Pregnancy-associated plasma protein A: circulating levels during normal pregnancy

The development of specific and sensitive electroimmunoassays for a recently identified high molecular weight alpha-2 mobile pregnancy-specific protein (pregnancy-associated plasma protein A, PAPP-A or SP4) is described. These assays have permitted the detection of circulating levels of PAPP-A (10 microgram/L) as early as the fifth week of pregnancy. In all 18 subjects studied, the levels of PAPP-A rose from first detection in the first trimester until delivery at term. The development of these assays now permit the evaluation of PAPP-A measurement as a diagnostic test of early pregnancy and as an index of fetal well-being throughout gestation.     

Pregnancy-associated plasma protein A and alpha-fetoprotein and prediction of adverse perinatal outcome

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.     

Pregnancy-associated plasma protein-A (PAPP-A) and hCG in early pregnancy

Pregnancy-associated plasma protein-A (PAPP-A) is a recently described glycoprotein of unknown biological function. The development of a radioimmunoassay enabled us to measure plasma levels of PAPP-A and human chorionic gonadotrophin (hCG) in 12 non-pregnant volunteers and in 159 women in early pregnancy attending the outpatient clinic for legal abortion. PAPP-A but not hCG was measurable in all non-pregnant women. In pregnant patients (with 36 to 86 days of amenorrhea) hCG reached a peak value (163.1-197.6 ng/ml) between the 9th and the 13th week whereas PAPP-A steadily increased throughout this period of pregnancy. Between the 6th and the 13th week after the last menstrual period, levels of PAPP-A increased proportionally more than hCG. This work provides the first evidence of a PAPP-A production in non-pregnant subjects and the very early marked increase of PAPP-A secretion during pregnancy.     

Pregnancy-associated plasma protein A, free beta-hCG, nuchal translucency, and risk of pregnancy loss

OBJECTIVE: To estimate the likelihood of clinical early and late pregnancy loss as a function of first-trimester maternal serum analytes and fetal nuchal translucency measurements. METHODS: Study subjects were recruited for a National Institute of Child Health and Human Development-sponsored multicenter cohort study initially designed to study the detection of Down syndrome during the first trimester of pregnancy. The cohort consisted of women who had a live fetus between 10 and 14 weeks of gestation and had no significant vaginal bleeding. Women with prior fetal trisomy (T21/18) and those with structural or chromosomal abnormalities in the index pregnancy were excluded. First-trimester screening consisted of pregnancy-associated plasma protein A (PAPP-A), free beta-hCG, and nuchal translucency. Pregnancy loss rates in women with various levels of PAPP-A, free beta-hCG, or nuchal translucency (less than 1st, less than 5th, more than 95th, and more than 99th percentile) were compared with losses in women with normal values (5th to 95th percentile). RESULTS: The mean gestational age at screening of 7,932 women meeting study criteria was 12.1 weeks. Loss rates were only 0.36% at less than 20 weeks after normal free beta-hCG, PAPP-A, and nuchal translucency. Conversely, low levels of PAPP-A and free beta-hCG as well as increased nuchal translucency were individually associated with increased early loss. These associations persisted after controlling for maternal age and race using logistic regression analysis. CONCLUSION: Normal values of PAPP-A, free beta-hCG, and nuchal translucency are associated with a very low risk of pregnancy loss at less than 20 weeks.     

Pregnancy-associated plasma protein A (PAPP-A) in non-pregnant subjects

A newly developed enzyme immunoassay technique was applied to the measurement of pregnancy-associated plasma protein A (PAPP-A) in the serum of women in the proliferative and luteal phases of the cycle, in hysterectomized and postmenopausal women and in the serum and seminal plasma of males. PAPP-A was detected in some individuals in all the categories of women and in seminal plasma but not in male serum. It is surmised that there must be a source of PAPP-A other than the placenta and that PAPP-A may be a maternal protein whose biosynthesis is stimulated by pregnancy rather than a product peculiar to the trophoblast.     

Pregnancy-associated plasma protein-A polymorphism and the risk of recurrent pregnancy loss

Pregnancy-associated plasma protein-A (PAPP-A)/insulin-like growth factor-binding protein-4 (IGFBP4) protease is a member of the metzincin family of metalloproteases, known as a sensitive biomarker of adverse pregnancy outcomes. Recently, a missense A/C (Tyr/Ser) polymorphism (dbSNP: rs7020782) in the PAPPA gene has been reported. To examine the association between recurrent pregnancy loss (RPL) and this polymorphism, a case-control study of 215 cases with two or more pregnancy losses (PLs) and 420 fertile controls was performed. Genotyping of the PAPPA polymorphism was determined by allelic discrimination using fluorogenic probes and the 5′ nuclease assay. Sixty-nine cases (32.1%) were heterozygous and 11 cases (5.1%) were homozygous for the C allele of PAPPA; the respective figures were 127 (30.2%) and 11 (2.6%) in the controls. Women carrying the C allele had a tendency to increased risk of RPL (AA genotype [reference]; AC genotype: odds ratio [OR], 1.17; 95% confidence interval [CI], 0.82–1.68; CC genotype: OR, 2.06; 95% CI, 0.87–4.90), but it was not significant. Women with three or more PLs had a similar tendency (AA genotype [reference]; AC genotype: OR, 1.04; 95% CI, 0.66–1.64; CC genotype: OR, 2.20; 95% CI, 0.82–5.91). The risk of RPL with at least one PL after 9 weeks’ gestation significantly increased in women carrying the C allele (AA genotype [reference]; AC genotype: OR, 1.54; 95% CI, 0.95–2.49; CC genotype: OR, 2.83; 95% CI, 1.00–8.05; AC + CC genotypes: OR, 1.65; CI, 1.04–2.62). This is the first report on the PAPPA gene polymorphism in women with RPL, demonstrating some association between the investigated polymorphism and the risk of RPL.     

Pregnancy-associated protein-A does not improve predictability of pregnancy success or failure over human chorionic gonadotropin levels in early normal and abnormal pregnancy

In the present study we sought to compare levels of PAPP-A and hCG produced by different types of pregnancy: normal, ectopic, threatened abortion and molar pregnancy after evacuation. The gestations ranged from 13 to 122 days. Serum levels of both PAPP-A and hCG were measured and compared. Chi squares analysis were predictive only for increasing trends in hCG as well as decreasing trends of both hCG and PAPP-A. Analysis of variance and linear discriminant function used to evaluate results suggested that PAPP-A did not improve predictability of hCG. The values of PAPP-A levels for the postevacuation molar pregnancies barely exceeded the lower limit of detection; thus, no meaningful comparisons could be made.     

The prediction of pregnancy failure by measurement of pregnancy-associated plasma protein A (PAPP-A) following in vitro fertilization and embryo transfer

Circulating PAPP-A was measured serially in five patients following successful IVF-ET. PAPP-A concentrations were consistently normal in all three patients in whom pregnancies progressed normally to term. Depressed levels of PAPP-A were observed in one patient who miscarried spontaneously at 17 weeks' gestation despite ultrasound evidence of normal fetal development. Circulating PAPP-A was not detected in the fifth patient, whose tubal pregnancy ruptured at 8 weeks. These data are discussed in relation to surveillance of pregnancies following IVF-ET.     

Pregnancy-associated plasma protein A interaction with heparin: a critical appraisal.

Positive affinity chromatography on heparin-Sepharose has proved a most crucial step in the purification of pregnancy-associated plasma protein A (PAPP-A). In this chromatographic procedure, PAPP-A was purified almost 500-fold from term pregnancy serum. Further purification was achieved by gel filtration and negative immunoaffinity chromatography. Both PAPP-A and free heparin inhibited granulocyte elastase (HGE) activity. Whereas free heparin inhibited only in hypotonic buffers, PAPP-A inhibited HGE in hypertonic buffers also. However, PAPP-A did not inhibit other proteases (trypsin, chymotrypsin, plasmin, fibroblast collagenase) or proteolytic cascades (complement activation). Since heparin was not detected in the purified PAPP-A, the inhibition of HGE was not due to desorbed or leeched heparin ligand.     

Does ultrasound examination render biochemical tests obsolete in the prediction of early pregnancy failure?

Serum levels of fetal, placental and maternal hormones and proteins [alpha-fetoprotein (AFP), human chorionic gonadotrophin, human placental lactogen, schwangerschaftsprotein 1, pregnancy associated plasma protein-A (PAPP-A), oestradiol-17 beta, progesterone, pregnancy zone protein] were measured in 108 women with bleeding during the first half of pregnancy. Ultrasound examination at the time of each blood sampling revealed a fetal heart action on at least one occasion in 77 women. Spontaneous abortion occurred in 42 pregnancies, 31 of these showed no ultrasound sign of fetal life, whilst the fetal heart action was observed repeatedly until abortion in the remaining 11 women. Abnormally low levels of PAPP-A were most likely to indicate pregnancy failure, in particular if the fetal heart action was seen at the time of blood sampling. The predictive value, sensitivity and relative risk of a single depressed PAPP-A level were respectively 49, 89 and 41%, the predictive value of a normal result being 99%. With the exception of AFP, all other biochemical indices examined were consistently in the normal range in this group of women. If ultrasound findings were not considered, the biochemical indices were of comparable value in the prediction of spontaneous abortion. PAPP-A levels were uniformly depressed in all patients who spontaneously aborted, frequently weeks before this event, in the presence of a live fetus.     

Does ultrasound examination render biochemical tests obsolete in the prediction of early pregnancy failure?

Summary. Serum levels of fetal, placental and maternal hormones and proteins [β-fetoprotein (AFP), human chorionic gonadotrophin, human placental lactogen. schwangerschaftsprotein 1, pregnancy associated plasma protein-A (PAPP-A), oestradiol-17β, progesterone, pregnancy zone protein] were measured in 108 women with bleeding during the first half of pregnancy. Ultrasound examination at the time of each blood sampling revealed a fetal heart action on at least one occasion in 77 women. Spontaneous abortion occurred in 42 pregnancies, 31 of these showed no ultrasound sign of fetal life, whilst the fetal heart action was observed repeatedly until abortion in the remaining 11 women. Abnormally low levels of PAPP-A were most likely to indicate pregnancy failure, in particular if the fetal heart action was seen at the time of blood sampling. The predictive value, sensitivity and relative risk of a single depressed PAPP-A level were respectively 49, 89 and 41%, the predictive value of a normal result being 99%. With the exception of AFP, all other biochemical indices examined were consistently in the normal range in this group of women. If ultrasound findings were not considered, the biochemical indices were of comparable value in the prediction of spontaneous abortion. PAPP-A levels were uniformly depressed in all patients who spontaneously aborted, frequently weeks before this event, in the presence of a live fetus.     

Endocrinologic events in early pregnancy failure

Fourteen women experiencing early pregnancy failure have been studied during the time of conception and at frequent intervals until spontaneous abortion occurred. Serial measurements of serum estradiol, progesterone, 17α-hydroxyprogesterone, prolactin, human placental lactogen (hPL), and human chorionic gonadotropin (hCG) were determined; regular sonar scanning allowed the time of fetal death to be determined to within 7 days in six patients and a diagnosis of blighted ovum to be made in the remainder. In all patients serum progesterone and estradiol concentrations were within the normal range up to 7 weeks but appeared to decrease from about 8 weeks' gestation whether or not a living fetus was present. The placenta continued to produce hCG and hPL but, despite the continuing presence of hCG, the levels of 17α-hydroxyprogesterone declined to concentrations below those associated with normal pregnancy. These data suggest that the placenta may require a particular stimulus to take over production of progesterone and estradiol.     

Recurrent early pregnancy failure.

Some of the new developments that are improving our understanding of the mechanisms underlying recurrent early pregnancy failure are reviewed. Etiologies such as genetic causes, structural causes, chronic maternal disorders, drugs, environmental pollutants, endocrine causes, and immunologic causes are discussed, along with strategies for management.     

Contemporary management of early pregnancy failure

Early pregnancy failure is a common pregnancy complication. This paper reviews the terminology, diagnosis, and treatment of early pregnancy failure. Although surgical curettage has been the standard of care for more than 50 years, additional treatment options exist which appear to be satisfactory to patients. Manual vacuum curettage in the office is an effective alternative to electric vacuum curettage in an operating room. Nonsurgical treatments, including expectant and medical management, are reasonable alternatives depending on the clinical situation and the patient's desires. Clinicians need to understand how these options compare to provide appropriate counseling to patients.     

The yolk sac in early pregnancy failure

An attempt was made to visualize the yolk sac in 845 patients scheduled for chorionic villi sampling. The distribution of yolk sac diameters and the interpolating growth curve up to 11 weeks of development were analyzed in 239 pregnant women who were delivered of normal infants. The highest visualizing rate of the yolk sac in normal pregnancies was 97 at 7 weeks of gestation. A total of 130 miscarriages occurred before chorionic villi sampling. In these cases, the diameter of the yolk sac versus crown-rump length tended to be larger than found in normal pregnancies. The visualizing rate of the yolk sac in miscarriages after the embryo had been formed was significantly higher in those women who demonstrated fetal heart activity (82.1%) than in those who did not (54.5%). On the other hand, the yolk sac was observed in 44% of miscarriages without a visible embryo. These findings suggest different types of missed abortion. An abnormal karyotype was observed in 23 of 29 chromosomal analyses performed on aborted specimens. An abnormal karyotype was observed in all eight cases with only a yolk sac-like structure within the gestational sac.     

Low plasma HLA-G protein concentrations in early gestation indicate the development of preeclampsia later in pregnancy

OBJECTIVE: The aim of this study was to determine whether circulating HLA-G levels, early in pregnancy, predict the subsequent development of preeclampsia (PE). STUDY DESIGN: Plasma samples, collected longitudinally during the first, second, and third trimesters, from 12 PE patients and 12 matched control patients were tested for HLA-G protein using a validated sandwich ELISA. RESULTS: First and second trimester HLA-G levels in PE were significantly lower than in control patients (first trimester, 1.25 microg/mL vs 1.95 microg/mL, P=.029; second trimester, 1.11 microg/mL vs 1.90 microg/mL, P=.024). CONCLUSION: Our results indicate that HLA-G levels in plasma from women who subsequently develop PE are lower than control patients, as early as the first trimester. This suggests that determination of circulating HLA-G protein concentration may be useful as an early predictor for the development of PE.