Second-trimester pregnancy associated plasma protein-A levels are reduced in Cornelia de Lange syndrome pregnancies.

Maternal serum samples were collected from 19 pregnancies which resulted in the birth of a child with the classical Cornelia de Lange syndrome phenotype ascertained by careful clinical review. Using specific immunoassays, the serum levels of pregnancy associated plasma protein-A, free-beta human chorionic gonadotrophin and inhibin A were investigated. Pregnancy associated plasma protein-A was detectable in all cases but the levels were significantly reduced in second-trimester maternal serum from 18 affected pregnancies. Expressed as multiples of the median (MOM), the results ranged from 0.03 MOM to 0.71 MOM with an overall median value of 0.21 MOM (Mann-Whitney p<0.001). From these data it is possible to estimate a probability that any given level of this serum marker is associated with an affected pregnancy. One further sample taken in the first trimester from an affected pregnancy at 11 weeks' gestation had a normal pregnancy associated plasma protein-A level (1.22 MOM). Less markedly reduced levels were found for free beta human chorionic gonadotrophin and inhibin A. We conclude that second-trimester maternal serum pregnancy associated plasma protein-A measurements may be of value as an adjunct to ultrasonography in the prenatal diagnosis of Cornelia de Lange syndrome. A table of likelihood ratios is presented.     

Second-trimester maternal serum analyte levels associated with fetal trisomy 13.

The aim of this study was to determine whether pregnancies affected by fetal trisomy 13 are associated with second-trimester maternal serum analyte levels different from those typical of the unaffected population. Pregnancies with trisomy 13 were identified through cytogenetics laboratories. Those which had second-trimester maternal serum screening analyte measurements were further evaluated. Maternal serum analyte levels for each case and five matched controls were statistically analysed by matched ranked-sum analysis. 28 cases of fetal trisomy 13 were identified. The median AFP, uE3 and hCG levels were 1.35 MoM, 0.71 MoM and 0.90 MoM, respectively. Only uE3 levels were statistically different (p < 0.01) from those for the unaffected population. These data suggest that second-trimester maternal serum AFP, uE3 and hCG levels are not useful in detecting fetal trisomy 13 and protocols already existing for Down syndrome or trisomy 18 screening will not detect the majority of cases of this aneuploidy.     

Second-trimester maternal pregnancy-associated plasma protein a and inhibin a levels in fetal trisomies

OBJECTIVE: The aim of this study was to determine whether fetal trisomy is associated with altered levels of second-trimester maternal pregnancy-associated plasma protein A (PAPP-A) and inhibin A. METHODS: Maternal serum PAPP-A and inhibin A concentrations were measured at 15-17 weeks of gestation in 14 singleton pregnancies with fetal trisomy and in 56 matched pregnant controls. RESULTS: PAPP-A levels in the trisomy group were significantly lower than in controls. The inhibin A level with fetal trisomy 21 was slightly higher than the control group, but levels were not different between trisomies 18 and 13 and controls. CONCLUSION: Fetal trisomies 21, 18, and 13 are associated with a reduction in second-trimester maternal PAPP-A levels; trisomies 18 and 13 are not associated with increased inhibin A levels, unlike trisomy 21.     

Low levels of pregnancy-associated plasma protein-A in asymptomatic women destined for miscarriage

In an asymptomatic cohort, serum pregnancy-associated protein-A (PAPP-A) levels among women destined to miscarry were 14% of those seen with ongoing pregnancies. Levels were as low 3 weeks before diagnosis as on the day of diagnosis, suggesting that PAPP-A levels might predict future miscarriage.     

Circulating levels of pregnancy-associated plasma protein-A (PAPP-A) and human chorionic gonadotrophin (hCG) in intrauterine and extrauterine pregnancies

Summary. Pregnancy-associated plasma protein-A (PAPP-A) and human chorionic gonadotrophin (hCG) have been measured in the plasma of pregnant and non-pregnant women attending the outpatient clinic for suspicion of pregnancy. The plasma concentrations obtained were grouped into intrauterine or extrauterine pregnancies and compared with values obtained in non-pregnant patients with similar periods of amenorrhoea. Patients with ectopic pregnancies had slightly lower PAPP-A levels and significantly lower hCG concentrations than those in women with normal intrauterine pregnancies. Non-pregnant women had very low hCG and PAPP-A levels compared with those in pregnant patients. These data suggest that in patients with extrauterine pregnancies the poorly sustained ectopic trophoblast is unable to produce normal concentrations of hCG and probably PAPP-A and that the slightly diminished levels of PAPP-A in ectopic pregnancies might be derived from a decidual production.     

Maternal midtrimester serum AFP and free beta-hCG levels in in vitro fertilization twin pregnancies

We aimed to compare the levels of alpha-fetoprotein (AFP) and free beta-human chorionic gonadotrophin (beta-hCG) levels as multiples of the median (MoM) values between spontaneous and in vitro fertilized (IVF) twin pregnancies. The control group of spontaneous singleton pregnancies was used for calculating the gestational age specific median levels of the values. Within a cohort of 19 310 pregnancies, 145 twin pregnancies were identified. The data were collected from Down syndrome (DS) screening programmes in four University catchment areas in Finland between 1994-98. Maternal midtrimester serum marker levels were measured across gestational weeks 14-18. There were no fetal chromosome anomalies in either of the twin groups or the singleton group. Serum AFP of 145 and beta-hCG values of 39 spontaneous twin pregnancies were compared to the values of 6548 singleton pregnancies. In IVF twins 30 AFP and 29 beta-hCG values were compared to the levels of the control group. Both AFP and beta-hCG values were twice as high in the spontaneous twin pregnancies (medians 2.18 and 1.83 MoM respectively) as in the singleton group (medians 1.00 and 1.00 MoM respectively). In IVF twin pregnancies beta-hCG levels were higher (median 2.20 MoM) than in spontaneous twins (p=0.08), whereas no significant difference was found in AFP levels (2.30 MoM). In conclusion, the higher levels of beta-hCG levels in IVF twin pregnancies should be considered in DS screening to avoid high false positive rates.     

Maternal serum pregnancy-associated plasma protein-A and free beta-human chorionic gonadotrophin in pregnancies conceived with fresh and frozen-thawed embryos from in vitro fertilization and intracytoplasmic sperm injection

OBJECTIVE: Maternal serum pregnancy-associated plasma protein-A (PAPP-A) and free beta-human chorionic gonadotrophin (beta-hCG) are useful markers in the screening of Down syndrome in the first trimester. We investigated the effect of intracytoplasmic sperm injection (ICSI), freezing and thawing of embryos on the levels of these two analytes in assisted reproduction pregnancies. METHODS: We recruited 149 women who conceived after assisted reproduction with fresh embryos (92 from conventional IVF and 57 from ICSI), 85 women who conceived with frozen-thawed embryos (54 from conventional IVF and 31 from ICSI) and 401 women with spontaneous conceptions as controls. The concentrations of PAPP-A and free beta-hCG were measured between 10 and 14 weeks and were converted to multiples of medians (MoM) for comparisons. RESULTS: Median PAPP-A MoMs were significantly reduced in ICSI pregnancies in the fresh and frozen-thawed embryo subgroups (0.70 and 0.66 MoM respectively) and in the IVF fresh embryo subgroups (0.83 MoM), as compared to controls (1.00 MoM). Free beta-hCG MoM was significantly reduced in the IVF fresh embryos subgroup (0.87 MoM), but not in the other three subgroups. CONCLUSION: Further studies for exploring the underlying pathophysiology and adjustment in the marker levels for screening of Down syndrome are warranted in pregnancies conceived after assisted reproduction.     

Histomorphometric characteristics of first trimester chorionic villi in pregnancies with low serum pregnancy-associated plasma protein-A levels: relationship with placental three-dimensional power doppler ultrasonographic vascularization

Objective.?To evaluate histomorphometric vascular characteristics from samples obtained by chorionic villus sampling (CVS) in pregnancies with low serum pregnancy-associated plasma protein-A (PAPP-A) levels and to relate these findings to three-dimensional (3D) placental volume and power Doppler vascularization.

Methods.?Immediately before CVS, placental 3D-power Doppler ultrasonography was performed at 11?+?0 to 13?+?6 weeks in 12 pregnancies with PAPP-A concentrations <0.3 multiples of median (MoM) as well as in 11 control women. Using a standardized setting placental volume, vascularization index (VI), flow index (FI), and vascularization flow index (VFI) were measured. Histomorphometric parameters of villi were blindly evaluated with a video-computerized-image-analysis system.

Results.?Pregnancies with low PAPP-A showed a significantly reduced number of capillary vessels per villus cross-section (p?=?0.005) and a smaller capillary diameter (p?=?0.041). Placental vascular indices were significantly related to the number of fetal capillary vessels per villus (VI: r?=?0.51, p?=?0.03; FI: r?=?0.48, p?=?0.04; VFI: r?=?0.56, p?=?0.01).

Conclusions.?Differences in placental vascularization are present in first trimester in pregnancies with low PAPP-A and they are associated to altered 3D placental Doppler indices.     

Potential role of pregnancy-associated plasma protein-A in human reproduction

By radioimmunoassay, pregnancy-associated plasma protein-A (PAPP-A) was undetectable in matched follicular and luteal phase serum samples (n = 17) or in the peripheral circulation of normal males (n = 17). However, seminal plasma (91.5%), cervical mucus (100%) and pre-ovulatory follicular fluid (99.6%) were consistently PaPP-A positive. In addition to PAPP-A, four circulating protease inhibitors (PIs) were detected in pooled seminal plasma whereas pooled follicular fluid contained an additional six. Follicular concentrations of serum PIs were inversely related to molecular size. By contrast, PAPP-A formed a positive concentration gradient across the blood-reproductive tract barrier suggesting PAPP-A production within the reproductive tract. A minor proportion (1.7%) of ejaculated spermatozoa were coated with PAPP-A, as demonstrated by direct immunofluorescence. Since PAPP-A specifically inhibits leucocyte elastase, it is suggested that PAPP-A coated spermatozoa were "selected" to overcome localized phagocytic-proteolytic degradation. The physiological significance of these findings are discussed in relation to human reproduction.     

Endometrial and plasma concentrations of pregnancy-associated plasma protein-A (PAPP-A)

Summary. Pregnancy-associated plasma protein-A (PAPP-A), oestradiol and progesterone levels have been measured by radioimmunoassay in plasma and in endometrial homogenates of 30 women undergoing hysterectomy. Results were grouped according to the histological stages of the endometrium. In plasma, oestradiol and progesterone concentrations changed from proliferative to secretory stages in the well-established pattern of the menstrual cycle, but PAPP-A levels did not change. In endometrium, oestradiol levels were high during the proliferative stage and low in inactive and secretory endometrium. Endometrial PAPP-A and progesterone concentrations increased from inactive to secretory stages, but only the increase in PAPP-A was statistically significant. A positive correlation observed between endometrial PAPP-A concentrations and plasma oestradiol/progesterone ratio suggests a possible hormonal control for the presence of PAPP-A in the uterus.     

Endometrial and plasma concentrations of pregnancy-associated plasma protein-A (PAPP-A)

Pregnancy-associated plasma protein-A (PAPP-A), oestradiol and progesterone levels have been measured by radioimmunoassay in plasma and in endometrial homogenates of 20 women undergoing hysterectomy. Results were grouped according to the histological stages of the endometrium. In plasma, oestradiol and progesterone concentrations changed from proliferative to secretory stages in the well-established pattern of the menstrual cycle, but PAPP-A levels did not change. In endometrium, oestradiol levels were high during the proliferative stage and low in inactive and secretory endometrium. Endometrial PAPP-A and progesterone concentrations increased from inactive to secretory stages, but only the increase in PAPP-A was statistically significant. A positive correlation observed between endometrial PAPP-A concentrations and plasma oestradiol/progesterone ratio suggests a possible hormonal control for the presence of PAPP-A in the uterus.     

Second trimester levels of pregnancy associated plasma protein-A in cases of trisomy 18

In a study of 70 cases of trisomy 18 and 450 matched controls in the second trimester we have measured the maternal serum levels of the analytes alpha feto protein (AFP), free beta-human chorionic gonadotrophin (hCG) and pregnancy associated plasma protein-A (PAPP-A). We have found the median multiple of the median (MoM) of maternal serum free beta-hCG to be significantly lower (0.327) than normal, as was the level of AFP (0.600). Levels of PAPP-A were reduced even further (0.108). Of the markers associated with trisomy 18 at this time PAPP-A was the most discriminatory, being lower than the 5 per cent centile of normal in 93 per cent of cases, compared with 57 per cent of cases for free beta-hCG and 32 per cent of cases for AFP. Combining free beta-hCG and PAPP-A or all three markers with maternal age would have the ability to detect 74 per cent of cases at a 0.5 per cent false positive rate (or 64 per cent at a 0.1 per cent false positive rate). Unlike in cases of trisomy 21, the low PAPP-A values observed in the first trimester are continued into the second trimester. Whether the good discriminatory power of PAPP-A can be realized in second trimester screening programmes will depend on developing two stage screening algorithms. This approach is unlikely to be better than the excellent detection rates achievable with free beta-hCG, PAPP-A and nuchal translucency in the first trimester.     

The disappearance rate of pregnancy-associated plasma protein-A (PAPP-A) after the end of normal and abnormal pregnancies

PAPP-A is a macromolecular glycoprotein associated with human pregnancy. In vitro, PAPP-A is produced by explant cultures of trophoblast and decidua. The present work was undertaken to see if the presence of decidua had any effect on the disappearance rate of PAPP-A after removal of the placenta either by surgery or by spontaneous delivery. PAPP-A was measured before and at different times after a normal delivery (n = 6), after a termination of early pregnancy (n = 11) and after surgery for ectopic pregnancy (n = 8). The half life of PAPP-A after normal delivery (52.9 +/- 25.8 h, SD) was significantly (p less than 0.03) less than after a first trimester termination (93.9 +/- 41.6 h). After surgery for ectopic pregnancy in patients with curetted decidua, PAPP-A disappeared significantly faster (p less than 0.005) then in patients with intact decidua (84.1 +/- 17.8 vs 241.2 +/- 81.5 h). These results indicate that PAPP-A continues to be produced by the decidua after removal of the trophoblast in early pregnancy.     

First trimester maternal serum pregnancy-associated plasma protein-A is a predictive factor for early preterm delivery in normotensive pregnancies

Abstract

In this study, we investigated whether the concentrations of pregnancy-associated plasma protein-A (PAPP-A) or free β-hCG (fβhCG) in the first trimester can identify women at increased risk of subsequent preterm delivery in the absence of hypertensive disorders. Preterm and early preterm deliveries are defined as those deliveries before completing 37 and 34 weeks, respectively. A total of 868 women were enrolled into this study. According to the level of the markers, the patients were evaluated in three groups: 1 – maternal serum level ≤5th percentile, 2 – between 5th and 95th percentiles, 3 – ≥95th percentile. In the group of patients with a PAPP-A level ≤5th percentile [≤0.35 multiples of the median (MoM)], mean gestational age (GA) at delivery, mean birth weight and the number of the cases with early preterm delivery were significantly lower than the others. Mean level of PAPP-A was significantly lower in cases with early preterm than term deliveries (0.58?±?0.32 versus1.09?±?0.69; p?=?0.01). Maternal serum level of fβhCG did not show significant difference between these groups (0.84?±?0.45 versus 1.17?±?0.77; p?=?0.15). Low levels of maternal serum PAPP-A (≤0.35 MoM) (Odds ratio?=?7; 95% confidence interval 1.8–27.7; p?=?0.0048) significantly predicted early preterm delivery in normotensive pregnancies. Women with low levels of PAPP-A at first trimester have a higher risk of early preterm delivery even in the absence of hypertensive disorders.     

A comparison between maternal serum free beta-human chorionic gonadotrophin and pregnancy-associated plasma protein A levels in first-trimester twin and singleton pregnancies

OBJECTIVES: To determine the levels of first-trimester free beta-human chorionic gonadotrophin (free betahCG), pregnancy-associated plasma protein A (PAPP-A) and nuchal translucency (NT) in twin pregnancies. METHODS: The study included 93 patients with twin pregnancy and 4,977 with singletons who underwent first-trimester testing using free betahCG, PAPP-A and NT at 10-13 weeks of gestational age. RESULTS: In twin pregnancies, the maternal serum free betahCG level was 2.18 higher and the PAPP-A level was 2.38 higher than in singleton pregnancies. These marker levels were significantly higher than the expected 2.0 multiples of the median (MoM). In contrast, NT values did not differ between twins and singletons. CONCLUSION: These data may be used to establish first-trimester combined screening for twin pregnancies.     

Screening for trisomy 21 in twin pregnancies in the first trimester using free beta-hCG and PAPP-A, combined with fetal nuchal translucency thickness

In the first trimester of pregnancy the biochemical markers free beta-hCG and pregnancy associated plasma protein-A (PAPP-A) are used for the prenatal screening of trisomy 21, either alone or in combination with nuchal translucency (NT) thickness. In this study, I have analysed the distribution of these biochemical markers in 159 twin pregnancies and compared this with 3466 singleton pregnancies. On average free beta-hCG values are 2.099 times greater in twins than in singletons and PAPP-A some 1.86 times greater. The width of the analyte distribution in twins is very similar to that in singleton pregnancies. Using statistical modelling techniques I have predicted that at a 5% false positive rate the detection rate in twins discordant for trisomy 21 will be 52% and in twins concordant for trisomy 21 will be 55%, if correction for twin pregnancy is carried out using the 'pseudo risk' approach. The detection rate using biochemical parameters is less than that achievable for twins using NT (75%). However, the combination of NT and maternal serum biochemistry will give detection rates approaching 80%. These rates are some 10% less than in singleton pregnancies, but nevertheless combining NT and biochemistry will allow high rates of detection of affected twins with the benefit of ultrasound and NT being able to specifically locate the affected twin. Twin screening using both modalities should be considered when introducing first trimester screening.     

A first trimester trisomy 13/trisomy 18 risk algorithm combining fetal nuchal translucency thickness,maternal serum free beta-hCG and PAPP-A

This study examines 45 cases of trisomy 13 and 59 cases of trisomy 18 and reports an algorithm to identify pregnancies with a fetus affected by trisomy 13 or 18 by a combination of maternal age fetal nuchal translucency (NT) thickness, and maternal serum free beta-hCG and PAPP-A at 11-14 weeks of gestation. In this mixed trisomy group the median MoM NT was increased at 2.819, whilst the median MoMs for free beta-hCG and PAPP-A were reduced at 0.375 and 0.201 respectively. We predict that with the use of the combined trisomy 13 and 18 algorithm and a risk cut-off of 1 in 150 will for a 0.3% false positive rate allow 95% of these chromosomal defects to be identified at 11-14 weeks. Such algorithms will enhance existing first trimester screening algorithms for trisomy 21.