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Keywords:

  • adverse outcome;
  • free β-hCG;
  • NT;
  • PAPP-A;
  • prenatal screening;
  • preterm delivery;
  • trisomy

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Objectives

To examine the clinical utility of the first-trimester markers of aneuploidy in their ability to predict preterm delivery.

Methods

We examined 54 722 singleton pregnancies with no chromosomal abnormality and with complete outcome data that had undergone screening for trisomy 21 by a combination of fetal nuchal translucency (NT) thickness and maternal serum free β-human chorionic gonadotropin (β-hCG) and pregnancy-associated plasma protein-A (PAPP-A) at 11 + 0 and 13 + 6 weeks' gestation. The biochemical markers were converted to multiples of the median (MoM) of the expected normal median for a pregnancy of the same gestation and the measurements of fetal NT were expressed as the difference (delta) from the normal median NT for crown–rump length. The association between free β-hCG, PAPP-A and delta NT and the incidence of preterm delivery before 37 weeks or early preterm delivery before 34 weeks was assessed by comparing the relative incidence at a number of MoM or delta NT cut-offs and at various centile cut-offs. At various marker levels the likelihood ratios (LR) for preterm delivery and early preterm delivery were also calculated after excluding other adverse pregnancy complications.

Results

The risk of preterm delivery increased with decreasing maternal serum PAPP-A. In the 3132 cases delivering before 37 weeks the PAPP-A MoM was 0.91 and in the 1060 cases delivering before 34 weeks the PAPP-A MoM was 0.90. At the 5th centile of the normal outcome group for PAPP-A (0.415 MoM) the odds ratios for delivery before 37 weeks and before 34 weeks were 1.92 and 2.35, respectively. The respective values for the 5th centile of free β-hCG (0.41 MoM) were 1.18 and 1.08 and for the 95th centile of delta NT they were 0.91 and 0.77, respectively.

Conclusions

Low levels of maternal serum PAPP-A are associated, in the absence of an abnormal karyotype, with an increased risk of preterm or early preterm delivery. The LR profiles provided at various levels of PAPP-A may be of some help in counseling women with such results and may raise awareness among healthcare professionals for increased surveillance in such cases. Copyright © 2007 ISUOG. Published by John Wiley & Sons, Ltd.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

In the first trimester of pregnancy the placentally derived biochemical markers pregnancy-associated plasma protein-A (PAPP-A) and free β-human chorionic gonadotropin (β-hCG) are increasingly being used in conjunction with the ultrasound measurement of nuchal translucency thickness (NT) as part of screening programs for trisomy 21 and other aneuploidies in which approximately 90% of such anomalies can be identified1–7 for a false positive rate of 5%. Preliminary studies8 have shown that reduced levels of these biochemical markers—particularly PAPP-A—may be of potential value in identifying those pregnancies that may result in adverse outcome. One such adverse outcome is preterm birth, which occurs in around 5% of births in developed countries to 25% in developing countries9. The adverse events resulting from preterm birth impose a considerable burden on scarce healthcare resources. Preterm infants are at increased risk for a range of adverse neonatal outcomes, including chronic lung disease, severe brain injury and neonatal sepsis. In later life they have an increased risk for motor and sensory impairments, learning difficulties and behavioral problems10. The greatest burden of morbidity and mortality occurs among the group that are delivered early, before 32 weeks' gestation11. A health economic assessment of the consequences of preterm birth during the first 10 years of life in the UK has recently been published12. For children born before 28 weeks' gestation the cumulative cost of hospital inpatient admission was £22 322; at 28–31 weeks it was £19 055; at 32–36 weeks it was £7393; and at 37–40 weeks it was £3409. However, the main burden of preterm birth exists in the developing countries.

Because of the clinical burden associated with preterm delivery a clinical strategy that could identify pregnancies at risk would be extremely beneficial.

In this study we examine the clinical utility of the first-trimester markers of aneuploidy in their ability to predict spontaneous preterm delivery in a large cohort of women prospectively screened during the first trimester.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

All women booked for maternity care at the following UK hospitals were offered screening for trisomy 21 by a combination of fetal NT and maternal serum free β-hCG and PAPP-A at 11 + 0 to 13 + 6 weeks' gestation: Harold Wood Hospital, Romford (between June 1998 and December 2003); King George Hospital, Goodmayes (between July 2001 and December 2003); Kent and Canterbury Hospital, Canterbury (between July 2002 and December 2003); William Harvey Hospital, Ashford (between July 2002 and December 2003); Queen Elizabeth The Queen Mother's Hospital, Margate (between July 2002 and December 2003); King's College Hospital, London (between January 1999 and February 2000); and those attending The Fetal Medicine Centre, London (between July 1999 and December 2003). The women received an information leaflet about the service and gave details about their demographic characteristics and medical history, which were entered into computer databases (PIA-Fetal Database, ViewPoint, Webling, Germany) at Harold Wood Hospital and The Fetal Medicine Centre.

Maternal serum free β-hCG and PAPP-A were measured using the Kryptor analyzer (Brahms AG, Berlin, Germany) as previously described1 and an ultrasound examination was carried out to measure fetal NT and crown–rump length (CRL) and to diagnose any major fetal abnormalities. All scans were carried out by sonographers who had obtained The Fetal Medicine Foundation Certificate of Competence in the 11 + 0 to 13 + 6-week scan (www.fetalmedicine.com). Patient-specific risks were calculated by a multivariate approach using biochemical population parameters as outlined in a previous study1, likelihood ratios based on delta NT as outlined in a previous study13 and the gestational age-related risk of trisomy 21 at the time of screening14. Data on pregnancy outcome were obtained from the cytogenetics laboratories, the National Chromosomal Anomaly Register, the patients themselves, their general practitioners or the maternity units in which they delivered. In the case of all the women screened by the Harold Wood laboratory, pregnancy outcome was additionally obtained from hospital midwifery or patient administration computer records and matched to the prenatal screening records by a locally derived record linkage software.

All biochemical markers were converted to multiples of the median (MoM) of the expected normal median for a pregnancy of the same gestational age using values established in a previous study8 corrected for maternal weight15, 16, self-recorded smoking status15, 17 and ethnicity15, 18. To take account of gestational variation in fetal NT, we expressed the measured fetal NT as the difference from the normal median NT13, 19 at the measured CRL, this being the delta NT. The delta NT approach has been shown to be more appropriate than the conventional MoM approach for handling NT data and calculating patient-specific risks13.

The two fetal databases were searched for records that had complete outcome information, including gestational age at delivery (completed weeks), fetal birth weight and pregnancy outcome. The women were assigned to two groups—the normal pregnancy group and the preterm delivery group. The normal pregnancy group was defined as those pregnancies in which a live fetus was delivered after 37 complete weeks of gestation and whose birth weight was above the 10th centile of normal for gestational age20. The preterm delivery group excluded those small for gestational age (SGA) but included those with other obstetric complications such as abruption and pre-eclampsia. The group was classified into two subgroups, those with a spontaneous delivery prior to 37 completed weeks (preterm delivery) and those with delivery prior to 34 weeks (early preterm delivery). Cases included in this study were not part of our previous study8 but were part of those included in a recent study of PAPP-A and ADAM1221.

The association between free β-hCG, PAPP-A and delta NT and the incidence of preterm or early preterm delivery was assessed by comparing the relative incidence at a number of MoM cut-offs and at various centile cut-offs. At various marker levels the likelihood ratio (LR) for early and preterm delivery was also calculated.

Statistical analysis was carried out with the procedures as described using Analyse-It (Analyse-It Software Ltd, Leeds, UK), a statistical add-in for Excel or SPSS Version 13 (SPSS Ltd, Woking, UK).

This paper is the third in a study of adverse pregnancy outcome in a large cohort of women. Previous studies have focused on the prediction of impending fetal death22 and the prediction of SGA23. Using data from these previous studies and from the present study we also calculated the LR for any of these adverse pregnancy outcomes at various PAPP-A MoM levels.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

The computer search identified 54 722 singleton pregnancies with no chromosomal abnormality and with complete outcome data. Of these, there were 47 770 livebirths at term of appropriately grown neonates (normal group), 3132 livebirths before 37 weeks of appropriately grown neonates (preterm group) of which 1060 delivered before 34 weeks (early preterm group), and 3820 pregnancies which were excluded from further analysis because they resulted in fetal death or an SGA livebirth. The characteristics of the normal pregnancy group and the preterm group are summarized in Table 1.

Table 1. General characteristics of the study groups
 Normal (n = 47 770)Preterm delivery (n = 3132)
Maternal age (years)  
 Median32.0032.00
 Mean31.4831.3
 SD5.525.80
Maternal weight (kg)  
 Median63.5063.50
 Mean63.6764.40
 SD10.8911.97
Smoking status (%)  
 Smokers10.616.1
 Non-smokers88.482.9
 Not stated1.01.0
Ethnicity (%)  
 Afro-Caribbean5.27.0
 Asian9.111.4
 Caucasian81.477.7
 Other4.13.8
 Not stated0.20.1
Previous births (%)  
 None43.254.2
 138.128.7
 214.111.4
 33.53.3
 40.71.6
 > 40.40.8
Crown–rump length (mm)  
 Median62.862.8
 Mean63.263.3
 SD8.68.8
Gestational age at delivery (weeks)  
 Median40.035.0
 Mean39.634.1
 SD1.242.70
Birth weight (kg)  
 Median3.472.41
 Mean3.512.37
 SD0.4360.817

In pregnancies resulting in preterm and early preterm delivery there was a reduction in median PAPP-A; after log10 transformation of MoMs and comparison using t-tests of unequal variance (Table 2) only the reduced PAPP-A was statistically significant. The median delta NT was also reduced by 0.005 mm and 0.020 mm in the preterm and early preterm groups, respectively, with only the latter achieving statistical significance (P = 0.034). At the 5th centile of PAPP-A in the normal group (0.415 MoM), the odds ratios for delivery before 37 weeks and before 34 weeks were 1.92 and 2.35, respectively. The equivalent values for free β-hCG at the 5th centile of the normal group (0.41 MoM) were 1.18 and 1.08, respectively. At a delta NT ≥ 95th centile of the normal group, the odds ratios for those delivering before 37 weeks and before 34 weeks were 0.91 and 0.77, respectively. The detection rates at these 5% cut-offs are summarized in Table 3.

Table 2. Median multiples of the median (MoM) for free β-human chorionic gonadotropin (β-hCG) and pregnancy-associated plasma protein-A (PAPP-A), probability of difference from controls and odds ratio at the 5th centile of normal (OR 5th) (corresponding to 0.41 MoM free β-hCG and 0.415 MoM PAPP-A)
Preterm deliveryFree β-hCGPAPP-A
Median MoMPOR 5thMedian MoMPOR 5th
< 37 weeks0.9770.1231.180.910< 0.0011.92
< 34 weeks1.0040.2991.080.903< 0.0012.35
Table 3. Detection rate for fetal loss at the 5th centile of normal for pregnancy-associated plasma protein-A (PAPP-A) and free β-human chorionic gonadotropin (β-hCG) and at the 95th centile for delta nuchal translucency thickness (NT)
Preterm deliveryDetection rate (%)
PAPP-AFree β-hCGDelta NT
< 37 weeks10.35.14.4
< 34 weeks12.44.93.7

The individual LRs for the preterm and early preterm delivery groups at each specific MoM level of PAPP-A are shown in Figure 1, with the individual data points and the solid lines representing the best fit through the data points using an S parameter regression data fit. For the preterm delivery group the regression coefficient (r) was 0.994 for PAPP-A. The best-fit equation for PAPP-A was described by:

  • equation image

For the early preterm delivery group the regression coefficient (r) was 0.981 for PAPP-A. The best-fit equation for PAPP-A was described by:

  • equation image

PAPP-A was more predictive of early preterm delivery at lower PAPP-A MoM than was free β-hCG, with a LR at 0.2 MoM of 7.5 compared with 3.

thumbnail image

Figure 1. Likelihood ratio (LR) for preterm delivery (< 37 weeks, ⧫ and ———) and early preterm delivery (< 34 weeks, ▴ and equation image) based on the pregnancy-associated plasma protein-A multiples of the median (PAPP-A MoM). Symbols represent individual data points while the smoothed lines represent the best fit to the data.

Download figure to PowerPoint

If the analysis was restricted to only those births prior to 32 weeks (408 cases) then the median MoM PAPP-A was reduced to 0.871, which was statistically significantly different from the controls (P < 0.001) and the odds ratio at the 5th centile of normal was 2.99. At the 5th centile of normal for PAPP-A the detection rate would have been 15%.

Low PAPP-A seems to be a predictor of a number of adverse pregnancy complications22–24. Using data from all of these publications it is possible, rather than constructing individual likelihood ratio plots for each adverse outcome, to produce an overall likelihood of any adverse outcome as shown in Figure 2, with the individual data points and the solid lines representing the best fit through the data points using an S parameter regression data fit. The regression coefficient (r) was 0.990 and the best fit equation was described by:

  • equation image

At the 5th centile of normal PAPP-A MoM the detection rate for all adverse outcomes investigated was 10% and at the 1.5th centile it was 6%.

thumbnail image

Figure 2. Likelihood ratio (LR) for any adverse pregnancy outcome based on the pregnancy-associated plasma protein-A multiples of the median (PAPP-A MoM). Symbols represent individual data points while the smoothed line represents the best fit to the data.

Download figure to PowerPoint

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

The data from this study demonstrate that the first-trimester markers of aneuploidy, particularly PAPP-A, are also predictive of preterm and early preterm delivery. The data on biochemical markers in relation to preterm delivery in our current study largely confirm the initial observations we made in our earlier smaller study8 and confirm the data presented recently from other studies25–27. Since the introduction of first-trimester screening for aneuploidy using maternal serum PAPP-A and free β-hCG in conjunction with fetal NT thickness, more data in limited studies have become available—but the clinical usefulness of the data provided is often obscured by the wide range of presentation of the data. Table 4 summarizes the published data with respect to the various biochemical marker levels, odds ratios and detection rates and population sizes in the various studies thus far. The presentation of our data in terms of likelihood ratios for preterm delivery at any marker level for either PAPP-A or free β-hCG should enable clinicians to better assess an individual's risk and to use this information when counseling the patient about invasive testing, or when the results of invasive testing have identified a normal karyotype.

Table 4. Summary of various studies of pregnancy-associated plasma protein-A (PAPP-A) and free β-human chorionic gonadotropin (β-hCG) in preterm and early preterm delivery
    Serum PAPP-ASerum β-hCG
   GA at < 5th centile MoM  < 5th centile MoM 
   deliveryMedian OR or RRMedian OR or RR
ReferenceTotal nCases (n)(weeks)MoMOR or RRDR< 0.5 MoMMoMOR or RRDR< 0.2 MoM
  1. DR, detection rate; NS, not stated; OR, odds ratio; RR, relative risk.

Ong et al.84489192< 370.9781.567.8 0.9221.145.7 
  47< 340.9332.9814.9 0.9201.708.5 
Smith et al.258469326< 37 2.410.7  0.53.1 
  86< 32 2.914.0  1.17.0 
Yaron et al.31162243< 37   1.07   NS
Santolaya-Forgas et al.3214519< 371.12       
De Leon et al.3314519< 37    0.91   
Krantz et al.27801287< 34 2.39.4  1.15.2 
Dugoff et al.26332191< 37 1.738.53  NSNS 
 395249< 33 1.879.45  NSNS 
Morssink et al.3480087< 370.98   0.94   
Tul et al.35113641< 37NS   NS   
  17< 341.10   1.06   
This study50 9023132< 370.9101.9210.3 0.9771.185.1 
  1060< 340.9032.3512.4 1.0041.084.9 
  408< 320.8712.9915.0     

In those cases with increased risk for preterm or early preterm delivery a policy of tocolytic administration could be considered. Although such treatment has been used for many years, recent systematic reviews of randomized control trials have reported almost no significant reduction in the number of preterm or early preterm deliveries28. However the prophylactic administration of progesterone at 20–24 weeks to women with a previous preterm birth does half the rate of recurrence29. Studies in which cervical length and previous history are used to identify a subgroup of women (analogous to aneuploidy risk stratification) who may benefit from the prophylactic use of progesterone are ongoing. Certainly a combination of previous history and cervical length can identify about 70% of those destined to deliver prematurely with a false positive rate of 10%30. One way, therefore, of following up women with increased risk for preterm delivery based on a low level of PAPP-A would be to perform cervical length measurement at 22–24 weeks' gestation and to re-define the risk. However further work needs to be done in incorporating PAPP-A levels into the overall risk algorithm.

We believe that there is now sufficient evidence to use lowered PAPP-A as part of a structured approach for identifying adverse pregnancy outcome, although at this time there are no data to support specific interventions or treatments for these women. In our own practice prenatal screening reports with a low PAPP-A (less than 0.3 MoM—equivalent to the 1.5th centile of normal) are automatically flagged for the obstetrician to instigate further follow up and monitoring. Further refinements will no doubt follow as more experience is gained in managing potential adverse pregnancy outcomes.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

This study was supported by a grant from The Fetal Medicine Foundation (Charity No: 1037116) and by a grant from NHS R&D (RF4 : Risk Assessment in Pregnancy) to KS.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  • 1
    Spencer K, Souter V, Tul N, Snijders R, Nicolaides KH. A screening program for trisomy 21 at 10–14 weeks using fetal nuchal translucency, maternal serum free β-human chorionic gonadotropin and pregnancy associated plasma protein-A. Ultrasound Obstet Gynecol 1999; 13: 231237.
  • 2
    Tul N, Spencer K, Noble P, Chan C, Nicolaides KH. Screening for trisomy 18 by fetal nuchal translucency thickness and maternal serum free β-hCG and pregnancy associated plasma protein-A at 10–14 weeks of gestation. Prenat Diagn 1999; 19: 10351042.
  • 3
    Spencer K, Ong C, Skentou H, Liao AW, Nicolaides KH. Screening for trisomy 13 by fetal nuchal translucency and maternal serum free beta-hCG and pregnancy associated plasma protein-A at 10–14 weeks of gestation. Prenat Diagn 2000; 20: 411416.
  • 4
    Spencer K, Liao AW, Skentou H, Cicero S, Nicolaides KH. Screening for triploidy by fetal nuchal translucency and maternal serum free β-human chorionic gonadotropin and pregnancy associated plasma protein-A at 10–14 weeks of gestation. Prenat Diagn 2000; 20: 495499.
  • 5
    Spencer K, Spencer CE, Power M, Dawson C, Nicolaides KH. Screening for chromosomal abnormalities in the first trimester using ultrasound and maternal serum biochemistry in a one-stop clinic: a review of three years prospective experience. BJOG 2003; 110: 281286.
  • 6
    Avgidou K, Papageorghiou A, Bindra R, Spencer K, Nicolaides KH. Prospective first-trimester screening for trisomy 21 in 30,564 pregnancies. Am J Obstet Gynecol 2005; 192: 17611767.
  • 7
    Nicolaides KH, Spencer K, Avgidou K, Faiola S, Falcon O. Mutlitcenter study of first-trimester screening for trisomy 21 in 75 821 pregnancies: results and estimation of the potential impact of individual risk-orientated two-stage first-trimester screening. Ultrasound Obstet Gynecol 2005; 25: 221226.
  • 8
    Ong CYT, Liao AW, Spencer K, Munim S, Nicolaides KH. First trimester maternal serum free β human chorionic gonadotrophin and pregnancy associated plasma protein A as predictors of pregnancy complications. BJOG 2000; 107: 12651270.
  • 9
    Steer P. The epidemiology of preterm labour. BJOG 2005; 112 (Suppl 1): 13.
  • 10
    Marlowe N, Wolke D, Bracewell MA, Samara N. Neurological and developmental disability at six years of age after extremely preterm birth. N Engl J Med 2005; 352: 919.
  • 11
    Veen S, Ens-Dokkum MH, Schreuder AM, Verloove-Vanhorick SP, Brand R, Ruys JH. Impairments, disabilities, and handicaps of very preterm and very-low-birthweight infants at five years of age. The Collaborative Project on Preterm and Small for Gestational Age Infants (POPS) in The Netherlands. Lancet 1991; 338: 3336.
  • 12
    Petrou S. The economic consequences of preterm birth during the first 10 years of life. BJOG 2005; 112 (Suppl 1): 1015.
  • 13
    Spencer K, Bindra R, Nix ABJ, Heath V, Nicolaides KH. Delta-NT or NT MoM: which is the most appropriate method for calculating accurate patient-specific risks for trisomy 21 in the first trimester? Ultrasound Obstet Gynecol 2003; 22: 142148.
  • 14
    Snijders RJM, Sundberg K, Holzgreve W, Henry G, Nicolaides KH. Maternal age- and gestation-specific risk for trisomy 21. Ultrasound Obstet Gynecol 1999; 13: 167170.
  • 15
    Spencer K, Ong CYT, Liao AWK, Nicolaides KH. The influence of ethnic origin on first trimester biochemical markers of chromosomal anomalies in the first trimester. Prenat Diagn 2000; 20: 491494.
  • 16
    Spencer K, Bindra R, Nicolaides KH. Maternal weight correction of maternal serum PAPP-A and free β-hCG when screening for trisomy 21 in the first trimester of pregnancy. Prenat Diagn 2003; 23: 851855.
  • 17
    Spencer K, Bindra R, Cacho AM, Nicolaides KH. The impact of smoking status when screening for chromosomal anomalies using maternal serum biochemistry and fetal nuchal translucency thickness in the first trimester of pregnancy. Prenat Diagn 2004; 24: 169173.
  • 18
    Spencer K, Heath V, El-Sheikhah A, Ong CYT, Nicolaides KH. Ethnicity and the need for correction of biochemical and ultrasound markers of chromosomal anomalies in the first trimester: a study of Oriental, Asian and Afro-Caribbean populations. Prenat Diagn 2005; 25: 365369.
  • 19
    Snijders RJM, Noble P, Sebire N, Souka A, Nicolaides KH. UK multicentre project on assessment of risk for trisomy 21 by maternal age and fetal nuchal translucency thickness at 10–14 weeks of gestation. Lancet 1998; 18: 519521.
  • 20
    Yudkin PL, Aboualfa M, Eyre JA, Redman CW, Wilkinson AR. New birth weight and head circumference centiles for gestational ages 24 to 42 weeks. Early Hum Dev 1987; 15: 4552.
  • 21
    Cowans NJ, Spencer K. First-trimester ADAM12 and PAPP-A as markers for intrauterine fetal growth restriction through their roles in the insulin-like growth factor system. Prenat Diagn 2007; 27: 264271.
  • 22
    Spencer K, Cowans NJ, Avgidou K, Nicolaides KH. First-trimester ultrasound and biochemical markers of aneuploidy and the prediction of impending fetal death. Ultrasound Obstet Gynecol 2006; 28: 637643.
  • 23
    Spencer K, Cowans NJ, Avgidou K, Molina F, Nicolaides KH. First-trimester biochemical markers of aneuploidy and the prediction of small-for-gestational age fetuses. Ultrasound Obstet Gynecol 2007. DOI: 10.1002/uog.5165.
  • 24
    Spencer K, Yu CK, Cowans NJ, Otigbah C, Nicolaides KH. Prediction of pregnancy complications by first-trimester maternal serum PAPP-A and free beta-hCG and with second-trimester uterine artery Doppler. Prenat Diagn 2005; 25: 949953.
  • 25
    Smith GCS, 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: 17621767.
  • 26
    Dugoff L, Hobbins JC, Malone FD, Porter TF, Luthy D, Comstock CH, Hankins G, Berkowitz RL, Merkatz I, Craigo SD, Timor-Tritsch IE, Carr SR, Wolfe HM, Vidaver J, D'Alton ME. 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: 14461451.
  • 27
    Krantz D, Goetzl L, Simpson JL, Thom E, Zachary JM, Hallahan TW, Silver R, Pergament E, Platt LD, Filkins K, Johnson A, Mahoney M, Hogge WA, Wilson RD, Mohide P, Hershey D, Wapner RJ. First Trimester Maternal Serum Biochemistry and Fetal Nuchal Translucency Screening (BUN) Study Group. Association of extreme first-trimester free human chorionic gonadotropin-β, pregnancy-associated plasma protein A, and nuchal translucency with intrauterine growth restriction and other adverse pregnancy outcomes. Am J Obstet Gynecol 2004; 191: 14521458.
  • 28
    Gyetvai K, Hannah ME, Hodnett ED, Ohlsson A. Tocolytics for preterm labor: a systematic review. Obstet Gynecol 1999; 94: 869877.
  • 29
    Sanchez-Ramos L, Kaunitz AM, Delke I. Progesterone agents to prevent preterm birth: A meta-analysis of randomized controlled trials. Obstet Gynecol 2005; 105: 273279.
  • 30
    To MS, Skentou CA, Royston P, Yu CKH, Nicolaides KH. Prediction of patient-specific risk of early preterm delivery using maternal history and sonographic measurement of cervical length: a population-based prospective study. Ultrasound Obstet Gynecol 2006; 27: 362367.
  • 31
    Yaron Y, Heifetz S, Ochshorn Y, Lehavi O, Orr-Urtreger A. Decreased first trimester PAPP-A is a predictor of adverse pregnancy outcome. Prenat Diagn 2002; 22: 778782.
  • 32
    Santolaya-Forgas J, De Leon JA, Cullen Hopkins R, Castracane VD, Kauffman RP, Sifuentes GA. Low pregnancy-associated plasma protein-A at 10 + 1 to 14 + 6 weeks of gestation and a possible mechanism leading to miscarriage. Fetal Diagn Ther 2004; 19: 456461.
  • 33
    De Leon J, Sifuentes G, Hopkins C, Noble V, Gimpel T, Myles T, Santolaya-Forgas J. Maternal serum free β-hCG levels in uncomplicated pregnancies at the 10th–15th week of gestation and the development of obstetric complications. J Reprod Med 2004; 49: 8992.
  • 34
    Morssink LP, Kornman LH, Hallahan TW, Kloosterman MD, Beekhuis JR, de Wolf BTHM, Mantingh A. Maternal serum levels of free β-hCG and PAPP-A in the first trimester of pregnancy are not associated with subsequent fetal growth retardation or preterm delivery. Prenat Diagn 1998; 18: 147152.
  • 35
    Tul N, Pusenjak S, Osredkar J, Spencer K, Novak-Antolic Z. Predicting complications of pregnancy with first-trimester maternal serum free β-hCG, PAPP-A and inhibin-A. Prenat Diagn 2003; 23: 990996.