Paula Cosper

Pregnancy outcome following genetic amniocentesis at 11–14 versus 16–19 weeks' gestation

Objective To compare pregnancy complications in women having genetic amniocentesis at 11–14 weeks versus those undergoing amniocentesis at 16–19 weeks gestation. Methods A genetics data base was used to identify patients retrospectively, those who had genetic amniocenteses by three experienced operators during a 4-year period. The study group consisted of women who had amniocenteses at 11–14 weeks gestation. For each study patient (early amniocentesis), two controls (amniocentesis at 16–19 weeks) were identified and matched for maternal age, race, and the number of prior spontaneous abortions. An immediate postprocedure complication was defined as any vaginal bleeding, rupture of membranes, or fetal loss occurring up to 30 days after the amniocentesis. A later complication was defined as any fetal death longer than 30 days after the amniocentesis, any preterm delivery, any infant weighing less than the tenth percentile for gestational age, and any neonatal death. Immediate and later complications were compared between the study and control groups. Results The study group consisted of 314 patients who were matched to 628 controls. Women who had a genetic amniocentesis performed at 11–14 weeks were significantly more likely to have post-procedure amniotic fluid leakage (2.9 versus 0.2%), post-procedure vaginal bleeding (1.9 versus 0.2%), and a fetal loss within 30 days of the amniocentesis (2.2 versus 0.2%) than women undergoing genetic amniocentesis at 16–19 weeks gestation. Four of the seven patients (57%) with a fetal loss within 30 days of an early amniocentesis had procedure-related complications, such as amniotic fluid leakage, bleeding, and infection, that caused the pregnancy to be lost. No differences were noted between the two groups in the number of preterm deliveries, later fetal deaths, neonatal deaths, or newborns weighing less than the tenth percentile for gestational age. Conclusion Genetic amniocentesis at 11–14 weeks is associated with more post-procedure complications and a higher fetal loss rate within 30 days of the procedure than a genetic amniocentesis performed at 16–19 weeks gestation.

Nutrient Levels in Amniotic Fluid from Women with Normal and Neural Tube Defect Pregnancies

We analyzed nutrient levels in amniotic fluid obtained during the second trimester of normal, uncomplicated pregnancies from 221 women who delivered apparently healthy infants and from 8 with neural tube defect (NTD) pregnancies. Folate was measured by microbiological assay, vitamin B12 by a radiobinding method, and zinc, copper and iron by atomic absorption spectrophotometry. We found that the mean amniotic fluid nutrient levels of normal pregnancies were 24.7 nmol/l for folate, 600 pmol/l for vitamin B12, and 1.7, 1.9, and 9.0 mumol/l for zinc, copper and iron, respectively. Amniotic fluid folate, zinc, copper and iron levels of NTD pregnancies were similar to those found during normal pregnancy, however, vitamin B12 levels were markedly lower than those of normal pregnancies.

Second-trimester cystic hygroma: prognosis of septated and nonseptated lesions

Objective To compare karyotypic, ultrasonographic, and prognostic features of septated cystic hygromas and nonseptated cystic hygromas in second-trimester fetuses. Methods A computerized ultrasound data base was used to identify fetuses diagnosed with cystic hygromas at 14–22 weeks gestation. Photographs from the initial ultrasound were reviewed retrospectively for hygroma type (septated or nonseptated) and any abnormal structural findings. Fetal karyotypes were obtained from amniotic fluid, aspiration of hygroma pouches, or fetal tissue culture. Pregnancy outcome information was obtained from hospital charts and physician office records. Ultrasound findings were then compared with fetal karyotype results and pregnancy outcome data. Results From 1990 to 1995, 61 fetuses with cystic hygromas were identified. Karyotypes were obtained in 55 fetuses, and pregnancy outcome was available for 59. Abnormal karyo-type was present in 42 of 55 fetuses (76%). The most common chromosomal abnormality in septated hygromas was the 45, X karyotype. Trisomy 21 was the most common chromosomal abnormality in nonseptated hygromas. Compared with fetuses with nonseptated cystic hygromas, those with septated cystic hygromas were more likely to be aneuploid (33 of 39 [85%] versus nine of 16 [56%]; P = .03), more likely to develop hydrops (27 of 45 [60%] versus three of 16 [19%]; P = .005), and less likely to be live-born (one of 44 [2%] versus four of 15 [27%]; P = .01). Conclusions Fetuses with septated cystic hygromas are more likely to be aneuploid and to develop hydrops, and thus are less likely to survive than fetuses with nonseptated hygromas.

Decreased levels of amniotic fluid α-fetoprotein associated with Down syndrome

Abstract Low maternal serum α-fetoprotein levels have been associated with fetal aneuploidies. Amniotic fluid α-fetoprotein levels have been reported to be low with Down syndrome (trisomy 21) but not with other fetal trisomies. We compared the amniotic fluid α-fetoprotein levels from 25 cases of autosomal trisomy (18 of trisomy 21, four of trisomy 13, three of trisomy 18) diagnosed by midtrimester fetal cytogenetic studies with those from matched, cytogenetically normal pregnancies. With these normal pregnancies used as controls, statistical analyses were performed on the data for all the trisomic fetuses, on the data for trisomy 21 only, and on the data for trisomies 13 and 18 combined. Amniotic fluid α-fetoprotein levels were significantly lower in the 25 trisomic cases compared with controls, 0.77 ± 0.34 versus 1.03 ± 0.34 mg/dl (p 0.40). These findings suggest that the low maternal serum levels of α-fetoprotein reported in cases of Down syndrome may be related to reduced amniotic fluid concentrations. However, the reduced maternal serum α-fetoprotein levels reportedly associated with trisomies 13 and 18 do not seem to be explained by low amniotic fluid concentrations.

Second case report of del(4) (q25q27) and review of the literature

We report a malformed infant with a de novo interstitial deletion of 4q. This is the second patient reported with del(4) (q25q27). Although there are several common features such as marked hypotonia, cardiac abnormalities, cleft palate, and micrognathia noted in our case and that of Chudley et al. (1988), we conclude from our comparison of the seven previously reported cases involving deletions of bands 4(q25q27) that a specific phenotype cannot yet be described for this deletion.

Relationship between amniotic fluid and maternal blood nutrient levels

To study the relationships between amniotic fluid and maternal blood nutrient concentrations, we obtained amniotic fluid and blood samples simultaneously from 76 pregnant women at around 17 weeks gestation. Folate and vitamin B-12 levels were measured by microbiological assay and radioassay, respectively, and zinc, copper and iron levels by atomic absorption spectrophotometry. Mean concentrations of plasma and red blood cell (RBC) folate and plasma copper of the pregnant women were 38 (+/- 1, SD), 1,501 (+/- 374) nmol/L, and 32.7 (+/- 4.8) mumol/L, respectively, all of which were higher than those of healthy non-pregnant controls (p < 0.001). Mean concentrations of plasma vitamin B-12, zinc and iron levels and RBC zinc were 320 (+/- 130) pmol/L, 12.2 (+/- 2.3), 21.7 (+/- 6.1) and 177 (+/- 30) mumol/L and these were similar to those of non-pregnant controls. Amniotic fluid folate, zinc, copper and iron concentrations were 21 (+/- 13) nmol/L, 1.4 (+/- 0.6), 1.7 (+/- 0.6) and 6.8 (+/- 2.1) mumol/L, respectively, which were significantly lower than plasma levels (p < 0.001). However, this relationship was reversed for vitamin B-12 (650 +/- 420 pmol/L). Significant correlations were found between amniotic fluid and maternal plasma and RBC for folate, and between amniotic fluid and maternal plasma for vitamin B-12 (p < 0.001). No such correlations were observed for zinc, copper and iron. There was no correlation between amniotic fluid and/or blood nutrient concentrations and pregnancy outcome including birth weight of infants.

The utility of fetal biometry as an adjunct to the multiple-marker screening test for Down syndrome

OBJECTIVEnOur purpose was to investigate fetal biometry as an adjunct to the multiple-marker screen (maternal age, serum alpha-fetoprotein, estriol, and human chorionic gonadotropin) for Down syndrome.nnnSTUDY DESIGNnFifty-two cases of Down syndrome were compared with 7514 normal fetuses. The measured/predicted femur length ratio had the best discriminant value (1.0 +/- 0.11 vs 0.93 +/- 0.13, p < 0.0001). Multivariate gaussian algorithms were developed and each computed a likelihood ratio for Down syndrome. The trivariate algorithm incorporated the three maternal analytes, whereas the quadrivariate version also included the femur length ratio. The study population included 38 cases of Down syndrome and 1098 euploid controls. The midtrimester risk was the product of the age-related risk and the likelihood ratio.nnnRESULTSnThe relative difference in the femur length ratio between normal and affected fetuses was small in comparison to that of the maternal serum analytes. At a risk cutoff of > or = 1:190 the detection rates were similar and actually favored the trivariate algorithm but differed only by one case of Down syndrome.nnnCONCLUSIONnThe addition of the measured/predicted femur length ratio had a negligible effect on the performance of the multiple-marker screening test.

Multiple Marker Screening Test: Identification of Fetal Cystic Hygroma, Hydrops, and Sex Chromosome Aneuploidy

The goal of this study was to determine if the multiple marker screening test (maternal serum alpha-fetoprotein, unconjugated estriol, human chorionic gonadotrophin, and maternal age) detects fetal Turner syndrome or just cystic hygroma/hydrops. Multiple marker screening tests from 4 groups were compared: 1) Turner syndrome with hydrops/ hygroma group (n = 10) = fetuses with cystic hygroma/hydrops and a 45X karyotype, 2) Turner syndrome without hydrops/hygroma (n = 9) = sonographically unremarkable fetal Turner syndrome or Turner mosaic, 3) hydrops group (n = 8) = all cases of fetal cystic hygroma/hydrops excluding Turner syndrome, 4) sex chromosome aneuploidy group (n = 16) = other sonographically normal fetal sex chromosome aneuploidies. Positive screening tests (Down syndrome risk > or = 1:190 or MSAFP > or = 2.5 MOM) were found in 60% (6/10) of the Turner syndrome with hydrops/hygroma group, but only 11% (1/9) of the Turner syndrome without hydrops/hygroma group (P = .04). The incidence of positive screening tests in the Hydrops group was 75% (6/8), while it was only 12.5% (2/16) in the other sex chromosome aneuploidy group. We conclude that the multiple marker screening test identifies fetuses with cystic hygroma/hydrops, and may do so independently of the etiology of the hydrops.

Amniotic fluid α-fetorotein levels and pregnancy outcome

Elevated and low levels of maternal serum α-fetoprotein in the midtrimester of pregnancy have been linked with, adverse events in later gestation, such as fetal and neonatal deaths, chromosomal abnormalities, and low birth weight infants. It is not known if this same association with poor pregnancy outcome is also true of amniotic fluid α-fetoprotein. In this study, α-fetoprotein was obtained from the fluid of 1060 women undergoing genetic amniocentesis for advanced maternal age. Poor pregnancy outcome was defined as (1) a fetal or neonatal death, (2) preterm delivery; or (3) low birth weight infants. Amniotic fluid α-fetoprotein was compared to each type of adverse outcome. No significant association with a poor pregnancy outcome in later gestation was noted. Although serum α-fetoprotein in the midtrimester of pregnancy may relate to certain poor outcomes in later gestation, midtrimester amniotic fluid α-fetoprotein offers no predictive value for the course of events in later gestation.

A prenatally ascertained X;Y translocation characterized using conventional and molecular cytogenetics†

Translocations between the X and Y chromosomes are rare, and reported cases of females having such translocations usually involve a breakpoint on the long (q) arm of the Y chromosome at Yq11.2, deleting the sex-determining region Y (SRY) gene located at Yp11.31 [Hecht et al., 1980; Ballabio et al., 1988; Hsu, 1994; Kusz et al., 2001; Speevak et al., 2001]. Most reported non-mosaic cases to date that involve breakpoints on the short (p) arm of the Y chromosome are males [Zuffardi et al., 1982; Hsu, 1994], presumably because of the presence of the SRY gene. Of note there have been reports of mosaicism with female phenotypes and a presumably intact SRY gene [Giltay et al., 2001; Gimelli et al., 2006]. To our knowledge, only two reports describe a non-mosaic X;Y translocation involving Yp andpresenting with a female phenotype. Thefirst report documented a female with a Yp11 breakpoint translocated onto Xq22 resulting in a dicentric X;Y chromosome with deletion of the SRY region which was verified by Southern blot analysis [Bernstein et al., 1987]. The second report described a 14-yearold girl with a non-mosaic X;Y translocation with a breakpoint at Yp11.2 and Xp22.3, in which the SRY gene had been deleted [Baralle et al., 2000]. Breakpoints on the X chromosome for X;Y translocations are varied and can have important clinical implications, depending on what genes are deleted. XY females often have Turner syndrome, and can present with physical characteristics such as mental retardation and primary or secondary amenorrhea; however the most common presentation is short stature due to the deletion of the short stature homeobox (SHOX) gene at Xp22.33 [Speevak et al., 2001]. The SHOX gene is found on both the X and Y chromosomes in the pseudoautosomal regions (PAR1) on the p arms, and since all PAR1 genes escape X inactivation, both sex chromosomes express this gene. Interestingly, SHOX is the only gene within PAR1 known to cause disease due to haploinsufficiency [Blaschke and Rappold, 2006]. SHOX haploinsufficiency has been reported in patients not only with Turner syndrome, but also Leri–Weill dyschondrosteosis, a disorder characterized by mesomelic short stature, radial/tibial bowing, and Madelung deformity of the wrist, but even within families, clinical presentation varies with regards to severity of deformities and may not manifest until after the first decade of life [Spranger et al., 1999; Clement-Jones et al., 2000; Blaschke and Rappold, 2006; Shanske et al., 2007]. Therefore, it is important for patientswith known SHOX deletions to undergo periodical skeletal surveys. Another issue faced by patients with a female phenotype and Y chromosome material is an increased risk for gonadoblastoma. Gonadoblastomas are benign tumors composed of aggregates of germ cells and immature Sertoli cells and granulosa surrounded by ovarian stromal cells [Scully, 1970; Tsuchiya et al., 1995; Lau, 1999; Giltay et al., 2001; Horn et al., 2005; Gimelli et al., 2006]. Patients presenting with XY gonadal dysgenesis and a lack of SRY expression in the presence of Y chromosome material will develop gonadal tumors in 20–30% of cases [Rimoin and Emery, 2007]. The increased risk is thought to be due to the expression of the testisspecific protein Y-encoded gene (TSPY1) near the Y centromere at Yp11.2 [Giltay et al., 2001; Li et al.,