Effects of environmental factors on perinatal outcome: neurological development in cases of intrauterine growth retardation and school performance of children perinatally exposed to ionizing radiation.

We performed two studies to investigate environmental factors in relation to neurological development in infants. The first, a field study, examined the elementary school performance of 929 children who were born from mothers exposed to the atomic bombing of Hiroshima, Japan, August 6, 1945. The most severe mental retardation was observed in the group exposed between 8 and 15 weeks following fertilization, and the second most severely damaged group was exposed between 16 and 25 weeks. The second, a clinical investigation, examined infants in the perinatal center who survived intrauterine growth retardation (IUGR). Those who survived with abnormal neurological development had a mean growth arrest corresponding to a uterine height of 27 weeks of gestation. This was at an earlier stage than those who survived with normal neurological development and had a mean growth arrest corresponding to 29-30 weeks of gestation. A smaller head circumference at birth was closely correlated with abnormal neurological sequelae. These results indicate that the brain development of the fetuses may have been affected by neurotoxic events similar to ionizing radiation. We emphasize the importance of avoiding neurotoxic stress to pregnant women when the fetus is in the critical period of neuronal development, before 27 weeks of gestational age.

Significance of cardiovascular malformations in cystic hygroma: a new interpretation of the pathogenesis.

Fetuses with cystic hygroma or loose skin of the neck were studied chromosomally and phenotypically to clarify the relation between neck abnormality and cardiovascular malformations. Of 12 fetuses, 9 had chromosome abnormalities: 4 with 45,X, 3 with trisomy 21, one each with trisomy 13, dup 6q. One had normal chromosomes. Two cases, in which chromosome analysis was unsuccessful, were morphologically suspected to be trisomy 13. Nine of the 12 fetuses had either bilateral cystic hygroma of the neck (7 cases) or nuchal bleb (2 cases: trisomy 13 and dup 6q). Two of the 3 remaining cases (trisomy 21) had loose skin of the neck, and one had edematous swelling of the skin of the neck. Except for the last case of trisomy 21, 11 fetuses (91.7%) had severe and/or rare cardiovascular malformations. They were divided into 3 major groups: a) spectrum of hypoplastic left heart syndrome (45,X and dup 6q), b) double outlet right ventricle, agenesis of semilunar valve (trisomy 13), and c) abnormality of atrioventricular orifice or valves (trisomy 21). One fetus with normal chromosomes had persistent left superior vena cava instead of absent right one and calcification of myocardium. Histological observation of edematous skin demonstrated the abnormal distribution of lymph vessels, including their absence. Some cases showed hypoplastic thymus. To integrate the findings of the present study and the descriptions in the literature, a pathogenesis is hypothesized in relation to migration of neural crest cells and extracellular matrix.

Histologic observation of the ductus arteriosus in premature infants with intrauterine growth retardation.

The ductus arteriosus of 19 premature infants with intrauterine growth retardation (IUGR) (study group) was compared histologically with that of 22 infants without IUGR (control group). The two groups exhibited no significant differences in gestational age, age at death, and frequency of disseminated intravascular coagulation. Maternal complications, that is, pregnancy-induced hypertension, cesarean section, and low umbilical artery oxygen tension values, were seen more frequently (p < 0.01) in the study group than in the control group. The histologic changes of ductus arteriosus, such as fragmentation, coagulation necrosis of the intimal elastic lamina, hemorrhage with necrosis, and loosening of elastic fibers and muscles in the tunica media, were seen more frequently in the study group. These findings are suggestive of both the maturation process and the prenatal hypoxic response of premature IUGR fetuses with chronic hypoxia. These changes may have produced subsequent patent ductus arteriosus, which in turn may have induced pulmonary hemorrhage.

Intrauterine infection, magnesium sulfate exposure and cerebral palsy in infants born between 26 and 30 weeks of gestation.

OBJECTIVE: To identify prenatal events associated with cerebral palsy (CP) in infants born between 26 and 30 weeks of gestation. STUDY DESIGN: Case (n=22)-control (n=170) study was performed using a logistic regression model. RESULTS: Significant association of intrauterine infection with increased risk of CP was found in a logistic regression model that controlled for abnormal FHR patterns, placental infection, fetal acidosis at birth (umbilical artery pH<7. 1), and low Apgar score (<7) (odds ratio (OR) 5.47, 95% confidence interval (CI) 1.46-20.4). Magnesium sulfate exposure was associated with decreased risk (OR 0.13, CI 0.03-0.66) after exclusion of premature rupture of the membranes and abruptio placentae. In the magnesium exposure group, cases were infants born less than 28 weeks of gestation (3/21 vs. 0/61, P=0.015). CONCLUSION: In this case-control study, both intrauterine infection and magnesium sulfate exposure were significant factors related to the occurrence of cerebral palsy.

Treatment for necrotizing enterocolitis perforation in the extremely premature infant (weighing less than 1,000 g).

The frequency of necrotizing enterocolitis (NEC) in the extremely premature infant (less than 1,000 g) is still high and it is very difficult for infants weighing less than 1,000 g with NEC perforation to survive. In our institutes, the management protocol for NEC perforation in infants weighing less than 1,000 g includes peritoneal drainage under local anesthesia, administration of coagulating factor XIII, and the usual treatment for septic shock. During the past 3 years, four infants weighing less than 1,000 g with NEC perforation have survived using this protocol without laparotomy. This management protocol is the treatment of choice in infants in very poor condition or infants weighing less than 1,000 g with NEC perforation.

Comparison of circulatory effects between arginine vasopressin (AVP) and dopamine in conscious newborn goats.

By using conscious chronically instrumented newborn goats, the circulatory effect of arginine vasopressin (AVP) (20 mIU/kg/ min) was studied, assuming a potential use for AVP to treat circulatory failure in the newborn, and the results were compared with those of dopamine (20 micrograms/kg/min). The AVP infusion decreased heart rate (HR) and cardiac output (CO) significantly, and increased systemic arterial pressure (SAP) and pulmonary arterial wedge pressure (PAWP) significantly, but did not change pulmonary arterial pressure (PAP) appreciably. The dopamine infusion did not change HR, SAP, and PAWP but increased CO and PAP significantly. Right atrial pressure (RAP) increased significantly in both groups. The pulmonary vascular resistance (PVR) increased significantly in both groups. The systemic vascular resistance (SVR) increased significantly in the AVP group, but did not change during experiments in the dopamine group. The calculated PVR/SVR ratios decreased significantly from the baseline value after initiation of the AVP infusion. In contrast, the dopamine infusion increased PVR/SVR ratios significantly throughout the experiments. Persistent pulmonary hypertension of the newborn (PPHN) is a syndrome characterized by right-to-left shunting of blood at the level of the foramen ovale and ductus arteriosus. AVP may reduce the shunting of blood by elevating only SAP selectively.

[Fungal keratitis in a daily disposable soft contact lens wearer]. / Kératite fongique et lentilles cornéennes jetables Journalières.

A case of fungal keratitis was diagnosed in a young female who had been wearing daily disposable soft contact lenses for 2 Years. No risk factor was demonstrated and specific treatment was effective. This case emphasizes that patients must be aware of the importance of hygiene as daily disposable contact lenses must be discarded daily.

[The perinatal risk factors and periventricular leukomalacia (PVL) in premature infants--relationship between fetal heart rate decelerations and PVL].

Periventricular leukomalacia (PVL) has recently been recognized as an important risk factor of neurological impairment in premature infants. We studied 29 PVL cases on perinatal risk factors comparing with a non-PVL matched control group retrospectively. Variable decelerations were more frequently observed with statistical significance in the PVL group in the intrapartum period. Then another study was conducted to evaluate the relationship between fetal heart rate (FHR) decelerations and cystic PVL prospectively. Since January 1993 through December 1994 we studied 209 low birth weight infants (31.1 +/- 3.2 weeks, 1,424 +/- 419 g) who had been subjected to intrapartum FHR monitoring and postnatal sonographic intracranial examinations sequentially every 7 days until discharge. Cystic PVL was detected in 6 of 209 cases (2.9%) and occurred only in infants who had revealed severe variable deceleration or prolonged deceleration (6/37, 16%) in intrapartum FHR monitoring. We conclude that in low birth weight infants intrapartum severe variable deceleration or prolonged deceleration might play a causal role in cystic PVL.

Effects of supplemental oxygen on urinary 8-hydroxy-2'-deoxyguanosine levels in extremely low birth weight infants.

As the effects of supplementary oxygen on urinary excretion of 8-hydroxy-2'-deoxyguanosine (8-OHdG) are poorly understood, urinary 8-OHdG levels (ng/mg creatinine) were determined longitudinally on the postnatal day (PND) 1, 3, and 30 in 16 neonates with birth weight < 1000 g. No supplementary oxygen was required in 9 neonates during the first 24 h of life. Urinary 8-OHdG level on PND 1 was inversely correlated with birth weight in these 9 neonates (P = 0.0323) and was higher in four with birth weight < 750 g than five with birth weight > 750 g (41.0 ± 6.9 vs. 5.6 ± 2.7, respectively, P = 0.0200). Median urinary 8-OHdG on PND 1 of these 9 neonates was significantly lower than that of 7 neonates with oxygen (9.3 vs. 60.2, respectively), although there were no significant differences in clinical background, such as birth weight, between the two groups. Five of the 9 did not require supplemental oxygen at all during the first 30 days of life. Median urinary 8-OHdG levels were consistently significantly lower in the 5 neonates than in 11 neonates with oxygen transiently or persistently (9.3 vs. 54.6, 19.1 vs. 61.4, and 28.3 vs. 145 on PND 1, 3, and 30, respectively), although there were no differences in clinical background, such as birth weight, between the two groups. Urinary 8-OHdG on PND 30 was significantly positively correlated with supplemental oxygen dose on PND 30 (P < 0.0001), but not with birth weight in the 16 neonates. These results suggest that higher supplemental oxygen tension caused higher urinary 8-OHdG in this population.

Radiographic findings of diaphragmatic hernia and hypoplastic lung.

OBJECTIVE: Congenital diaphragmatic hernia (CDH) has a poor prognosis, despite intensive management. The prognosis of CDH is correlated with hypoplastic lung, but it is difficult to measure the degree of hypoplasia. The aims of this study were, therefore, to examine the relationship between chest X-ray and prognosis, and to assess whether the radiographic findings were a good indicator of hypoplastic lungs in patients with CDH. STUDY DESIGN: Fifty neonates with CDH were classified radiographically into apex and hilar types. To assess the differences in clinical course between these two groups, gestational age, birth weight, prenatal diagnosis, survival rate, requirement of extracorporeal membrane oxygenation (ECMO) therapy and lung area on X-rays were analyzed. RESULTS: In all, 32 cases were of the apex type and 18 were hilar. The survival rate of the hilar group (33%) was significantly worse than that of the apex group (81%) (P<0.001). The hilar group required ECMO therapy more frequently than did the apex group. CONCLUSIONS: The present results show a significant correlation between survival rate and the findings of chest X-rays in CDH. Radiographic findings are thus a good clinical indicator of the prognosis of CDH in neonates.

[The efficacy of prophylactic antibiotic and tocolytic therapy for premature rupture of the membranes--a prospective randomized study].

A comparative study in patients with premature rupture of the membranes (PROM) from 25 to 34 weeks of gestation was carried out, prospectively. Group 1 (34 patients) was given aggressively intrauterine therapy including the administration of tocolytic agents (ritodrine and/or magnesium sulfate) and prophylactic antibiotics (AB-PC 2g/day). Group 2 (41 patients) was managed conservatively with bed rest only. At the time of admission to the study, there were no clinical signs of infection, fetal distress, or active labor in either group. All patients were delivered if the pregnancy had reached 35 weeks of gestation or later, had established labor, or developed evidence of chorioamnionitis or fetal distress. Prolongation for more than 72 hours was greater in group 1 than in group 2. There was no difference in the incidence of chorioamnionitis, postpartum endometritis, or placental infection in the groups. However, the incidence of a low Apgar score (7 < at 5 min), requiring artificial ventilation, and infection was more common in group 1. It is concluded that the use of antibiotics and tocolytics might make the management of PROM more complicated.

The effect of nicardipine on maternal and fetal hemodynamics and uterine blood flow in chronically instrumented pregnant goats.

This study was designed to clarify the maternal and fetal hemodynamics of nicardipine (0.02 mg/kg) administered intravenously to unanesthetized, chronically instrumented pregnant goats. Nicardipine produced a significant increase in maternal heart rate and cardiac output, and a significant decrease in maternal mean arterial blood pressure and systemic vascular resistance. These changes persisted for about 30 minutes. There were no consistent changes in maternal pulmonary hemodynamics. Uterine arterial blood flow (UBF) decreased significantly (about 15%) after 5 minutes of the injection and returned to the control value within 30 minutes. A significant correlation between the decreases in UBF and maternal diastolic blood pressure was observed after 5 minutes of the injection. The fetal heart rate, blood pressure and acid-base status did not change after the injection of nicardipine. These observations of pregnant goats suggest that nicardipine might be a useful agent for the treatment of acutely hypertensive crises in pregnant patients.

Variation of des-gamma-carboxyprothrombin (PIVKA-II) levels in cord blood throughout gestation.

The variation of des-gamma-carboxyprothrombin (PIVKA-II, protein induced by vitamin K absence) levels in umbilical cord blood throughout gestation was examined using a highly sensitive method, electrochemiluminescence immunoassay (ECLIA). PIVKA-II levels in infants without any complications were low, but modestly high, exceeding the normal range of healthy adults during the preterm period, followed by a remarkable increase after the 37th week of gestation. Among infants complicated with severe preeclampsia a marked increase of PIVKA-II levels was observed in preterm infants, showing a good correlation with the existence ofinfarctions on the placenta. On the other hand, among infants complicated with preterm premature rupture of the membranes (PROM) in which antibiotics were administered during the prenatal period, a moderate elevation of PIVKA-II levels was observed. These data suggest that the normal range of PIVKA-II in fetuses is modestly high compared with adults and any deficient status of vitamin K would not exist throughout the preterm period. Nevertheless, the vitamin K status might readily fall into a deficient condition in term infants. Furthermore, it is notable that vitamin K deficiency would be induced in complicated gestation with severe preeclampsia and medication with antibiotics.

National survey of periventricular leukomalacia in Japan.

BACKGROUND: Clarification of the present status of periventricular leukomalacia (PVL) in Japan. METHODS: Questionnaires were mailed to the leading neonatal intensive care units (NICU) and rehabilitation centers for children. RESULTS: The incidence of PVL in the group of surviving preterm infants of gestational ages less than 33 weeks was 4.8-4.9% on ultrasound and 7.7-7.9% on magnetic resonance imaging and/or computed tomography. The incidence of PVL did not decrease between 1990 and 1994. The incidence of PVL in the NICU varied from 0 to 47.1%. Infants from multiple pregnancies had a higher incidence (9.1%) of PVL than those from single pregnancies (6.2%). The proportion of PVL in all patients in rehabilitation centers with cerebral palsy (CP) has increased recently. CONCLUSIONS: It was roughly calculated that about 750 cases of CP with PVL occurred annually in Japan, thus accounting for about one-third of the total number of cases of CP.

Echocardiographic findings of pulmonary atresia or critical pulmonary stenosis and intact ventricular septum in utero.

BACKGROUND: Neonates with right ventricular outflow obstruction and intact ventricular septum show serious hemodynamic problems, such as severe hypoxemia, congestive heart failure due to massive tricuspid regurgitation, respiratory distress related to huge pulmonary hypoplasia or ventricular dysfunction due to right ventricle-coronary communication. Recent advances in fetal diagnosis include many cases of in utero diagnosis of pulmonary atresia or critical pulmonary stenosis and intact ventricular septum. METHOD: Among the fetuses examined from April 1994 to March 1998, five fetuses were found with pulmonary atresia (PA) or critical pulmonary stenosis (CPS). Fetal echocardiograms were reviewed to elucidate the accuracy of fetal information and the efficacy of fetal diagnosis in the perinatal management of patient with CPS or PA and intact ventricular septum. RESULTS: The five cases were divided into two groups: two with a very small right ventricle (group 1) and three with a tripartite right ventricle (group 2). Fetal cardiomegaly and right atrial dilatation were prominent in group 2, whereas cardiac sizes were normal in group 1. Serial fetal examination in one group 2 fetus revealed developing right ventricular hypertrophy in utero. All group 2 cases showed massive tricuspid regurgitation (TR). Estimated right ventricular pressures from TR always exceeded the systemic blood pressures of gestational age-matched neonates. Reversed flow through the ductus arteriosus was recorded in both groups and ductus-dependent pulmonary circulation after birth was anticipated. Patency of both tricuspid and pulmonary valves was difficult to recognize in utero, as was right ventricle-coronary artery communication. Four of the five cases were maternally transported and survived palliative and/or definitive intervention. One fetus with chromosomal abnormality was observed without intervention during infancy and received palliative surgery when she was two years old. CONCLUSION: Fetal hemodynamic information was useful for making decisions not only after birth, but also in utero, and may eventually result in improving the prognosis of babies with PA/CPS. Serial observation of the fetuses with PA/CPS may also suggest the possible pathogenesis of PA/CPS in utero.

Neonatal 24-hour urinary C-peptide and birth weight in infants of diabetic mothers.

OBJECTIVE: Our purpose was to investigate the relationship between the birth weights and 24-h urinary C-peptide in infants of diabetic mothers. METHODS: Sixty pregnancies with gestational diabetes mellitus (DM) were enrolled. Neonatal urine was collected for the first and second 24 h for measuring C-peptide. Birth weights were classified into 3 categories according to the Japanese standard curves; heavy-for-date (HFD), appropriate-for-date (AFD), and light-for-date (LFD). Unpaired t-test was used for comparison of 24-h urinary C-peptide in the 3 birth weight categories, with P-value <0.05. There were 7 HFD, 47 AFD, and 6 LFD infants. Birth weight averaged 3.9+/-0.7, 3.0+/-0.4, and 2.3+/-0.3 kg, respectively. RESULTS: Insulin concentrations of the umbilical artery were significantly higher in HFD than in AFD, and significantly higher in AFD than in LFD (49.5+/-45.1, 16.8+/-15.2, and 6.3+/-6.1 microU/ml). During the first 24 h, urinary C-peptide was significantly higher in HFD than in AFD (2.73+/-1.52 vs. 0.76+/-0.81 microg/day), and significantly higher in AFD than in LFD (0.27+/-0.27). On the second day, there was no longer statistical significance. CONCLUSIONS: Measurement of 24-h urinary C-peptide revealed that, among infants of diabetic mothers, HFD infants continue to secrete more insulin than AFD and LFD infants for the first 24 h.

Fetal glioblastoma: rapid growth during the third trimester.

We present a case of fetal glioblastoma which appeared after 28 weeks' gestation. The first ultrasonographic finding was an enlarged fetal head with right shifted falx cerebri at 31 weeks' gestation. At 33 weeks, a large and high echogenic mass in the left hemisphere and right enlarged ventricle was identified. Magnetic resonance imaging showed that the tumor was localized in the left hemisphere and a margin of the tumor was defined. Because fetal well-being judging from biophysical parameters was good and we considered that the tumor was resectable, a male fetus weighing 2,670 g was delivered at 34 weeks' gestation by cesarean section. However, he was inoperable due to consumptive coagulopathy and rapid growth of the tumor, and died on the 41st day of life.

Experimentally produced sinusoidal fetal heart rate pattern in the chronically instrumented fetal lamb.

A sinusoidal fetal heart rate and elevated fetal arginine vasopressin levels were found in two bled fetal lambs. Arginine vasopressin was continuously infused intravenously in chronically instrumented fetal lambs at rates ranging between 1.0 and 90 mlU/kg/min. No sinusoidal heart rate occurred in 21 experiments on six control animals with intact vagal nerves. Atropine at doses less than 0.4 mg had no effect (six experiments on three animals). Higher doses of atropine (greater than 1.2 mg) resulted in sinusoidal heart rate (24 experiments on six animals). Twenty-three infusions were performed in five bilaterally vagotomized fetuses, and the sinusoidal heart rate was successfully induced in 17 experiments. The arginine vasopressin infusion rate was less than 1.5 mlU/kg/min on the six occasions in which the sinusoidal heart rate did not appear. All sinusoidal heart rate patterns were associated with fluctuation of fetal arterial pressure at the same frequency. There was a linear correlation between the amplitude of sinusoidal heart rate and magnitude of arterial blood pressure fluctuation. The amplitude of sinusoidal heart rate increased with the concentration of arginine vasopressin infused. Modification of sinusoidal heart rate pattern was attempted with use of sympathetic agonists and antagonists. The possible etiology and mechanisms of sinusoidal heart rate pattern are discussed.

Effect of arginine vasopressin on arterial oxygen partial pressure in the chronically catheterized fetal lamb.

Fetal plasma 2,3-Diphosphoglycerate (2,3-DPG) and glucose levels were observed during infusion of arginine vasopressin into 6 chronically catheterized fetal lambs. Low dose infusion of arginine vasopressin (5-10 mIU/min.) did not change fetal arterial blood gases significantly. At a high concentration of vasopressin (20-40 mIU/min.), infusion for 60 minutes increased fetal arterial pO2 by approximately 5 mmHg (p less than 0.005 by paired t-test), and decreased pCO2 by approximately 2 mmHg (p less than 0.005 by paired t-test) without significant changes in pH. Neither low nor high dose infusion of arginine vasopressin was accompanied by significant changes in 2,3-DPG or the glucose level.