Anthony Johnson

Amniotic septostomy for the treatment of twin oligohydramnios-polyhydramnios sequence

Objective: To report our experience with intentional puncture of the intervening membrane (‘septostomy’) for the treatment of the twin oligohydramnios-polyhydramnios sequence (TOPS). Methods: 12 patients were diagnosed with TOPS based on ultrasonographic findings. A 20- to 22-gauge spinal needle was used to puncture the membrane between the twins without any attempt at amnioreduction in 9 patients, while the procedure was combined with amnioreductions in 3 patients. Results: Gestational age was 23.1 ± 3.3 weeks at the time of septostomy and 31.1 ± 4.4 weeks at delivery. Rapid accumulation of fluid around the ‘stuck’ fetus occurred in all cases following a single procedure. Three of the 24 fetuses died in utero and 1 died on the fifth day of life, for a combined survival of 83.3%. In the survivors, the septostomy to delivery interval ranged between 0.6 and 13 weeks (mean ± SD 8.3 ± 4.8). Conclusion: Amniotic septostomy is a promising new method for the management of TOPS and is associated with survival rates that are better than, or comparable to, more invasive modalities. A multicenter trial comparing septostomy to other modalities is warranted.

Randomised controlled trial to assess acceptability of phenobarbital for childhood epilepsy in rural India

BACKGROUNDnThe use of phenobarbital for childhood epilepsy is controversial because of reported behavioural side-effects; however, whether this research can validly be extrapolated to developing countries is not clear. We undertook a randomised comparison of phenobarbital and phenytoin to assess the acceptability and efficacy of phenobarbital as monotherapy for childhood epilepsy in rural India.nnnMETHODSnBetween August, 1995, and February, 1996, 109 unselected children aged 2-18 years with partial and generalised tonic-clonic epilepsy were identified by population screening. 15 families declined to take part. 94 children were randomly allocated treatment with phenobarbital (1.5 mg/kg daily for 2 weeks; maintenance dose 3.0 mg/kg daily; n = 47) or phenytoin (2.5 mg/kg daily then 5.0 mg/kg daily; n = 47). Children were followed up for 12 months. The primary outcome measure was the frequency of behavioural side-effects; behaviour was assessed by the Conners parent rating scale for children aged 6 years and older, and by the preschool behaviour screening questionnaire (BSQ) for those aged 2-5 years, at 12 months or at withdrawal from treatment. Analysis was by intention to treat.nnnFINDINGSnThe mean log-transformed scores on the behaviour rating scales did not differ significantly between the phenobarbital and phenytoin groups (Conners 2.64 [SD 0.71] vs 2.65 [0.89], p = 0.97; n = 32 in each group: BSQ 2.12 [1.31] vs 2.18 [1.02], p = 0.94; n = 4 vs 3). The odds ratio for behavioural problems (phenobarbital vs phenytoin) was 0.51 (95% CI 0.16-1.59). There was no excess in parental reports of side-effects for phenobarbital. We found no difference in efficacy between the study drugs (adjusted hazard ratio for time to first seizure from randomisation 0.97 [0.28-3.30]).nnnINTERPRETATIONnThis evidence supports the acceptability of phenobarbital as a first-line drug for childhood epilepsy in rural settings in developing countries.

Pre-eclampsia and expression of heparin-binding EGF-like growth factor

BACKGROUNDnPre-eclampsia is a disorder of pregnancy associated with poor extravillous cytotrophoblast invasion and above-normal rates of apoptosis in the trophoblast. Heparin-binding epidermal-growth-factor-like growth factor (HB-EGF) has strong cytoprotective activity and is an important signalling protein that regulates trophoblast invasion during early placentation. We aimed to establish whether HB-EGF expression is altered in placentae of pre-eclamptic women.nnnMETHODSnWe assessed the expression of HB-EGF mRNA and protein by in-situ hybridisation and immunohistochemical techniques, respectively, in archived placental tissues from pregnancies terminated at around 20 weeks of gestation, and from women delivering between weeks 19 and 35 of gestation with preterm labour, small for gestational age infants, or pre-eclampsia.nnnFINDINGSnHB-EGF mRNA and protein were expressed in villous and extravillous cytotrophoblast cells up to week 35 of gestation in placentae from women who delivered preterm. Similar levels of HB-EGF protein were found in the placentae of women who were not in labour. HB-EGF expression was reduced about five-fold (p=0.0001) in pre-eclamptic pregnancies. Fetal growth retardation, which has been linked with shallow trophoblast invasion and moderate apoptosis, was associated with placentae expressing intermediate levels of HB-EGF.nnnINTERPRETATIONnIn pre-eclampsia, deficient HB-EGF signalling during placental development could impair trophoblast survival, differentiation, and invasion, leading to poor placental perfusion and hypertension.

Routine prenatal diagnosis of aneuploidy by FISH studies in high-risk pregnancies

This study is a prospective clinical trial with fluorescent in situ hybridization (FISH) as a routine test for prenatal detection of the most common aneuploidies in high-risk pregnancies. Since April 1996, FISH studies with multicolor, commercially available, specific probes for chromosomes 13, 18, 21, X, and Y have been routinely performed in our cytogenetic laboratory on uncultured chorionic villous samplings (CVS), amniotic fluid samples, or fetal blood obtained by cordocentesis from patients with major or minor fetal anomalies detected by ultrasonography. Among the 4,193 prenatal samples analyzed between April 1996 and June 1998, routine FISH studies were ordered by the referring physicians on 301 (7.2%) cases. Aneuploidies were detected in 32 (10.6%) samples. Fourteen trisomy-21, 10 trisomy-18, 3 trisomy-13, 4 monosomies of X, and 1 case of triploidy were diagnosed by FISH. All 1,505 hybridizations were informative, and all 301 results were available and reported to the referring physicians in 24-48 hr. All relevant FISH results were confirmed by subsequent cytogenetic analysis. In 10 (3.8%) cases with normal FISH results, the final cytogenetic analysis revealed abnormal chromosomal rearrangements that could not be detected by the routine FISH studies. We conclude that rapid FISH analysis of interphase, uncultured fetal cells is an accurate and very sensitive method for routine prenatal diagnosis of the most common aneuploidies in high-risk pregnancies.

Congenital diaphragmatic hernia: associated anomalies and antenatal diagnosis. Outcome-related variables at two Detroit hospitals.

This retrospective study reviews the medical records of 77 fetuses and babies with congenital diaphragmatic hernia (CDH) referred to two hospitals in Detroit from 1986 through 2000. The aims were to examine the effects on outcome of multiple variables, especially the type of CDH, associated anomalies, and ultrasound prognostic parameters. Ultrasound measurements of head (HC), chest (CC), and abdominal circumferences (AC) were obtained from videotapes. ANOVA and chi-square analysis were used to determine statistical significance between groups and proportions. Eighty-nine percent (65/73) of pregnancies resulted in live births, and 54% (35/65) of patients survived past 30 days. Liveborn patients with low APGAR scores were less likely to survive. Forty-three percent (30/70) had major associated anomalies, with cardiac anomalies constituting about 52% (33/64) of the major associated anomalies. Seventy percent of patients with isolated CDH survived versus 36% of patients with both CDH and cardiac anomalies. Sixty-seven percent (8/12) of fetuses antenatally diagnosed before 25 weeks of gestation survived past 30 days of birth. The survival rate of right-sided CDH with liver herniation was 80% (8/10), compared with 29% (4/14) for left-sided CDH with liver herniation ( p =0.088). There was a significant linear relationship ( r =0.603, p =0.029) between CC/AC and CC/HC among patients with CDH; survivors had higher CC/AC and CC/HC values than nonsurvivors. These results support the utility of CC/AC and CC/HC measurements and the presence of liver herniation as important prognostic factors that can be used in antenatal counseling and in planning clinical trials.

Nasal Bone Evaluation in Fetuses With Down Syndrome During the Second and Third Trimesters of Pregnancy

Objective. This study examined the use of three‐dimensional ultrasonography for evaluating the fetal nasal bone, as a sonographic marker of Down syndrome, during the second and early third trimesters of pregnancy. Methods. Forty fetuses, including 20 with trisomy 21, were scanned once by three‐dimensional ultrasonography. A midline sagittal view of the facial profile was used to analyze the volume data. Independent examiners reviewed blinded and randomly allocated volume data sets for the nasal bone. Interobserver reliability was evaluated for the sonographic presence or absence of the nasal bone. Logistic regression determined the contribution of this parameter to the presence of Down syndrome. Results. Both examiners showed substantial agreement in scoring whether the nasal bone was visualized by three‐dimensional ultrasonography (P < .001). They identified 40% to 45% of fetuses with abnormalities using the absence of the nasal bone as a sonographic marker. However, a substantial number of fetuses with abnormalities were also found to have a nasal bone present. The nasal bone was visualized in 80% to 90% of fetuses without abnormalities. Conclusions. Three‐dimensional ultrasonography can be used to evaluate the fetal nasal bone with substantial interobserver agreement during the second and early third trimesters of pregnancy. A nonvisualized nasal bone identified 40% to 45% of fetuses with Down syndrome in this study.

Three-dimensional power Doppler ultrasonography during pregnancy.

Objectives. To present the appearance of fetal and placental vascular anatomic structures by three‐dimensional power Doppler ultrasonography. Methods. Three‐dimensional multiplanar imaging, surface rendering, and volume rendering were combined with power Doppler ultrasonography to show the methods, imaging artifacts, and diagnostic potential of this technology during pregnancy. Results. Fetuses with normal and abnormal vascular anatomic structures were evaluated by three‐dimensional power Doppler ultrasonography. The combination of several imaging modalities (e.g., threedimensional multiplanar imaging, surface rendering, and volume rendering) with power Doppler ultrasonography is shown. Conclusions. Three‐dimensional power Doppler ultrasonography is an important adjunctive method that can be used to characterize normal vascular development and circulatory anomalies of the fetus.

Estimation of time of fetal death in the second trimester by placental histopathological examination.

It has been suggested that certain placental histopathological changes may be useful in predicting the time of death in stillborn fetuses. We retrospectively evaluated 36 placentas from therapeutic terminations in which the time interval between fetal death and delivery was relatively short and well-documented to determine the earliest stillbirth-associated changes and the utility of placental examination in timing death in the second trimester. In each case, termination had been initiated by creating fetal asystole with intracardiac KCl injections. The gestational age ranged from 18–23 wk. The time from asystole to placental delivery range was 2.8–52.0 h. Placental groups were categorized by time intervals from asystole to delivery: I,<12h[n = 4(11%)]; II, 12–24 h [n = 15 (42%)]; III, 24–36 h [n = 14 (39%)]; IV, > 36 h [n = 3 (8%)]. Among eight histopathologic changes involving the umbilical cord or chorionic villi evaluated, only three were present in a significant number of cases and also appeared to be the result of stillbirth. Degeneration of cord vascular smooth muscle was present in 33% of umbilical cords in group I, but was seen in 100% of cords in groups II–IV; the extent of these changes increased significantly with increasing time intervals. Intravascular karyorrhexis was present in villous blood vessels in 75, 73, 64, and 100%, respectively, for groups I–IV. Villous blood vessel luminal abnormalities were seen in 25, 7, 21, and 67%, respectively, for groups I–IV. These findings indicate that these are the earliest morphological changes in stillbirth in second trimester placentas, but they cannot be used to accurately predict time of death in the relatively short time intervals evaluated in this study.

Fetal Obstructive Uropathy in Trisomy Syndromes

Fetal obstructive uropathy has seldom been described in trisomy syndromes, and its relationship to these syndromes remains unclear. Five trisomic male fetuses, four with trisomy 18 and one with trisomy 21, were identified out of 110 fetuses evaluated for fetal obstructive uropathy. We performed detailed examination on the urinary tracts of four of these fetuses, three with trisomy 18 and one with trisomy 21, following termination in the second trimester. All four had a markedly distended urinary bladder (megacystis), abdominal wall distension, and a small, poorly developed urethra thoughout its full length. All four also had poor development of the prostate with virtual absence of glandular development, as compared to age-matched controls. Posterior urethral valves were not identified in any case. Three of the fetuses (two with trisomy 18 and one with trisomy 21) had unilateral or bilateral hydroureters, and resulting renal tubulocystic or glomerulocystic change. Review of this database reveals an unexpectedly high frequency of trisomies, particularly trisomy 18, suggesting that the relationship may not be coincidental. Abnormal prostate development may be causally related to fetal obstructive uropathies and may be an under-recognized trait in trisomy syndromes. Karyotypic analysis of all fetuses with obstructive uropathy is important since in utero surgical intervention may be contraindicated in cases of fetal aneuploidy.

Screening for aneuploidy

Over the past 15 years, biochemical screening for chromosomal abnormalities, particularly Downs syndrome, has advanced from being extremely naive, to now somewhat more sophisticated. Sensitivities have gone from 20% to 60-70%. Considerable work is still required to not only increase the sensitivity, but also the specificity to keep health care costs down.