Vertical transmission of HIV-1: maternal immune status and obstetric factors. The European Collaborative Study.

OBJECTIVE: To estimate the effect of maternal factors and events around the time of delivery on HIV-1 vertical transmission risk. DESIGN: Prospective study. SETTING: Twenty-two obstetric and paediatric clinics in seven European countries. PATIENTS OR OTHER PARTICIPANTS: Mothers identified as HIV-infected before or at delivery and their children. MAIN OUTCOME MEASURE: Paediatric HIV infection. RESULTS: By November 1995, 1846 mothers with 1945 children had been enrolled. The vertical transmission rate was 16.4% (95% confidence interval, 14.5-18.3). Parity, maternal age, race, mode of HIV acquisition, injecting drug use and sex of infant were not statistically significantly associated with risk of transmission. Children delivered vaginally were more likely to be infected than those delivered by Caesarean section. However, in vaginal deliveries the procedures used, duration of ruptured membranes or length of second-stage labour were not related to transmission. Transmission increased almost linearly with decreasing CD4 cell count, but there was no such trend for CD8 cell count. Women with CD4 cell counts below 200 x 10(6)/l were significantly more likely to deliver early (chi 2 for trend, 14.02; P < 0.001). Very premature infants were at increased risk of infection, but after about 35 weeks gestation the transmission rate remained stable, with no increase in late pregnancy. This trend was confirmed after allowing for maternal CD4 cell count. CONCLUSIONS: The rate of vertical transmission increases linearly with decreasing maternal CD4 cell count. Women with fewer than 200 x 10(6) CD4 cells/l have an increased risk of premature delivery, which would affect timing of interventions. The stable transmission rate after 35 weeks gestation suggests little acquisition of infection during late pregnancy.

HIV-1 proviral DNA polymerase chain reaction detection in chorionic villi after exclusion of maternal contamination by variable number of tandem repeats analysis.

OBJECTIVE: The study of the placental HIV infection in cases of seropositive pregnant women after exclusion of maternal contamination of chorionic villi samples by variable number of tandem repeats (VNTR) analysis. METHODS: We studied 30 HIV-positive women: 17 terminated their pregnancy (11 in the first trimester and six in the second) and 13 delivered at term (one was a twin gestation). We selected chorionic villi and ruled out maternal contamination by VNTR analysis. DNA from chorionic villi and cord and maternal blood were tested for HIV by PCR. All infants underwent a paediatric follow-up. RESULTS: All maternal blood samples tested positive for HIV-1 by polymerase chain reaction. No maternal contamination was revealed and HIV was found in six out of 11 first trimester placentas, in all second trimester samples, and in 10 out of 14 at term. Cord blood tested positive in all second trimester cases and in seven out of 14 liveborns. In no case was HIV found in cord blood without infection of the corresponding placenta; conversely, three placentas tested positive but cord blood was negative. Two infants were HIV-positive, 11 were uninfected (one case was lost to follow-up). CONCLUSION: Our study indicates that HIV-1 can infect the placenta from first trimester onwards. HIV was found in two-thirds of our cord blood samples but it is possible that some viral DNA in cord blood may have come from infected placental cells. Additional studies are needed to assess the source of HIV in cord blood and the possible contribution of placental or maternal cells infected with HIV to vertical transmission of the virus.

Maturation of hypothalamic-pituitary-gonadal function in normal human fetuses: circulating levels of gonadotropins, their common alpha-subunit and free testosterone, and discrepancy between immunological and biological activities of circulating follicle-stimulating hormone.

The recent availability of both cordocentesis, a low risk and effective technique for fetal blood sampling, and ultrasensitive/highly specific two-site immunofluorometric assays (IFMA) for pituitary and chorionic glycoprotein hormone (I-LH, I-FSH, and I-CG) measurement prompted us to study the maturation of hypothalamic-pituitary-gonadal function in 114 normal human fetuses (49 females and 65 males) from 17-40 weeks gestation. The subjects were selected from 216 consecutive cordocenteses carried out for rapid karyotyping and diagnosis of fetal infection or hematological disorders. In addition, FSH bioactivity (B-FSH) was measured by rat Sertoli cell aromatase induction assay, glycoprotein hormone alpha-subunit (alpha-SU) by RIA, and circulating free testosterone (fT) by direct analog technique. No significant cross-reactions were recorded in the different measurement methods. In particular, alpha-SU did not interfere in any IFMA, and CG cross-reactivity in LH IFMA was 0.5%. Circulating I-LH, I-FSH, and B-FSH levels at 17-24 weeks gestation were significantly higher in female than in male fetuses (I-LH, 48 +/- 4 vs. 6.3 +/- 0.7 U/L; I-FSH, 35 +/- 2 vs. 0.7 +/- 0.1 U/L; B-FSH, 131 +/- 17 vs. 43.4 +/- 5.4 U/L). During the last weeks of gestation, a significant decrease in I-LH and I-FSH levels was seen in both female and male fetuses (I-LH, 0.24 +/- 0.05 and 1.0 +/- 0.3 U/L; I-FSH, 0.45 +/- 0.1 and 0.5 +/- 0.1 U/L), while serum B-FSH remained elevated, but the previously recorded difference between sexes disappeared (54.3 +/- 7.2 and 58.7 +/- 7.3 U/L). Circulating I-CG and alpha-SU levels at midgestation were elevated in both female and male fetuses (I-CG, 117 +/- 29 and 191 +/- 44 U/L; alpha-SU, 143 +/- 16 and 105 +/- 9 micrograms/L, respectively) and decreased thereafter (I-CG, 42 +/- 9 and 26 +/- 6 U/L; alpha-SU, 60 +/- 15 and 37 +/- 6 micrograms/L). Serum fT levels at midgestation were significantly lower in females than in males (4.3 +/- 0.9 vs. 10.0 +/- 0.8 pmol/L) and increased until term, when the difference between sexes disappeared (16.2 +/- 1.8 vs. 17.6 +/- 1.6 pmol/L).(ABSTRACT TRUNCATED AT 400 WORDS)

Placental transport of leucine, phenylalanine, glycine, and proline in intrauterine growth-restricted pregnancies.

L-[1-13C]Leucine, [1-13C]glycine, L-[1-13C]phenylalanine, and L-[1-13C]proline were infused as a bolus into the maternal circulation of seven appropriate for gestational age at 30.3 +/- 3.0 wk and 7 intrauterine growth-restricted pregnancies at 26.5 +/- 1.0 wk gestation to investigate placental transport in vivo. Umbilical venous samples were obtained at the time of in utero fetal blood sampling at 450 +/- 74 sec from the bolus injection. In normal pregnancies the fetal/maternal (F/M) enrichment ratios for leucine (0.76 +/- 0.06) and phenylalanine (0.77 +/- 0.06) were higher (P < 0.01) than the F/M ratios for glycine (0.18 +/- 0.04) and proline (0.22 +/- 0.02). This suggests that these two essential amino acids rapidly cross the placenta in vivo. Compared with the essentials, both glycine and proline had significantly lower F/M enrichment ratios, which were not different from each other. The results support the hypothesis that amino acids with high affinity for exchange transporters cross the placenta most rapidly. In intrauterine growth-restricted pregnancies, the F/M enrichment ratio was significantly lower (P < 0.01) for L-[1-13C]leucine (0.76 +/- 0.06 vs. 0.48 +/- 0.07) and for L-[1-13C]phenylalanine (0.77 +/- 0.06 vs. 0.46 +/- 0.07) compared with appropriate for gestational age pregnancies reflecting impaired transplacental flux. The F/M enrichment ratio did not differ for [1-13C]glycine (0.18 +/- 0.04 vs. 0.17 +/- 0.03), and L-[1-13C]proline (0.22 +/- 0.02 vs. 0.18 +/- 0.04).

Plasma beta-endorphin, beta-lipotropin, and met-enkephalin concentrations during pregnancy in normal and drug-addicted women and their newborn.

Most studies of plasma beta-endorphin concentrations in pregnant women show that these are highly elevated. This might indicate a role for opiate peptides during pregnancy and in the fetus-mother relationship. We measured plasma beta-endorphin, beta-lipotropin, and met-enkephalin concentrations in normal and drug-addicted women during pregnancy, labor, and delivery, and in their newborn infants. Peptides were measured by RIA after extraction and concentration on silica columns and separation by high pressure liquid chromatography. In both normal and drug-addicted mothers we found an increase in plasma beta-endorphin during pregnancy, without a concomitant increase in plasma beta-lipotropin or metenkephalin. Only beta-lipotropin increased dramatically in both groups at delivery, whereas beta-endorphin and met-enkephalin remained unchanged. Peptide concentrations in umbilical plasma were similar to those in peripheral plasma of the mothers. On day 1 of life plasma beta-endorphin, beta-lipotropin, and met-enkephalin concentrations in the newborn from normal mothers were higher than in nonpregnant adult subjects and gradually decreased toward normal adult values by day 5 of life. Plasma beta-endorphin, beta-lipotropin, and met-enkephalin concentrations of newborn infants of drug-addicted mothers increased dramatically on day 2 and 3 of life, up to 1000-fold the concentrations of normal adults, and remained elevated up to 40 days after birth. In conclusion, beta-endorphin, beta-lipotropin, and met-enkephalin concentrations during pregnancy are not affected by drug addiction, whereas in the newborn of drug addicted mothers concentrations of these compounds are markedly increased.

Placental transfer to diazepam and its disposition in the newborn.

Diazepam (DZ) placental transfer in pregnant women at term, following single or repeated drug administration by various routes, was evaluated. DZ and its metabolite N-demethyldiazepam (NDZ) were constantly present in umbilical cord plasma at concentrations comparable to the mother's shortly after drug administration. N-methyloxazepam (MOX) was detected in cord plasma only in a limited number of cases following chronic DZ treatment. Postmortem analysis of fetal tissue concentrations showed accumulation of NDZ in heart and lungs. Differences in NDZ concentrations between venous cord (VC) and arterial cord (AC) plasms suggest metabolic degradation of DZ in the fetus. The DZ apparent plasma half-life in the newborn was found to be longer (31 plus or minus 2 hr) than previously observed in infants and children. The low drug clearance appears to be linked to reduced urinary excretion of hydroxylated metabolites, suggesting limited capability to dispose of DZ in the newborn.

Cationic amino acid transporter activity in the syncytiotrophoblast microvillous plasma membrane and oxygenation of the uteroplacental unit.

The purpose of this study was to determine whether there is any relationship between the activity of cationic amino acid transporters in the microvillous plasma membrane (MVM) of the syncytiotrophoblast and the oxygenation of the uteroplacental unit. Oxygenation data were obtained at the time of caesarean section from the uterine veins, the maternal radial artery and the umbilical vessels of 7 normal (AGA) and 13 intrauterine growth restricted (IUGR) pregnancies. Microvillous plasma membranes were isolated from the same placentas and the activity of the system y(+) and y(+)L cationic amino acid transporters determined by measuring (3)H- l -arginine uptake in the presence and absence of l -glutamine. In IUGR pregnancies uterine venous Po(2) was significantly higher (AGA=44.7+/-8.0 mmHg; IUGR=57.2+/-2.3 mmHg, P< 0.05) and umbilical venous Po(2) was significantly lower (AGA=33.4+/-3.0 mmHg; IUGR=25.1+/-2.0 mmHg, P< 0.05) than in AGA pregnancies. System y(+)L activity, but not system y(+) activity, was inversely correlated with uterine venous Po(2) (P< 0.01; r(2)=0.4) in AGA and IUGR pregnancies. In IUGR pregnancies without associated maternal pre-eclampsia, y(+)L activity, but not y(+) activity, was also directly related to the umbilical O(2) content difference (P< 0.01; r(2)=0.9). A significant negative correlation was found between system y(+) and the umbilical O(2) content difference in AGA pregnancies (P< 0.01; r(2)=0.9). Our data are consistent with the hypothesis that in IUGR fetuses uterine oxygenation is not reduced and can be increased. The inverse correlation between system y(+)L activity and uterine venous Po(2) and the correlations with umbilical venous-arterial O(2) content difference suggest a relationship between cationic amino acid transporter activity and oxygen tension in the uteroplacental unit.

Uterine Doppler velocimetry and placental hypoxic-ischemic lesion in pregnancies with fetal intrauterine growth restriction.

We tested the hypothesis that Doppler velocimetry of the ascending uterine arteries (Ut.DV) in cases of fetal intrauterine growth restriction (IUGR) can reflect the presence of hypoxic-ischaemic lesions of the placenta, and whether this prediction is affected by the maternal blood pressure status.Ut.DV was obtained within 7 days of delivery in 90 consecutive pregnancies with IUGR and in 37 uneventful control pregnancies. Abnormal Ut.DV was defined as an average of a (left and right systolic)/diastolic ratio >2.6 and diastolic notching. After delivery, pathological studies were performed with attention paid to macroscopic and microscopic evidence of hypoxic or ischaemic placental lesions related to uteroplacental vascular pathological features. In patients with IUGR, the total rate of placental lesions was significantly higher in the presence of abnormal Ut.DV compared to the presence of normal Ut.DV (relative risk, 6.35; 95 per cent confidence interval=5.2-7.3). The rate and the severity of these lesions was not significantly different between normotensive and hypertensive pregnancies (87 versus 93 per cent;P =0.2). When Ut.DV was normal, the rate of placental lesions was similar between IUGR cases and control pregnancies (14 versus 8 per cent;P =0.69). The perinatal outcome was not significantly different in any of the normotensive and the hypertensive pregnancies with growth-restricted fetuses and abnormal Ut.DV.The presence of abnormal Doppler velocimetry of the uterine arteries in pregnancies with fetal intrauterine growth restriction is may be in fact an important indicator of hypoxic or ischaemic placental lesions. This abnormal Doppler velocimetry is independent of the maternal blood pressure status.

Post-zygotic origin of complete maternal chromosome 7 isodisomy and consequent loss of placental PEG1/MEST expression.

Maternal UPD of chromosome 7 is associated with pre- and postnatal growth retardation (IUGR, PNGR) and Silver-Russell syndrome (SRS [MIM 180860]). We report a case of IUGR in a newborn with SRS stigmata. Using combined haplotyping and cytogenetic-FISH studies we characterized the lymphocytes, umbilical cord and four placental cotyledons. The results are consistent with complete maternal isodisomy 7 and trisomy 7 mosaicism of post-zygotic origin. The trisomic cell line was prevalent in trophoblast cells from two placental cotyledons. Trisomy 7 of post-zygotic origin is a frequent finding, but maternal isodisomy 7, due to trisomic rescue has never been reported. PEG1/MEST expression was evaluated on placenta cDNA and a specific transcript was revealed only in the cotyledons with a high percentage of trisomic cells and the presence of the paternal chromosome 7 contribution, but not in the placental biopsies with maternal isodisomy 7. The histological features of the four placental fragments revealed that isodisomy 7 correlates with a pattern of cotyledonary hyper-ramification due to an increase of the branching angiogenesis, which could be the result of a defect of angiogenesis caused by the absence of PEG1 product. The severe hypo-ramification of the two cotyledons, showing trisomy 7 mosaicism, may be due to the triplicate dosage of genes on chromosome 7. The delayed fetal growth could be the phenotypic effect of the imbalance between imprinted and non-imprinted genes on chromosome 7 in the fetus or the result of abnormal placental function during pregnancy.

A multiple infusion start time (MIST) protocol for stable isotope studies of fetal blood.

A new approach utilizing multiple infusion start times for two stable isotopes of leucine was applied to seven pregnancies in order to assess equilibration times for isotopic studies when a single fetal blood sample is available. Two infusates, one containing l -[1-(13)C]-leucine and the other l -[5,5,5-D3]-leucine, were given as a primed constant infusion in the maternal circulation at fetal blood sampling (FBS). In five patients l -[1-(13)C]-leucine infusion was started at time zero (T(0)) whereas l -[5,5,5-D3]-leucine infusion began 30 min later, and both were continued until the umbilical sample was obtained at 149.7+/-8.8 min. In order to assure non-steady state conditions, in two patients the first infusion started at T(0)and the second 17 and 6 min before FBS was performed at 115 and 154 min, respectively. The fetal/maternal ratio for l -[5,5,5-D3]-leucine over the fetal/maternal ratio for l -[1-(13)C]-leucine was 0.98+/-0.03, indicating steady state conditions for both infusions for the first six patients. In the last patient the ratio was 0.51, indicative of non-steady state conditions for the shortest infusion time. Our results show that a single fetal sample can provide data for fetal amino acid enrichments reflecting multiple time points. Leucine steady state is achieved 20 min after a primed continuous infusion both in the maternal and fetal circulations.

An evaluation of fetal glucogenesis in intrauterine growth-retarded pregnancies.

The presence of fetal glucogenesis was evaluated in nine patients with pregnancies complicated by intrauterine growth retardation (IUGR) at the time of fetal blood sampling (FBS) between 29 and 35 weeks of pregnancy. Eight were singleton pregnancies and one was a twin pregnancy in which blood samples were obtained from both twins. A maternal primed-constant infusion of D(U-13C]glucose was performed, and the presence of fetal glucogenesis was assessed by a comparison of steady-state maternal and fetal glucose enrichments. No significant difference was present between maternal and fetal molar percent excess ([MPE] P = .97), and the mean fetal to maternal (F/M) MPE ratio (0.99 +/- 0.01) was not significantly different from 1 (P = .76). F/M MPE ratio was independent of the time of FBS and umbilical venous glucose and lactate concentrations. Thus fetal glucogenesis is not demonstrable in a group of fairly severe growth-retarded fetuses after an overnight fast with this relatively noninvasive approach.

The relationship of maternal and fetal glucose concentrations in the human from midgestation until term.

The relationship between maternal and fetal glucose concentrations was investigated in pregnant women at different gestational ages. Maternal and fetal blood samples were obtained during 14 fetoscopies (17 to 21 weeks), four umbilical cord samples (32 to 36 weeks), nine elective cesarean sections with appropriate for gestational age (AGA) fetuses (35 to 39 weeks) and nine elective cesarean sections with small for gestational age (SGA) fetuses (34 to 37 weeks). A significant linear relationship between maternal and fetal glucose concentrations was demonstrated at midgestation (P less than .001) and at late gestation (P less than .001). At equal maternal concentrations there were no significant differences in fetal glucose concentration between the cord samples obtained in late gestation and those obtained at cesarean section. At midgestation fetal glucose concentration is independent of and may exceed maternal concentration at maternal glucose levels less than 4.44 mmol/L. Furthermore, the relationship between maternal and fetal concentrations at maternal glucose concentrations greater than 4.44 mmol/L is significantly different at midgestation from that at late gestation (P less than .01); at equal maternal concentrations there were higher glucose concentrations in the mid trimester fetus. In late gestation as the maternal glucose concentration increases there is an increase in the maternal arterial-umbilical arterial glucose concentration difference and the umbilical glucose/oxygen quotient (P less than .003) reflecting increased glucose utilization by the fetus. There were no significant differences between AGA and SGA babies with respect to these relationships.

The impact of gestational age and fetal growth on the maternal-fetal glucose concentration difference.

OBJECTIVE: To test whether the human fetus accommodates to the increasing glucose requirements of late pregnancy with an increased maternal-fetal glucose concentration gradient and whether there are differences in pregnancies with fetal growth restriction (FGR) according to clinical severity. METHODS: Umbilical venous glucose concentration was measured in 77 normal pregnancies (appropriate for gestational age [AGA]) and 42 pregnancies complicated by FGR at the time of fetal blood sampling. In 40 AGA and in all FGR cases, a maternal "arterialized" blood sample was collected simultaneously. Growth-restricted fetuses were subdivided into three groups according to fetal heart rate (FHR) recordings and Doppler measurements of the umbilical artery pulsatility index (PI): group 1 (normal FHR and PI; 12 cases), group 2 (normal FHR, abnormal PI; 17 cases) and group 3 (abnormal FHR and PI; 13 cases). RESULTS: In normal pregnancies with increasing gestational age, there was a significant decrease (P < .001) of umbilical venous glucose concentration and a significant increase of the maternal-fetal glucose concentration difference (P < .001). In addition, there was a significant relation between fetal and maternal glucose concentrations (P < .001). In FGR pregnancies, the maternal-fetal glucose concentration difference was significantly higher in fetuses of groups 2 and 3 compared with normal pregnancies and FGR pregnancies of group 1. CONCLUSION: In human pregnancy, the fetal glucose concentration is a function of both gestational age and the maternal glucose concentration. In FGR pregnancies, as an accommodation of the fetus to a restricted placental size and placental glucose transport capacity, the maternal-fetal glucose concentration difference is increased, and this increase is a function of the clinical severity.

Laparoscopically assisted vaginal removal of ovarian dermoid cysts.

Dermoid cysts were diagnosed by transvaginal sonography in 19 patients who subsequently underwent laparoscopy to confirm the nature and extent of the lesion and the mobility of the adnexa. Eighteen patients underwent surgery after the ovary was exteriorized through a posterior colpoceliotomy. No intraoperative complications were observed, and sonographic follow-up at 3 and 6 months after surgery showed a normal sonographic ovarian pattern. Laparoscopically assisted vaginal removal of dermoid cysts should be considered as an alternative to laparotomy and operative laparoscopy in cases when adnexal mobility is proven and vaginal extraction is feasible.

Peak velocity of the outflow tract of the aorta: correlations with acid base status and oxygenation of the growth-retarded fetus.

OBJECTIVE: To correlate the peak velocities of the aortic outflow tract of growth-retarded fetuses with fetal acid base status and oxygenation measured in utero. METHODS: Thirty-one growth-retarded fetuses with abnormal umbilical pulsatility index (PI) measurements underwent fetal blood sampling. Blood pH, carbon dioxide pressure (PCO2), oxygen pressure (PO2), oxygen saturation, lactate concentration, and hemoglobin concentration were measured. Using color Doppler equipment, we measured the peak velocities of the outflow tract of the aorta, pulmonary artery, and ductus arteriosus before fetal blood sampling. RESULTS: The peak velocities measured in the outflow tract of the aorta, pulmonary artery, and ductus were significantly lower in growth-retarded fetuses than in 140 normal fetuses of comparable weight. The correlation observed between pulmonic and aortic peak velocities was significant (r = 0.84), as was that between pulmonic and ductal peak velocities (r = 0.74). Growth-retarded fetuses with abnormal aortic peak velocities had significantly lower values of PO2, oxygen content and pH, and had higher lactate concentration and PCO2 than did growth-retarded fetuses with normal peak velocities. Estimated fetal weight and umbilical PI (mean +/- standard deviation) were not significantly different in these two groups. Moreover, significant direct correlations were found between proximal aortic peak velocities and lactate concentrations (correlation coefficient 0.71, P < .0001) and O2 content (P < .02, r = 0.42). CONCLUSION: For growth-retarded fetuses, Doppler peak velocity in these vessels is significantly lower than in normal fetuses of comparable weight. Aortic, pulmonic, and ductal peak velocity correlated significantly. Growth-retarded fetuses with abnormally low peak velocity in the outflow tract of the aorta have a higher risk of acidemia and hypoxia than those with normal velocities.

Losses of heterozygosity in endometrial adenocarcinomas: positive correlations with histopathological parameters.

We analyzed 37 samples of endometrial adenocarcinoma for loss of heterozygosity (LOH) by using a panel of 44 microsatellites located in 29 chromosomal regions. The aim of our study was to investigate the existence of a possible preferential involvement of some tumor suppressor genes in endometrial carcinogenesis. The analysis was performed on tumoral tissue and on a corresponding normal tissue by the use of polymerase chain reaction (PCR) and the comparison of the amplified alleles. We observed significative LOH (>20%) in the chromosomal regions of 2q14 (33.33%), 7q35 (24.00%), 10q22.1 (37. 50%), 11q13-q14 (44.12%), 15q26 (40.63%), 17p13 (25.71%), and 17q21. 3 (37.04%). We defined a 1-cM minimal common deletion in 11q13-q14 between D11S911 and D11S937 markers. A statistical analysis revealed a positive correlation between LOH of 11q13-q14 and clinicopathological data.

Congenital malformations due to antiepileptic drugs.

To identify the major risk factors for the increased incidence of congenital malformations in offspring of mothers being treated for epilepsy with antiepileptic drugs (AEDs) during pregnancy and, to determine the relative teratogenic risk of AEDs, we prospectively analyzed 983 offspring born in Japan, Italy, and Canada. The incidence of congenital malformations in offspring without drug exposure was 3.1%, versus an incidence with drug exposure of 9.0%. The highest incidence in offspring exposed to a single AED occurred with primidone (PRM; 14.3%), which was followed by valproate (VPA; 11.1%), phenytoin (PHT; 9.1%), carbamazepine (CBZ; 5.7%), and phenobarbital (PB; 5.1%). The VPA dose and level positively correlated with the incidence of malformations. This study first determined a cut-off value of VPA dose and level at 1000 mg/day and 70 microg/ml, respectively, to avoid the occurrence of malformations. The incidence of malformations increases as the number of drugs increases, and as the total daily dose increases. Specific combinations of AEDs such as VPA + CBZ and PHT + PRM + PB produced a higher incidence of congenital malformations. The incidence of malformations was not associated with any background factors studied except for the presence of malformations in siblings. These results indicate that the increased incidence of congenital malformations was caused primarily by AEDs, suggesting that malformations can be prevented by improvements in drug regimen, and by avoiding polypharmacy and high levels of VPA (more than 70 microg/ml) in the treatment of epileptic women of childbearimg age.

Intrauterine growth in the offspring of epileptic women: a prospective multicenter study.

The aim of the present study was to evaluate the risk of intrauterine growth delay in the offspring of epileptic mothers and to quantify the risks of intrauterine exposure to antiepileptic drugs (AEDs). Data concerning 870 newborns, prospectively collected in Canada, Japan and Italy, using the same study design, were pooled and analyzed. The overall proportion of newborns whose body weight (7.8%) or head circumference (11.1%) at birth were below the 10th percentile was not increased. However, logistic regression analysis showed that the risk of small head circumference was significantly higher in Italian than in Japanese (RR 4.2; 95% CI: 2.2-8.0) or Canadian children (RR 2.6; 95% CI: 1.1-6.5), and in children exposed to polytherapy (RR 2.7; 95% CI: 1.2-6.3), phenobarbital (PB) (RR 3.6; 95% CI: 1.4-9.4) and primidone (PRM) (RR 4.5; 95% CI: 1.5-13.8). Country was also the only factor affecting low body weight, with Italian children having a higher risk than Japanese (RR 5.2; 95% CI: 2.6-10.4) or Canadian (RR 8.8; 95% CI: 2.0-38.1) children. Due to the small categories, the influence of AED doses and plasma concentrations was studied for each individual AED, without adjustment for the other potential confounding factors. A clear dose-dependent effect was found for PB and PRM in terms of both small head circumference and low body weight, and a concentration-dependent effect for PB in terms of small head circumferences. The size of the difference between the Italian and the other two populations, which is only partially explained by differences in therapeutic regimens, suggests that genetic, environmental and ethnic factors also need to be taken into account when considering possible explanations.

Blood flow through the ductus venosus in human fetus: calculation using Doppler velocimetry and computational findings.

The present study was performed to assess a new method to calculate the blood flow rate through the ductus venosus (DV) in normal human fetuses using available echo-Doppler data. Color Doppler sonographic unit was used to study DV flow in 26 normal fetuses between 20 and 36 wk of gestation. Maximal velocity flow tracings and vessel diameters were obtained at the isthmic and the outlet portion of the DV. Time-averaged velocities in the DV were measured from the recorded tracings. The velocity distribution in the two investigated cross-sectional areas of the DV was evaluated by means of computational model simulations and the velocity shape coefficients h(in) and h(out), (i.e., the ratios between the maximal and mean spatial velocities) were calculated as a function of vessel geometry. These values allowed us to convert maximal Doppler velocities into mean spatial velocities for each fetus. Blood flow rate was evaluated both at the isthmus and at the outlet of the vessel by means of two formulae based on the ultrasonographic measures and the results of the computational model. The value of the DV blood flow rate was calculated as the average between the results provided by the two formulae. The velocity distributions both at the isthmus (h(in) = 0.677 +/- 0.040) and the outlet (h(out) = 0.374 +/- 0.072) of the ductus are skewed toward the inner wall. Ductus geometry, i.e., the isthmic/outlet diameter ratio, affects the shape of the velocity profiles in the vessel, particularly that at the outlet. The coefficients of variation for repeated measurements of the ductal diameters were 9.5 +/- 7.7% and 6.7 +/- 4.9% at the isthmus and the outlet, respectively. The two formulae gave values statistically identical for the time-average blood flow rate (36.3 +/- 22.1 vs. 39.4 +/- 24.0 mL/min; R = 0.946, p = NS). The mean percent difference between the results of the two formulae was 7.1%. Thus, in human fetuses, the use of the two formulae based on both Doppler data and computational model simulations makes it possible to calculate the ductal flow rate. When the difference between the calculations of the two formulae exceeds the 30% of their average value, it is convenient to adopt the flow rate value calculated at the isthmus instead of the average of the two measures. The measurements at the outlet of the ductus were more difficult to obtain, and the spatial velocity profile at the outlet depends more on the DV anatomy.

Fetal amino acids in normal pregnancies and in pregnancies complicated by intrauterine growth retardation.

Plasma amino acid concentrations were measured in normal (AGA) and intrauterine growth retarded (IUGR) percutaneous umbilical blood sampling (PUBS) performed for prenatal diagnosis or at elective cesarean section. IUGR fetuses present significantly lower concentrations of most amino acids, with a significant reduction of the umbilical veno-arterial difference for total alpha-amino nitrogen. These findings are present early in growth retarded fetuses and may be potentially responsible for the growth retardation.