Free Beta Research Articles

First-trimester screening in triplets

The purpose of this study was to determine the performance of Down syndrome screening in triplet pregnancy. Nuchal translucency (NT; n = 794), nasal bone (n = 219), and biochemistry (n = 198) were evaluated in triplet pregnancy. Screening performance was evaluated with the use of delta and Gaussian models. The median multiples of the median values for free beta human chorionic gonadotropin and pregnancy-associated plasma protein A were 2.86 and 3.48, respectively. A significant correlation in delta NT within pregnancy was observed (0.46-0.68). The modeled false-positive rates were 11.7%, 7.4%, and 8.9% with the delta model and 11.9%, 6.6%, and 12.0% with the Gaussian model for NT, NT + nasal bone, and NT + biochemistry. Based on simulation, the detection rate at 12 weeks' gestation was 78%, 93%, and 80% for NT, NT + nasal bone, and NT + biochemistry at a 10% false-positive rate using either the delta or Gaussian models. In triplet pregnancy, the addition of nasal bone lowers the false-positive rate of nuchal translucency screening. More data are required on the effectiveness of biochemistry.

Impact of type 1 diabetes and glycemic control on fetal aneuploidy biochemical markers

To determine the influence of type 1 diabetes mellitus (T1DM) on the first trimester serum markers of fetal aneuploidy; pregnancy-associated plasma protein-A (PAPP-A) and free beta subunit of human chorionic gonadotropin (free β-hCG) and to evaluate the influence of glycemic control on these parameters in the pregnant diabetic women. Retrospective study. Data were extracted from electronic obstetric and laboratory databases at two Danish University Hospitals. Based on 36 415 pregnancies without T1DM (non-T1DM) and 331 pregnancies with T1DM; β-hCG and PAPP-A were obtained at 8+0 to 14+2 gestational weeks. Medians for PAPP-A and free β-hCG were generated and multiple of the normal gestation-specific median (MoM) values were calculated for each separate pregnancy. After adjustment for maternal weight, ethnicity and smoking status, MoM values were compared across the T1DM and non-T1DM groups, respectively. Additionally, the relationship between PAPP-A MoM and HgbA1C was examined in 348 T1DM pregnancies by Spearman's rank correlation. MAIN OUTCOME MEASURES. Difference in biochemical marker levels between T1DM and non-T1DM. PAPP-A was 0.86 MoM in T1DM pregnancies and 1.01 MoM in non-T1DM pregnancies, p < 0.0001. Conversely, free β-hCG was not altered in T1DM pregnancies (T1DM 0.99 MoM, non-T1DM 0.98 MoM; p=0.14). There was a significant inverse correlation between HgbA1C and PAPP-A (rho=-0.12, p=0.02). In T1DM pregnancies, PAPP-A MoM values were lower than in non-T1DM pregnancies. This suggests that correction should be considered in first trimester biochemical screening for fetal aneuploidy in T1DM women.

First‐trimester stepwise sequential prenatal screening for Down syndrome using NT and maternal age

The measurement of the fetal nuchal translucency thick-ness (NT) combined with maternal age and maternalblood biochemical markers [free beta human chorionicgonadotrophin (free βhCG) and pregnancy-associatedplasma protein A (PAPP-A)] is widely accepted and nowthe most commonly used method for screening Downsyndrome (DS) in the first trimester. Most often, mater-nal blood is taken during the NT visit, and it usuallyrequires a week or two to measure biochemistry andproduce a final report. A one-stop clinic assessment ofrisk model has been proposed, but most clinics do nothave sufficient clinical volume to afford it financially(Spencer

First trimester Down syndrome screening with dried blood spots using a dual analyte free beta hCG and PAPP‐A immunofluorometric assay

To determine the effectiveness of first trimester Down syndrome screening with dried blood spots using a dual analyte free beta human chorionic gonadotrophin (hCG)/pregnancy-associated plasma protein A (PAPP-A) immunofluorometric assay. An initial retrospective study of 54 Down syndrome cases and 1064 control specimens was performed followed by a series of 146,513 specimens from routine screening. Detection rates at a fixed 5% false-positive rate were determined separately based on reference data from the retrospective study set and then adjusted based on the routine screening study set. On the basis of the retrospective analysis, the estimated detection rate using free beta hCG, PAPP-A and maternal age varied from 78% at 9 weeks of pregnancy to 70% at 13 weeks of pregnancy. Using a combined protocol, including NT, the detection rate varied from 92 to 90% between 9 and 13 weeks of gestation. Adjusting distribution parameters based on the routine screening dataset reduced the detection rate by at most 1%. Analysis of free beta hCG and PAPP-A using a dual analyte dried blood spot assay is an effective tool in Down syndrome screening, adding an important option for those considering implementation or modification of existing prenatal screening programs.

Evaluation of Down's syndrome screening methods using maternal serum biochemistry in the second trimester pregnancy

To provide basis for selecting the suitable method of Down's syndrome biochemical screening in the second trimester pregnancy. A total of 30 547 singleton pregnancies between 14 and 20(+ 6) weeks of pregnancy were collected and analyzed for maternal serum alpha-fetoproteins (AFP) and human chorionic gonadotrophin, free beta subunit (beta-HCG) with or without unconjugated estriol (uE3). The screening risks were calculated using the software Lifecycle. The detection rates and the cost of per Down's syndrome detected were calculated and compared. And four different methods were compared in a series of 64 serum samples from Down's syndrome pregnancies. (1) Among the 64 affected cases, the detection rate of Down's syndrome was improved no matter in the double test (DT) or in the triple test (TT) if software Lifecycle (LC) was used to evaluate risks. And it was not suitable to evaluate risks with software 2T-Risks in the triple tests. (2) In the cohort of 30 547 singleton pregnancies, the detection rate of Down's syndrome with project DT-LC, which was double test using AFP and free beta-HCG together with software Lifecycle, and project TT-LC, which was triple test using AFP, free beta-HCG and uE3 together with software Lifecycle, was 56.25% and 57.14%, respectively. The former project was better because it decreased the false positive rate at a lower running cost. The DT-LC is an effective screening strategy for second trimester detection of fetal Down's syndrome in mainland China.

Decreased PAPP-A is associated with preeclampsia, premature delivery and small for gestational age infants but not with placental abruption

Objective To investigate links between first trimester Down's syndrome screening markers and adverse pregnancy outcomes; preeclampsia (PE), small for gestational age (SGA), preterm delivery (PD) and placental abruption (PA) in spontaneous, chromosomally normal pregnancies. Study design Cohort study in a university hospital. Data during pregnancy were routinely collected from a total study population of 2844 pregnant women between 2005 and 2007. Four study groups were pregnancies with PE ( N = 175), PA ( N = 17), PD ( N = 213) and SGA ( N = 275) plus a reference group with normal outcome ( N = 2164). The median MOMs of maternal serum concentrations of pregnancy associated plasma protein A (PAPP-A) and free beta human chorionic gonadotropin (fβ-hCG) were compared using two-tailed pooled t-tests, continuous variables were compared using Student's two-way t-tests, and Chi-square tests were used to analyse dichotomous variables. Fisher's exact test was used when there were fewer than five units in any of the classes. Results The median MOM of maternal serum PAPP-A was significantly lower in women with PE, PD and SGA (0.79, 0.80 and 0.79 MOM, respectively) than in the reference group (0.99 MOM) ( p < 0.01). The median MOM of maternal serum fβ-hCG was also significantly lower in the SGA group (0.90 MOM) and in the PE and PD groups (0.86 and 0.92 MOM) than in the reference group (0.99 MOM, p = 0.02). There was no detectable difference between the biochemical markers in the PA group and the reference group. No statistical difference was found between NT MOMs in the reference and study groups. Conclusion The concentrations of first trimester screening (FTS) serum markers were lower in pregnancies where PE, PD and SGA occurred. In the latter two cases, there was an inverse association between incidence and PAPP-A and fβ-hCG values. However, the development of PA during pregnancy could not be predicted from biochemical marker concentrations. The mechanism behind PA is probably less dependent on the placenta than on the decidua.

Predicting the risk of pre‐eclampsia between 11 and 13 weeks' gestation by combining maternal characteristics and serum analytes, PAPP‐A and free β‐hCG

To determine if a simplified model for predicting pre-eclampsia (PEC) can be developed by combining first-trimester serum analytes, pregnancy-associated plasma protein A (PAPP-A) and free beta human chorionic gonadotrophin (β-hCG), and maternal characteristics. A retrospective cohort study of patients seen for first-trimester aneuploidy screening from 2003 to 2009. The 5th, 10th, 90th, and 95th percentiles for the analyte multiples of the medians (MoMs) for our population were determined and evaluated for association with PEC. Univariate and backward stepwise logistic regression analyses were performed and the area under the receiver operating characteristic (ROC) curves [area under curve (AUC)] used to determine the best models for predicting PEC. Among 4020 women meeting the inclusion criteria, outcome data was available for 3716 (93%). There were 293 cases of PEC. The final model identified a history of pre-gestational diabetes [aOR 2.6, 95% confidence interval (CI) 1.7-3.9], chronic hypertension (cHTN) (aOR 2.6, 95% CI 1.7-3.9), maternal body mass index (BMI) > 25 (aOR 2.5, 95% CI 1.9-3.4), African American race (aOR 1.8, 95% CI 1.3-2.6), and PAPP-A MoM < 10th percentile (aOR 1.6, 95% CI 1.1-2.4) to be significant predictors of PEC (AUC = 0.70, 95% CI 0.65-0.72). Low first-trimester PAPP-A levels are associated with the development of PEC; however, the model was only modestly efficient in its predictive ability.

First‐trimester serum PAPP‐A and fβ‐hCG concentrations and other maternal characteristics to establish logistic regression‐based predictive rules for adverse pregnancy outcome

To determine the clinical relevance of maternal characteristics and first-trimester serum concentrations of pregnancy-associated plasma protein A (PAPP-A) and free beta human chorionic gonadotrophin (fβ-hCG) in predicting placenta-related complications, miscarriage and preterm delivery. DESIGN, SETTING AND POPULATION: A historical cohort study of data of the National Institute for Public Health and the Environment of first-trimester screening tests performed between July 2002 and May 2006 was done. Data from 28 566 (64.1%) tests were eligible for analysis. By logistic regression, predictive rules were made based on PAPP-A and fβ-hCG concentrations, maternal smoking, maternal weight and age, low birth weight, stillbirth and hypertensive disorders, miscarriage and preterm birth. Predictive values were analysed with the area under the curve (AUC) of receiver operating curves (ROC). Predictive for placenta-related complications were low PAPP-A, low fβ-hCG, smoking and weight (AUC 54%). For miscarriage low PAPP-A, low fβ-hCG and maternal age (MA) were predictive (AUC 78%) and for preterm delivery low PAPP-A, smoking, MA and maternal weight (AUC 55%). Only the predictive model for miscarriage had a clinically relevant predictive value of 28%. Results together do not justify closer surveillance of chromosomally normal pregnancies with PAPP-A or fβ-hCG levels below the fifth percentile.

Proteomics and Down syndrome screening: a validation study

In a previous discovery study, we identified seven potential screening markers for Down syndrome (DS). Here, we report on an extended study to validate the discriminative potential of these markers. Concentrations of the seven analytes were measured using bead-based multiplexed immunoassays in maternal serum from 27 DS pregnancies and 27 matched controls. Control samples were matched to the cases by gestational age (exact day), maternal weight ( ± 5 kg), and maternal age ( ± 1 year) and by closest sample date. Prediction values were obtained for current screening markers [pregnancy-associated plasma protein A (PAPP-A), free beta human chorionic gonadotrophin (fβ-hCG) and nuchal translucency (NT)] and seven markers identified before based on concentration fold ratios between DS and controls. Models were fitted based on data of the discovery study or this study and also tested on both datasets. A significantly higher fold ratio was only found for epidermal growth factor (EGF) (-1.96; p = 0.006). In the prediction model for the current dataset, EGF improved the detection rate (DR) of DS by 5.7% [at a fixed 5% false-positive rate (FPR)] when added to the currently used screening markers. Validation of previously identified biomarkers only confirmed EGF for further consideration as a DS screening marker. This underlines the importance of validating biomarkers; in this study, limiting the range of plausible biomarkers to only one suitable biomarker.

Prospective experience with contingent screening strategy for Down syndrome in Estonia

The purpose of this study was to establish the first-trimester screening for Down syndrome (DS) in Estonia and to evaluate the potential of a contingent screening in the population of pregnant women. A prospective cohort study included non-selected pregnancies during the programme of first-trimester screening for DS in a 4-year period at a single centre. The following screening tests were evaluated: measurement of nuchal translucency (NT) and serum screening [pregnancy-associated plasma protein A and free beta subunit of human chorionic gonadotropin (fβ-HCG)]; results were given as combined screening. After first-trimester screening, contingent screening protocol was used, and women were divided into three groups: high risk, low risk and an intermediate risk group. In the last group, a second-trimester triple test (AFP; total HCG and uE3) was also performed. The study group consisted of 3,194 non-selected pregnancies. In 1,387 (43.4%) women, first-trimester serum screening showed low risk (risk ≤ 1:5,000), and no future testing was performed, in 30 (0.9%) women screening test showed high risk (risk ≥ 1:50) and a diagnostic test was offered, and in 1,777 (55.7%) women repeated risk calculation in the second trimester was done. During the study period, there were 17 cases of trisomy 21, of which 15 (88.3%) were detected with the described screening programme. In conclusion, two-step contingent sequential screening is a better choice for Down syndrome screening in Estonia instead of previously used second-trimester screening, and it offers the advantage of earlier diagnosis.

Early vaginal bleeding has no impact on markers used in first trimester aneuploidy screening

To assess the impact of early vaginal bleeding on the levels of markers used in first trimester screening for aneuploidy. A retrospective analysis was carried out on the free beta human chorionic gonadotrophin (beta-hCG) and pregnancy associated plasma protein-A (PAPP-A) levels and nuchal translucency thickness in 49 653 women with a normal singleton fetus who had first trimester combined screening for Down Syndrome in three centres. Median MoMs and the distribution of log MoMs of the two markers were compared in two groups-7470 women who self-reported vaginal bleeding and 42 183 women who reported no vaginal bleeding at any stage prior to the screening test. The overall median MoM free beta-hCG and that in the bleeding and non-bleeding group were 0.9854, 1.0012 and 0.9832, and for PAPP-A were 1.0407, 1.0413 and 1.037. There was no significant difference between the bleeding and non-bleeding group by median test (p = 0.080) or by t-test comparing log MoMs (p = 0.1305) for free beta-hCG and for PAPP-A with median test (p = 0.5071) or by t-test comparing log MoMs (p = 0.1740). For delta nuchal translucency (NT) there was also no significant difference between the bleeding and non-bleeding group (p = 0.055). Vaginal bleeding has little or no impact on first trimester marker levels and no correction is necessary.

Distributions of current and new first‐trimester Down syndrome screening markers in twin pregnancies

To study the distributions of pregnancy-associated plasma protein A (PAPP-A), the free beta subunit of human chorion gonadotrophin (fbeta-hCG), A Disintegrin and Metalloprotease 12 (ADAM12) and Placental Protein 13 (PP13) in first trimester twin pregnancies. Serum marker concentrations were measured in monochorionic and dichorionic twin pregnancies and singleton controls to study differences in multiples of the gestation-specific normal medians (MoMs). Median PAPP-A and fbeta-hCG MoMs were 2.03 and 1.87 for monochorionic twins (n = 116) and 2.18 and 1.89 for dichorionic twins (n = 650). Furthermore, ADAM12 and PP13 MoMs were 1.66 and 1.56 for monochorionic twins (n = 51) and 1.64 and 1.53 for dichorionic twins (n = 249). No statistically significant differences between monochorionic and dichorionic twin pregnancies were found. Correlations between markers in these pregnancies did not differ from singletons. For first-trimester screening, different parameters for monochorionic and dichorionic twin pregnancies is not necessary. Furthermore, if ADAM12 and PP13 will be adopted as screening markers, the presented median MoM values, standard deviations and correlation coefficients for twin pregnancies may contribute to a proper twin risk estimation.

Trisomy 18 and 13 screening: consequences for the Dutch Down syndrome screening programme

Edwards syndrome (trisomy 18) and Patau syndrome (trisomy 13) are the second and third most common autosomal trisomies after Down syndrome (trisomy 21). Most infants with a trisomy 18 or 13 die in utero and the others within the first year of life. Especially, in case of trisomy 13, there is an increased risk of severe and early onset pre-eclampsia (Boyd et al., 1987). To enable an early termination of trisomy 18 and 13 pregnancies, and to avoid maternal complications, screening for trisomy 18 and 13 seems a sensible option, especially since modelling has shown that current first trimester screening can detect both chromosomal anomalies with a high detection rate (DR) and low false positive rate (FPR) (Tul et al., 1999; Spencer et al., 2000). From January 2007 a governmentally approved national screening programme for Down syndrome has been implemented in the Netherlands, using the first trimester combined test [pregnancy-associated plasma protein A (PAPP-A), the free beta subunit of human choriongonadotrophin (fβ-hCG) and nuchal translucency (NT)]. The government license for this screening programme is strictly confined to screening for trisomy 21. Under the current license, it is not allowed to report on the risks for trisomy 18 and 13. However, since an increasing number of health care providers know the potential role of serum screening for trisomy 18 and 13, including some who already counsel their patient regarding these anomalies and since these trisomies are associated with early maternal complications it was recently decided to file a request to extend the government license to Edwards and Patau’s syndrome. This request is currently under review. The aim of this article is to predict the consequences for the Dutch screening programme in terms of DR and FPR if trisomy 18 and 13 screening is introduced, using an accepted algorithm and retrospective data of the Dutch programme.

First trimester screening for trisomy 21 in gestational week 8-10 by ADAM12-S as a maternal serum marker

BackgroundA disintegrin and metalloprotease 12 (ADAM12-S) has previously been reported to be significantly reduced in maternal serum from women with fetal aneuploidy early in the first trimester and to significantly improve the quality of risk assessment for fetal trisomy 21 in prenatal screening. The aim of this study was to determine whether ADAM12-S is a useful serum marker for fetal trisomy 21 using the mixture model.MethodIn this case control study ADAM12-S was measured by KRYPTOR ADAM12-S immunoassay in maternal serum from gestational weeks 8 to 11 in 46 samples of fetal trisomy 21 and in 645 controls. Comparison of sensitivity and specificity of first trimester screening for fetal trisomy 21 with or without ADAM12-S included in the risk assessment using the mixture model.ResultsThe concentration of ADAM12-S increased from week 8 to 11 and was negatively correlated with maternal weight. Log MoM ADAM12-S was positively correlated with log MoM PAPP-A (r = 0.39, P < 0.001), and with log MoM free beta hCG (r = 0.21, P < 0.001). The median ADAM12-S MoM in cases of fetal trisomy 21 in gestational week 8 was 0.66 increasing to approx. 0.9 MoM in week 9 and 10. The use of ADAM12-S along with biochemical markers from the combined test (PAPP-A, free beta hCG) with or without nuchal translucency measurement did not affect the detection rate or false positive rate of fetal aneuploidy as compared to routine screening using PAPP-A and free β-hCG with or without nuchal translucency.ConclusionThe data show moderately decreased levels of ADAM12-S in cases of fetal aneuploidy in gestational weeks 8-11. However, including ADAM12-S in the routine risk does not improve the performance of first trimester screening for fetal trisomy 21.

Estimating the effect of gestational age on test performance of combined first-trimester screening for Down syndrome: a preliminary study

To establish how different methods of estimating gestational age (GA) affect reliability of first-trimester screening for Down syndrome. Retrospective single-center study of 100 women with a viable singleton pregnancy, who had first-trimester screening. We calculated multiples of the median (MoM) for maternal-serum free beta human chorionic gonadotropin (free beta-hCG) and pregnancy associated plasma protein-A (PAPP-A), derived from either last menstrual period (LMP) or ultrasound-dating scans. In women with a regular cycle, LMP-derived estimates of GA were two days longer (range -11 to 18), than crown-rump length (CRL)-derived estimates of GA whereas this discrepancy was more pronounced in women who reported to have an irregular cycle, i.e., six days (range -7 to 32). Except for PAPP-A in the regular-cycle group, all differences were significant. Consequently, risk estimates are affected by the mode of estimating GA. In fact, LMP-based estimates revealed ten "screen-positive" cases compared to five "screen-positive" cases where GA was derived from dating-scans. Provided fixed values for nuchal translucency are applied, dating-scans reduce the number of screen-positive findings on the basis of biochemical screening. We recommend implementation of guidelines for Down syndrome screening based on CRL-dependent rather than LMP-dependent parameters of GA.

737: Impact of smoking on first trimester dried blood free beta HCG and PAPP-A

737: Impact of smoking on first trimester dried blood free beta HCG and PAPP-A

Increased time-to-pregnancy and first trimester Down's syndrome screening

Time-to-pregnancy (TTP) is a clinical tool used to measure uterine receptivity and a couples' fertility in spontaneously conceived pregnancies. The objective of this study was to examine the effects of TTP on first trimester Down's syndrome (DS) markers in spontaneous, chromosomally normal pregnancies and to compare the results to those in IVF pregnancies. A case-control study was conducted amongst patients attending a university hospital in Finland. During 2005-2007 data on pregnant women in Kuopio, with singleton pregnancies, routinely collected by the Department of Obstetrics and Gynaecology of Kuopio University Hospital and Eastern Finland Laboratory Centre were compiled. The data comprised information gathered in first trimester DS screening [age of the mother, serum hCG free beta subunit (fbeta-hCG) and pregnancy-associated plasma protein A (S-PAPP-A) levels and the nuchal translucency (NT) of the fetus], body mass index, method of conception [spontaneous or in vitro fertilization (IVF)], TTP (in spontaneous pregnancies), maternal chronic diseases, smoking habits of the mother, outcome of the pregnancy and prior pregnancy complications. Spontaneous pregnancies were classified into three groups by TTP: 0-12 months (the reference group, N = 1164), 13-24 months (N = 112) and > or = 25 months (N = 70). Screening data from IVF pregnancies (N = 39) were collected for comparison. The size of the total study population was 1385. The median/geometric mean multiple of median (MOM) of S-PAPP-A was significantly lower (P < 0.01) in women with a TTP over 25 months (0.89/0.83 MOM) and in the IVF group (0.95/0.84 MOM) compared with the reference group (1.01/1.03 MOM). However, first trimester S-fbeta-hCG and NT MOMs were not statistically different between the study groups. Consequently, the proportion of DS screening positives was significantly higher in women with TTP > or = 25 months (12.9 versus 2.1%), but not in the IVF group (2.6%). A TTP of over 2 years altered the levels of DS screening serum markers to levels similar to those observed in IVF pregnancies, with a decrease in PAPP-A levels compared with the reference group. These results raise the possibility that such changes could be related to subfertility rather than to the use of assisted reproductive technology.

OP03.01: A critical review of the benefits and limits of MRI as a complementary method for the diagnosis of fetal malformations

Down syndrome risk. Of the 56 cases of trisomy 21 (1,2%), 25 were males and 31 females (P = 0,74). Detection rate for trisomy 21 was 84% in males and 87% in females (P=0,8). Free beta HCGMoM, NTMoM and PAPPAMoM were not significantly different between male and female trisomy 21 fetuses. Conclusions: There is a trend towards female fetuses having a higher chance of increased risk at the combined test. There are no gender differences in the detection rate of trisomy 21. Whether risk assessment protocols need to become gender specific needs further investigation.

OP03.03: Diagnostic sensitivity and clinical value of prenatal ultrasound, post-mortem magnetic resonance imaging and conventional autopsy for late miscarriage and stillbirth

Down syndrome risk. Of the 56 cases of trisomy 21 (1,2%), 25 were males and 31 females (P = 0,74). Detection rate for trisomy 21 was 84% in males and 87% in females (P=0,8). Free beta HCGMoM, NTMoM and PAPPAMoM were not significantly different between male and female trisomy 21 fetuses. Conclusions: There is a trend towards female fetuses having a higher chance of increased risk at the combined test. There are no gender differences in the detection rate of trisomy 21. Whether risk assessment protocols need to become gender specific needs further investigation.

Is maternal renal disease a cause of elevated free β‐hCG in first trimester aneuploidy screening?

To asses whether supra elevated levels of maternal serum free beta hCG in the first trimester are associated with impaired renal function. A cohort of 553 women with maternal serum free beta-hCG greater than 5 multiple of median (MoM) with a single euploid fetus was matched with a control of the same maternal age (+/-1 year), ethnic origin and with a free beta-hCG within the range 0.50-1.50 MoM. Screening samples were analysed for serum creatinine and estimated glomerular filtration rate was calculated. Renal function in the two groups was compared. The database was examined to find outcomes registered as known renal disease amongst the high free beta-hCG group. In the group with a supra elevated free beta-hCG MoM there was a significant reduction in estimated glomerular filtration rate (eGFR) (122.85, 95% CI 120.43-124.74 vs 118.80, 95% CI 114.90-121.59; p = 0.009) suggesting a small but increased risk of renal disease. The presence of renal disease should also be considered as one potential cause of supra elevated levels of free beta-hCG in addition to the possibility of paternally derived triploidy and trisomy 21.