Differential expression of human placental PAPP-A2 over gestation and in preeclampsia

IntroductionPregnancy Associated Plasma Protein A2 (PAPP-A2) is a pregnancy related insulin-like growth factor binding protein-5 (IGFBP-5) protease, known to be elevated in preeclampsia. As the insulin-like growth factors are important in human implantation and placentation, we sought to determine the expression pattern of PAPP-A2 over human gestation in normal and preeclamptic pregnancies to evaluate its role in placental development and the pathogenesis of preeclampsia.MethodsPlacental basal plate and chorionic villi samples, maternal and fetal cord blood sera were obtained from preeclamptic and control pregnancies. Formalin-fixed tissue sections from across gestation were stained for cytokeratin-7, HLA-G, and PAPP-A2. PAPP-A2 immunoblot analysis was also performed on protein lysates and sera.ResultsPAPP-A2 expression is predominately expressed by differentiated trophoblasts and fetal endothelium. Chorionic villi show strong expression in the first trimester, followed by a progressive decrease in the second trimester, which returns in the third trimester. PAPP-A2 expression is not impacted by labor. PAPP-A2 is increased in the basal plate, chorionic villi and maternal sera in preeclampsia compared to controls, but is not detectable in cord blood.DiscussionPAPP-A2 is differentially expressed in different trophoblast populations and shows strong down regulation in the mid second trimester in chorionic villous samples. Both maternal sera and placental tissue from pregnancies complicated by preeclampsia show increased levels of PAPP-A2. PAPP-A2 levels are not altered by labor. Additionally, PAPP-A2 cannot be detected in cord blood demonstrating that the alterations in maternal and placental PAPP-A2 are not recapitulated in the fetal circulation.     

Three-dimensional ultrasound measurement of the placental volume in early pregnancy: method and correlation with biochemical placenta parameters.

Placental size has been an interesting topic of research for many years. The main aim of this study was to investigate the feasibility of measuring the placental volume at the end of the first trimester using three-dimensional (3D) ultrasound and to correlate these volumes to known placental functional indices and to factors affecting the placenta. Women with singleton pregnancies at the end of the first trimester were included into this study. The volume data of the placentae were correlated to the crown-rump length (CRL), placenta-associated plasma protein A (PAPP-A), free beta-human chroangiogonadotropin (f-beta-hCG) and other factors that may affect the placental size or function. A total of 1462 pregnancies could be evaluated. Comparison between CRL and placental volume proved a significant correlation (r=0.43, P< 0.001). Due to the observed proportional growth of CRL and placental volume, a quotient (placental volume/CRL) was calculated for each case. There were no differences between placenta/CRL-quotients in relation to gravidity, parity or smoking. Correlations could be established between the placental volume and PAPP-A and f-beta-hCG (PAPP-A: r=0.28, P< 0.001, f-beta-hCG: r=0.10, P< 0.001). The measurement of the placenta in the first trimester can be performed in a high percentage of cases. The placenta/CRL quotient represents a simple method to compare placentae from different gestational days. The correlation between placental volume and maternal serum screening parameters might provide a chance to refine first trimester Down's syndrome serum screening. Future studies will be needed to evaluate the possible clinical use of first trimester placental volume measurements.     

First trimester combined test for Down syndrome screening in unselected pregnancies — A report of a 13-year experience

ObjectiveTo analyze the performance of the first trimester Down syndrome screening in a single medical center in Northern Taiwan.Materials and methodsFrom April 1999 to June 2012, a total of 25,104 pregnant women at gestational age of 10 weeks to 13 weeks 6 days received first trimester “combined test” for Down syndrome screening. The test combines the ultrasound scan of nuchal translucency thickness and maternal biochemical serum levels of pregnancy-associated plasma protein A (PAPP-A) and free beta-human chorionic gonadotropin (β-hCG). A positive screen was defined as an estimated Down syndrome risk ≥1/270, and either chorionic villous sampling or amniocentesis was performed for fetal chromosomal analyses.ResultsSeventy-eight of the 25,104 pregnancies were proven to have fetal chromosome anomalies. The detection rates for trisomy 21, trisomy 18, Turner syndrome, and other chromosome anomalies were 87.5% (21/24), 69.2% (9/13), 81.8% (9/11), and 60% (18/30), respectively, with a false positive rate (FPR) of 5.4% (1353/25,026). Further evaluation of the detection rates for trisomy 21, by gestational age at 11, 12, and 13 weeks, were 92.3%, 87.5%, and 66.7%, respectively.ConclusionThe first trimester combined test is an effective screening tool for Down syndrome detection with an acceptable low false positive rate. The best timing of screening will be between 11 and 12 weeks' gestation.     

Expression of pregnancy-associated plasma protein-A (PAPP-A) during human villous trophoblast differentiation in vitro

Pregnancy-associated placental protein-A (PAPP-A), first isolated from maternal serum, has been identified as a metalloprotease cleaving insulin-like growth factor binding protein-4 (IGFBP-4). The source of PAPP-A during pregnancy is unclear. We therefore investigated PAPP-A expression during in vitro human villous cytotrophoblast cell (CT) differentiation into syncytiotrophoblast (ST). CT were isolated from normal first trimester, second trimester and term placentae (n=10) and cultured to form ST. PAPP-A mRNA was quantified by real-time PCR, and PAPP-A protein expression was studied by immunocytochemistry and TRACE technology with specific monoclonal antibodies. PAPP-A mRNA expression in total placental extracts increased during the course of pregnancy. PAPP-A protein was detected in the cytoplasm of both CT and ST. ST formation in vitro was associated with a 19-fold increase in PAPP-A mRNA expression and an 8-fold increase in PAPP-A secretion into the culture medium. No significant difference in PAPP-A production was observed between cultured cells isolated from early and term placentae. In conclusion, PAPP-A production in vitro, is associated to the differentiation of villous cytotrophoblast cells into syncytiotrophoblast, independently of the age of gestation.     

Maternal serum hyperglycosylated human chorionic gonadotrophin (HhCG) in the first trimester of pregnancies affected by Down syndrome,using a sialic acid-specific lectin immunoassay

In a series of 54 cases of pregnancies complicated by Down syndrome and 224 unaffected pregnancies we examined maternal serum levels of hyperglycosylated human chorionic gonadotrophin (HhCG) in samples collected in the first trimester (11-13 weeks) using a sialic acid-specific lectin immunoassay. We compared these levels with those of other potential first trimester serum markers [free beta-hCG, pregnancy-associated plasma protein A (PAPP-A) and total hCG (ThCG)] and modeled detection rates and false-positive rates of various biochemical markers in conjunction with fetal nuchal translucency (NT) and maternal age using an maternal age standardized population. Maternal serum HhCG in cases of Down syndrome were significantly elevated (median MoM 1.97) with 24/54 (44%) of cases above the 95th centile for unaffected pregnancies. Free beta-hCG was also elevated (median MoM 2.09) with 33% of cases above the 95th centile. PAPP-A levels were reduced (median MoM 0.47) with 38% below the 5th centile. ThCG levels, whilst elevated (median MoM 1.34), had only 20% of cases above the 95th centile. Maternal serum HhCG levels were not correlated with fetal NT but showed significant correlation with ThCG and free beta-hCG and with PAPP-A in the Down syndrome group (r=0.536). Maternal serum HhCG levels in cases with Down syndrome had a significant correlation with gestational age, increasing as the gestation increased. When HhCG was combined together with fetal NT, PAPP-A and maternal age, at a 5% false-positive rate the modeled detection rate was 83%, some 6% lower than when free beta-hCG was used and some 4% better than when ThCG was used. Maternal serum HhCG is unlikely to be of additional value when screening for Down syndrome in the first trimester.     

A sensitive enzyme immunoassay for pregnancy-associated plasma protein A (PAPP-A): a possible first trimester method of screening for down syndrome and other trisomies

Pregnancy-associated plasma protein A (PAPP-A) is a large glycoprotein produced mainly by the trophoblast during pregnancy and released into the maternal circulation. Its biological function is unknown. In the second trimester i.e. when Down syndrome (DS) screening is routinely performed, the level of maternal serum PAPP-A was found to be within the normal range in pregnancies affected by fetal trisomy 21. However, PAPP-A was shown to be a potent marker for DS before 14 weeks of gestation. Only radioimmunoassays (RIAs) based on labelled antigen competition reached the required sensitivity for early pregnancy PAPP-A determinations; but they have a very short shelf life due to inherent tracer half-life and, in the case of PAPP-A, instability of the labelled antigen after three weeks. We describe a convenient and novel enzyme immunoassay (ELISA) with high sensitivity and a long shelf life.     

First-trimester biochemical markers for Down syndrome

The value of maternal serum pregnancy-associated protein A (PAPP-A), free and total beta human chorionic gonadotrophin (fbetahCG, betahCG) and alpha-fetoprotein (AFP) in screening for Down syndrome (DS) in early pregnancy has been assessed. To evaluate the different biochemical markers, 32 DS pregnancies and 267 controls were used for AFP, betahCG and PAPP-A. A subgroup of those (17 DS and 136 controls) were used to evaluate fbetahCG. All analytes were determined in fresh serum samples. Our results give support to the feasibility of maternal serum levels of PAPP-A as the best biochemical marker for DS in the first trimester, and either betahCG or fbetahCG as the second marker. No differences were found between betahCG and fbetahCG distribution levels as expressed as MoMs in normal and DS pregnancies in this study.     

Nuchal Translucency Thresholds in Prenatal Screening for Down Syndrome and Trisomy 18

ObjectiveTo determine if nuchal translucency (NT) can be used as a first trimester triage marker in prenatal screening for Down syndrome and trisomy 18.MethodsData from first trimester prenatal screening in 77 443 women were stratified by maternal and gestational ages. They were then analyzed to identify NT thresholds above or below which only positive (high-risk) or negative (low-risk) results were reported by a first trimester prenatal screening test combining PAPP-A, free β-hCG and NT.ResultsCombined prenatal screening was always positive for Down syndrome when NT thickness exceeded 4.0 mm. As women aged, this upper NT threshold value changed according to gestational age. In women aged 35 to 37 years, combined prenatal screening was always positive when NT exceeded 2.8 mm, 3.0 mm, and 3.4 mm at 11, 12, and 13 weeks of gestation, respectively. In women over 42 years of age, the upper threshold value for NT was 1.8 mm, 2.4 mm, and 2.7 mm at 11, 12, and 13 weeks of gestation, respectively. In women less than 35 years of age, we identified lower threshold values below which combined prenatal screening for Down syndrome was always negative.ConclusionIn prenatal screening for Down syndrome and trisomy 18, it is possible to identify NT threshold values above which biochemical screening provides no additional benefit. In pregnancies in which NT is above the established upper cut-offs, invasive prenatal screening can be offered without delay.     

Non-invasive prenatal screening of fetal Down syndrome by maternal plasma DNA sequencing in twin pregnancies

Non-invasive prenatal screening for fetal Down syndrome (NIFTY) by maternal plasma sequencing was performed in 12 subjects with twin pregnancies, including 11 with normal fetuses and 1 with discordant fetal Trisomy 21. For every sample, it was processed, sequenced and reported as soon as it was collected as other clinical samples for singleton pregnancies. The NIFTY test was negative in the 11 pregnancies carried normal fetuses, and was positive (high risk) in the case with discordant fetal Trisomy 21. The sensitivity and specificity were both 100%. This small case series suggested the NIFTY as a screening test for fetal Trisomy 21 is feasible in twin pregnancies.     

Down’s Syndrome Screening in the First Trimester with Additional Serum Markers: Indian Parameters

Objective

To derive a risk calculation algorithm suitable for use in India when screening for Down’s syndrome using four first-trimester maternal serum markers either alone or with ultrasound nuchal translucency (NT).

Methods

Stored maternal serum samples (??20 °C) from 411 singleton unaffected pregnancies were retrieved and measured for pregnancy-associated plasma protein (PAPP-A), free β-human chorionic gonadotropin (hCG), placental growth factor and α-fetoprotein. Samples were taken at 10–13 weeks’ gestation. Equations were derived to express marker levels in multiples of the gestation-specific normal median, adjusted for maternal weight. Gaussian model parameters were derived and compared with six published non-Indian studies; NT parameters were derived from 27,647 women screened in India. On the basis of the maternal age distribution in 64,473 Indian women screened in 2016–2017, the model was used to predict test performance.

Results

The model predicted a detection rate for a serum-only protocol of 80% for a 5% false-positive rate. Using a 1 in 250 at term Down’s syndrome risk cut-off, the predicted detection rate was 78% and the false-positive rate was 4.1%. When NT was also included, the rates were 95% for 5% and 90% for 1.4%, respectively.

Conclusion

First-trimester screening using four serum markers only can be carried out in India. Performance is expected to be similar to the second-trimester Quad test and will also facilitate early screening for preeclampsia and open spina bifida. A protocol of NT plus the four serum markers enhances the performance compared with NT, PAPP-A and free β-hCG.

     

Insulin-like Growth Factor Binding Protein-3 in the Detection of Fetal Down Syndrome Pregnancies

Objective: To study the usefulness of maternal serum insulin-like growth factor binding protein-3, a potential cell growth inhibitor, in second trimester prenatal screening for fetal Down syndrome.Methods: Three hundred and forty-two samples from normal pregnancies and nine fetal Down syndrome pregnancies were analyzed for insulin-like growth factor binding protein-3 levels by radioimmunoassay. Data were converted to multiples of median (MoM) and analyzed statistically to compare the differences between control and Down syndrome pregnancies.Results: The mean insulin-like growth factor binding protein-3 MoM of Down syndrome–affected pregnancies (1.09) was significantly higher than that of the normal pregnancies (1.00) (P < .01). Insulin-like growth factor binding protein-3, in combination with maternal serum alpha-fetoprotein (MSAFP), hCG, and maternal age, detected 89% of Down syndrome pregnancies at a screen positive rate of 2.1%. This compares favorably to the standard combination of MSAFP, hCG, and unconjugated estriol (E3), which had a 66.7% Down syndrome detection rate and a 4.1% screen positive rate in our study samples.Conclusion: This retrospective analysis suggested that the inclusion of insulin-like growth factor binding protein-3 into the triple screen program to replace unconjugated E3 might enhance the detection rate of fetal Down syndrome pregnancies. These data need to be confirmed by a larger prospective study.     

Maternal serum and amniotic fluid levels of macrophage inhibitory cytokine 1 in Down syndrome and chromosomally normal pregnancies

OBJECTIVES: To measure maternal serum and amniotic fluid levels of macrophage inhibitory cytokine-1 (MIC-1) in Down syndrome and normal pregnancies, assessing the utility of MIC-1 as a prenatal marker of Down syndrome. METHODS: Stored serum from 64 Down syndrome and 399 control pregnancies, collected at 8 to 17 weeks of pregnancy, and stored amniotic fluid from 17 Down syndrome and 53 controls, collected at 15 to 19 weeks of pregnancy, were retrieved for analysis. MIC-1 was measured using an established in-house ELISA, blinded to sample type. RESULTS: In maternal serum, MIC-1 levels are not altered in Down syndrome in either the first or second trimester. Levels, expressed as median (95% CI) multiples of the median (MoM), in the Down syndrome cases and controls were 1.07 (0.9-1.1) MoM and 1.0 (0.95-1.03) MoM respectively. In amniotic fluid, MIC-1 levels were significantly decreased compared to controls, 0.52 (0.44-0.64) MoM versus 1.0 (0.85-1.08) MoM (p < 0.0001). CONCLUSION: MIC-1 is decreased in amniotic fluid but not in maternal serum in Down syndrome pregnancies. MIC-1 will not be useful as a prenatal marker of Down syndrome.     

Between pregnancy biological variability of first trimester markers of Down syndrome and the implications for screening in subsequent pregnancies: an issue revisited

OBJECTIVES: To assess the level of correlation of first trimester biochemical and biophysical markers of Down syndrome between different pregnancies in the same individual. To assess the impact that between pregnancy biological variability has on the likelihood that women who are at increased risk in a first pregnancy being also at increased risk in a subsequent pregnancy. METHODS: During a three period women attending the OSCAR clinic at Harold Wood Hospital have had the opportunity to have first trimester screening for Down syndrome and other aneuploidies using the maternal serum biochemical markers free beta-human chorionic gonadotrophin (hCG) and pregnancy associated plasma protein-A (PAPP-A) in conjunction with fetal nuchal translucency (NT) thickness and maternal age. Of the 111,105 women undergoing such screening, the computer records were examined for women who had more than one pregnancy. The results from 1002 women with two normal singleton pregnancies were available for analysis. Marker correlations (as MoM) were established between the pregnancies and the proportion of women likely to be at increased risk in each pregnancy estimated, as was the likelihood of women being at increased risk in both pregnancies. RESULTS: For fetal NT there was no correlation between NT MoM in the first and second pregnancy (r = 0.0959, p > 0.10). For maternal serum free beta-hCG MoM a significant correlation was found (r = 0.3976, p < 0.001), as was also found for PAPP-A MoM (r = 0.4371, p < 0.001). CONCLUSION: The implication for such between pregnancy marker association is that women who have an increased risk of Down syndrome in one pregnancy are two or three times more likely to repeat this event in their next pregnancy. This information may be useful in counselling women when undergoing first trimester screening in a subsequent pregnancy.     

Molecular weight forms of inhibin A,inhibin B and pro-alphaC in maternal serum,amniotic fluid and placental extracts of normal and Down syndrome pregnancies

BACKGROUND: Inhibin A, an established prenatal marker of Down syndrome (DS), exists in the maternal circulation in a number of isoforms. The present study explored whether specific inhibin A isoforms may be selectively increased in DS, offering the prospect of improved marker performance. METHODS: Second trimester maternal serum, placental extracts and amniotic fluid (AF) pools from both normal and DS pregnancies were fractionated by a combined immunoaffinity (IA) chromatography, preparative polyacrylamide gel electrophoresis (Prep-PAGE) and electroelution procedure. Inhibins A, B and pro-alphaC were determined in the eluted fractions by specific enzyme-linked immunosorbent assays (ELISAs) and the profiles of immunoactivity (IA) characterized in terms of molecular weight (MW) and percentage recovery. RESULTS: The MW patterns of inhibin A and pro-alphaC in maternal serum and AF were similar between DS and control pregnancies, both showing peaks between 25-40 k and approximately 65 k. AF contained, in addition, a higher proportion of <30 k inhibins A and B, and <25 k pro-alphaC forms. There were large differences in the inhibin forms present in DS placentae, with more 70 k and less 30-40 k inhibin A than in controls. CONCLUSIONS: The present data suggest that the processing, cleavage or secretion of inhibin MW forms by the DS placenta differs from normal. However, these differences are not reflected in maternal serum and so improvements in serum screening will not be afforded by measuring specific inhibin A isoforms.     

Frequency and clinical consequences of extremely high maternal serum PAPP-A levels

A multicentre study was carried out to determine the frequency and clinical consequences of extremely high maternal serum pregnancy-associated plasma protein (PAPP)-A. There was a total of 79 pregnancies with PAPP-A exceeding 5.0 multiples of the gestation-specific median in a series of 46 776 pregnancies tested (0.2%) at the 7 collaborating centres. Five pregnancies were lost to follow-up, one miscarried and one with Noonan's syndrome was terminated. Of the remaining 72 that ended in a live birth, one infant had gastroschisis and five pregnancies had obstetric complications: pre-eclampsia, pregnancy-induced hypertension, gestational diabetes and two with growth retardation. Among women with high PAPP-A and no complications or adverse outcomes, there was no evidence of a substantial change in the levels of other Down syndrome markers or the extent of nuchal translucency. Three analytical methods were used to assay PAPP-A and yielded different frequencies of extremely high levels (0.05%, 0.4% and 0.6%) possibly owing to cross-reaction with another substance. We conclude that women with high PAPP-A can be reassured that there is no reason to suppose that the outcome of pregnancy will differ from those with normal levels, provided other markers are normal. If, as more centres move their Down syndrome screening practice to the first trimester, additional cases emerge with Noonan's syndrome or gastroschisis and raised PAPP-A, this advice will need to be modified.     

Diagnosis of fetal acrania during the first trimester nuchal translucency screening for Down syndrome.

OBJECTIVES: Prenatal screening during the first-trimester using fetal nuchal translucency (NT) measurement and maternal serum levels of free beta-human chorionic gonadotropin (hCG) and pregnancy-associated plasma protein-A (PAPP-A) has become an established method for the detection of fetal Down syndrome. Increasing evidence has shown that some of the fetal structural abnormalities could be identified during NT scanning. Second trimester maternal serum alpha-fetoprotein (MSAFP) measurements and ultrasound scans have been widely used in clinical practice to identify fetal neural tube defects (NTDs). In this study, we evaluated the effectiveness of early diagnosis of fetal acrania during NT scanning. METHODS: We reviewed the medical records of 5890 pregnancies that were delivered in our hospital between January 1, 1999 and January 31, 2001. Among them, 3600 pregnant women received NT-based Down syndrome screening at 10-13 weeks' gestation. Pregnancies with fetal NTDs were evaluated and their maternal serum levels of free beta-hCG and PAPP-A were compared with those of the normal control pregnancies. RESULTS: Seven of the 3600 pregnancies were identified with fetal acrania and all of them were detected during first-trimester NT scanning. Among the seven cases, five had measurements of maternal serum concentration free beta-hCG and PAPP-A concentration, yet there were not significant difference between the pregnancies with fetal acrania and those of the control pregnancies (PAPP-A, 1.13 vs. 0.96; free beta-hCG, 1.10 vs. 1.06; P>0.05). Two of the seven affected patients did not have maternal serum biochemical measurements due to the immediate termination of pregnancies. CONCLUSIONS: We demonstrated that pregnancies with fetal acrania could be easily identified at the time of NT scanning. Careful ultrasound inspection of fetal structure during NT measurements at 10-13 weeks of gestation provides an encouraging advantage for early diagnosis of fetal acrania.     

Ischemia-modified albumin in pregnancy

Objective

In normal pregnancies, a hypoxic intrauterine environment seems necessary for early trophoblast development. In this context, maternal serum levels of ischemia-modified albumin (IMA) are elevated, reflecting the oxidative stress associated with placental development. The aim of this study was to evaluate IMA and pregnancy-associated plasma protein A (PAPP-A) in mothers bearing small-for-gestational-age (SGA) fetuses compared to normal pregnancies.

Study design

A prospective study was performed between June 2010 and June 2011. Serum total albumin, IMA and PAPP-A concentrations were determined in 81 pregnant women in three different periods: 1st trimester, 2nd trimester and postpartum. Two groups of subjects were retrospectively identified: Group (1) mothers bearing appropriate-for-gestational-age (AGA) fetuses, and Group (2) mothers bearing SGA fetuses. Serum total albumin and IMA concentrations were determined in 198 non-pregnant women as controls.

Results

Serum IMA concentrations increase during gestation. IMA/albumin serum levels in the 1st trimester were significantly higher in subjects of Group (2) (p < 0.05), whereas values of serum PAPP-A MoM were significantly lower (p < 0.05).

Conclusions

Elevated IMA serum levels together with low levels of PAPP-A were detected in the 1st trimester in mothers bearing SGA fetuses, and this may reflect early placental changes occurring before clinical manifestation of SGA.     

Prenatal Screening for and Diagnosis of Aneuploidy in Twin Pregnancies

ObjectiveTo provide a Canadian consensus document with recommendations on prenatal screening for and diagnosis of fetal aneuploidy (e.g., Down syndrome and trisomy 18) in twin pregnancies.OptionsThe process of prenatal screening and diagnosis in twin pregnancies is complex. This document reviews the options available to pregnant women and the challenges specific to screening and diagnosis in a twin pregnancyOutcomesClinicians will be better informed about the accuracy of different screening options in twin pregnancies and about techniques of invasive prenatal diagnosis in twins.EvidencePubMed and Cochrane Database were searched for relevant English and French language articles published between 1985 and 2010, using appropriate controlled vocabulary and key words (aneuploidy, Down syndrome, trisomy, prenatal screening, genetic health risk, genetic health surveillance, prenatal diagnosis, twin gestation). Results were restricted to systematic reviews, randomized controlled trials, and relevant observational studies. Searches were updated on a regular basis and incorporated in the guideline to August 2010. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies The previous Society of Obstetricians and Gynaecologists of Canada guidelines regarding prenatal screening were also reviewed in developing this clinical practice guideline.ValuesThe quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table 1).Benefits, harms, and costsThere is a need for specific guidelines for prenatal screening and diagnosis in twins These guidelines should assist health care providers in the approach to this aspect of prenatal care of women with twin pregnancies.Summary StatementsFetal nuchal translucency combined with maternal age is an acceptable first trimester screening test for aneuploidies in twin pregnancies. (II-2)First trimester serum screening combined with nuchal translucency may be considered in twin pregnancies It provides some improvement over the performance of screening by nuchal translucency and maternal age by decreasing the false-positive rate. (II-3)Integrated screening with nuchal translucency plus first and second trimester serum screening is an option in twin pregnancies. Further prospective studies are required in this area, since it has not been validated in prospective studies in twins (III)Non-directive counselling is essential when invasive testing is offered (III)When chorionic villus sampling is performed in non-monochorionic multiple pregnancies, a combination of transabdominal and transcervical approaches or a transabdominal only approach appears to provide the best results to minimize the likelihood of sampling errors. (II-2)RecommendationsAll pregnant women in Canada, regardless of age, should be offered, through an informed counselling process, the option of a prenatal screening test for the most common clinically significant fetal aneuploidies. In addition, they should be offered a second trimester ultrasound for dating, assessment of fetal anatomy, and detection of multiples. (I-A)Counselling must be non-directive and must respect a woman's right to accept or decline any or all of the testing or options offered at any point in the process. (III-A)When non-invasive prenatal screening for aneuploidy is available, maternal age alone should not be an indication for invasive prenatal diagnosis in a twin pregnancy. (II-2A) If non-invasive prenatal screening is not available, invasive prenatal diagnosis in twins should be offered to women aged 35 and over. (II-2B)Chorionicity has a major impact on the prenatal screening process and should be determined by ultrasound in the first trimester of all twin pregnancies (II-2A)     

Maternal serum leptin concentration during the second trimester of pregnancy: association with fetal chromosomal abnormalities

Recent studies suggest that leptin, the product of the obese gene, is produced by the placenta during pregnancy. The present study addressed the question whether second trimester maternal serum leptin could be altered by fetal Down syndrome or Edwards syndrome. Maternal serum leptin concentrations were measured in 18 pregnancies complicated with Down syndrome, six pregnancies complicated with Edwards syndrome and 183 uncomplicated pregnancies during the second trimester of pregnancy. The present results demonstrate that leptin concentrations in uncomplicated pregnancies slightly decrease from the 16th week of pregnancy, reaching a minimum of 18.8 ng/ml around the 20th week, and then rapidly increase to 28.2 ng/ml by the 24th week. Leptin correlation with maternal body weight decreases from r=0.695 at 16-17 week of gestation to r=0.544 at >22 weeks of gestation. There was no significant difference between the mean MoMs of Down syndrome- (0.926) or Edwards syndrome- (0.960) affected pregnancies and normal pregnancies (1.002). A weak correlation (r=0.18, p<0.02) was observed between corrected leptin MoMs and human chorionic gonadotrophin (hCG) MoMs in normal pregnancies. It is assumed that around the 20th week of pregnancy placental leptin production is activated or at least is accelerated and it is added to the amount of leptin produced by maternal adipose tissue. Fetal Down syndrome or Edwards syndrome does not seem to alter maternal leptin concentration and therefore leptin cannot be used as a marker for these chromosomal abnormalities in the early second trimester of pregnancy.     

Resistin in mid-trimester amniotic fluid in trisomy 21

Abstract

Objective: The aim of this study was to examine whether resistin is present in second trimester amniotic fluid from trisomy 21 (also known as Down’s syndrome) pregnancies and whether its concentration differs compared with euploid pregnancies.

Methods: The study cohort consisted of 58 women in the mid-trimester of pregnancy who underwent amniocentesis for prenatal diagnosis, 31 of whom carried a single fetus with diagnosed trisomy 21 (study group) and the rest with normal karyotype (control group, n?=?27). Groups were matched for maternal and gestational age. Levels of resistin in amniotic fluid were measured by a commercially available enzyme-linked immunosorbent assay (ELISA) kit.

Results: Resistin was detected in all amniotic fluid samples. Its median concentration in the second trimester amniotic fluid of trisomy 21 pregnancies (2.1?ng/ml) was statistically significantly lower (p value <0.001) in comparison with that in euploid pregnancies (3.3?ng/ml).

Conclusions: Resistin is a physiologic constituent of second trimester amniotic fluid. Lower levels of amniotic fluid resistin in pregnancies with trisomy 21 may reflect altered metabolic pathways in utero that could possibly be related with phenotypic features of the syndrome.