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Obstetrics & Gynecology 2006;107:161-166
© 2006 by The American College of Obstetricians and Gynecologists
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ORIGINAL RESEARCH

Pregnancy-Associated Plasma Protein A and Alpha-fetoprotein and Prediction of Adverse Perinatal Outcome

Gordon C. S. Smith, MD, PhD1, Imran Shah, MSc1, Jennifer A. Crossley, PhD2, David A. Aitken, PhD2, Jill P. Pell, MD3, Scott M. Nelson, MB, PhD4, Alan D. Cameron, MD4, Michael J. Connor, MD, DSc2 and Richard Dobbie, BSc5

From the 1Department of Obstetrics and Gynaecology, Cambridge University, Cambridge; 2Institute of Medical Genetics, Yorkhill National Health Service Trust, Glasgow; 3Department of Public Health, Greater Glasgow National Health Service Board, Glasgow; 4Department of Obstetrics and Gynaecology, Glasgow University, Glasgow; and 5Information & Statistics Division, Common Services Agency, Edinburgh, United Kingdom.


   ABSTRACT
TOP
ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVE: To describe the association between pregnancy associated plasma protein A (PAPP-A), alpha-fetoprotein (AFP) and adverse perinatal outcome.

METHODS: We conducted a multicenter prospective cohort study of 8,483 women attending for prenatal care in southern Scotland between 1998 and 2000. The risk of delivering a small for gestational age infant, delivering preterm, and stillbirth were related to maternal serum levels of PAPP-A and AFP.

RESULTS: Women with a low PAPP-A were not more likely to have elevated levels of AFP. Compared with women with a normal PAPP-A and a normal AFP, the odds ratio for delivering a small for gestational age infant for women with a high AFP was 0.9 (95% confidence interval [CI] 0.5–1.6), for women with a low PAPP-A was 2.8 (95% CI 2.0–4.0), and for women with both a high AFP and a low PAPP-A was 8.5 (95% CI 3.6–20.0). The odds ratio for delivering preterm for women with a high AFP was 1.8 (95% CI 1.3–2.7), for women with a low PAPP-A was 1.9 (95% CI 1.3–2.7), and for women with both a low PAPP-A and a high AFP was 9.9 (95% CI 4.4–22.0). These interactions were statistically significant for both outcomes (P = .03 and .04, respectively). There was a nonsignificant trend toward a similar interaction in relation to stillbirth risk. Of the women with the combination of a low PAPP-A and high AFP, 32.1% (95% CI 15.9–52.4) delivered a low birth weight infant.

CONCLUSION: Low maternal serum levels of PAPP-A between 10 and 14 weeks and high levels of AFP between 15 and 21 weeks gestation are synergistically associated with adverse perinatal outcome.

LEVEL OF EVIDENCE: II-2

Insulin-like growth factor II (IGF-II) is expressed in high levels in trophoblast and is thought to have a key role in the control of trophoblast invasion.1 Recent evidence indicates that the activity of the IGF system may be important in very early human pregnancy. A number of studies have related maternal circulating concentrations of pregnancy-associated plasma protein A (PAPP-A), a trophoblast derived protease for IGF binding proteins 4 and 5, to eventual perinatal outcome. These studies have shown that low levels of PAPP-A are associated with increased risks of intrauterine growth restriction, preterm birth, and stillbirth. These associations are evident even when confined to samples obtained in the first 10 weeks postconception.5,6 Consistent with this, mice that are null mutant for the gene encoding PAPP-A have severe early onset intrauterine growth restriction.7

It has been appreciated for many years that, in the absence of congenital abnormality, high maternal serum levels of alpha-fetoprotein (AFP) in the second trimester of pregnancy are associated with an increased risk of adverse perinatal outcome.8 AFP is the major fetal oncotic protein and, when the fetus is structurally normal, high maternal circulating levels are thought to reflect a defect in placentation. It is not yet known, however, whether the placental defect associated with increased placental permeability to AFP is related to the activity of the IGF system. The aim of this study was to describe the relationship between low PAPP-A, high AFP, and intrauterine growth restriction, preterm birth, and stillbirth.


   MATERIALS AND METHODS
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ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
We used data from the Combined Ultrasound and Biochemical Screening9 study, a prospective, noninterventional, multicenter study of screening for Down syndrome. The study evaluated the use of ultrasound measurement of fetal nuchal translucency in combination with analysis of maternal serum PAPP-A and the free ß subunit of human chorionic gonadotrophin as a first trimester screening test for Down syndrome in a routine prenatal clinic setting. Information leaflets about the study were sent to women with the notification of their first appointment for prenatal care. Those women whose first visit was at 14 weeks of gestation or less were invited to participate, and those who agreed signed a consent form. Participation in the study involved measuring nuchal translucency at the time of the first ultrasound and obtaining additional blood at the time of phlebotomy for routine prenatal investigations. No results were reported to either the obstetrician or patient, and prenatal care was not modified in any way by participation in the study. Ethical approval was obtained from the Scottish Multicenter Research Ethics Committee. Fifteen Scottish maternity units participated in the Combined Ultrasound and Biochemical Screening study during a 2-year period between 1997 and 1999, and 98.6% of records came from births in 11 of the hospitals. Ninety-eight percent of the births occurred between May 1998 and July 2000. Births to women recruited to the study constituted 28.6% of all births in the 11 hospitals during that period.

Maternal levels of PAPP-A were measured from blood obtained at the time of the first prenatal visit (10–14 weeks) as part of the Combined Ultrasound and Biochemical Screening study. Maternal levels of AFP were determined by two methods. First, we performed record linkage of the Combined Ultrasound and Biochemical Screening database to the database of the laboratory information management system for the prenatal screening program of the West of Scotland Regional Genetics Service of the Institute of Medical Genetics in Glasgow. Second, part of the cohort was followed up by manual retrieval of the case notes, and the AFP level was obtained directly from the case record. PAPP-A was assayed between 10 and 14 weeks gestation and AFP between 15 and 21 weeks. The outcome of the pregnancy was ascertained by linkage of the Combined Ultrasound and Biochemical Screening database to the Scottish Morbidity Record10 and the Scottish Stillbirth and Infant Death Enquiry.11 The Scottish Morbidity Record is a national register of perinatal outcome data,10 and the Scottish Stillbirth and Infant Death Enquiry is a national register that routinely classifies all perinatal deaths in Scotland.11 The Scottish Stillbirth and Infant Death Enquiry has data on 100% of registered stillbirths,11 and the Scottish Morbidity Record contains data on 99.6% of certified births.10 The record linkage and the details of the other data sources and definitions are described in detail elsewhere.6,12 The study cohort (N = 8,483) for the current analysis was defined by women who participated in the Combined Ultrasound and Biochemical Screening study, who had both PAPP-A and AFP results documented, and who could be linked to the Scottish Morbidity Record where singleton birth occurred at or after 24 weeks gestation.

Small for gestational age (SGA) was defined on the basis of centiles derived from the cohort, and preterm birth was defined as delivery before 37 completed weeks of gestation. Socioeconomic status was estimated on the basis of the postal code of the mother's residence, according to Carstairs socioeconomic-deprivation categories (based on 1991 Census data on car ownership, employment status, number of occupants per household room, and social class within postal-code sectors of residence that contain, on average, about 1,600 residents).13 Higher scores indicate residence within areas of greater deprivation.

Maternal serum levels of PAPP-A and AFP were expressed as multiples of the median (MoM) for gestational age, as is conventional for biochemical indices in pregnancy that vary with week of gestation. Because PAPP-A and AFP levels vary inversely with maternal weight, MoM were corrected for maternal weight using reciprocal-linear regression. This is widely employed in prenatal screening and is described in detail elsewhere.14 Separate PAPP-A MoM were estimated for smokers, because PAPP-A is reduced by 15% among smokers.9 Low PAPP-A was defined as the lowest 5% of values for gestational age (≤ 0.4 MoM), and high AFP was defined as the top 5% of values for gestational age (≥ 1.7 MoM). Univariate comparison of continuous variables was performed using the Mann-Whitney U test and categorical data using the Fisher exact test. All P values were 2-tailed. Statistical significance was assumed at P < .05. Multivariate analysis was performed using logistic regression.15 Cases with missing data on covariates were dropped from the multivariate analysis. Interaction terms were assessed using the likelihood ratio test. All statistical analyses were performed using the Stata 8 software package (Stata Corporation, College Station, TX).


   RESULTS
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ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The linked database contained 11,729 records of women who had a PAPP-A documented and had a Scottish Morbidity Record. Three (0.03%) records were excluded because the gestational age at delivery was less than 24 weeks, 2 (0.02%) because of missing data on sex of the baby, and 3 (0.03%) because of missing data on weight. Of the remaining 11,721 births, 8,483 (72.4%) had an AFP level recorded, and these women constituted the study cohort. The characteristics of the study cohort are described in Table 1.


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  		Table 1. Characteristics of Study Population (N = 8,483)

 

Low PAPP-A was associated with an increased risk of delivering an SGA infant, preterm birth, and stillbirth (Table 2). An elevated AFP was associated with an increased risk of preterm birth and stillbirth (Table 2). Women with a low level of PAPP-A were not at increased risk of having a high AFP (odds ratio 1.3, 95% confidence interval [CI] 0.9–1.9). Adjusting each factor for the other was without material effect on the strength of associations (Table 3). Similarly adjusting for maternal characteristics had a minimal effect on the strength of the associations (Table 3).


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  		Table 2. Univariate Associations Between Pregnancy-Associated Plasma Protein A and Alpha-fetoprotein and Outcome

 

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  		Table 3. Multivariate Analysis of Association Between Pregnancy-Associated Plasma Protein A, Alpha-fetoprotein, and Maternal Characteristics in Predicting Adverse Perinatal Outcome

 

We then studied outcome for high AFP and low PAPP-A, either singly or in combination, with reference to women with normal values of both AFP and PAPP-A (this is a different referent category from Table 3 and thus odds ratios differ slightly from Table 3). The odds ratio for delivering a small for gestational age infant for women with a high AFP was 0.9 (95% CI 0.5–1.6), for women with a low PAPP-A was 2.8 (95% CI 2.0–4.0), and for women with both a high AFP and a low PAPP-A was 8.5 (95% CI 3.6–20.0). The odds ratio for delivering preterm for women with a high AFP was 1.8 (95% CI 1.3–2.7), for women with a low PAPP-A was 1.9 (95% CI 1.3–2.7), and for women with both a low PAPP-A and a high AFP was 9.9 (95% CI 4.4–22.0). The odds ratio for antepartum stillbirth for women with a high AFP was 2.5 (95% CI 0.6–10.9), for women with a low PAPP-A was 2.2 (95% CI 0.5–9.7), and for women with both a low PAPP-A and a high AFP was 36.7 (95% CI 8.0–167.6). Receiver operating characteristic curve analysis of PAPP-A, AFP, and maternal characteristics in predicting adverse outcome is shown in Table 4. There were statistically significant positive interactions (Fig. 1) between PAPP-A and AFP in the risk of delivering a SGA infant (P = .03), preterm birth (P = .04) and a trend toward a positive interaction in the risk of stillbirth (P = .14). Of the women with the combination of a low PAPP-A and high AFP, 32.1% (95% CI 15.9–52.4) delivered a low birth weight infant.


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  		Table 4. Receiver Operating Characteristic Curve Analysis of Pregnancy-Associated Plasma Protein A, Alpha-fetoprotein, and Maternal Characteristics in Predicting Adverse Outcome

 


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  		Fig. 1. Odds ratios for combinations of low pregnancy-associated plasma protein A and high alpha-fetoprotein in predicting delivery of a small for gestational age infant (A), preterm delivery (B), and stillbirth (C). The odds ratios for interaction terms between a low pregnancy-associated plasma protein A and a high alpha-fetoprotein were 3.4 (95% CI 1.2–9.8, P = .03) for small for gestational age, 2.8 (95% CI 1.1–7.2, P = .04) for preterm birth and 6.6 (95% CI 0.5–78.9, P = .14) for stillbirth. All odds ratios are referent to women with both a normal pregnancy-associated plasma protein A and a normal alpha-fetoprotein. SGA, small for gestational age; AFP, alpha-fetoprotein; PAPPA, pregnancy-associated plasma protein A.

Smith. PAPP-A, AFP, and Perinatal Outcome. Obstet Gynecol 2006.

 


   DISCUSSION
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
A number of lines of evidence support an important role for the activity of the IGF system in the first trimester of pregnancy in determining perinatal outcome. Insulin-like growth factor II is highly expressed in trophoblast and is likely to control both maternal and placental tissues at the site of implantation.1 Low maternal levels of PAPP-A, a trophoblast-derived protease for IGF binding proteins-4 and IGF binding proteins-5,16 are associated with increased risks of intrauterine growth restriction, preterm birth, and stillbirth. Mice which are null mutant for the PAPP-A gene are also at increased risk of early-onset intrauterine growth restriction,7 which supports a causal role for PAPP-A in determining outcome.

Many previous studies had shown that high maternal levels of the fetal oncotic protein, AFP, were associated with an increased risk of complications in later pregnancy.8 It was not apparent, however, whether PAPP-A was a marker for the same placental defect that leads to high rates of placental transfer of AFP. The present study had 3 major findings. First, we show that women who had low levels of PAPP-A were not more likely to have elevated levels of AFP in the second trimester of pregnancy. This suggests that the pathophysiologic process leading to high placental transfer rates of AFP is not related to the IGF system, insofar as it can be assessed by circulating levels of PAPP-A. Second, we show that adjustment for the levels of PAPP-A had a minimal effect on the strength of association between AFP and adverse outcome, and vice versa. If low levels of PAPP-A and high levels of AFP were markers of the same underlying defect in placental function, it would have been anticipated that adjustment of 1 factor for the level of the other would have resulted in a weaker association. The lack of an effect of such adjustment suggests that low PAPP-A and high AFP are consequences of distinct processes and that extreme levels indicate different aspects of placental dysfunction. Finally, we show the combination of a low PAPP-A and a high AFP was synergistically associated with adverse outcome. This indicates that the consequences of the 2 underlying processes must interact. These clinical observations indicate complexity in the placental determinants of adverse perinatal outcome and underline the importance of understanding the biology of trophoblast function in early pregnancy as a determinant of complications in late pregnancy.

The combination of low PAPP-A and high AFP is not likely to be clinically useful as a means of population-based screening to identify women at high risk of pregnancy complications. Relatively few women will have the combination of a low PAPP-A and a high AFP. Consequently, the sensitivity of this test will be low and would not, in itself, justify population-based screening for these outcomes. However, maternal serum levels of PAPP-A and AFP are used in Down syndrome screening, and inevitably, this process will identify women who have the combination of both a low PAPP-A and a high AFP. Women with this combination had a 32.1% risk of delivering a low birth weight neonate (< 2,500 g), a composite outcome of poor growth and preterm birth. The current data justify very close surveillance of these women, because they have a high absolute risk of adverse outcome. Serial umbilical artery Doppler flow velocimetry may be the preferred method of surveillance, because its use has been shown to reduce perinatal mortality in high-risk pregnancies.17

The data sources employed in the present study also included measurement of the free ß subunit of human chorionic gonadotrophin in the first trimester of pregnancy and human chorionic gonadotrophin in the second. We did not analyze whether these factors were associated with adverse outcome, because previous studies have shown the former is not independently associated with adverse outcome,2 and the latter is only weakly associated.18 Moreover, the number of cases in the present study were insufficient to study third- or fourth-order interactions or interactions associated with more extreme values of PAPP-A or AFP.

In conclusion, we show that low PAPP-A and high AFP synergistically predict preterm birth and intrauterine growth restriction. We speculate that the synergistic predictive ability of these tests reflects the combined effect of 2 independent pathophysiologic processes in early placental development.


   Footnotes
 
The record linkage was funded by the Foundation for the Study of Infant Deaths. The Combined Ultrasound and Biochemical Screening study was funded by the Chief Scientist's Office of the Scottish National Health Service Executive and the Fetal Medicine Foundation.

Corresponding author: Gordon C. S. Smith, MD, PhD, Professor of Obstetrics and Gynaecology, Cambridge University, Rosie Maternity Hospital, Cambridge, CB2 2SW, United Kingdom; e-mail: gcss2{at}cam.ac.uk.

doi:10.1097/01.AOG.0000191302.79560.d8


   REFERENCES
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Irwin JC, Suen LF, Martina NA, Mark SP, Giudice LC. Role of the IGF system in trophoblast invasion and pre-eclampsia. Hum Reprod 1999;14 suppl:90–6.[Abstract/Free Full Text]

2. Smith GC, Stenhouse EJ, Crossley JA, Aitken DA, Cameron AD, Connor JM. Early pregnancy levels of pregnancy-associated plasma protein a and the risk of intrauterine growth restriction, premature birth, preeclampsia, and stillbirth. J Clin Endocrinol Metab 2002;87:1762–7.[Abstract/Free Full Text]

3. Dugoff L, Hobbins JC, Malone FD, Porter TF, Luthy D, Comstock CH, et al. First-trimester maternal serum PAPP-A and free-beta subunit human chorionic gonadotropin concentrations and nuchal translucency are associated with obstetric complications: a population-based screening study (the FASTER Trial). Am J Obstet Gynecol 2004;191:1446–51.[Medline]

4. Krantz D, Goetzl L, Simpson JL, Thom E, Zachary J, Hallahan TW, et al. Association of extreme first-trimester free human chorionic gonadotropin-beta, pregnancy-associated plasma protein A, and nuchal translucency with intrauterine growth restriction and other adverse pregnancy outcomes. Am J Obstet Gynecol 2004;191:1452–8.[Medline]

5. Smith GC, Stenhouse EJ, Crossley JA, Aitken DA, Cameron AD, Connor JM. Early pregnancy origins of low birth weight. Nature 2002;417:916.[Medline]

6. Smith GC, Crossley JA, Aitken DA, Pell JP, Cameron AD, Connor JM, et al. First-trimester placentation and the risk of antepartum stillbirth. JAMA 2004;292:2249–54.[Abstract/Free Full Text]

7. Conover CA, Bale LK, Overgaard MT, Johnstone EW, Laursen UH, Fuchtbauer EM, et al. Metalloproteinase pregnancy-associated plasma protein A is a critical growth regulatory factor during fetal development. Development 2004;131:1187–94.[Abstract/Free Full Text]

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

9. Crossley JA, Aitken DA, Cameron AD, McBride E, Connor JM. Combined ultrasound and biochemical screening for Down's syndrome in the first trimester: a Scottish multicentre study. BJOG 2002;109:667–76.[Medline]

10. Cole SK. Scottish maternity and neonatal records. In: Chalmers I, McIlwaine GM, editors. Perinatal audit and surveillance. London (UK): Royal College of Obstetricians and Gynaecologists; 1980. p. 39–51.

11. Information and Statistics Division NHS Scotland. Scottish perinatal and infant mortality report 2000. Edinburgh (UK): ISD Scotland Publications; 2001.

12. Smith GC, Wood AM, Pell JP, White IR, Crossley JA, Dobbie R. Second-trimester maternal serum levels of alpha-fetoprotein and the subsequent risk of sudden infant death syndrome. N Engl J Med 2004;351:978–86.[Abstract/Free Full Text]

13. McLoone P, Boddy FA. Deprivation and mortality in Scotland, 1981 and 1991. BMJ 1994;309:1465–70.[Abstract/Free Full Text]

14. Neveux LM, Palomaki GE, Larrivee DA, Knight GJ, Haddow JE. Refinements in managing maternal weight adjustment for interpreting prenatal screening results. Prenat Diagn 1996;16:1115–9.[Medline]

15. Hosmer DW, Lemeshow S. Applied logistic regression. New York (NY): John Wiley & Sons; 2000.

16. Laursen LS, Overgaard MT, Soe R, Boldt HB, Sottrup-Jensen L, Giudice LC, et al. Pregnancy-associated plasma protein-A (PAPP-A) cleaves insulin-like growth factor binding protein (IGFBP)-5 independent of IGF: implications for the mechanism of IGFBP-4 proteolysis by PAPP-A. FEBS Lett 2001;504:36–40.[Medline]

17. Neilson JP, Alfirevic Z. Doppler ultrasound for fetal assessment in high risk pregnancies. Cochrane Database Syst Rev 2000;2:CD000073.

18. Walton DL, Norem CT, Schoen EJ, Ray GT, Colby CJ. Second-trimester serum chorionic gonadotropin concentrations and complications and outcome of pregnancy. N Engl J Med 1999;341:2033–8.[Abstract/Free Full Text]




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