HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by BUTLER, E. L. Articles by RAMUS, R. M. Search for Related Content PubMed PubMed Citation Articles by BUTLER, E. L. Articles by RAMUS, R. M.

Association Between Maternal Serum Alpha-Fetoprotein and Adverse Outcomes in Pregnancies With Placenta Previa

From the Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas.

Address reprint requests to: Erin L. Butler, MD Department of Obstetrics and Gynecology University of Texas Southwestern Medical Center at Dallas 5323 Harry Hines Boulevard Dallas, TX 75390-9032 E-mail: erin.butler{at}utsouthwestern.edu

	Abstract

Top Abstract Materials and Methods Results Discussion References

 
Objective: To determine whether increased maternal serum alpha-fetoprotein (MSAFP) level at 15–20 weeks’ gestation is a marker of adverse outcomes in women with placenta previa at delivery.

Methods: We conducted a retrospective cohort study of singleton pregnancies complicated by placenta previa, diagnosed sonographically, and confirmed at delivery. All women had MSAFP screening at 15–20 weeks’ gestation and delivered nonanomalous live-born infants at or after 24 weeks’ gestation.

Results: One hundred seven women with placenta previa delivered during the study. Fourteen (13%, 95% CI 7%, 21%) had MSAFP at least 2.0 multiples of the median (MoM). They were significantly more likely than those with lower MSAFP levels to have one or more of the following outcomes: hospitalization for antepartum bleeding before 30 weeks’ gestation (50% versus 15%), delivery before 30 weeks’ gestation (29% versus 5%), or preterm delivery for pregnancy-associated hypertension before 34 weeks’ gestation (14% versus none). The MSAFP cutoff of 2.0 MoM provided the best combination of sensitivity and specificity for those outcomes, using receiver operating characteristic curves.

Conclusion: Women with placenta previa who also have high MSAFP levels are at increased risk of bleeding in the early third trimester and preterm birth. We did not find women who required cesarean hysterectomy, including those with placenta accreta, to consistently have elevated MSAFP.

Placenta previa occurs in approximately one in 200 deliveries and can cause second- or third-trimester hemorrhage, prolonged hospitalization, placental separation, and preterm delivery.¹ At least 5% of such pregnancies have associated placental invasion (placenta accreta), which can necessitate hysterectomy.¹ Once bleeding develops, it is likely to complicate the remainder of the pregnancy. However, it is difficult to predict which women with previa will develop early sequelae and those whose pregnancies will be uneventful. Finding markers for complications in women with previa might help obstetricians treat their pregnancies.

Unexplained elevation of maternal serum alpha-fetoprotein (MSAFP) has been associated with several pregnancy complications, including preterm birth, fetal growth restriction (FGR), preeclampsia, and placental separation.^2–4 In women with placenta previa at delivery, MSAFP elevation in the early second trimester has been reported as a risk factor for placenta accreta.^5,6 The extent to which women with MSAFP elevation and previa are at risk of other pregnancy complications has not been reported. We examined the relationship between elevated MSAFP in midgestation and adverse pregnancy outcomes in women who have placenta previa.

	Materials and Methods

Top Abstract Materials and Methods Results Discussion References

 
We conducted a retrospective cohort study of women with singleton gestations who had MSAFP screening at 15–20 weeks’ gestation and placenta previa at delivery. They were delivered at Parkland Memorial Hospital between January 30, 1990 and June 14, 1999 and were found through our computerized database, which contains selected obstetric data for all women who deliver at our hospital. Perinatal research nurses assessed the data for completeness and consistency before electronic storage. Placenta previa was diagnosed by antepartum ultrasound examination and confirmed at delivery. Histologic examination was done by our placental pathologist in all cases of suspected placenta accreta. For the purpose of this study, women with the pathologic diagnosis of placenta accreta, increta, or percreta were considered to have placenta accreta. Only pregnancies that resulted in deliveries of live-born infants of at least 24 weeks’ gestation were included. No infant had a major anomaly in the immediate neonatal period.

We routinely offer pregnant women serum screening at 15–20 weeks’ gestation. Screening for MSAFP was offered during the entire study, and screening with hCG began in November 1992. Approximately 8000 women per year (60%) received those tests. Maternal serum alpha-fetoprotein and hCG values were determined by chemiluminescence assay using an ACS 180 (Bayer Diagnostics, Norwood, MA). Maternal serum alpha-fetoprotein multiples of the median (MoM) values were derived for our population, using multiple logistic regression to adjust for gestational age, maternal weight, ethnicity, and insulin-dependent diabetes mellitus. Additionally, hCG MoM values were derived for our population, after adjusting for gestational age and maternal weight.

At our hospital, when MSAFP was at least 2.0 MoM, a basic ultrasound examination was done to confirm gestational age, to exclude multiple gestations or fetal deaths, and to screen for placental or fetal abnormalities. The laboratory cutoff for our neural tube defect screening program was 2.5 MoM, thus women with MSAFP at least 2.5 MoM also were offered targeted ultrasound examinations and amniocenteses. For calculating the MSAFP MoM, last menstrual period (LMP) was used to date the pregnancy provided it was within 1 week of the estimate obtained by sonographic biparietal diameter; otherwise the biparietal diameter was used. Our obstetric estimate of gestational age was also based on LMP if it was within 1 week of sonographic estimate of gestational age in the first trimester or within 2 weeks in the second trimester. That estimate correlated well with the sonographic (r = .97) and pediatric (r = .89) estimates of gestational ages in our population.⁷

Pregnancy outcomes included hospitalization for antepartum bleeding, preterm delivery, pregnancy-associated hypertension, placental separation, placenta accreta, and nonelective cesarean hysterectomy. We constructed receiver operating characteristic (ROC) curves for those outcomes in order to select MSAFP MoM cutoff values that best combined sensitivity and specificity. The likelihood of each outcome was assessed at various MSAFP and hCG MoM cutoffs. Statistical analysis was done with Student t test for continuous variables, Pearson ² test for categorical variables, and Mantel-Haenszel ² test for trend. P < .05 was statistically significant.

	Results

Top Abstract Materials and Methods Results Discussion References

 
One hundred seven women with second-trimester MSAFP screening were delivered of nonanomalous, live-born infants at or after 24 weeks’ gestation and had placenta previa at delivery. Among adverse outcomes, the most frequent was antepartum bleeding before 30 weeks’ gestation that required hospitalization. The ROC curve of sensitivity and false-positive rate of various MSAFP thresholds for that outcome is shown in Figure 1. A cutoff of 2.0 MoM yielded a sensitivity of 33% with a false-positive rate of only 8%. We also constructed ROC curves for the outcomes of preterm birth before 30 and 34 weeks’ gestation, pregnancy-associated hypertension before 34 weeks’ gestation, and placental separation. The cutoff of 2.0 MoM yielded the best overall accuracy, with a sensitivity of at least 33% and false-positive rate below 10% for each outcome. For example, for the outcomes of preterm birth at or before 30 and 34 weeks, an MSAFP at least 2.0 MoM had sensitivities of 44% and 43%, respectively, with false-positive rates of 10% and 9%, respectively.

View larger version (12K): [in this window] [in a new window]   Figure 1. Receiver operating characteristic curve of sensitivity and specificity of various maternal serum alpha-fetoprotein multiples of the median (MoM) cutoffs for antepartum bleeding before 30 weeks’ gestation. Arrow depicts 2.0 MoM.

Maternal demographics and selected pregnancy characteristics for women with and without MSAFP at least 2.0 MoM are presented in Table 1. There were no significant differences between groups in maternal age, ethnicity, percentage of nulliparous women, or percentages with anterior placenta or prior cesarean delivery.

	Discussion

Top Abstract Materials and Methods Results Discussion References

A MEDLINE search using the terms "alpha-fetoprotein" and "placenta previa" from 1966 through 1999 did not identify any citations that described increase in pregnancy complications among women with elevated MSAFP levels in the setting of placenta previa (with the exception of placenta accreta and cesarean hysterectomy). Several others have reported increased incidence of placenta accreta in women with persistent previa and MSAFP elevation.^5,6,8 Zelop and colleagues⁵ found that women with placenta accreta who required cesarean hysterectomy were significantly more likely to have second-trimester MSAFP elevation than women with previa but no placental invasion. Kupferminc and colleagues⁶ reviewed a series of women who had nonelective cesarean hysterectomies and found that those with placenta accreta were more likely to have had MSAFP elevation. Although women with MSAFP levels at least 2.0 MoM had increased incidence of placenta accreta (21% versus 13%) and cesarean hysterectomy (36% versus 26%), neither finding reached statistical significance. Sample size might have precluded us from finding that relationship.

We also considered the possibility that, to a certain extent, the pregnancy complications we encountered might have been attributable to MSAFP elevation rather than to previa itself. Several series evaluated the likelihood of those complications in women with MSAFP elevation and normal placentation. Among women with MSAFP elevation, antepartum bleeding was reported in 8%, preterm birth before 34 weeks’ gestation in 5%, placental separation in 7%, and pregnancy-induced hypertension in 4%.^3,4,9 Each of those outcomes was more than twice as common in our series of women with placenta previa.

The major limitation of this study was that it was retrospective. Most women who had placenta previa at serum screening in the second trimester no longer had previa at third-trimester follow-up. Therefore, it was unclear whether patient counseling or pregnancy management should be altered with those findings in the second trimester.

This study raises important issues that a prospective study might better address. We want to know whether women with placenta previa and MSAFP elevation are more likely to have persistence of previa and other pregnancy complications. It would be interesting to evaluate the relationship between bleeding early in pregnancy, MSAFP elevation, and persistence of placenta previa, and to determine whether the subgroup with those characteristics is at particular risk for complications. Although the pathophysiology underlying those complications is not completely understood, increased diffusion of MSAFP across the placental interface has been associated with placental sonolucencies, placental infarcts, and evidence of fetomaternal hemorrhage.^9,10 In pregnancies with MSAFP elevation, sonolucencies have not been associated with adverse outcomes without other complications; however, that has not been addressed specifically in the setting of placenta previa. Placental findings on ultrasound and MSAFP elevation might better predict which women with previa will develop pregnancy complications. It might help with counseling women with placenta previa and to define a subset of women who might benefit from more intensive prenatal surveillance.

	Footnotes

 
PII S0029-7844(00)01095-4

Received May 11, 2000. Received in revised form August 4, 2000. Accepted September 28, 2000.

	References

Top Abstract Materials and Methods Results Discussion References

 
1. Cunningham FG, MacDonald PC, Gant NF, Leveno KJ, Gilstrap LC, Hankins GDV, et al. Obstetrical hemorrhage. In: Williams Obstetrics, 20th ed. Appleton & Lange: Stamford, CT 1997:755–6.

2. Milunsky A, Jick SS, Bruell CL, MacLaughlin DS, Tsung Y, Jick H, et al. Predictive values, relative risks, and overall benefits of high and low maternal serum -fetoprotein screening in singleton pregnancies: New epidemiologic data. Am J Obstet Gynecol 1989; 161:291–7.[Medline]

3. Brazerol WF, Grover S, Donnenfeld AE. Unexplained elevated maternal serum -fetoprotein and perinatal outcome in an urban clinic population. Am J Obstet Gynecol 1994;171:1030–5.[Medline]

4. Waller DK, Lustig LS, Cunningham GC, Feuchtbaum LB, Hook EB. The association between maternal serum alpha-fetoprotein and preterm birth, small for gestational age infants, preeclampsia and placental complications. Obstet Gynecol 1996;88:816–22.[Abstract]

5. Zelop C, Nadel A, Frigoletto FD, Pauker S, MacMillan M, Benacerraf BR. Placenta accreta/percreta/increta: A cause of elevated maternal serum alpha-fetoprotein. Obstet Gynecol 1992;80:693–4.[Abstract/Free Full Text]

6. Kupferminc MJ, Tamura RK, Wigton TR, Glassenberg R, Socol ML. Placenta accreta is associated with elevated maternal serum alpha-fetoprotein. Obstet Gynecol 1993;82:266–9.[Abstract/Free Full Text]

7. McIntire DD, Bloom SL, Casey BM, Leveno KJ. Birthweight in relation to morbidity and mortality among newborn infants. N Engl J Med 1999;340:1234–8.[Abstract/Free Full Text]

8. Hung T, Shau W, Hsieh C, Chiu T, Hsu J, Hsieh T. Risk factors for placenta accreta. Obstet Gynecol 1999;93:545–50.[Abstract/Free Full Text]

9. Bernstein IM, Barth RA, Miller R, Capeless EL. Elevated maternal serum alpha-fetoprotein: Association with placental sonolucencies, fetomaternal hemorrhage, vaginal bleeding, and pregnancy outcome in the absence of fetal anomalies. Obstet Gynecol 1992;79: 71–4.[Abstract/Free Full Text]

10. Salafia CM, Silberman L, Herrera NE, Mahoney MJ. Placental pathology at term associated with elevated midtrimester serum -fetoprotein concentration. Am J Obstet Gynecol 1988;158: 1064–6.[Medline]

This article has been cited by other articles:

				G. J. Mizejewski Physiology of Alpha-Fetoprotein as a Biomarker for Perinatal Distress: Relevance to Adverse Pregnancy Outcome Experimental Biology and Medicine, September 1, 2007; 232(8): 993 - 1004. [Abstract] [Full Text] [PDF]

				L. Dugoff, J. C. Hobbins, F. D. Malone, J. Vidaver, L. Sullivan, J. A. Canick, G. M. Lambert-Messerlian, T. F. Porter, D. A. Luthy, C. H. Comstock, et al. Quad Screen as a Predictor of Adverse Pregnancy Outcome Obstet. Gynecol., August 1, 2005; 106(2): 260 - 267. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by BUTLER, E. L. Articles by RAMUS, R. M. Search for Related Content PubMed PubMed Citation Articles by BUTLER, E. L. Articles by RAMUS, R. M.