Volume 174, Number 5 Letters 1669 Am J Obstet Gynecol

Table I. Comparison of Down syndrome screening protocols by use of prospective data

Total patients screened*

Patients >35 yr old (%)

Protocol No. of DS cases Unaffected DS

Triple test 112,466 177 6 33 6.2 4.5 62 AFP plus free ~-hCG 120,097 149 6 20 5.9 4.4 75

1FPR FPR DE (%) (%) (%)

DS, Down syndrome;/FPR, initial false-positive rate; FPt~ false-positive rate; DE, detection efficiency; hCG, human chorionic gonad- otropin.

*Data represent metaanalysis of 13 worldwide prospective studies. Specific references are available from the authors on request.

These data have had a major impact on usage patterns of Down syndrome screening protocols described by Kell- ner et al. For example, in the United Kingdom in 1991 s >10 times as many patients were screened annually with the triple-marker protocol used by Kellner et al. (47,966 patients) compared with a free ~-human chorionic gona- dotropin-maternal serum AFP double-analyte protocol (4288 patients). Recent data from Cuckle et al., 3 however, indicate that this pattern has reversed and currently fewer than half as many patients are screened with the triple marker (54,184 patients) of KeIlner et al. compared with free ~-human chorionic gonadotropin-maternal serum AFP analysis (121,160 patients). Indeed, in the United Kingdom there remain only 6 of 67 screening laborato- ries using triple screening.

Although counterintuitive, it is clear that the specific analytes chosen rather than the number (single, double, or triple) are critical to maximizing detection efficiency in Down syndrome screening. The report of Kellner et al. has prompted us to focus on this issue with large pub- lished data sets. We hope that the data presented will be of use in the United States as policies on screening prac- tices evolve.

James N. Macri, PhD

Research Division, NTD Laboratories, 403 Oakwood Road, Huntington Station, NY 11746

Kevin Spencer;, MS

Department of Clinical Biochemistry, Oldchurch Hospital, Romford, Essex, United Kingdom RM7 0BE

REFERENCES 1. Spencer K, Macri JN, Coombes EJ, Ward AM. Antenatal

screening for Down's syndrome. BMJ 1993;306:1616. 2. MacriJN, Spencer K, Garver K, Buchanan PD, Say B, Carpen-

ter NJ, et al. Maternal serum free beta hCG screening: results of studies including 480 cases of Down syndrome. Prenat Diagn 1994;14:97-103.

3. Cuckle HS, Ellis AR, SethJ. Provision of screening for Down's syndrome. BMJ 1995;311:512.

6/8/72218

Need for placental and experimental pathologic examination to determine pathogenetic influences of chronically present intraamniotic meconium To the Editors: We have hypothesized that after soluble meconium components diffuse to placental and umbili- cal vessels they produce fetal vasoactivity and hypoperfu-

sion. 1 Montgomery et al. retorted (Montgomery LD, Bel- fort MA, Saade GR, Moise KJ Jr, Vedernikov YP. Meco- nium inhibits the contraction of umbilical vessels induced by the thromboxane A 2 analog U46619. AM J OBSTET GYNECOL 1995;173:1075-8). They performed ex- periments m investigate our findings but used radically different methods. Their discussion did not mention a highly relevant article of 1991. 2 With experimental find- ings similar to. ours, Sepulveda et al. explained the risk of stillbirth complicating maternal cholestatic disease of pregnancy. They wrote, "This is the first report that pro- rides experimental evidence of the possible role of bile acids in those mechanisms that trigger fetal asphyxia in pregnancies complicated by intrahepatic cholestasis of pregnancy."2

Our methods included placement of umbilical cord venous segments in 37 ~ C Krebs solution transport media controlled for temperature, pH, and 95% oxygen and 5% carbon dioxide, a To avoid influences induced by labor and delivery, we used tissue from umbilical cords of moth- ers delivered by scheduled repeat cesarean section. These considerations enabled accurate investigation of intrinsic vasocontractility and of effects induced by fresh 1% meconium solution.

Montgomery et al. used umbilical cords obtained after vaginal delivery or cesarean section done because of pro- longed labor. That would have altered intrinsic proper- ties of the vessels, as would have their subsequent immer- sion of vascular segments in cold Krebs solution. They later used the thromboxane A 2 analog U46619 as a ter- minal vasoconstrictor. This agent exerts its effect on smooth muscle through a cell surface receptor. Because meconium contains bile, a powerful detergent, exposure of biologic membranes to meconium disrupts the bio- logic activity of membrane-bound hormone receptors. We therefore understand why Montgomery et al. ob- served inhibition of vasoactivity by 1% meconium, even after the meconium had been washed out of the organ bath.

Because only a minority of fetuses are exposed to intraamniotic meconium for many hours or days, fetal meconium discharge usually is not complicated by a det- rimental outcome. Placental findings can identify chronic exposure, the most severe manifestation of which is meconium-induced vascular necrosis. Those cases have the highest risk of cerebral palsy and other disorders. Naeye has recently endorsed this consideration?

Further investigations should resolve whether fetal

1670 Letters May 1996 AmJ Obstet Gynecol

vasoactivity and hypoperfusion are important pathophysi- ologic mechanisms and whether diffusible meconium components enter the fetal circulation and directly inflict cellular damage in vital organs.

Scott Hyde, PhD

Department of Pathology, St. Francis Hospital, 6161 S. Yale Ave., Tulsa, OK 74136

Geoffrey Altshule~, MB, BS Department of Pathology, University of Oklahoma Health Sciences Cent< PO. Box 26901, Oklahoma City, OK 73190

REFERENCES t. Mtshuler G, Hyde S. Meconium-induced vasocontraction: a

potential cause of cerebral and other fetal hypoperfusion and of poor pregnancy outcome. J Child Neurol 1989;4:137-42.

2. Sepulveda WH, Gonzalez C, Cruz MA, Rudolph MI. Vasocon- strictive effect of bile acids on isolated human placental chori- onic veins. EurJ Obstet Gynecol Reprod Biol 1991;42:211-5.

3. Naeye RL. Can meconium in the amniotic fluid injure the fetal brain? Obstet Gynecol 1995;86:720-4.

6/8/72214

Reply To the Editors: We thank Hyde and Altshuler for their interest in our work. We acknowledge that there are dif- ferences in the experimental design used by Altshuler and Hyde ~ and that used in our study. The most striking of these differences is the P o 2 concentration used in the Methods section. Altshuler and Hyde maintained their organ baths at a P o 2 concentration of 95%. In work done by Sepulveda et al.2 similar Po 2 concentrations were used. A PO 2 concentration of 95% is significantly higher than that to which these vessels are normally exposed. This higher concentration of oxygen will cause vasoconstric- tion on the basis of hyperoxia, making any conclusions regarding vasoconstriction suspect. In our Methods the organ baths were bubbled with a more physiologic gas mixture (2.5% oxygen and 8.07% carbon dioxide, bal- ance nitrogen).

Differences in the reactivity of umbilical vessels on the basis of whether the source patient has labored are diffi- cult to quantify and to our knowledge have not been studied. If the stressors of labor are somehow postulated to decrease the amount of vasoconstrictive activity in um- bilical vessels, as implied by Hyde and Altshuler, then it would also have to be agreed that the stressors causing the initial passage of meconium in utero would also decrease the vasoconstrictive properties of the umbilical vessels. Thus the hypothesis that meconium passed in utero causes vasoconstriction is questionable at best.

Our transport and dissection media were cold Krebs- bicarbonate solution. The cold solution, rather than 37 ~ C solution, was used to preserve the tissue during the short preparation period. Once the vascular rings were prepared, they were placed immediately in a 37 ~ C bath.

In conclusion, we believe that our findings place doubt on the ability of meconium to cause vasoconstriction of umbilical vessels. Certainly it would be premature to

postulate that meconium-induced vasoconstriction of umbilical vessels causes damage to the fetal brain.

Lynn D. Montgomery, MD, and Michael A. Belfort, MD

Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Bayloz College of Medicine, One BaylorPlaza, Houston, TX 77O30

REFERENCES 1. Altshuler G, Hyde S. Meconium-induced vasoconstriction: a

potential cause of cerebral and other fetal hypoperfusion and poor pregnancy outcome. J Child Neurol 1989;4:137-42.

2. Sepulveda WH, Gonzalez C, Cruz MA, Rudolph MI. Vasocon- strictive effect of bile acids on isolated human placental chori- onic veins. Eur J Obstet Gynecol Reprod Biol 1991;42:211-5.

6/8/72215

Fetal blood redistribution in postterm pregnancies To the Editors: I read with interest the article by Bar-Hava et al. (Bar-Hava I, Divon MI, Sardo M, Barnhard Y. Is oligohydramnios in postterm pregnancy associated with redistribution of fetal blood flow? A~ J OBsaxT G~ECOL 1995;173:519-22). The authors report that in oligohy- dramnios associated with postterm pregnancy the fetal blood flow resistance index values in the umbilical, middle cerebral, and renal arteries and the ratios among them do not differ significantly from those of controls. In our own material, 80.8% of postterm fetuses had normal resistance and pulsatility index values in the renal arteries. At a gestation length of 41 to 43 weeks, we found only one incidence of oligohydramnios. In this case the blood flow index values were normal in the umbilical, cerebral, and renal arteriesJ In contrast, of 41 growth- retarded fetuses at gestational ages of 28 to 39 weeks, we found 5 cases of oligohydramnios (12.2%). Of these, one fetus had an abnormal pulsatility index value in the renal artery.

The amount of the amniotic fluid depends, to a great extent, on fetal urinary output. The latter hinges on renal perfusion only in part, insofar as glomerular filtration and renal tubular function also play a role. It appears therefore that the quantity of the amniotic fluid depends on the ability of the kidney to reabsorb fluids. This may be subject to periodic changes that cause impedance to flow in the fetal renal arteries, a phenomenon that appears to be prevalent in fetal growth restriction. The fact that the fetal blood flow ratios (renal vs middle cerebral, umbilical vs naiddle cerebral, renal vs umbilical arteries) have shown no significant differences between normal preg- nancies and those complicated by oligohydramnios may be explained by this phenomenon. In general, the ratios provide more reliable information than do the blood flow index values in the various individual arteries (cere- bral, umbilical) alone. 2

Abnormal cerebral arterial versus umbilical cord arte- rial resistance index values and oligohydramnios are in-