in the first 12 h of life; odds ratio 8.0 [2.0, 31.3]), receipt of a fluid bolus in the first 12 h of life (OR 19.7 [4.6, 84.3]), need for cardiopulmonary resuscitation in the first 72 h (OR 6.9 [1.5, 31.3]) and pneumothorax in the first 72 h of life (OR 27.0 [4.3, 167.2]). When analyses were restricted to infants who were not given a fluid bolus, the associations with chorioamnionitis and placental abruption were attenuated. When excluding infants who had a pneumothorax, the associations with placental abruption and multiple gestation were attenuated. Restriction of infants with systolic blood pressure < 33 mmHg resulted in attenuation of associations with pre-eclampsia and multiple gestation. These analyses suggest the possibility that potentially modifiable postnatal events may be involved as intervening factors linking chorioamnionitis, placental abruption and multiple gestation with subsequent intraparenchymal echodensity.

Trends in mortality and cerebral palsy in a geographically based cohort of very low birth weight neonates born between 1982 to 1994.

OBJECTIVE: To analyze whether the increasing survival of very low birth weight infants during the 1980s and 1990s has increased the risk of cerebral palsy among survivors. METHODS: The study cohort consisted of 2076 consecutively born infants, with birth weights of 500 to 1500 g and no major anomaly, born July 1, 1982, through June 30, 1994, to residents of a 17-county region in North Carolina. These infants had a mean birth weight of 1096 g (standard deviation, 251 g) and a mean gestational age of 29 weeks (standard deviation, 3 weeks). One thousand five hundred sixty-eight infants (76%) survived to 1 year adjusted age, at which point 1282 infants (82%) were examined at our medical center. The diagnosis of cerebral palsy was made only if the examining pediatrician and a pediatric physical therapist agreed on the diagnosis. To analyze trends across time, the Cochran-Armitage chi2 test and logistic regression were applied to data for infants categorized into six 2-year epochs according to year of birth. RESULTS: Mortality did not change significantly through 1990, and then began to decrease in 1990 to 1994. During the study period, mortality decreased from 36.8% between 1982 and 1984, to 13.8% between 1992 and 1994. The prevalence of cerebral palsy among survivors was constant from 1982 to 1988 (11.3%), decreased slightly from 1988 to 1990 (9.2%), and was lowest in 1990 to 1994 (5.2%). These secular trends in mortality and cerebral palsy risk remained significant when adjusted for gestational age, gender, and race. When adjusted for surfactant use, the trend in mortality was no longer significant, whereas the trend in cerebral palsy risk persisted. CONCLUSIONS: The increasing survival of very low birth weight infants in the 1980s and 1990s has not resulted in an increased prevalence of cerebral palsy among survivors.

Intrauterine infection and the risk of cerebral palsy in very low-birthweight infants.

Very low-birthweight infants constitute more than one-quarter of all new cases of cerebral palsy. We performed a case-control study of associations between antenatal maternal infection and cerebral palsy in very low-birthweight infants. Cases and controls were selected from a cohort of 1238 consecutive infants who: (1) had birthweights between 500 and 1500 g and no major congenital anomaly; (2) were born 1 January 1986 to 31 December 1993 to a mother residing in 1 of 17 counties in north-west North Carolina; and (3) were delivered at the only tertiary obstetric referral centre in those same 17 counties. A total of 984 of these infants (79%) survived to 1 year of age (adjusted for degree of prematurity) and were scheduled for a multidisciplinary examination; 815 (83%) came as scheduled. Excluding two cases attributable to post-neonatal events, 62 cases of cerebral palsy were identified. Controls were the two infants, without cerebral palsy, born closest in time to each case. Medical records were reviewed by a nurse who was not aware of which subjects were cases. Among possible markers of intra-amniotic infection, those associated most strongly with cerebral palsy were chorioamnionitis diagnosed by an obstetrician (odds ratio [OR] adjusted for gestational age [95% confidence limits] = 2.6 [1.0, 6.5]), antepartum maternal temperature > 37.8 degrees C (OR = 2.6 [1.1, 6.0]), uterine tenderness (OR = 2.6 [0.8, 9.3]), maternal receipt of antibiotics (OR = 2.2 [1.0, 4.7]) and neonatal sepsis in the first week of life (OR = 2.9 [0.9, 8.9]). All of these associations were stronger for diplegia than the other clinical subtypes of cerebral palsy. The association with chorioamnionitis and spastic diplegia persisted when adjusted for maternal magnesium sulphate receipt, maternal betamethasone receipt, method of delivery (vaginal vs. abdominal), acidosis on the neonate's initial arterial blood gas, systolic blood pressure < 30 mmHg and the diagnosis of major neonatal neurosonographic abnormality.

Prenatal events and the risk of cerebral palsy in very low birth weight infants.

The purpose of this study was to analyze associations between prenatal factors and cerebral palsy in a geographically based cohort of very low birth weight infants. Cases (n = 80) and controls had birth weights of 500-1,500 g and were born in 1978-1989, to a resident of one of 17 counties in northwest North Carolina. Medical records were reviewed for data about prenatal and neonatal factors. Associations were analyzed separately for three clinical forms of spastic cerebral palsy (hemiplegia, diplegia, and quadriplegia) and for cerebral palsy with and without antecedent major cranial ultrasound abnormalities. The following factors were associated most strongly with an increased risk of cerebral palsy: multiple gestation, chorioamnionitis, maternal antibiotics, antepartum vaginal bleeding, and labor lasting less than 4 hours. Preeclampsia and delivery without labor were associated with a decreased risk. Evidence of confounding was found for each of these associations, except for those with chorioamnionitis and labor lasting less than 4 hours. The association with chorioamnionitis was stronger for diplegia (compared with hemiplegia and quadriplegia) and for cerebral palsy without major cranial ultrasound abnormalities. Associations with antepartum vaginal bleeding (increased risk) and preeclampsia (decreased risk) were stronger for cerebral palsy occurring with major cranial ultrasound abnormality.

Survival and developmental disability in infants with birth weights of 501 to 800 grams, born between 1979 and 1994.

OBJECTIVE: Because the survival rate has increased for extremely low birth weight neonates, many have raised the concern that the rate of developmental disability among survivors will also increase. To address this concern, we analyzed changes over time in survival and major neurosensory impairment in a sample of extremely low birth weight infants born between July 1, 1979, and June 30, 1994. METHODS: The study sample included 513 infants with birth weights of 501 to 800 g who were cared for in either of the two neonatal intensive care units that serve a 17-county region in northwest North Carolina and who were born to mothers residing in that region. At 1 year of age (corrected for gestation), survivors were examined by a pediatrician and were tested using the Bayley Scales of Infant Development. Major neurosensory impairment was defined as cerebral palsy, a Bayley Mental Developmental Index <68, or blindness. A total of 209/216 (97%) of survivors were examined at 1 year of age. Epoch of birth was defined as follows: epoch 1, July 1, 1979 to June 30, 1984; epoch 2, July 1, 1984 to June 30, 1989; and epoch 3, July 1, 1989 to June 30, 1994. RESULTS: Survival rates for epochs 1, 2, and 3 were, respectively, 24/120 (20%), 63/175 (36%), and 129/218 (59%). In contrast, the proportions with a major neurosensory impairment did not increase over time; rates for successive epochs were 6/24 (25%), 17/61 (28%), and 26/124 (21%). Rates of cerebral palsy were 3/24 (13%), 12/61 (20%), and 9/124 (7%); rates of delayed mental development were 4/24 (17%), 12/61 (20%), and 17/124 (14%); and rates of blindness were 2/24 (8%), 0/62, and 5/124 (4%), respectively. CONCLUSIONS: This analysis suggests that the increasing survival of extremely low birth weight neonates since the late 1970s has not resulted in an increased rate of major developmental problems identifiable at 1 year of age.

Outcome at 4 to 5 years of age in children recovered from neonatal chronic lung disease.

Outcomes were compared for 31 very-low-birthweight children recovered from chronic lung disease and 31 very-low-birthweight controls. All children had been free of major abnormalities on neonatal cranial ultrasonography. At 4 to 5 years of age, children were examined by a pediatrician and tested by a psychologist who administered the Wechsler Preschool and Primary Scale of Intelligence-Revised. Despite similar medical outcomes, the children who had had neonatal chronic lung disease had lower Full-scale IQs (median 83 vs 87) and Performance IQs (79 vs 90). Median Verbal IQ was similar in the two groups (85 vs 87). A higher proportion of children who had had chronic lung disease had Full-scale IQ < 70 (8/31 [26%] vs 1/31 [3%]) and Performance IQ < 70 (8/31 [26%] vs 0/31). These effects persisted after adjustment for confounding factors.

Response to dexamethasone in ventilated preterm infants: effect of radiographic subtype of chronic lung disease.

We compared the response to prolonged treatment with dexamethasone in two groups of ventilated preterm infants: one whose chest radiographs showed homogenous opacity, and one whose radiographs showed cystic changes and hyperinflation. Forty-nine infants were treated with dexamethasone for 42 days, beginning when they were 15 to 27 days old, had no evidence of sepsis or patent ductus arteriosus, and had experienced no decrease in ventilator support for 24 hours. Forty-nine controls were selected who met these criteria for dexamethasone treatment. All had birthweights of 500 to 1250 g. Two radiographs made between 14 and 28 days of age were reviewed. Among infants with homogeneous opacity (19 dexamethasone, 26 controls), dexamethasone was associated with fewer days on assisted ventilation (median [interquartile range]: 7 [3-11] versus 23 [9-40]; p = 0.001). Among those with cystic changes and hyperexpansion (30 dexamethasone, 23 controls), no difference was found between dexamethasone treated infants and controls (17 [7-34] versus 32 [16-47]; p = 0.9). Thus, the effect of dexamethasone on days of ventilation was attenuated in infants with cystic changes and hyperinflation.

Follow-up of preterm infants treated with dexamethasone for chronic lung disease.

OBJECTIVE: To study the outcome of prolonged treatment with dexamethasone sodium phosphate in preterm infants who depend on assisted ventilation. DESIGN: Longitudinal follow-up using historic controls. SETTING: Regional intensive care nursery. PARTICIPANTS: Sixty-one very-low-birth-weight infants treated with a 42-day course of dexamethasone and 61 historic controls matched for birth weight, gestational age, race, and sex. All 122 subjects required assisted ventilation for at least 15 days. INTERVENTION: Infants were given dexamethasone sodium phosphate at a dose of 0.5 mg/kg per day. The dose was then tapered over 42 days. MEASUREMENTS/MAIN RESULTS: Infants treated with dexamethasone received assisted ventilation for a median of 33 days; controls, a median of 47 days (P < .05). One hundred infants survived; 94 were examined at age 1 year. The two groups were similar with respect to the proportions hospitalized for respiratory infection in the first year of life and the proportions with weight, length, and head circumference below the fifth percentile. Rates of cerebral palsy were also similar between the two groups, as were median Bayley Mental and Psychomotor developmental index scores. CONCLUSIONS: Dexamethasone treatment was associated with fewer days of assisted ventilation, but not with improved outcome at age 1 year. More assessment should be made of dexamethasone's effect on long-term outcome before dexamethasone becomes widely used in preterm infants who depend on assisted ventilation.

Reliability of interpretation of cranial ultrasound examinations of very low-birthweight neonates.

The authors studied intra- and inter-reader reliability of the interpretation of cranial ultrasound examinations of very low-birthweight infants. A radiologist read 173 films, 88 of which he had read previously; the other 85 had been read previously by a second radiologist. For the diagnoses of subependymal hemorrhage and intraventricular hemorrhage, intra-reader agreement was similar to inter-reader agreement. 98 ultrasound films were read initially as showing subependymal hemorrhage; in nine cases the second reading did not agree. In five of 58 cases read initially as showing intraventricular hemorrhage, the second reading did not agree. Similarly, of 32 cases read initially as showing intraparenchymal echo-density, four were interpreted as negative on second reading. For all three diagnoses, disagreement occurred often enough to cause substantial misclassification bias when cranial ultrasound is used for clinical research.

Serum bilirubin levels, intracranial hemorrhage, and the risk of developmental problems in very low birth weight neonates.

To study whether elevated levels of bilirubin in the neonatal period increase the risk of developmental problems for very low birth weight neonates, the investigators used data from a geographically based sample of 495 very low birth weight neonates, born January 1, 1985, to December 31, 1989, who survived to 1 year of adjusted age. Maximum neonatal bilirubin levels were found in medical records. A developmental problem was defined as either cerebral palsy or a Bayley Mental Developmental Index of less than 68 at 1 year adjusted age. Potentially confounding factors were controlled using logistic regression. To control for the effects of intracranial abnormalities (eg, intraventricular hemorrhage), separate logistic regression analyses were carried out for three strata, defined according to the results of cranial ultrasonography. In these analyses, the following odds ratios (with 95% confidence limits) were found for the association of maximum neonatal bilirubin concentration and developmental problems: for subjects without intracranial abnormalities, 0.9 (0.7, 1.9); for subjects with uncomplicated intracranial hemorrhage, 1.5 (0.8, 2.5); for subjects with complicated intracranial hemorrhage or intraparenchymal echo-densities, 1.2 (0.4, 3.6). In summary, in analyses controlled for confounding factors, maximum neonatal bilirubin level was not consistently associated with the risk of developmental problems identifiable at 1 year.

Outbreak of Candida bloodstream infections associated with retrograde medication administration in a neonatal intensive care unit.

An outbreak of candidemia involving five infants receiving total parenteral nutrition in the neonatal intensive care unit was investigated. Cultures of the intravenous fluids demonstrated that the retrograde medication syringe fluids were significantly more likely to be contaminated with Candida than were other fluids being administered to the infants (p less than 0.001). Candidemia was significantly associated with total parenteral nutrition (p = 0.04) and retrograde medication administration (p = 0.02). A survey of nursing practice found that reuse of the retrograde syringes was the most likely cause of contamination. Molecular typing showed that the strains of Candida albicans that were isolated from the bloodstream were also found in the retrograde syringes and that at least three strains of C. albicans and one strain each of Candida tropicalis and Candida parapsilosis were involved. In vitro growth curves demonstrated that Candida species had a selective growth advantage versus bacteria in the total parenteral nutrition fluid. An in vitro simulation of the retrograde medication administration system suggested that the outbreak probably developed after the frequency of changing intravenous tubing was decreased from every 24 hours to every 72 hours. The outbreak was terminated by using syringes only once and resuming intravenous tubing changes every 24 hours. Retrograde medication administration in association with total parenteral nutrition may increase the risk of Candida line infection.

Open spina bifida: does cesarean section delivery improve prognosis?

Records were reviewed retrospectively on 72 infants with open spina bifida followed from birth through one year of age. Thirty-two infants were born by cesarean section and 40 vaginally. The following variables were compared between the two groups: 1) mortality in the nursery and between nursery discharge and one year of age, 2) incidence of meningitis in the neonatal period, 3) length of initial hospital stay, and 4) neurologic and developmental status at one year. No significant differences were noted between the two groups. Although it has been suggested that cesarean section may improve the prognosis for infants with open spina bifida, our data do not support that conclusion.

Walker-Warburg syndrome with cleft lip and cleft palate in two sibs.

Two sibs are reported with Walker-Warburg syndrome including hydrocephalus, agyria, anterior chamber dysgenesis, and encephalocele. In addition, both had cleft lip and cleft palate and intrauterine growth retardation, findings not previously noted in this condition.