Fetal fraction of cell-free DNA in pregnancies after fresh or frozen embryo transfer following assisted reproductive technologies.

STUDY QUESTION: Is the fetal fraction (FF) of circulating cell-free DNA (cfDNA) affected in pregnancies following ART treatment with either fresh or frozen embryo transfer (ET) compared with natural conception? SUMMARY ANSWER: This study shows a significant reduction in the FF in ART patients compared with naturally conceived pregnancies, which seems to be more pronounced after fresh ET compared with frozen ET. WHAT IS KNOWN ALREADY: Non-invasive prenatal testing (NIPT) is based on cfDNA in maternal blood, of which about 10% is of placental origin and thus represents the fetal karyotype. Validation studies have demonstrated a high sensitivity, specificity and positive predictive value of NIPT for the detection of fetal trisomy 21, 18 and 13. Nevertheless, the FF of cfDNA is an important factor for NIPT test accuracy. Several studies have found a reduction in FF for pregnancies following ART in comparison with natural conception. However, knowledge on how the FF is affected in ART pregnancies after fresh ET compared with frozen ET is very limited. STUDY DESIGN, SIZE, DURATION: The study was designed as a case-control study. A total of 54 women with an ongoing pregnancy following ART treatment were included. After exclusion for different reasons, statistical analyses were based on 23 NIPT samples from pregnant women treated with fresh ET and 26 NIPT samples from pregnant women treated with frozen-thawed ET in a modified natural cycle. Women were included between February 2018 and November 2018. The results were compared with a control group of 238 naturally conceived pregnancies with a high-risk result from the combined first trimester screening (cFTS). PARTICIPANTS/MATERIALS, SETTING, METHODS: The study included women from the Fertility Clinics at Copenhagen University Hospital Hvidovre and Copenhagen University Hospital Rigshospitalet. Blood samples for NIPT analysis were drawn between 11 + 0 and 14 + 2 weeks of gestation and were all analyzed at the NIPT Center at Copenhagen University Hospital Hvidovre. The NIPT-test was performed by massive-parallel whole-genome sequencing. The FF was determined using the SeqFF algorithm. MAIN RESULTS AND THE ROLE OF CHANCE: We found a reduction in FF in ART patients compared with naturally conceived pregnancies, and the reduction was more pronounced for ART pregnancies after fresh ET (mean FF = 0.049) compared with frozen ET (mean FF = 0.063) (multivariate analysis adjusted for maternal BMI, P = 0.02). Another multivariate analysis, adjusted for BMI and multiples of median (MoM) values for pregnancy-associated plasma protein-A (PAPP-A), demonstrated a significantly reduced FF for ART pregnancies (mean FF = 0.056) compared with naturally conceived pregnancies (mean FF = 0.072) (P < 0.0001). We found that FF was significantly reduced with increasing maternal BMI (P < 0.0001) and with decreasing MoM values of PAPP-A (P = 0.003). LIMITATIONS, REASONS FOR CAUTION: A limitation of our study design was the relatively small sample size. Another limitation was that the control group was not matched with the ART-treated women. The majority of the women from the control group had a high risk from cFTS, thereby their biochemical markers were diverging. However, the biochemical markers for the ART-treated women with fresh or frozen ET were not divergent within the subgroups. WIDER IMPLICATIONS OF THE FINDINGS: Concurrent with other studies demonstrating a reduced FF for singleton pregnancies after ART treatment compared with naturally conceived pregnancies, we found a reduction in FF between the two groups. This is one of the first studies to examine FF in ART pregnancies after fresh ET compared with frozen ET, hence the existing knowledge is limited. We find that FF is even more reduced in pregnancies following fresh ET compared with frozen ET, which might possibly reflect the predisposition of being small for gestational age after fresh ET compared with natural cycle frozen ET. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by the A.P. Møller og Hustru Chastine Mc-Kinney Møllers Fond til almene Formaal (the A.P. Møller Foundation for General Purposes). All authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER: NA.

Noninvasive prenatal testing and maternal obesity: A review.

Noninvasive prenatal testing (NIPT) has become a popular screening test for the most common fetal aneuploidies. The performance of NIPT is affected by several factors including maternal obesity, which results in a greater rate of no-calls for obese pregnant women. Guidelines regarding NIPT in prenatal screening have been published, but with few and divergent recommendations on the issue. We aimed to review the medical literature, guidelines from scientific societies and information material from commercial NIPT providers on no-calls and maternal obesity. We systematically identified medical literature and guidelines from scientific societies using the database MEDLINE. Information material from commercial NIPT providers was found via a systematic search on Google.com. Nine medical studies investigating the association between maternal obesity and NIPT no-calls were included. They all showed the same trend: increasing no-call rate with increasing maternal obesity. The no-call rate ranged from 0% to 4.2% for women with body mass index (BMI) 18.5-24.9 and from 5.4% to 70.1% for women BMI ≥40. We identified 17 scientific societies with guidelines and 13 commercial NIPT providers. All were checked for information material on no-calls and maternal obesity. To allow comparison, all guidelines were examined to answer the same three predefined questions. Of the 17 included scientific societies, 13 (76.5%) mentioned the association between maternal obesity and NIPT no-calls, two (11.8%) specified weight limits and three (17.6%) advised against NIPT for severely obese pregnant women. None of the 13 commercial NIPT providers provided specific recommendations, but four (30.8%) cite maternal obesity as a potential cause for a no-call. Because of the increasing number of patients in this group, we advocate updated recommendations to guide decision making in prenatal screening for obese pregnant women.

Glycodelin is internalized by peripheral monocytes.

Glycodelin is produced by the endometrial cells during the luteal phase and first trimester of pregnancy and plays a role in the regulation of the endometrial immunology. However, the molecular connection between glycodelin and the maternal immune system is not clear. To better understand the possible physiological interaction between the endometrium and the maternal immune system, we investigated (1) whether glycodelin binds to mainly peripheral monocytes, and in case (2) whether the binding to the membrane only depends on the protein backbone or a carbohydrate structure is needed, and in case (3) whether glycodelin is internalized after binding to the membrane. We demonstrated that glycodelin - with or without the carbohydrate structure - was preferentially bound and internalized to peripheral monocytes. Surprisingly, we found signals in the nucleus of the monocytes indicating a potential regulating effect of glycodelin may be exerted through the nucleus. However, further studies should be performed to confirm this finding.

Soluble urokinase plasminogen activator receptor (suPAR) as a biomarker of early pregnancy location and viability compared with hCG, progesterone and estradiol.

A circulating biomarker of early pregnancy outcome independent of ultrasonography and gestational age is a coveted goal. This study evaluated soluble urokinase plasminogen activator receptor (suPAR), a well-described marker of inflammation and immunological activation, for this purpose, and compared it with established early pregnancy biomarkers of the luteoplacental phase: progesterone, estradiol and hCG. We merged data from two prospective first trimester cohorts to conduct a case-control study comparing these analytes in women who had either a live birth, a miscarriage or an ectopic pregnancy. The ability to predict pregnancy location and viability was assessed by areas under the receiver operating characteristic curves (AUC). Comparing women irrespective of gestational age with a live birth, miscarriage or ectopic pregnancy showed significantly lower suPAR values in the latter group (2.4 vs. 2.4 vs. 2.0 µg/L, p = 0.032, respectively), as were all other analytes. Before 6 weeks' gestation, suPAR was significantly inferior to progesterone, estradiol and hCG in pregnancy location and viability prediction (in 124 pregnancies, suPAR AUClocation = 0.69 [CI: 0.54-0.83] and AUCviability = 0.58 [CI: 0.48-0.69], while progesterone AUClocation = 0.95 [CI: 0.87-1.00] and AUCviability = 0.84 [CI: 0.75-0.92]). After 6 weeks' gestation, suPAR prediction improved but was inferior to hCG, progesterone and estradiol (in 188 pregnanices, suPAR AUClocation = 0.71 [CI: 0.63-0.78] and AUCviability = 0.70 [CI: 0.63-0.78] compared with hCG AUClocation = 0.96 [CI: 0.93-0.99] and AUCviability = 0.96 [CI: 0.93-0.98]). Collectively, suPAR is less useful as a predictor of early pregnancy outcome than hCG, progesterone and estradol.

Prediction of Preeclampsia in Nulliparous Women according to First Trimester Maternal Factors and Serum Markers.

OBJECTIVE: To evaluate the performance of maternal risk factors (BMI and mean arterial pressure [MAP]) and first-trimester maternal serum markers in the early prediction of preeclampsia (PE) in nulliparous women. MATERIAL AND METHODS: This was a case-cohort study based on a cohort of 14,207 nulliparous women. A total of 213 cases with term PE (from 37 weeks + 0 days) and 55 cases with preterm PE (before 37 weeks + 0 days) were identified and validated. Randomly, 449 controls were selected. Serum samples previously collected for the double test (pregnancy-associated plasma protein A [PAPP-A] and free ß human chorionic gonadotrophin [hCGß]) as part of the first-trimester screening program were retrieved and analyzed for placental growth factor (PlGF), soluble fms-like tyrosine kinase 1 (sFlt-1), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and neutrophil gelatinase-associated lipocalin (NGAL). Concentrations were transformed to multiples of the median (MoM). Multivariate regression analysis was used for prediction models. Receiver-operating characteristics (ROC) curves were used for evaluation of the screening performance. RESULTS: In preterm PE, the PlGF (0.79 MoM), sFlt-1 (0.86 MoM), NGAL (1.15 MoM), and PAPP-A (0.89 MoM) medians were significantly altered. In term PE, PlGF (0.90 MoM) and NT-proBNP (0.86 MoM) medians were significantly reduced. The combination of MAP and PlGF yielded a 39% detection rate of preterm PE for a 10% false-positive rate. The combination of MAP, BMI, and PlGF yielded a 33% detection rate of term PE with a 10% false-positive rate. CONCLUSION: First-trimester MAP, maternal serum PlGF, and NGAL are markers of preterm PE. Maternal serum sFlt-1 is a significant marker of preterm PE, but only early in the first trimester. First-trimester maternal serum NT-proBNP is not a predictor of PE. Screening performance for PE with these markers individually or in combination is modest.

Maternal serum laeverin (aminopeptidase Q) measured in the first trimester of pregnancy does not predict preeclampsia.

Objective: The aim of this study was to compare the laeverin level in maternal serum from first trimester (11-14 weeks) of pregnancy between normal pregnancies and pregnancies that later developed preeclampsia (PE). Material and methods: This was a case-cohort study. The laeverin concentration was measured in cases with preterm PE (n = 55), term PE (n = 95), and a reference group of randomly selected women with normal pregnancy outcome (n = 200) in stored serum samples collected from the double-test as part of the combined first trimester trisomy 21 screening program. The samples were thawed and analyzed for laeverin. The median gestational age at blood sampling was 77 days (range 57-96 days). Multiple regression analysis was performed to establish a normal median. Concentrations were converted to multiples of the median (MoM) and groups were compared using the Mann-Whitney U-test. Results: In the reference group, laeverin was significantly correlated with gestational age (r = 0.18, p = .01) and its concentration ranged from 41-393 µg/L. No significant differences in the median laeverin MoM were found between the reference group (1.01 MoM) and cases with preterm PE (0.98 MoM) or term PE (0.96 MoM). Conclusions: First trimester maternal serum laeverin level cannot be used to predict preeclampsia.

Serum anti-Müllerian hormone concentration before and after salpingectomy for ectopic pregnancy.

RESEARCH QUESTION: Does salpingectomy for ectopic pregnancy affect the ovarian reserve measured by changes in pre- and post-operative levels of anti-Müllerian hormone (AMH)? DESIGN: This is a prospective observational multicentre study of 64 women treated with salpingectomy for an ectopic pregnancy. AMH was measured in serum samples collected at admission before salpingectomy and at follow-up (median time to follow-up [interquartile range] was 3 [3-4] months). Changes in serum AMH levels were investigated using Wilcoxon signed-rank test and the relationship between changes in AMH and age, time to follow-up, and pre-operative serum AMH level was investigated using linear regression analysis. The biological variation of AMH was also calculated. RESULTS: Serum AMH levels did not differ significantly before and after salpingectomy (median ∆AMH [follow-up value minus admission value] 0.40 pmol/l, interquartile range -2.0 to 4.0 pmol/l). ΔAMH was independent of age, time to follow-up and pre-operative serum AMH level. The intra-individual biological variation for AMH ranged from 12.1% to 26.3%, depending on time between the two samples. CONCLUSIONS: This is the first paired study to investigate serum AMH values before and after salpingectomy in an unselected population of women presenting with an ectopic pregnancy, including both patients who conceived naturally and following fertility treatment. It was found that salpingectomy for ectopic pregnancy had no short-term effect on serum AMH levels, and changes in AMH levels were independent of age, time to follow-up, and pre-operative serum AMH level. Furthermore, the study demonstrated a 6-month biological variation of AMH of less than 30%.

Non-Invasive Prenatal Testing (NIPT) in pregnancies with trisomy 21, 18 and 13 performed in a public setting - factors of importance for correct interpretation of results.

OBJECTIVES: We have established an open source platform for non-invasive prenatal testing (NIPT) based on massively parallel whole-genome sequencing in a public setting. The objective of this study was to investigate factors of importance for correct interpretation of NIPT results to ensure a high sensitivity and specificity. STUDY DESIGN: This investigation is a retrospective case-control study performed in a public NIPT center. The study included 108 aneuploid cases and 165 euploid controls. MPS was performed on circulating cell-free DNA in maternal blood. The pipeline included automated library preparation and sequencing on a HiSeq1500 (Illumina). The software programmes WISECONDOR and SeqFF were used for data analysis of aneuploidy status and fetal fraction of cell-free DNA, respectively. Lower limit of fetal fraction for aneuploidy testing was 0.02. RESULTS: We identified four false negative aneuploidy cases of which two were explained by a vanishing twin. The number of no-call cases due to low fetal fraction was 8 out of 273 (2.9%). The sensitivity and specificity, when no-calls and vanished twins were excluded, were 100% and 99.5% for T21, 91% and 99.2% for T18, and 100% and 99.6% for T13. By multiple regression analysis we found a significant association between fetal fraction and gestational age, maternal BMI and ART treatment. CONCLUSION: With a non-commercial open source NIPT set-up having the same high test-performance as reported by large private laboratories, we show that fetal fraction, a vanishing twin, BMI, gestational age and ART treatment are important factors in the interpretation of NIPT results.

Comparison of two immunoassay systems for hCGß and PAPP-A in prenatal screening for trisomy 21, 18, and 13 in the first trimester.

OBJECTIVES: The biochemical serum markers free ß-human chorionic gonadotropin (hCGß) and pregnancy associated plasma protein A (PAPP-A), used in screening for trisomy 21 (T21), trisomy 18 (T18), and trisomy 13 (T13) during the first trimester, can be measured on different laboratory instruments e.g. Kryptor (Brahms) and Cobas (Roche). We compared the performance of these two analytical instruments when used for first trimester combined testing. DESIGN AND METHODS: Serum samples from 944 singleton pregnant women attending for first trimester combined testing were routinely assayed for hCGß and PAPP-A on Kryptor, and re-analyzed on Cobas. In addition, serum samples from 70 pregnant women carrying a fetus affected by T21, T18 or T13, were re-assayed on Cobas. RESULTS: For the screening population, the hCGß and PAPP-A results in multiples of the median (MoM) from Kryptor and Cobas were significantly lower on Cobas when compared to Kryptor. The number of pregnant women with a risk above 1:300 for T21 was 48 for both Cobas and Kryptor, although a few patients only had a high risk with one of the methods. Overall, the screen positive rate was 5.1% for both instruments. In the trisomy groups the calculated risks for T21, T18, and T13 agreed well between Cobas and Kryptor. CONCLUSIONS: The screen positive rate for T21 (5.1%) did not differ between the two analytical platforms in our screening population, although PAPP-A measurements form Cobas were significantly lower than those from Kryptor. The calculated risks for the pregnancies affected by trisomies using hCGß MoM and PAPP-A MoM from Kryptor agreed well with those from Cobas.

Discordant non-invasive prenatal testing (NIPT) - a systematic review.

With a high sensitivity and specificity, non-invasive prenatal testing (NIPT) is an incomparable screening test for fetal aneuploidy. However, the method is rather newly introduced, and experiences with discordant results are few. We did a systematic review of literature reporting details of false positive and false negative NIPT results. Discordant sex chromosome results were not included. We identified 22 studies reporting case details. In total, 206 discordant cases were included, of which 88% were false positive and 12% false negative. Details on maternal age, gestational age, platform/company, Z-score, fetal fraction, results and explanation were specified. The main reasons for discordant results were confined placental mosaicism, maternal copy number variation, vanished twin, maternal cancer and true fetal mosaicism. A very high percentage of cases (67%) were reported with no obvious biological or technical explanation for the discordant result. The included cases represent only a minor part of the true number of false positive or false negative NIPT cases identified in fetal medicine clinics around the world. To ensure knowledge exchange and transparency of NIPT between laboratories, we suggest a systematic recording of discordant NIPT results, as well as a quality assurance by external quality control and accreditation. © 2017 John Wiley & Sons, Ltd.

Affinity purification of native glycodelin from amniotic fluid for biological investigations and development of a glycodelin ELISA for clinical studies.

INTRODUCTION: Glycodelin is a glycoprotein with different oligosaccharides that are responsible for its diverse biological functions in contraception and immunosuppression. Therefore, it is necessary to have access to adequate amounts of glycodelin with retained carbohydrate structure for functional studies because the carbohydrate part can be lacking or be insufficient in recombinant glycodelin from prokaryotic and eukaryotic cell systems. METHODS AND RESULTS: Native glycodelin was purified from amniotic fluid by a series of affinity chromatography steps and had many glycosylated forms verified by mass spectrometry. About 7.5 mg glycodelin was obtained from 1.5 L amniotic fluid. No high molecular mass forms of glycodelin were found in amniotic fluid. Aliquots of the purified glycodelin were used as an immunogen in rabbits for antibody production against glycodelin and a calibrator in a highly sensitive glycodelin enzyme-linked immunosorbent assay (ELISA) with a detection limit of about 1 µg/L. CONCLUSIONS: Native glycodelin was purified from amniotic fluid and used as an immunogen for raising a rabbit antibody against glycodelin and a calibrator in a highly sensitive glycodelin ELISA. We found no high molecular mass forms of glycodelin in amniotic fluid. Aliquots of the purified glycodelin were set aside for functional studies which are in progress.

The maternal age-related first trimester risks for trisomy 21, 18 and 13 based on Danish first trimester data from 2005 to 2014.

OBJECTIVES: Most currently used age-related risks of T21, T18 and T13 are based on estimates of the live-birth prevalence, and describe an exponential increase of risk by increased maternal age. We investigated the first trimester prevalence of T21, T18 and T13 in a large population of Danish women. METHODS: From the Danish Cytogenetic Central Registry we got the information of all pre- and postnatally diagnosed fetuses with T21, T18 or T13 between 2005 and 2014 in Denmark. Information on the total number of births and maternal age at birth were gathered from StatBank Denmark. RESULTS: The total number of included women was 605 853. The total number of T21 cases was 1564, T18 cases was 401 and T13 cases was 157. The overall first trimester prevalence per 10 000 pregnancies was 25.8 for T21, 6.6 for T18 and 2.6 for T13. Boltzmann sigmoidal model (Y = Bottom + (top-bottom / (1 - exp (V50 - X) / slope)) was found to best describe the age-related risk of T21, T18 and T13. CONCLUSION: We found that the age-related risks are better described by sigmoidal functions, contrary to the widely assumed exponential functions. Our results indicate a lower age-related a priori risk of T21, T18 and T13 compared to widely used risk models. © 2016 John Wiley & Sons, Ltd.

Investigation on the ability of first trimester glycodelin and angiopoietin-2 to predict small-for-gestational age pregnancies at delivery.

BACKGROUND: The aim was to investigate whether first trimester glycodelin and angiopoietin-2 can predict small-for-gestational age (SGA) at delivery, individually or in combination. METHODS: In this case-control study we measured glycodelin and angiopoietin-2 on serum from 170 singleton pregnant women delivering SGA neonates and 985 singleton pregnant women delivering normal-weighted neonates. All values were converted to multiples of the medians (MoM). RESULTS: Pregnant women delivering SGA neonates had lower first trimester glycodelin and angiopoietin-2 MoM values [median (interquartile range)] compared with pregnant women delivering normal-weighted neonates for glycodelin: 0.86 (0.58-1.24) vs. 1.03 (0.74-1.45), p<0.001, and for angiopoietin-2: 0.89 (0.69-1.19) vs. 1.01 (0.78-1.31), p<0.001. The prediction performances of the biomarkers showed that the areas under the curve (AUC) were 0.59 (glycodelin), 0.58 (angiopoietin-2), and 0.60 (glycodelin and angiopoietin-2). CONCLUSIONS: We demonstrated that first trimester glycodelin and angiopoietin-2 were associated with SGA, but they were, individually and in combination, poor predictors of SGA at delivery. The AUCs were low which indicate low detection rates and high false positive rates.

First trimester PAPP-A2, PAPP-A and hCGß in small-for-gestational-age pregnancies.

BACKGROUND: Pregnancy-associated plasma protein-A2 (PAPP-A2) is a recently discovered protease that cleaves a subset of insulin-like growth factor binding proteins (IGFBP). The molecular function suggests its involvement in the IGF system that is vital for fetal growth and development. Our objectives were to establish first trimester median curves of PAPP-A2, PAPP-A and hCGß for singleton normal pregnancies and to investigate whether an altered level of one or more of the biomarkers is associated with small-for-gestational-age (SGA) neonates before and after stratification according to maternal hypertension and/or proteinuria. METHODS: This was a case-control study based on 985 pregnant women delivering normal-weighted neonates and 170 pregnant women delivering SGA neonates. PAPP-A2 was measured by ELISA. PAPP-A and hCGß were measured by an automatic analyzer. Median curves from 8+1 to 14+0 were established and all concentration values were converted to multiples of the median (MoM) values. RESULTS: Before stratification the SGA cases had unaffected PAPP-A2 MoM and hCGß MoM levels but lower PAPP-A MoM compared with normal controls. After stratification the SGA normotensive subgroup had lower PAPP-A2 MoM and PAPP-A MoM levels than the normal normotensive subgroup. Severe preeclamptic women delivering SGA neonates had higher PAPP-A2 MoM compared to the normotensive women delivering SGA neonates. CONCLUSIONS: Pregnant women delivering SGA neonates did not have altered levels of PAPP-A2 or hCGß but had lower PAPP-A level in the first trimester compared with pregnant women delivering normal-weighted neonates. Pregnancies complicated with severe preeclampsia and SGA may be associated with high PAPP-A2 level.

[Non-invasive prenatal testing is a breakthrough in prenatal screening]. / Noninvasiv prænatal test er et gennembrud inden for prænatal screening.

Non-invasive prenatal testing (NIPT) using cell-free fetal DNA from the peripheral blood of the pregnant woman has become a possibility within recent years, but is not yet implemented in Denmark. NIPT has proven to be very efficient in the screening for especially trisomi 21. This article summarizes the basics behinds the most used NIPT techniques and describes which genetic conditions this method may detect. Finally, the future aspects of implementing NIPT in the prenatal screening programme in Denmark are discussed.

Mining of hospital laboratory information systems: a model study defining age- and gender-specific reference intervals and trajectories for plasma creatinine in a pediatric population.

BACKGROUND: The knowledge of physiological fluctuation and variation of even commonly used biochemical quantities in extreme age groups and during development is sparse. This challenges the clinical interpretation and utility of laboratory tests in these age groups. To explore the utility of hospital laboratory data as a source of information, we analyzed enzymatic plasma creatinine as a model analyte in two large pediatric hospital samples. METHODS: Plasma creatinine measurements from 9700 children aged 0-18 years were obtained from hospital laboratory databases and partitioned into high-resolution gender- and age-groups. Normal probability plots were used to deduce parameters of the normal distributions from healthy creatinine values in the mixed hospital datasets. Furthermore, temporal trajectories were generated from repeated measurements to examine developmental patterns in periods of changing creatinine levels. RESULTS: Creatinine shows great age dependence from birth throughout childhood. We computed and replicated 95% reference intervals in narrow gender and age bins and showed them to be comparable to those determined in healthy population studies. We identified pronounced transitions in creatinine levels at different time points after birth and around the early teens, which challenges the establishment and usefulness of reference intervals in those age groups. CONCLUSIONS: The study documents that hospital laboratory data may inform on the developmental aspects of creatinine, on periods with pronounced heterogeneity and valid reference intervals. Furthermore, part of the heterogeneity in creatinine distribution is likely due to differences in biological and chronological age of children and should be considered when using age-specific reference intervals.

Recent progress in the utility of anti-Müllerian hormone in female infertility.

PURPOSE OF REVIEW: To discuss the recent developments in the utility of anti-Müllerian hormone (AMH) in the context of female infertility. RECENT FINDINGS: AMH measurements have entered the clinical practice in counseling of women before in-vitro fertilization (IVF) treatment. AMH measurements can predict both poor and hyperresponse, and can enable clinicians to individualize the treatment strategies. In natural conception, AMH is a good predictor of age at menopause, but it is unclear whether AMH correlates with the fecund ability in the normal population. AMH has also proven its utility in the assessment of ovarian damage due to gonadotoxic treatment or ovarian surgery. Lastly, AMH might assist in the initial diagnosis of oligomenorrhea or amenorrhea, as high levels of AMH are suggestive of polycystic ovarian syndrome and seem to correlate with the severity of the syndrome. SUMMARY: AMH is a glycoprotein secreted by the granulosa cells of small growing follicles and indirectly reflects the primordial follicle pool. The ovaries contain a limited number of primordial follicles and their depletion marks the menopause. Thus, the remaining primordial follicle pool is referred to as the ovarian reserve. The clearest data for the clinical utility of AMH is in the context of IVF. The support for other indications is weaker, but rapidly increasing.

Are there characteristics of the false-negative cases from the first trimester combined screening programme for Down syndrome?

PURPOSE OF REVIEW: To review if there are any characteristics of false-negative cases from the first trimester combined screening programme for Down syndrome and by that to stimulate new approaches for improvements of the screening performance. RECENT FINDINGS: We are aware of only two studies based on screening results of false-negative cases. Screening results from false-negative cases show that maternal age is lower, nuchal translucency smaller, pregnancy-associated plasma protein-A level higher, ß-human chorionic gonadotropin level lower and crown-rump length bigger than among true positive cases. Around 50% of false-negative cases had a final risk between 1 : 300 and 1 : 1000. There might also be a difference in maternal smoking status, conception method, ethnicity and weight discrepancy between false-negative and true positive cases. New biomarkers and secondary sonographic markers may also characterize false-negative cases, but investigations on these subjects have not been done so far. Finally, we think that the organization of a screening programme in all its details is a very important factor when it comes to optimizing screening performance. SUMMARY: Screening parameters of false-negative cases tend toward the values of unaffected pregnancies with lower maternal age, smaller nuchal translucency, higher pregnancy-associated plasma protein-A level, lower ß-human chorionic gonadotropin level and bigger crown-rump length than among true positive cases.