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Obstetrics & Gynecology 1999;94:929-934
© 1999 by The American College of Obstetricians and Gynecologists
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ORIGINAL RESEARCH

Adverse Obstetric Outcome in Low- and High-Risk Pregnancies: Predictive Value of Maternal Serum Screening

M. VAN RIJN, MD, Y. T. VAN DER SCHOUW, PhD, A. M. HAGENAARS, MSc, G. H. A. VISSER, MD, PhD and G. C. M. L. CHRISTIAENS, MD, PhD

From the Department of Obstetrics and Gynecology, Utrecht University Medical Center, Utrecht; the Julius Center for Patient-Oriented Research, University Utrecht, Utrecht; and the Diagnostic Laboratory for Infectious Diseases and Perinatal Screening, National Institute of Public Heatlh and the Environment, Bilthoven, The Netherlands.

Address reprint requests to: G. C. M. L. Christiaens, MD, PhD, Department of Obstetrics and Gynecology, Utrecht University Medical Center, HP KE 04.123.1, PO Box 85090, 3508 AB Utrecht, The Netherlands, E-mail: l.christiaens{at}dog.azu.nl


   Abstract
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Abstract
Materials and Methods
 Results
 Discussion
 References
 
Objective: To determine whether the relationship between adverse pregnancy outcome and elevated maternal serum alpha-fetoprotein (MSAFP) and/or maternal serum hCG levels in women whose fetuses have no chromosomal abnormalities or neural tube defects is restricted to pregnancies with a priori elevated risk for pathology or also present in low-risk pregnancies.

Methods: The outcomes of pregnancy in two groups of patients with elevated MSAFP and/or maternal serum hCG values were compared with the outcomes of a reference group with normal serum values. The first study group consisted of 83 women without pre-existing risk for poor outcome as defined by the guidelines of the Dutch Society of Obstetrics and Gynecology. The second study group consisted of 62 women with a priori elevated risk according to these guidelines.

Results: Fetal or neonatal death, pregnancy-induced hypertension, placental abruption, placenta previa, preterm delivery, delivery of infants with birth weights in the 2.3rd percentile, and complications during the third stage of labor occurred significantly more often in patients with elevated values and low a priori risk than in women with normal values and without pre-existing risk factors. There was no significant increase in adverse pregnancy outcome in women with elevated values and high a priori risk compared with women with normal values and elevated a priori risk.

Conclusion: In women at low risk, elevated MSAFP and/or maternal serum hCG values are predictive of adverse pregnancy outcome. In women with a priori elevated risk, abnormal serum values do not increase this risk.

Women with elevated second-trimester maternal serum alpha-fetoprotein (MSAFP) levels whose fetuses do not have neural tube defects are known to have an increased risk of fetal death, delivery of a low birth weight infant, and preterm delivery.1,2 A similar association exists between high second-trimester maternal serum hCG levels and fetal death, preeclampsia, pregnancy-induced hypertension, preterm delivery, and placental pathology.3–6 The elevated levels of MSAFP and maternal serum hCG are thought to reflect early placental pathology that may be associated with problems later in pregnancy. Increased obstetric surveillance in women with unexplained elevated MSAFP and/or maternal serum hCG values has been recommended.7–11

The goal of this study was to determine whether elevated MSAFP and/or maternal serum hCG values are as predictive of adverse outcome in women with a priori high obstetric risk as in women with a priori low risk. This question is clinically relevant because in The Netherlands, as elsewhere, healthy women with uneventful pregnancies are cared for by midwives, general practitioners, nurse practitioners, and nurse midwives, whereas pregnant women who are at risk for adverse outcome are cared for by obstetricians.


   Materials and Methods
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Abstract
 Materials and Methods
Results
 Discussion
 References
 
Between March 1991 and January 1997, 7380 pregnant women underwent serum screening for neural tube defects and/or Down syndrome between 15 and 20 weeks’ gestation at the Utrecht University Medical Center, Utrecht, The Netherlands. Gestational ages were determined by first-trimester ultrasound. After exclusion of pregnancies with unknown outcome (n = 1164), twin gestations (n = 172), and pregnancies with fetuses with congenital anomalies associated with abnormal MSAFP and/or maternal serum hCG values (n = 29), there remained 6015 pregnancies for analysis.

The Dutch Society of Obstetrics and Gynecology developed guidelines for risk assignment to help physicians decide whether a pregnant woman should receive secondary or primary care during pregnancy. The most frequent conditions and histories indicating pre-existing elevated obstetric risk are summarized in Table 1Go. The guidelines were used to divide women with elevated MSAFP and/or maternal hCG levels into two groups: those with low a priori risk and those with high a priori risk. All medical and obstetric history information was obtained from hospital records and referring physicians or midwives. Because it would not have been feasible to collect the same detailed information for all 5870 women with normal MSAFP and maternal serum hCG values, the "random sample" function of the SPSS (SPSS, Inc., Chicago, IL) software package was used to create a reference group of 145 women with normal serum values. Two staff obstetricians, masked to serum values and pregnancy outcome, independently examined the medical histories of the patients and listed the 290 pregnancies as low risk or high risk. The two lists were cross-checked, and a third observer (the head of the department) made the final decisions in the case of the 81 patients (28%) whose pregnancies had been classified differently by the first two observers. Discrepancies in risk classification occurred in the case of patients with obstetric or medical histories not explicitly listed in the national guidelines (eg, assisted reproduction by intracytoplasmic sperm injection). The final risk classification of these pregnancies was based as much as possible on evidence-based medicine.


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  		Table 1. Indicators of Elevated Obstetric Risk, Determined at the Onset of Pregnancy (Based on Guidelines of the Dutch Society of Obstetrics and Gynecology)
 
Pregnancy outcome was defined as adverse if one of the following had occurred: fetal death, pregnancy-induced hypertension, placental abruption, placenta previa, preterm delivery (delivery at less than 34 weeks’ gestation), delivery of an extremely small for gestational age (SGA) infant (birth weight in the 2.3rd percentile), or complications during the third stage of labor (retained placenta and/or loss of at least 1000 mL of blood during or after vaginal delivery). A distinction was made between fetal death close to the time of blood sampling (at less than 20 weeks’ gestation) and later fetal death (at 20 weeks or more). A pregnancy resulting in an infant who remained alive 8 days after delivery was described as ending with a live-born child. Pregnancy-induced hypertension, pre-existent (or chronic) hypertension, and preeclampsia were classified according to the definitions of Davey and MacGillivray.12 Hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome was defined as a serum level of liver enzymes of more than 70 IU/L and a platelet count of less than 100 x 109/L.13

Serum tests were performed with the use of Amerlex-M kits (alpha-fetoprotein) (Amerlex IM4304), unconjugated estriol (Amerlex IM4044B), and whole hCG (Amerlex IM4094)) (Amersham Pharmacia Biotech UK Ltd, Buckinghamshire, UK). Second-trimester maternal serum levels of the markers were expressed as multiples of the median (MoM). Least-squares regression analysis was performed for weight correction of MSAFP and maternal serum hCG levels.14 The definition of elevated serum marker levels was based on their 99th percentiles in the screened population (2.66 MoM for MSAFP and 3.96 MoM for maternal serum hCG). These values were rounded off to 2.5 MoM for MSAFP and 4.0 MoM for maternal serum hCG, comparable with cutoff levels used in other studies. Until March 1996, obstetric management was not changed when elevated serum levels were found. Thereafter, women without elevated a priori risk and high values were seen by obstetricians at 24 weeks for blood pressure (BP) measurement, urinanalysis, ultrasound, and Doppler measurement of the umbilical arteries. The frequencies of prenatal consultations (and hence the opportunities for diagnosing fetal death before the woman was alerted herself by lack of fetal movement) therefore were largely unaltered because of serum values.

The {chi}2 test and unpaired t test were used for statistical analysis of obstetric history and maternal characteristics in serum marker level categories. A two-tailed P value of less than .05 was considered statistically significant. Associations between pregnancies with specific outcomes and serum marker levels were expressed as relative risks (RRs; the proportion of women with a certain outcome in the study group divided by the proportion of women with the same outcome in the reference group) and 95% confidence intervals (CIs). Relative risks were calculated separately for the two subgroups (high and low a priori risk).

To compare our results with previous studies, we consulted the MEDLINE database. References in this database date back to 1966. Used keywords were "fetoprotein," "AFP," "gonadotrophin," and "hCG," "pregnancy outcome," "death," and "pregnancy complications."


   Results
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Abstract
 Materials and Methods
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Discussion
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Table 2Go shows the maternal characteristics of the 6015 women. One hundred forty-five women (2.4%) had elevated MSAFP and/or maternal serum hCG values. Women with high MSAFP and/or maternal serum hCG values more often had pre-existing risk factors compared with women with normal MoM values (43% compared with 23%, P < .001).


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  		Table 2. Obstetric History and Maternal Characteristics
 
Nine hundred fifty-five women (15%) had one or more adverse outcomes. Relative risks and 95% CIs for each outcome in the study groups are presented in Table 3Go. Overall, women with elevated MSAFP or maternal serum hCG values had a three-fold increase in risk for adverse pregnancy outcome (RR 3.1, 95% CI 2.5, 3.7). If both MSAFP and maternal serum hCG levels were elevated, there was an almost five-fold increase in risk compared with the risk in women with normal values (RR 4.7, 95% CI 3.4, 6.5). Women with elevated MSAFP and/or maternal serum hCG values were at greater risk for fetal death, delivery before 34 weeks, delivery of an extremely SGA infant, placental abruption, and complications in the third stage of labor than were women with normal MSAFP and maternal serum hCG values. Additionally, women with elevated maternal serum hCG values (and with or without elevated MSAFP values) had a significantly higher risk for pregnancy-induced hypertension, preeclampsia, or HELLP syndrome. The median gestational age at which fetal death was detected was 28 weeks (range 17–41 weeks) for the group with normal MSAFP and maternal serum hCG values and 20 weeks (range 16–30 weeks) in the group with elevated values (P = .004). Isolated elevated MSAFP levels were predictive mainly of imminent fetal death and not of fetal death beyond 20 weeks’ gestation. The positive predictive value of elevated MSAFP and/or maternal serum hCG values for adverse pregnancy outcome when the described cutoff values were used was 41% (95% CI 33%, 49%) and the negative predictive value was 86% (95% CI 86%, 87%).


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  		Table 3. Relative Risks for Pregnancy Outcomes in Patients With Elevated Serum Marker Levels
 
When data from patients with a priori low risk and data from patients with a priori high risk were analyzed separately, abnormal MSAFP and/or maternal serum hCG levels were found to be predictive of an increase in risk for adverse outcome in the former group only (Table 4Go). Overall, women without a priori elevated risk had a 3.8-times-higher risk for adverse outcome when MSAFP and/or maternal serum hCG levels were elevated (95% CI 2.0, 7.1) compared with women in the same risk category who had normal marker levels. Adverse outcome occurred in 25% of the patients at low risk who had unexplained high MSAFP levels only, in 41% of those with high maternal serum hCG levels only, and in 69% of those in whom both MSAFP and maternal serum hCG levels were elevated. In women at high risk, unexplained elevated MSAFP and/or maternal serum hCG levels were not associated with change in risk for any adverse pregnancy outcome (RR 0.99, 95% CI 0.6, 1.6).


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  		Table 4. Relative Risks for Adverse Outcome in Patients With Elevated Serum Level Markers Without and With A Priori Elevated Obstetric Risk
 

   Discussion
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Abstract
 Materials and Methods
 Results
 Discussion
References
 
Reports on the relationship between elevated MSAFP levels and adverse pregnancy outcome date back to the start of maternal serum screening programs for neural tube defects in the 1970s.15–17 In seven studies with designs similar to ours, RR for an adverse outcome ranged from 1.6 to 3.8 in cases of elevated MSAFP levels and from 1.5 to 5.0 in cases of elevated maternal serum hCG levels.5,6,18–22 Both leakage of MSAFP through a defective placental barrier and an increased placental villous surface have been mentioned as explanations for the association between elevated MSAFP levels and adverse pregnancy outcome.2,23 A considerable proportion of pregnancy outcomes that are associated with elevated MSAFP levels (such as preeclampsia, placental abruption, placenta previa, and fetal growth restriction [FGR]) are associated with abnormalities of the placenta or placentation.23 The specific mechanism for maternal serum hCG level elevation in pregnancies with adverse outcomes is unknown, but placental immaturity (also related to growth restriction and prematurity) and uteroplacental underperfusion leading to placental vascular changes have been suggested.4,24,25

Our study confirms previous findings regarding the relationship between elevated MSAFP and/or maternal serum hCG levels and adverse pregnancy outcome.1–11,18–22 The higher risk of adverse pregnancy outcome if levels of one or both markers were elevated was significant, but only in women with low a priori risk. In women with pre-existing risk for adverse pregnancy outcome, the presence of elevated serum marker levels did not relate to further increase in risk. This is in agreement with the results of Phillips et al,26 who studied a high-risk urban population and found that elevated MSAFP levels did not have any additional predictive value with regard to adverse perinatal outcome.

The negative predictive value of maternal serum screening is too low for it to be useful as a screening instrument for adverse pregnancy outcome. However, the positive predictive value of 41% may justify intensified obstetric surveillance in women with unexplained elevated MSAFP and/or maternal serum hCG values. Repeat ultrasound and Doppler flow measurements from 24 weeks onward to rule out early-onset FGR or placental pathology, close supervision of maternal BP, and fetal monitoring are recommended.7–11 Whether medical and psychologic costs and benefits are balanced should be the subject of future studies.

Women with elevated MSAFP and/or maternal serum hCG levels usually are referred for second-trimester amniocentesis. This procedure involves a small (0.5%) risk of iatrogenic loss. Several studies have shown that the association between elevated marker levels and fetal death is independent of amniocentesis.27–29

Combining the guidelines of the Dutch Society of Obstetrics and Gynecology with the determination of marker levels improves differentiation between women with low risk and those with high risk. Ten percent of the women assigned to the low-risk group who had normal serum marker levels had adverse outcomes, compared with 43% of those with high a priori risk and/or elevated serum marker levels. Consequently, women with low risk who have unexplained elevated MSAFP and/or maternal serum hCG values have an increased risk of adverse pregnancy outcome and require intensified obstetric surveillance. Further studies are necessary to determine whether intensified obstetric surveillance can prevent all or some of these outcomes.


   Footnotes
 
The authors thank A. C. C. van Oppen, MD, PhD, for assistance in determining the a priori risk in the 290 patients and H. W. Bruinse, MD, PhD, for his valuable comments.

PII S0029-7844(99)00467-6

Received December 14, 1998. Received in revised form May 10, 1999. Accepted May 21, 1999.


   References
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 Materials and Methods
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 Discussion
 References
 
1. Katz VL, Chescheir NC, Cefalo RC. Unexplained elevations of maternal serum alpha-fetoprotein. Obstet Gynecol Surv 1990;45: 719–26.[Medline]

2. Thomas RL, Blakemore KJ. Evaluation of elevations in maternal serum alpha-fetoprotein: A review. Obstet Gynecol Surv 1990;45: 269–83.[Medline]

3. Gravett CP, Buckmaster JG, Watson PT, Gravett MG. Elevated second trimester maternal serum beta-HCG concentrations and subsequent adverse pregnancy outcome. Am J Med Genet 1992; 44:485–6.[Medline]

4. Gonen R, Perez R, David M, Dar H, Merksamer R, Sharf M. The association between unexplained second-trimester maternal serum hCG elevation and pregnancy complications. Obstet Gynecol 1992; 80:83–6.[Abstract/Free Full Text]

5. Benn PA, Horne D, Briganti S, Rodis JF, Clive JM. Elevated second-trimester maternal serum hCG alone or in combination with elevated alpha-fetoprotein. Obstet Gynecol 1996;87:217–22.[Abstract]

6. Morssink LP, Kornman LH, Beekhuis JR, De Wolf BT, Mantingh A. Abnormal levels of maternal serum human chorionic gonadotropin and alpha-fetoprotein in the second trimester: Relation to fetal weight and preterm delivery. Prenat Diagn 1995;15:1041–6.[Medline]

7. Cusick W, Rodis JF, Vintzileos AM, Albini SM, McMahon M, Campbell WA. Predicting pregnancy outcome from the degree of maternal serum alpha-fetoprotein elevation. J Reprod Med 1996; 41:327–32.[Medline]

8. Hurley TJ, Miller C, O’Brien TJ, Blacklaw M, Quirk JG Jr. Maternal serum human chorionic gonadotropin as a marker for the delivery of low-birth-weight infants in women with unexplained elevations in maternal serum alpha-fetoprotein. J Matern Fetal Med 1996;5: 340–4.[Medline]

9. Vaillant P, David E, Constant I, Athmani B, Devulder G, Fievet P, et al. Validity in nulliparas of increased beta-human chorionic gonadotrophin at mid-term for predicting pregnancy-induced hypertension complicated with proteinuria and intrauterine growth retardation. Nephron 1996;72:557–63.[Medline]

10. Hsieh TT, Hung TH, Hsu JJ, Shau WY, Su CW, Hsieh FJ. Prediction of adverse perinatal outcome by maternal serum screening for Down syndrome in an Asian population. Obstet Gynecol 1997;89: 937–40.[Abstract]

11. Wenstrom KD, Hauth JC, Goldenberg RL, DuBard MB, Lea C. The effect of low-dose aspirin on pregnancies complicated by elevated human chorionic gonadotropin levels. Am J Obstet Gynecol 1995; 173:1292–6.[Medline]

12. Davey DA, MacGillivray I. The classification and definition of hypertensive disorders of pregnancy. Am J Obstet Gynecol 1988; 158:892–8.[Medline]

13. Sibai BM. The HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets): Much ado about nothing? Am J Obstet Gynecol 1990;162:311–6.[Medline]

14. Reynolds TM, Penney MD, Hughes H, John R. The effect of weight correction on risk calculations for Down’s syndrome screening. Ann Clin Biochem 1991;28:245–9.

15. Seppala M, Ruoslahti E. Alpha-fetoprotein in maternal serum: A new marker for detection of fetal distress and intrauterine death. Am J Obstet Gynecol 1973;115:48–52.[Medline]

16. Garoff L, Seppala M. Prediction of fetal outcome in threatened abortion by maternal serum placental lactogen and alpha fetoprotein. Am J Obstet Gynecol 1975;121:257–61.[Medline]

17. Rodeck CH, Campbell S, Biswas S. Maternal plasma alpha-fetoprotein in normal and complicated pregnancies. Br J Obstet Gynaecol 1976;83:24–32.[Medline]

18. 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]

19. Simpson JL, Palomaki GE, Mercer B, Haddow JE, Andersen R, Sibai B, et al. Associations between adverse perinatal outcome and serially obtained second- and third-trimester maternal serum alpha-fetoprotein measurements. Am J Obstet Gynecol 1995;173: 1742–8.[Medline]

20. Haddow JE, Knight GJ, Kloza EM, Palomaki GE. Alpha-fetoprotein, vaginal bleeding and pregnancy risk. Br J Obstet Gynaecol 1986;93:589–93.[Medline]

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

22. Tanaka M, Natori M, Kohno H, Ishimoto H, Kobayashi T, Nozawa S. Fetal growth in patients with elevated maternal serum hCG levels. Obstet Gynecol 1993;81:341–3.[Abstract/Free Full Text]

23. Boyd PA. Why might maternal serum AFP be high in pregnancies in which the fetus is normally formed? Br J Obstet Gynaecol 1992;99:93–5.[Medline]

24. Lieppman RE, Williams MA, Cheng EY, Resta R, Zingheim R, Hickok DE, et al. An association between elevated levels of human chorionic gonadotropin in the midtrimester and adverse pregnancy outcome. Am J Obstet Gynecol 1993;168:1852–6.[Medline]

25. Wenstrom KD, Owen J, Boots LR, DuBard MB. Elevated second-trimester human chorionic gonadotropin levels in association with poor pregnancy outcome. Am J Obstet Gynecol 1994;171:1038–41.[Medline]

26. Phillips OP, Simpson JL, Morgan CD, Andersen RN, Shulman LP, Meyers CM, et al. Unexplained elevated maternal serum alpha-fetoprotein is not predictive of adverse perinatal outcome in an indigent urban population. Am J Obstet Gynecol 1992;166:978–82.[Medline]

27. Waller DK, Lustig LS, Smith AH, Hook EB. Alpha-fetoprotein: A biomarker for pregnancy outcome. Epidemiology 1993;4:471–6.[Medline]

28. Waller DK, Lustig LS, Cunningham GC, Golbus MS, Hook EB. Second-trimester maternal serum alpha-fetoprotein levels and the risk of subsequent fetal death. N Engl J Med 1991;325:6–10.[Abstract]

29. Wenstrom KD, Owen J, Davis RO, Brumfield CG. Prognostic significance of unexplained elevated amniotic fluid alpha-fetoprotein. Obstet Gynecol 1996;87:213–6.[Abstract]




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