Devereux N. Saller

Prenatal Screening for Down's Syndrome with Use of Maternal Serum Markers

Abstract Background. Approximately 35 percent of all cases of Downs syndrome in fetuses can be detected by measuring maternal serum alpha-fetoprotein during the second trimester in the general population of pregnant women. Recent case–control studies indicate that this detection rate could be approximately doubled by measuring serum levels of unconjugated estriol and chorionic gonadotropin, which are abnormally low and abnormally high, respectively, in women carrying fetuses affected by Downs syndrome. Methods. We prospectively screened 25,207 women and adolescents in the second trimester of pregnancy and assigned each a risk of fetal Downs syndrome with an algorithm that took into account measurements of all three serum markers in combination with maternal age. On this basis, 1661 subjects (6.6 percent) were initially assigned a second-trimester risk of fetal Downs syndrome of at least 1 in 190, and 962 (3.8 percent) were offered amniocentesis for chromosomal analysis after verification of gestationa...

Second-trimester maternal serum placental growth factor and vascular endothelial growth factor for predicting severe, early-onset preeclampsia.

OBJECTIVE To determine whether alterations in second-trimester maternal serum cytokine concentrations can identify women at risk for developing severe, early-onset preeclampsia. METHODS Patients with severe preeclampsia requiring delivery prior to 34 weeks (n = 20) were each matched by gestational age, gravidity, parity, and sample freezing time with three healthy controls who delivered at term (n = 60). By using second-trimester maternal sera originally collected for fetal aneuploidy screening, the concentrations of placental growth factor, vascular endothelial growth factor, granulocyte colony-stimulating factor, endothelin-1, and human chorionic gonadotropin were compared between patients and controls. Logistic regression analysis was used to estimate odds ratios for high versus low (median split) cytokine concentrations with respect to the development of severe, early-onset preeclampsia. Receiver operating characteristic (ROC) curves based on a second logistic regression, using actual cytokine values, were plotted to illustrate reciprocal impact on sensitivity and specificity. RESULTS Placental growth factor and vascular endothelial growth factor levels were significantly lower in patients than in controls. No significant differences were observed for the other cytokines. The odds ratios (with 95% confidence intervals) were 15.54 (3.29, 73.40) for vascular endothelial growth factor and 4.20 (1.35, 13.06) for placental growth factor. Receiver operating characteristic analysis of placental growth factor and vascular endothelial growth factor confirmed that both were useful in discriminating between patients and controls. Models combining both vascular endothelial growth factor and placental growth factor provided the best performance for identifying patients at risk for developing severe, early-onset preeclampsia, according to both odds ratios and ROC analyses. CONCLUSION Combined analysis of placental growth factor and vascular endothelial growth factor is potentially useful as a tool for early identification of patients at risk for developing severe, early-onset preeclampsia.

Multiple-marker screening in pregnancies with hydropic and nonhydropic Turner syndrome.

OBJECTIVE The combination of maternal serum alpha-fetoprotein, unconjugated estriol, and human chorionic gonadotropin levels and maternal age has been used to increase the sensitivity of screening for fetal Down syndrome and trisomy 18 in early-second-trimester pregnancies. We hypothesized that a unique pattern of these analytes also may be characteristic of fetal Turner syndrome, with or without hydrops. STUDY DESIGN We studied preamniocentesis, second-trimester maternal serum specimens from seven hydropic and eight nonhydropic cases of fetal Turner syndrome. Clinical and pathologic records were reviewed. Statistical analysis of the data was performed by the rank sum test. RESULTS In both hydropic and nonhydropic cases, alpha-fetoprotein levels were slightly reduced, and unconjugated estriol levels were markedly reduced. In hydropic pregnancies human chorionic gonadotropin levels were elevated, and nonhydropic pregnancies had low human chorionic gonadotropin levels (p = 0.001). CONCLUSIONS The results suggest that the morphologic defect of hydrops, rather than the aneuploidy itself, is responsible for the elevation in human chorionic gonadotropin. In conjunction with the low unconjugated estriol levels, the elevation in human chorionic gonadotropin levels will result in the prenatal identification of hydropic fetal Turner syndrome pregnancies as being at increased risk for fetal Down syndrome.

Serum triple-marker screening in in vitro fertilization and naturally conceived pregnancies

Objective To determine whether results of second-trimester maternal serum triple-marker screening for Down syndrome and open neural tube defects in singleton pregnancies conceived from in vitro fertilization (IVF) differ from those of pregnancies conceived spontaneously. Methods The screen-positive rates and triple-marker levels of patients conceiving singleton pregnancies by IVF were compared to age-adjusted standards. Results Sixty-nine singleton IVF pregnancies with maternal serum screening were identified. Twenty-one (30.4%) of the 69 IVF singleton pregnancies had a positive screen for Down syndrome compared with a 14.4% expected screen-positive rate for the maternal age distribution in our observed sample (P = .013). The screen-positive rate for open neural tube defects in the measured population was similar to anticipated values based on historic controls (5.8% in IVF patients versus 5.3% in the total population). The median levels of the triple markers were 0.95 multiples of the median (MoM) for alpha-fetoprotein (AFP), 0.90 MoM for unconjugated estriol (E3), and 1.22 MoM for hCG. Conclusion The increased hCG levels as well as the slightly lower AFP and unconjugated E3 levels may contribute to the higher Down syndrome screen-positive rate in this IVF singleton population. These results may be due to the number of embryos transferred, the maternal hormonal environment of the IVF process, or other factors. Pregnancies conceived by IVF may be twice as likely to have a positive maternal serum screening test. As additional data are collected, corrected standards should be determined.

Second‐trimester maternal serum inhibin A levels in fetal trisomy 18 and Turner syndrome with and without hydrops

The objective was to investigate whether cases of fetal trisomy 18 and Turner syndrome with and without hydrops were associated with alterations in the second‐trimester levels of maternal serum inhibin A. Twenty‐one cases of trisomy 18, 10 cases of Turner syndrome without hydrops and 12 cases of Turner syndrome with hydrops were identified. Five control samples were matched to each case for date of sample collection and completed week of gestation.

Current methods of prenatal screening for Down syndrome and other fetal abnormalities.

Prenatal diagnosis of Down syndrome is widely available, but the determination of which patients should undergo prenatal diagnosis is changing. With the recent acceptance of first-trimester and integrated screening as a part of routine clinical practice, there are now a variety of accepted screening protocols for Down syndrome and other aneuploidies. These choices can be confusing both to both patients and providers. The following discussion is meant to outline the various options in prenatal screening, and their individual advantages and disadvantages.

Second-trimester maternal serum analyte levels associated with fetal trisomy 13 †

The aim of this study was to determine whether pregancies affected by fetal trisomy 13 are associated with second‐trimester maternal serum analyte levels different from those typical of the unaffected population. Pregnancies with trisomy 13 were identified through cytogenetics laboratories. Those which had second‐trimester maternal serum screening analyte measurements were further evaluated. Maternal serum analyte levels for each case and five matched controls were statistically analysed by matched ranked‐sum analysis. 28 cases of fetal trisomy 13 were identified. The median AFP, uE3 and hCG levels were 1.35 MoM, 0.71 MoM and 0.90 MoM, respectively. Only uE3 levels were statistically different (p<0.01) from those for the unaffected population. These data suggest that second‐trimester maternal serum AFP, uE3 and hCG levels are not useful in detecting fetal trisomy 13 and protocols already existing for Down syndrome or trisomy 18 screening will not detect the majority of cases of this aneuploidy. Copyright

Levels of urinary beta‐core fragment, total oestriol, and the ratio of the two in second‐trimester screening for Down syndrome

Levels of beta‐core fragment and total oestriol in second‐trimester maternal urine samples were measured in 32 Down syndrome pregnancies and 206 control pregnancies. Beta‐core fragment and total oestriol values were corrected for the urinary creatinine level and expressed as multiples of the control medians (MOM). In addition, the ratio of the beta‐core fragment level to the total oestriol level, without creatinine correction, was calculated, and expressed as MOM values. The median beta‐core fragment, total oestriol, and ratio levels in Down syndrome cases were 5·42, 0·64, and 9·32 MOM, respectively. In the Down syndrome pregnancies, 66 per cent of the beta‐core fragment levels were above the 95th centile of control levels, while 22 per cent of the total oestriol levels were below the fifth centile of control levels. In combination with maternal age, measurement of beta‐core fragment and total oestriol levels in Down syndrome pregnancy resulted in an 80 per cent detection rate at a 5 per cent false‐positive rate. Use of the ratio resulted in a univariate detection rate of 72 per cent. In combination with maternal age, the ratio resulted in a detection rate of 81 per cent at a 5 per cent false‐positive rate. Based on this unmatched study, the measurement of a ratio of beta‐core fragment to total oestriol levels, without the need for creatinine correction, may be useful in screening for fetal Down syndrome in second‐trimester urine.

Placental metastases in a patient with recurrent breast carcinoma

We present an unusual case of extensive placental micrometastases of recurrent breast carcinoma. The discrepancy between the gross and histopathologic findings in this case suggests that in the absence of gross metastases, meticulous microscopic examination may reveal a higher incidence of metastases than has been reported previously.

Second-trimester maternal serum progesterone levels in Turner syndrome with and without hydrops and in trisomy 18

Placental proteins, such as inhibin A and hCG and its subunits, as well as the placental steroid progesterone, are elevated in second‐trimester maternal serum from cases of fetal Down syndrome. Since different cellular mechanisms are required for protein versus steroid synthesis and secretion, these data suggest that a generalized placental hypersecretory phenomenon is associated with Down syndrome. Inhibin A and hCG are also elevated in cases of Turner syndrome with hydrops, and are reduced in cases of Turner syndrome without hydrops and in trisomy 18. The objective of the present study was to determine maternal serum levels of the placental steroid progesterone in cases of Turner syndrome and trisomy 18. Twenty‐one cases of trisomy 18, 10 cases of Turner syndrome without hydrops and 12 cases of Turner syndrome with hydrops were identified and each matched to five control samples.