First trimester maternal serum free beta human chorionic gonadotrophin and pregnancy associated plasma protein A as predictors of pregnancy complications

Objective To examine the value of first trimester maternal serum free β human chorionic gonadotrophin (β hCG) and pregnancy associated plasma protein A (PAPP-A) as predictors of pregnancy complications.
Design Screening study.
Setting Antenatal clinics.
Population Singleton pregnancies at 10–14 weeks of gestation.
Methods Maternal serum free β hCG and PAPP-A were measured at 10–14 weeks of gestation in 5584 singleton pregnancies. In the 5297 (94.9%) pregnancies with complete follow up free β hCG and PAPP-A were compared between those with normal outcome and those resulting in miscarriage, spontaneous preterm delivery, pregnancy induced hypertension or fetal growth restriction and in those with pre-existing or gestational diabetes.
Results Maternal serum PAPP-A increased and β hCG decreased with gestation. The multiple of median maternal serum PAPP-A was significantly lower in those pregnancies resulting in miscarriage, pregnancy induced hypertension, growth restriction and in those with pre-existing or gestational diabetes mellitus, but not in those complicated by spontaneous preterm delivery. The level was < 10th centile of the reference range in about 20% of the pregnancies that subsequently resulted in miscarriage or developed pregnancy induced hypertension or growth restriction, and in 27% of those that developed gestational diabetes. Maternal serum free β hCG was < 10th centile of the reference range in about 15% of the pregnancies that subsequently resulted in miscarriage or developed pregnancy induced hypertension or growth restriction, and in 20% of those that developed gestational diabetes.
Conclusion Low maternal serum PAPP-A or β hCG at 10–14 weeks of gestation are associated with subsequent development of pregnancy complications.     

Association between first trimester maternal serum pregnancy associated plasma protein-A and adverse pregnancy outcome

AIMS: To investigate whether low pregnancy associated plasma protein-A (PAPP-A) levels in the first trimester of pregnancy are associated with subsequent intrauterine fetal growth restriction, stillbirth and preterm delivery. METHODS: A retrospective review of pregnancy outcomes was undertaken in women who had PAPP-A carried out in the first trimester of pregnancy at the time of nuchal translucency scan. Pregnancy outcomes were assessed by the review of medical records, and postal questionnaires. Delivery details were collected, including livebirth, neonatal birthweight and gestational age at delivery. The chi2 test was used to investigate the association between low first trimester serum PAPP-A levels and adverse fetal outcomes. Unpaired t-test was used for continuous variables. Sensitivities and specificities were then calculated. RESULTS: A total of 894 women who had blood collected for PAPP-A were identified, and data was obtained for 827 deliveries. Each had a normal karyotype. There were six intrauterine deaths, 13 babies with birthweights below the 3rd centile, 55 babies weighing below the 10th centile, and 96 women who delivered prematurely. Four of six intrauterine deaths had low PAPP-A levels (<0.5 multiples of the median), with a relative risk of 13.75. Low PAPP-A levels were associated with fetal weight below the 10th centile (P = 0.01) but not the 3rd centile. There was no statistically significant association between low maternal serum PAPP-A levels and preterm delivery. CONCLUSION: At 11-13 weeks' gestation, low maternal serum PAPP-A levels are associated with fetal death in utero and birthweight below the 10th centile. First trimester PAPP-A may be a useful tool for identifying pregnancies at risk of adverse fetal outcomes.     

Maternal serum levels of dimeric inhibin A in pregnancies affected by trisomy 21 in the first trimester.

Dimeric inhibin A was measured in maternal serum samples from 45 pregnancies affected by trisomy 21 and 493 samples from unaffected pregnancies at 10-14 weeks of gestation. Inhibin A levels in affected pregnancies were compared with levels of free beta-hCG and PAPP-A in the same series. In the trisomy 21 group, the median multiple of the median (MoM) inhibin A was not significantly elevated (1.28 vs 1.00) with only 15.5% being above the 95th centile. In contrast, the median MoM free beta-hCG was significantly increased (2.05 vs 1.00) with 36% above the 95th centile and PAPP-A was significantly reduced (0.49 vs 1.00) with 42% below the 5th centile. Inhibin A levels in the trisomy 21 group were significantly correlated with gestational age such that median levels rose from 1.04 at 11 weeks to 1.30 at 12 weeks and 1.67 at 13 weeks. These findings suggest that first trimester biochemical screening for trisomy 21, which is currently optimised using maternal serum free beta-hCG and PAPP-A and fetal nuchal translucency, will not benefit from the inclusion of inhibin A.     

ADAM12 as a marker of trisomy 18 in the first and second trimester of pregnancy.

BACKGROUND: ADAM12 (a disintegrin and metalloprotease 12) is a placentally derived glycoprotein that appears to be involved in growth and differentiation. The maternal serum concentration of ADAM12 appears to be a very good marker of trisomy 21 in the early first trimester when levels are reduced, and in the second trimester around 16-18 weeks levels are elevated. One small preliminary study of first trimester pregnancies with trisomy 18 found reduced levels in the maternal serum, and we examine herein the potential of ADAM12 as a marker of trisomy 18 in both the first and second trimester of pregnancy. MATERIALS AND METHODS: The concentration of ADAM12 was determined by a time-resolved immunofluorometric assay in 132 first and 12 second trimester cases of trisomy 18, and 389 first and 341 second trimester gestational age-matched control pregnancies. Medians of normal pregnancies were established by polynomial regression and used to determine the population distribution parameters for the trisomy 18 and control groups. Correlation with previously established pregnancy-associated plasma protein-A (PAPP-A) and free beta-human chorionic gonadotropin (beta-hCG) multiples of the median (MoMs) and nuchal translucency thickness (NT) MoM were determined and used to model the performance of first trimester screening with ADAM12 in combination with other first trimester markers. RESULTS: The maternal serum concentration of ADAM12 in the first trimester was significantly reduced with a median MoM of 0.829 (p < 0.001) and a mean log10 MoM SD of 0.2663 compared to 0.3353 in the controls. In the second trimester small series ADAM12 was significantly increased with a median MoM of 2.09 (p = 0.001) and a mean log10 MoM SD of 0.2607 compared to 0.4318 in controls. There was a significant correlation of ADAM12 MoM with gestational age (r = 0.510) in trisomy 18 cases, and the median MoM increased from 0.51 at 10 weeks to 1.28 at 13 weeks and 2.09 across the 14-18 week window. ADAM12 was correlated with PAPP-A (r = 0.1918) in the first trimester of cases with trisomy 18 but less so with NT (r = 0.1594) and free beta-hCG (r = 0.0938). Modeled detection rates incorporating ADAM12, free beta-hCG, and NT were 92% at 1% false positive rate (88% at 0.5%) A combination of all four markers had a detection rate of 96.5% at a false positive rate of 1% (95% at 0.5%). CONCLUSION: ADAM12 may be a useful addition to early screening for trisomy 18 alongside other chromosomal anomalies, particularly if biochemical screening can occur before 10 weeks.     

First trimester maternal serum analytes and second trimester uterine artery Doppler in the prediction of preeclampsia and fetal growth restriction

Objective

This study aimed to determine whether pregnancy-associated plasma protein-A (PAPP-A), free β-human chorionic gonadotropin (β-hCG), a disintegrin and metalloprotease 12 (ADAM12), and placenta protein 13 (PP13) in the first trimester, and uterine artery Doppler (UAD) in the second trimester, predict preeclampsia and fetal growth restriction (FGR).

Prediction of pregnancy complications by first-trimester maternal serum PAPP-A and free beta-hCG and with second-trimester uterine artery Doppler

BACKGROUND: Previous studies have shown an association between low first trimester maternal serum free beta-hCG and PAPP-A and subsequent development of pregnancy complications. Similarly, uterine artery Doppler in the late second trimester has shown that high impedance to flow is associated with increased risk for preeclampsia and fetal growth restriction. The objective of this study is to determine whether there is an association between the maternal serum concentration of PAPP-A and free beta-hCG at 11-13(+6) weeks with the uterine artery pulsatility index (PI) at 22-24 weeks, and secondly, to compare the screening characteristics of the two methods in the prediction of adverse pregnancy outcome. METHODS: Maternal serum PAPP-A and free beta-hCG at 11-13(+6) weeks and uterine artery PI at 22-24 weeks were measured in 4390 women with singleton pregnancies. Pregnancies with chromosomal defects or fetal anomalies were excluded. The biochemical and Doppler measurements were compared between those with normal outcome and those resulting in spontaneous preterm delivery, pre-eclampsia and fetal growth restriction (FGR). Detection rates using a combination of the biochemical and Doppler measurements were investigated. RESULTS: In the pregnancies resulting in pre-eclampsia (n = 64) and FGR (n = 172), the median PAPP-A was lower (0.844 and 0.813 MoM), the median uterine artery mean PI was higher (1.56 and 1.18) but the median free betahCG was not significantly different (0.923 and 0.933 MoM) than in the normal outcome group. In the preterm delivery group (n = 159), the median free beta-hCG (0.944 MoM) and uterine artery mean PI (1.06) were not significantly different from normal but the median PAPP-A (0.928 MoM) was significantly lower than normal. In screening for pre-eclampsia, the detection rate, for a 5% false-positive rate, was 14.1% for PAPP-A, 54.7% for uterine artery mean PI and 62.1% for a combination of PAPP-A and uterine artery mean PI. CONCLUSION: Maternal serum PAPP-A at 11-13(+6) of gestation is significantly lower in adverse pregnancy outcomes. The combination of first trimester serum PAPP-A and uterine artery mean PI at 22-24 weeks improves the screening efficacy for the prediction of pre-eclampsia.     

Association between congenital toxoplasmosis and preterm birth, low birthweight and small for gestational age birth

OBJECTIVE: To determine the association between congenital toxoplasmosis and preterm birth, low birthweight and small for gestational age birth. DESIGN: Multicentre prospective cohort study. SETTING: Ten European centres offering prenatal screening for toxoplasmosis. POPULATION: Deliveries after 23 weeks of gestation in 386 women with singleton pregnancies who seroconverted to toxoplasma infection before 20 weeks of gestation. Deliveries after 36 weeks in 234 women who seroconverted at 20 weeks or later, and tested positive before 37 weeks. METHODS: Comparison of infected and uninfected births, adjusted for parity and country of birth. MAIN OUTCOME MEASURES: Differences in gestational age at birth, birthweight and birthweight centile. RESULTS: Infected babies were born or delivered earlier than uninfected babies: the mean difference for seroconverters before 20 weeks was -5.4 days (95% CI: -1.4, -9.4), and at 20 weeks or more, -2.6 days (95% CI: -0.5, -4.7). Congenital infection was associated with an increased risk of preterm delivery when seroconversion occurred before 20 weeks (OR 4.71; 95% CI: 2.03, 10.9). No significant differences were detected for birthweight or birthweight centile. CONCLUSION: Babies with congenital toxoplasmosis were born earlier than uninfected babies but the mechanism leading to shorter length of gestation is unknown. Congenital infection could precipitate early delivery or prompt caesarean section or induction of delivery. We found no evidence for a significant association between congenital toxoplasmosis and reduced birthweight or small for gestational age birth.     

Maternal serum ADAM12s as a potential marker of trisomy 21 prior to 10 weeks of gestation

BACKGROUND: ADAM12s (a disintegrin and metalloprotease) is a placenta-derived glycoprotein that is involved in growth and differentiation and has been shown to be a potential first-trimester and second-trimester marker of trisomy 21 and other aneuploides. Maternal ADAM12s concentrations show a considerable temporal variation with gestational age and in the initial study levels were found to be significantly reduced in the early first trimester. Here we study the levels prior to 10 weeks of gestation to establish further the effectiveness or otherwise of ADAM12s as an early screening marker. MATERIALS AND METHODS: Samples collected as part of routine first-trimester screening were retrieved from storage. In total, ten samples from singleton pregnancies with trisomy 21 were identified and were collected between the 8th and 9th weeks of gestation-of these 80% had been identified by combined first-trimester screening. A series of 62 gestational age-matched samples from singleton pregnancies collected during the same period formed the control group. ADAM12s was measured by a new DELFIA assay incorporating two monoclonals (6E6 and 8F8). Results were expressed as multiples of the median (MoM). RESULTS: The median MoM ADAM12s at a median gestation of 9.3 weeks was 0.61 which was significantly lower than in the controls (p = 0.011) when compared by the Mann-Whitney test. The corresponding median pregnancy associated plasma protein (PAPP-A) was 0.30 and free beta-human chorionic gonadotropin (beta-hCG) 2.02. CONCLUSIONS: Combining the data from this study and from the only other published study with data prior to 10 weeks suggests that ADAM12s may have the potential as an early screening marker for trisomy 21, but may not be as reduced as first thought.     

Uterine artery Doppler in the investigation of pregnancies with raised maternal serum alpha-fetoprotein.

Uterine artery flow velocity waveforms (FVW) were obtained prospectively by continuous wave Doppler at 18-22 weeks gestation from 98 women with an unexplained elevation in maternal serum alpha-fetoprotein (MSAFP). A notch in either the left or right uterine artery FVW was present in 18 pregnancies of which seven resulted in perinatal death and six in the birth of very immature and/or severely growth retarded babies. Conversely, in 66 of 80 pregnancies the absence of a notch was associated with the livebirth of an infant beyond 32 weeks gestation, with a birthweight above the 5th centile. It is suggested that the presence of a notch in the uterine artery FVW is a good predictor of poor perinatal outcome.     

ADAM12 as a marker of trisomy 18 in the first and second trimester of pregnancy

Background. ADAM12 (a disintegrin and metalloprotease 12) is a placentally derived glycoprotein that appears to be involved in growth and differentiation. The maternal serum concentration of ADAM12 appears to be a very good marker of trisomy 21 in the early first trimester when levels are reduced, and in the second trimester around 16–18 weeks levels are elevated. One small preliminary study of first trimester pregnancies with trisomy 18 found reduced levels in the maternal serum, and we examine herein the potential of ADAM12 as a marker of trisomy 18 in both the first and second trimester of pregnancy.

Materials and methods. The concentration of ADAM12 was determined by a time-resolved immunofluorometric assay in 132 first and 12 second trimester cases of trisomy 18, and 389 first and 341 second trimester gestational age-matched control pregnancies. Medians of normal pregnancies were established by polynomial regression and used to determine the population distribution parameters for the trisomy 18 and control groups. Correlation with previously established pregnancy-associated plasma protein-A (PAPP-A) and free β-human chorionic gonadotropin (β-hCG) multiples of the median (MoMs) and nuchal translucency thickness (NT) MoM were determined and used to model the performance of first trimester screening with ADAM12 in combination with other first trimester markers.

Results. The maternal serum concentration of ADAM12 in the first trimester was significantly reduced with a median MoM of 0.829 (p < 0.001) and a mean log₁₀ MoM SD of 0.2663 compared to 0.3353 in the controls. In the second trimester small series ADAM12 was significantly increased with a median MoM of 2.09 (p = 0.001) and a mean log₁₀ MoM SD of 0.2607 compared to 0.4318 in controls. There was a significant correlation of ADAM12 MoM with gestational age (r = 0.510) in trisomy 18 cases, and the median MoM increased from 0.51 at 10 weeks to 1.28 at 13 weeks and 2.09 across the 14–18 week window. ADAM12 was correlated with PAPP-A (r = 0.1918) in the first trimester of cases with trisomy 18 but less so with NT (r = 0.1594) and free β-hCG (r = 0.0938). Modeled detection rates incorporating ADAM12, free β-hCG, and NT were 92% at 1% false positive rate (88% at 0.5%) A combination of all four markers had a detection rate of 96.5% at a false positive rate of 1% (95% at 0.5%).

Conclusion. ADAM12 may be a useful addition to early screening for trisomy 18 alongside other chromosomal anomalies, particularly if biochemical screening can occur before 10 weeks.     

Uterine artery Doppler in the investigatioin of pregnancies with raised maternal serum alphafetoprotein

Summary. Uterine artery flow velocity waveforms (FVW) were obtained prospectively by continuous wave Doppler at 18–22 weeks gestation from 98 women with an unexplained elevation in maternal serum alpha-fetoprotein (MSAFP). A notch in either the left or right uterine artery FVW was present in 18 pregnancies of which seven resulted in perinatal death and six in the birth of very immature and/or severely growth retarded babies. Conversely, in 66 of 80 pregnancies the absence of a notch was associated with the livebirth of an infant beyond 32 weeks gestation, with a birthweight above the 5th centile. It is suggested that the presence of a notch in the uterine artery FVW is a good predictor of poor perinatal outcome.     

Maternal serum free beta-hCG and PAPP-A in fetal sex chromosome defects in the first trimester

We have studied maternal serum free beta-hCG and PAPP-A, and fetal nuchal translucency (NT) in a series of 46 cases of fetal Turner's syndrome, 13 cases of other sex chromosomal anomalies and compared these with 947 control pregnancies in the first trimester. In cases of Turner's syndrome (45,X) the median fetal NT was significantly higher than in controls (4.76 MoM), the median PAPP-A was significantly lower (0.49 MoM), whilst the free beta-hCG was not significantly different (1.11 MoM). For NT, 93% (43/46) of cases were equal to or greater than the 95th centile of controls, for PAPP-A 35% (16/46) of cases were less than or equal to the 5th centile of controls and for free beta-hCG 15% (7/46) of cases were equal to or greater than the 95th centile of controls. For other sex chromosomal anomalies (47XXX, XXY, XYY) the median NT was increased (2.07 MoM) whilst PAPP-A was not significantly decreased (0.88 MoM) and free beta-hCG was not significantly different (1.07 MoM) from controls. Using a previously derived multivariate risk algorithm for trisomy 21, incorporating NT, PAPP-A, free beta-hCG and maternal age, 96% of the Turner's cases and 62% of the other sex chromosomal anomalies would have been identified.     

ADAM12s in maternal serum as a potential marker of pre-eclampsia

OBJECTIVE: To examine whether maternal serum ADAM12s, a potential first- and second-trimester marker of fetal aneuploidy and fetal growth, had altered concentrations in the first or second trimester of pregnancies subsequently developing pre-eclampsia. METHODS: ADAM12s was measured by a time-resolved fluoroimmunoassay developed by PerkinElmer Life Science. Maternal serum samples from women taking part in early first-trimester aneuploidy screening in whom the pregnancy resulted in pre-eclampsia (64) were identified from a cohort of 4,390 singleton pregnancies in which uterine artery Doppler mean Pulsatility Index (PI) had been measured at 22-24 weeks. From amongst those cases delivering a normal term infant with birth weight greater than the 10th centile for gestational age 240 cases were selected as gestational age-matched controls. A second study group consisting of maternal serum taken at 22-24 weeks at the time of uterine artery Doppler in a group of 12 women developing pre-eclampsia were compared with 86 matched controls from a previously studied cohort of 24 cases and 144 controls. Serum ADAM12s concentrations were converted to multiple of the median (MoM) to take account of gestational age variation. RESULTS: First-trimester maternal serum ADAM12s levels in women who developed pre-eclampsia were reduced with a median MoM of 0.71 which was further reduced in those delivering prior to 35 weeks (0.50). At the 5th centile of normal (0.48 MoM) ADAM12s identified 27% of cases with pre-eclampsia and 47% of those with early pre-eclampsia. Combining ADAM12s with PAPP-A from a previous study only resulted in a further 1% increase in detection of all women developing pre-eclampsia. However combining ADAM12s with mean PI increased the detection rate to 66%. In the second trimester at 22-24 weeks the maternal serum ADAM12s levels were increased in those women developing pre-eclampsia compared to controls (709 vs 486 ug/L, p = 0.045). CONCLUSION: ADAM12s in addition to being a potential marker of aneuploidy may also be a marker of pre-eclampsia. Further studies are required to see if this can improve on the clinical discrimination already provided by PAPP-A in the early first trimester.     

The influence of maternal insulin-dependent diabetes on fetal nuchal translucency thickness and first-trimester maternal serum biochemical markers of aneuploidy

OBJECTIVE: To evaluate the influence of maternal insulin dependent diabetes mellitus (IDDM) on maternal serum free beta-hCG, PAPP-A and fetal nuchal translucency (NT), thickness at 11 to 13(+6) weeks of gestation in a large cohort of women screened prospectively for chromosomal anomalies. METHODS: Information on maternal IDDM status, maternal serum biochemical marker levels and fetal NT were collected from the prenatal screening computer records in two first-trimester screening centres. In total the control group included 33 301 pregnancies of which 16 366 had NT and maternal serum biochemistry results and 16 305 with NT only. The IDDM group included 195 pregnancies of which 79 had NT and maternal serum biochemistry results and 127 with NT only. The median maternal weight corrected free beta-hCG and PAPP-A, expressed as multiple of the median (MoM), and fetal NT, expressed as delta values, in the IDDM and non-IDDM groups were compared. RESULTS: There were no significant differences between the IDDM and non-IDDM groups in median maternal weight corrected free beta-hCG (IDDM 0.87 MoM, 95% Confidence Interval 0.75 to 1.16 MoM, non-IDDM 1.00 MoM), median maternal weight corrected PAPP-A (IDDM 1.02 MoM, 95% Confidence Interval 0.83 to 1.05 MoM, non-IDDM 1.01 MoM), or mean delta NT (IDDM 0.0358 mm, non-IDDM 0.0002 mm). CONCLUSIONS: In pregnancies with maternal IDDM, first-trimester screening for chromosomal defects does not require adjustments for the measured fetal NT. However, more data are required before the possible reduction in maternal serum free beta-hCG and the reduction of PAPP-A suggested by the published world series can be considered sufficiently important to take into account in the calculation of risks for chromosomal defects.     

Maternal serum levels of total activin-A in first-trimester trisomy 21 pregnancies

Maternal serum total activin-A concentration was measured in 45 pregnancies affected by trisomy 21 and 493 control unaffected pregnancies at 10-14 weeks of gestation. In the trisomy 21 pregnancies total activin-A concentration was significantly higher (1.36 MoM of the unaffected pregnancies) and in 16% of cases the level was above the 95th centile of normal. The log10 SD for the control group and the trisomy 21 group were 0.17 and 0.22, respectively. The median pregnancy associated plasma protein-A (PAPP-A) in this trisomy 21 series was 0.49 and for free beta-hCG was 2.05. In the trisomy group there were significant positive associations between total activin-A and PAPP-A (0.6071) and free beta-hCG (0.4255). The low median difference and the high overlap in values between trisomic and unaffected pregnancies make total activin-A of little practical use in first-trimester screening for trisomy 21.     

Maternal serum alpha-fetoprotein (MSAFP) and fetal growth

Early mid-trimester screening of maternal serum alpha-fetoprotein (MSAFP) for the detection of neural tube defects is becoming a routine part of obstetrical care. In singleton pregnancies in the absence of fetal chromosomal abnormalities and anatomical anomalies high levels of AFP have been variably related to increased risk for low birthweight infant outcome. The overall relationship, if any, of maternal serum AFP to infant birthweight has, however, not been previously characterized. Between 15 and 20 weeks gestation, MSAFP values were determined for 110 women carrying single, anatomically and karyotypically normal fetuses. Statistical analysis utilizing polynomial and multilinear regression was used to determine the relationship of early mid-trimester MSAFP first to neonatal birthweight and then to gestational age and birthweight adjusted for gestational age. For every increase of one multiple of the median in MSAFP, neonatal birthweight fell 322 grams. This was accounted for almost entirely by decreased fetal growth; early mid-trimester MSAFP was linearly related to birthweight adjusted for gestational age ten times more strongly than to gestational age alone. The explanation for this relationship remains speculative, but the utility of routine AFP screening for the antenatal detection of intrauterine growth retardation certainly deserves further study.     

Poor maternal weight gain between 28 and 32 weeks gestation may predict small-for-gestational-age infants

In a retrospective analysis of 158 women considered to have had normal, low-risk pregnancies, 30 gave birth to infants with a birthweight less than the 10th centile for gestation. These 30 women had a significantly poorer mean increase in weight (0.99 kg) between 28 and 32 weeks gestation than the other 128 women (1.95 kg) who gave birth to infants with birthweights above the 10th centile for gestation. There was no statistically significant difference in booking weight, overall weight gain or other variables associated with low birthweight between the two groups of women which suggests that poor maternal weight gain specifically between 28 and 32 weeks gestation may predict small-for-gestational-age infants.     

Low levels of maternal serum PAPP-A in the first trimester and the risk of pre-eclampsia

BACKGROUND: Low levels of pregnancy associated plasma protein-A (PAPP-A) have been previously shown to be associated with pregnancies that subsequently develop pre-eclampsia. The objective of this study was to establish the relative risk for pre-eclampsia at various PAPP-A levels as an aid to counselling and follow up of pregnancies. METHODS: Maternal serum PAPP-A and free ss-human chorionic gonadotropin (ss-hCG) levels at 11 to 13 weeks of gestation from 224 singleton pregnancies that subsequently developed pre-eclampsia were compared to those from 47,770 normal singleton pregnancies resulting in live births after 37 weeks with birth weight greater than or equal to the 10th centile of normal for gestation. In all cases, the measured PAPP-A and free ss-hCG levels were expressed as multiple of the median (MoM). The association between metabolite levels and the incidence of pre-eclampsia was assessed by comparing the relative incidence at a number of MoM cut-offs and at various centiles. At various marker levels, the likelihood ratio for pre-eclampsia was also calculated. RESULTS: In the pre-eclampsia group the median PAPP-A MoM was significantly reduced (0.772 MoM, p < 0.0001) whilst the median free beta-hCG MoM was not different from controls (0.981 MoM, p = 0.26). With decreasing levels of PAPP-A, the likelihood ratio for pre-eclampsia increased. At the 5th centile of normal (PAPP-A MoM 0.415) the odds ratio was increased 4-fold and at this cut-off 15% of cases of pre-eclampsia would be identified. CONCLUSIONS: The graphical presentation of a likelihood ratio curve for pre-eclampsia at any PAPP-A MoM level is likely to be useful in counselling women with low levels of PAPP-A and a normal karyotype. Use of low levels of PAPP-A for selecting women for further follow-up with uterine artery Doppler may further improve the clinical discrimination.     

ADAM 12 as a first-trimester maternal serum marker in screening for Down syndrome

BACKGROUND: A Disintegrin And Metalloprotease 12 (ADAM 12) is a glycoprotein synthesised by placenta and it has been shown to be a potential first-trimester maternal serum marker for Down syndrome (DS) in two small series. Here we analyse further, the potential of ADAM 12 as a marker for DS in a large collection of first-trimester serum samples. MATERIALS AND METHODS: The concentration of ADAM 12 was determined in 10-14-week pregnancy sera from 218 DS pregnancies and 389 gestational age-matched control pregnancies, which had been collected as part of routine prospective first-trimester screening programs (DS = 105) or as part of previous research studies (DS = 113). ADAM 12 was measured using a semi-automated time resolved immunofluorometric assay and median values for normal pregnancies were established by polynomial regression. These medians were then used to determine population distribution parameters for DS and normal pregnancy groups. Correlation with previously established PAPP-A and free beta-hCG multiple of the medians (MoMs) and delta nuchal translucency (NT) were determined and used to model the performance of first-trimester screening with ADAM 12 in combination with other first-trimester markers at various time periods across the first trimester. The benefits of a contingent testing model incorporating early measurement of PAPP-A and ADAM 12 were also explored. RESULTS: The maternal serum concentration of ADAM 12 was significantly reduced (p = 0.0049) with an overall median MoM of 0.79 in the DS cases and a log(10) MoM SD of 0.3734 in the DS cases and 0.3353 in the controls. There was a significant correlation of ADAM 12 MoM in DS cases with gestational age (r = 0.375) and the median MoM increased from 0.50 at 10-11 weeks to 1.38 at 13 weeks. ADAM 12 was correlated with maternal weight (r(controls) = 0.283), PAPP-A (r(controls) = 0.324, r(DS) = 0.251) but less so with free beta-hCG (r(controls) = 0.062, r(DS) = 0.049) and delta NT (r(controls) = 0.110, r(DS) = 0.151). ADAM 12 was significantly (p = 0.026) lower in smokers (0.87 vs 1.00) and elevated in Afro-Caribbean women compared to Caucasian women (1.34 vs 1.00).Population modelling using parameters from this and an earlier study showed that a combination of ADAM 12 and PAPP-A measured at 8-9 weeks and combined with NT and free beta-hCG measured at 12 weeks could achieve a detection rate of 97% at a 5% false-positive rate or 89% at a 1% false-positive rate. PAPP-A and ADAM 12 alone at 8-9 weeks could identify 91% of cases at a 5% false-positive rate. Using this as part of a contingent-screening model to select an intermediate risk group of women for NT and free beta-hCG at 11-12 weeks would enable the detection of 92% of cases with a 1% false-positive rate at a cost of providing NT and free beta-hCG for 6% of women with 94% of women having completed screening by the 10th week of pregnancy. CONCLUSION: ADAM 12 in early first trimester is a very efficient marker of DS. In combination with existing markers, it offers enhanced screening efficiency in a two-stage sequential first-trimester screening program or in a contingent-screening model, which may have benefits in health economies where universal access to high quality ultrasound is difficult. More data on early first-trimester cases with DS are required to establish more secure population parameters by which to assess further the validity of these models.     

Birthweights in sickle cell trait pregnancies

Objectives  Available evidence on the effect of sickle cell trait (SCT) on birthweight is conflicting, not gestational age specific, and does not account for maternal and infant factors. The objectives of this study are to determine the contemporary mean birthweight, mean customised birthweight centile, and to analyse the risk of small-for-gestational-age (SGA) and large-for-gestational-age (LGA) babies in SCT pregnancies.
Design  Large retrospective cohort study.
Setting  London hospital.
Population  Singleton pregnancies between 24 and 42 completed weeks delivered between 2000 and 2005 in parturient with body mass index between 18.0 and 35.0 kg/m².
Methods  All qualifying pregnancies were identified on Terra Nova Healthware. Birthweight centiles of these cases were computed with Gardosi customised bulk centile calculator using collected data on maternal height, weight, ethnicity and parity, and the infant's gender, gestational age and birthweight. Birthweight and birthweight centiles of SCT and pregnancies with no haemoglobinopathy (control) were compared. Statistical analysis was performed using Stata version 9.2.
Main outcome measures  Birthweight and birthweight centiles.
Results  Five hundred and five SCT and 16 320 controls were analysed. The mean birthweight of SCT pregnancies was 3223 g, 57 g lower than controls ( P = 0.024). However, its mean birthweight centile was 49.0% similar to that of controls' 47.5% ( P = 0.320). There is an apparent risk of LGA babies in SCT pregnancies, but logistic regression analysis suggests that the odds are related to being an older non-white parturient and a male infant rather than SCT status.
Conclusions  SCT is not a risk factor for SGA or LGA infants.