PAPP-A Levels Research Articles

Correlation of Pregnancy-Associated Plasma Protein (PAPP-A) in Serum and Follicular Fluid with Oocyte and Embryo Quality in PCOS and non-PCOS Women Undergoing ICSI Cycle

Pregnancy-Associated Plasma Protein (PAPP-A) is a zinc metalloproteinase in the insulin growth factor system (IGFs) produced by the syncytiotrophoplast region of the placenta. It plays a critical function in the cleavage of IGFBP4. In the ovary IGFs, it regulates follicular and oocyte maturation, and steroidogenesis. While in polycystic ovarian syndrome (PCOS) Hyperinsulinemia and hyperandrogenemia it causes follicular environment changes and early ovulation resulting in lower oocyte and embryo quality in patients and this will decrease the success of pregnancy in women enrolled in the ICSI cycle. The present study aimed to assess the relationship of PAPP-A levels in serum and follicular fluid in women with PCOS and non-PCOS with oocyte and embryo quality in women undergoing ICSI cycle. 45 infertile Iraqi women were enrolled. Women with PCOS had to meet at least two of the three criteria set by the Rotterdam ESHRE/ASRMS criteria, the age of the included women ranged between 20-45 years. In non-PCOS patients, PAPP-A has higher level in serum and follicular fluid but without a statistically significant difference matching with PCOS group. In addition, there was no significant correlation between PAPP-A levels in serum and follicular fluid with oocytes and embryo characteristics. However, PAPP-A levels are higher in serum and follicular fluid in women with positive pregnancy but without significant differences. PAPP-A had no correlation with oocyte and embryo quality.

Correlation of Pregnancy-Associated Plasma Protein (PAPP-A) in Serum and Follicular Fluid with Oocyte and Embryo Quality in PCOS and non-PCOS Women Undergoing ICSI Cycle

Pregnancy-Associated Plasma Protein (PAPP-A) is a zinc metalloproteinase in the insulin growth factor system (IGFs) produced by the syncytiotrophoplast region of the placenta. It plays a critical function in the cleavage of IGFBP4. In the ovary IGFs, it regulates follicular and oocyte maturation, and steroidogenesis. While in polycystic ovarian syndrome (PCOS) Hyperinsulinemia and hyperandrogenemia it causes follicular environment changes and early ovulation resulting in lower oocyte and embryo quality in patients and this will decrease the success of pregnancy in women enrolled in the ICSI cycle. The present study aimed to assess the relationship of PAPP-A levels in serum and follicular fluid in women with PCOS and non-PCOS with oocyte and embryo quality in women undergoing ICSI cycle. 45 infertile Iraqi women were enrolled. Women with PCOS had to meet at least two of the three criteria set by the Rotterdam ESHRE/ASRMS criteria, the age of the included women ranged between 20-45 years. In non-PCOS patients, PAPP-A has higher level in serum and follicular fluid but without a statistically significant difference matching with PCOS group. In addition, there was no significant correlation between PAPP-A levels in serum and follicular fluid with oocytes and embryo characteristics. However, PAPP-A levels are higher in serum and follicular fluid in women with positive pregnancy but without significant differences. PAPP-A had no correlation with oocyte and embryo quality.

VP28.07: Impact of confined placental mosaicism on outcome of pregnancy

To assess the incidence of confined placental mosaicism (CPM) on CVS and amniocentesis in our population and to study the impact of CPM on the outcome of pregnancies with a structurally normal fetus at mid trimester anomaly scan and the association of abnormal first trimester serum biochemistry with CPM. This is a single centre study where all pregnancies that had an invasive procedure ie CVS or amniocentesis before 20 weeks of gestation from January 2011 till December 2020 were considered. The study included pregnancies that had mosaic pattern on CVS or amniocentesis. The incidence of CPM on CVS and amniocentesis was calculated. Fetal ultrasound in all trimesters, maternal serum biochemistry in the first trimester, presence of fetal growth restriction (FGR) and postnatal outcome were obtained. During the study period, of the 2081 Amniocentesis procedures 1 (0.05%) had CPM with tetraploidy mosaic confirmed by postnatal karyotype with normal outcome. Of 1144 CVS procedures performed 10/1144 (0.9%) were detected to have a mosaic pattern. 5/10 mosaic pattern obtained in pregnancies with fetal structural abnormalities were terminated before amniocentesis could be performed. 5/10 (0.44%) had structurally normal fetuses and hence Amniocentesis could be performed to confirm CPM. Of the four where first trimester serum biochemistry was available, three (75%) cases had low maternal serum PAPP-A (< 0.3). 2 of 5 cases had Trisomy 18, one had Trisomy 16 and one had Trisomy 21 mosaic pattern, all of which had normal antenatal and postnatal outcomes. 1/5 pregnancies had Trisomy 16 mosaic pattern which was found to have severe early onset FGR at 18 weeks and was terminated. Hence, 1/5 pregnancies with CPM had poor fetal outcome. The incidence of CPM in our study was about 0.44% on CVS and that on amniocentesis 0.05%. FGR was the only antenatal complication. We did not observe any maternal complications. Low maternal serum PAPP-A levels may indicate a higher possibility of obtaining a mosaic pattern on a CVS.

Hypertensive disorders in twin pregnancy

Hypertensive disorders such as gestational hypertension, preeclampsia, eclampsia and HELLP syndrome are one of the most common pregnancy-associated entities that imply substantial maternal-fetal mortality and morbidity. When hypertensive disorders are associated with a multiple pregnancy, the outset is established sooner, with a rapid evolution and a more severe development. Although, the pathophysiology of hypertensive disorders is not fully understood, there are several risk factors that could be identified. A multiple pregnancy implies additional risks due to specific features: larger or multiple placentas, failure of the uteroplacental unit to uphold the natural development of multiple fetuses or elevated risk of abnormal placental site. Hypertensive disorders include complications that are common for both single and multiple pregnancies, complications such as kidney failure, liver dysfunction, neurological or hematological malfunction, among others. Maternal features, including mean arterial blood pressure, uterine artery pulsatility index and blood levels of PAPP-A and/or PlGF could be determined at an early age and used as screening methods.

Association between low first trimester maternal serum PAPP-A levels and presence of unilateral or bilateral uterine artery diastolic notches

Objective Uterine artery impedance is known to have an effect on first trimester aneuploidy screening biomarkers. In this study we aim to compare first trimester screening parameters in women with and without uterine artery diastolic notches. Methods This retrospective case control study was conducted in a single tertiary center by obtaining medical records of women that admitted for first trimester pregnancy follow-up. Singleton pregnancies without structural anomalies, chromosomal anomalies and obstetric complications were included in the study. 268 women with first trimester unilateral uterine artery diastolic notches are constituted study group 1, 149 women with bilateral uterine artery diastolic notches constituted study group 2. 200 women were randomly selected as control group. Results Significantly decreased PAPP-A levels were found in both study groups. PAPP-A levels were even lower in women with bilateral notches in comparison to unilateral notches. Fetal birth weights and gestational ages at birth were also found significantly lower in study groups. Beta human chorionic gonadotropin levels and nuchal translucency measurements were found similar. Prevalence of false positive first trimester aneuploidy screening test results were significantly higher in women with bilateral uterine artery diastolic notches. Conclusion Presence of first trimester uterine artery diastolic notches, particularly the presence of bilateral diastolic notches, is related with decreased PAPP-A levels in first trimester aneuploidy screening and lead to higher false positive rates in first trimester aneuploidy screening and consequently more unnecessary invasive procedures.

Abstract 749: Plasma insulin-like growth factor 1-related biomarkers and risk of lethal prostate cancer

Abstract Background Experimental and epidemiologic evidence supports the role of plasma IGF-1 and risk of prostate cancer. About 5% of IGF-1 circulates in a free or bioavailable form, and is only weakly correlated with total IGF-1; we hypothesized that higher levels of free IGF-1 would be associated with risk of lethal prostate cancer. Methods Lethal prostate cancer was defined as fatal prostate cancer plus metastatic prostate cancer. Non-lethal prostate cancer was defined as cases in which the men remained free of known metastases for at least eight years. Using prospectively collected samples in a nested design, we identified 434 lethal cases and 524 men with non-lethal prostate cancer in two prospective cohorts: the Physicians' Health Study (mean years of follow-up 33.2) and the Health Professionals Follow-up Study (mean years of follow-up 18.5). Circulating levels in prediagnostic plasma samples were assayed for IGF-1-related biomarkers, including free and total IGF-1, acid labile subunit (ALS), pregnancy-associated plasma protein A (PAPP-A, a protease that cleaves the IGF complex), intact IGF binding protein 4 (IGFBP-4), and total IGFBP-4, with risk of lethal prostate cancer. We estimated odds ratios (ORs) and corresponding 95% confidence intervals (CI) for the associations between IGF-1-related biomarkers (in quartiles) and lethal prostate cancer using unconditional logistic regression models adjusted for age, height, weight, and body mass index. Subgroup analyses were conducted by time from blood draw to diagnosis, and tumor biomarkers, ERG as a marker of the TMPRSS2:ERG fusion, phosphatase and tensin homolog (PTEN) loss, and IGF-1 receptor (IGF1R) protein expression. Results We observed no significant association between free IGF-1 and lethal prostate cancer (pooled adjusted OR for the highest versus lowest group 0.93, 95% CI 0.64 to 1.35) after adjusting for potential covariates. However, men in the highest quartile of PAPP-A levels had 43% higher odds of developing lethal prostate cancer (pooled adjusted OR 1.43, 95% CI 1.05 to 1.95) compared to men in the lowest three quartiles. The positive association between PAPP-A and lethal prostate cancer was present among men without PTEN loss, but not among those with (P for interaction = 0.002). There were no significant differences across the two cohorts (P for heterogeneity &amp;gt; 0.05 for all) and no significant associations were observed between other plasma biomarkers and lethal prostate cancer. Conclusions We found no significant association between free IGF-1 and lethal prostate cancer, but provide suggestive evidence that higher PAPP-A levels are associated with an increased risk of developing lethal prostate cancer. This observation merits testing in other cohorts. Citation Format: Chaoran Ma, Ye Wang, Lorelei A. Mucci, Meir J. Stampfer, Michael Pollak, Kathryn L. Penney. Plasma insulin-like growth factor 1-related biomarkers and risk of lethal prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 749.

Use of FMF algorithm for prediction of preeclampsia in high risk pregnancies: a single center longitudinal study

ABSTRACT OBJECTIVE: This study aimed to assess the accuracy of The Fetal Medicine Foundation (FMF) screening algorithm for the prediction of preeclampsia. METHODS: Out of 138 women with high-risk pregnancies prospectively followed, 30 developed preeclampsia. The clinical examination and biochemical measurements were performed at first, second, early and late third trimester. RESULTS: A lower PAPP-A levels were found in the first trimester, while sFlt/PlGF was increased in the second and early third trimester in preeclampsia (p>0.05). FMF algorithm presented higher specificity (>70%), but had a drawback of lower sensitivity (35–77%). CONCLUSION: FMF algorithm had modest performance in the prediction of preeclampsia for high-risk pregnancies.

Impact of preimplantation genetic testing for aneuploidies (PGT-A) on first trimester biochemical markers – PAPP-A (placenta-associated plasma protein) and free β-hCG (human chorionic gonadotropin)

Objective The objective of the study was to study the effect of preimplantation genetic testing for aneuploidies (PGT-A) performed at blastocyst stage on the levels of first trimester biomarkers. Methods This is an observational, collaborative, retrospective study. Seven hundred and twenty-eight patients were included in the study. Patients were with singleton pregnancies resulting from either natural conception (NC), or assisted reproductive techniques (ARTs) with PGT-A and frozen embryo transfer (FET) (ART/PGT-A/FET) or after ART without PGT-A and fresh ET (ART/no PGT-A/fresh ET) or FET (ART/no PGT-A/FET), who had first trimester combined screening test between 11 and 14 gestational weeks. They were stratified into four groups: group A (ART/PGT-A/FET) – 143 patients; group B (ART/no PGT-A/FET) – 100 patients; group C (ART/no PGT-A/fresh ET) – 346 patients, and group D (NC) – 139 patients. Results Statistically significant differences among the examined groups were observed for maternal age, BMI, ethnicity, and parity. The median placenta-associated plasma protein (PAPP-A) was lowest in the group with ART/PGT-A/FET and the highest result was obtained in the group with ART/no PGT-A/FET. Statistically significant difference in the median PAPP-A levels was identified among the examined groups (p = .0186). When a subgroup analysis was performed, a statistically significant difference was observed in the median PAPP-A between ART/PGT-A/FET group versus ART/no PGT-A/FET group (p = .01) and NC versus ART/no PGT-A/FET (p = .01). A similar trend toward statistical significance was noted when comparing NC versus ART/no PGT-A/fresh ET (p = .06). Multivariate analysis elucidated that when age is present in the model, the effect of any method of conception or testing for aneuploidy disappears. The other factors (BMI, ethnicity, and parity) do not influence the levels of PAPP-A. The lowest median free human chorionic gonadotropin (β-HCG) was recorded in the NC group and the highest result was identified in the group with IVF/PGT-A/FET. No statistically significant difference was observed in the median concentration levels of free β-hCG among the compared groups (p = .5789) and when subgroup analysis was performed (p>.05). The normality of the distribution of variables was analyzed by the Kolmogorov–Smirnov test and the median PAPP-A and free βhCG concentration difference by the Wilcoxon rank-sum test with nonparametric ANOVA. Conclusions Testing for aneuploidy (PGT-A) and the decision to transfer either fresh or cryopreserved embryos (ET) appear not to affect the levels of first trimester biochemical markers. The findings of the present study should be a baseline for future studies and could be used to improve the antenatal screening counseling for women with ART pregnancies and PGT-A.

Comparison of First-Trimester Screening Biomarkers in Spontaneous (Natural) and In Vitro Fertilization Pregnancies

Objectives: The present study was designed to evaluate and compare the screening markers of spontaneous and in vitro fertilization (IVF) pregnancies in individuals who underwent combined screening in the first trimester of pregnancy. Materials and Methods: In this retrospective study, we examined the difference between natural and assisted-reproductive technology (ART) pregnancies in 2252 mothers from January 2011 to October 2019. In both groups, the first trimester screening parameters including NT, free beta-human chorionic gonadotropin (β-hCG), and PAPP-A were measured. Results: According to the results of the present study, BMI was higher in the group that became pregnant by IVF compared to the normal pregnancy group (P&lt;0.001). Additionally, in patients using IVF, the history of maternal disease was less frequent compared to the other group (P=0.003). Most cases of twin fetuses, dichorionic twin pregnancy, and fetal abnormality were seen in the IVF group. Although the β-hCG and free PAPP-A levels were high in the IVF group, no significant difference was observed. The group with spontaneous pregnancy had a higher penetration rate of nuchal translucency &lt;95th percentile compared to the IVF group (P&lt;0.001). The results of comparing the first trimester test showed that in the IVF group, 81.3% of patients were at low risk and 6.6% were at high risk, while in the normal pregnancy group, 78.9% of patients were at low risk and 7.0% of them were at low risk, indicating that the difference was not significant. Conclusions: Overall, although the risk of aneuploidy in IVF pregnancies was not higher compared to normal pregnancies, in IVF pregnancies, NI is associated with a high risk of fetal abnormalities. Therefore, NT sonography can help to diagnose fetal anomalies especially aneuploidy

Ultrasound placental image texture analysis using artificial intelligence to predict hypertension in pregnancy

Background The placental pathological changes in hypertensive disorders of pregnancy (HDP) starts early in pregnancy, the deep convolutional neural networks (CNN) can identify these changes before its clinical manifestation. Objective To compare the placental quantitative ultrasound image texture of women with HDP to those with the normal outcome. Methods The cases were enrolled in the first trimester of pregnancy, good quality images of the placenta were taken serially in the first, second, and third trimester of pregnancy. The women were followed till delivery, those with normal outcomes were controls, and those with HDP were cases. The images were processed and classified using validated deep learning tools. Results Total of 429 cases were fully followed till delivery, 58 of them had HDP (13.5%). In the first trimester, there was a significant difference in the placental length (p = .033), uterine artery PI (p = .019), biomarkers PAPP-A (p = .001) PlGF (p = .013) and placental image texture (p = .001) between the cases and controls. In the second trimester the uterine artery PI, serum PAPP-A (p = .010) and PlGF (p = .005) levels were significantly low among women who developed hypertension later on pregnancy. The image texture disparity between the two groups was highly significant (p < .001). The model “resnext 101_32x8d” had Cohen kappa score of 0.413 (moderate) and the accuracy score of 0.710 (good). In the first trimester the best sensitivity and specificity was observed for abnormal placental image texture (70.6% and 76.6%, respectively) followed by PlGF (64% and 50%, respectively), in the second trimester the abnormal image texture had the highest sensitivity and specificity (60.4% and 73.3%, respectively) followed by uterine artery PI (58.6% and 54.7%, respectively). Similarly in the third trimester, uterine artery PI had sensitivity and specificity of 60.3% and specificity of 50.7%, whereas the abnormal image texture had sensitivity and specificity of 83.5%. Conclusion Ultrasound placental analysis using artificial intelligence (UPAAI) is a promising technique, would open avenues for more research in this field.

First trimester combined screening test for aneuploidies in anti-Ro carriers pregnant women.

Anti-Ro/SSA and anti-La/SSB antibodies are associated with neonatal lupus and congenital heart block. Controversial results regarding perinatal outcomes are found and less is known about aneuploidy screening. The hypothesis is that the presence of anti-Ro and/or anti-La antibodies influences the levels of PAPP-A and ß-HCG, thus interfering in the calculation of risk of aneuploidies. Fifty-five anti-Ro/SSA positive pregnant women were included. The demographic characteristics and laboratory variables were studied. Data concerning chromosomopaties screening were also recorded. PAPP-A and β-HCG levels were calculated (as well as NT and CRL) and compared with a healthy cohort of 12971 pregnant women. PAPP-A levels in mg/mL were lower significatively. In anti-La/SS-B cohort, significant differences were found in PAPP-A in mg/mL and in MoM. Combined risks for Down syndrome (DS) in both groups were higher but the differences were due to age. Serum levels of PAPP-A were significative lower but not confirmed when adjusted to MoM. This will have to be confirmed in studies with a larger number of patients and to check whether there is an impact in the calculation of DS risk or not. They could represent a group of pregnant women with significantly a higher risk of adverse perinatal outcome. Key Points • Pregnant patients with anti-Ro/SS-A ant/or anti-La/SS-B antibodies have low PAPP-A levels compared with pregnant women without antibodies. • PAPP-A levels are used in obstetrics for aneuploidies screening in the first trimester, so in these patients, there could be more false positive screening. • In these findings are verified in trials with a larger number of patients, a correction variable would have to be applied for the aneuploidies screening calculation. • Also, low PAPP-A levels are correlated with poor placentation, that is to say, more risk of miscarriages, small fetus for gestational age, and preeclampsia. This is another topic to take into consideration in this population.

250 The role of low PAPP-A in assessing hypertension outcomes for maternal risk stratification

When below the 5th%, PAPP-A, a component of the first trimester aneuploidy screen (FTS), has been correlated with several adverse pregnancy outcomes, including pregnancy-related HTN. With cell free DNA testing (NIPT) now recommended for genetic screening rather than FTS, yet HTN remaining a leading cause of adverse outcomes, we sought to evaluate the relevance of PAPP-A as a biomarker for HTN related complications in pregnancy. This was a single-center retrospective cohort study with a primary outcome of interest defined as a composite of pregnancy-related HTN with/without chronic HTN in those with/without low PAPP-A on FTS. The study was powered to detect a 20% difference between groups, with review of 2450 consecutive women who had an FTS and delivered at our tertiary-level facility from 2011-2017. A cohort of 140 patients were identified with low PAPP-A (>5th% serving as controls). Chart review was conducted for multiple maternal and neonatal outcomes. Comparisons between groups were made for multiple outcomes. Analysis performed using SPSS & SAS. Of 2450 women, 267 (10.90%) met criteria for the composite hypertension (CH) outcome. Of these 267 patients, 39 (14.61%) had low PAPP-A. There was a statistically significant (P<0.01) association with low PAPP-A and risk of CH (OR 3.53 95% CI 2.38-5.23). An ROC curve was generated to determine the optimal PAPP-A percentile cut point for discriminating the CH outcome (Figure 1). The optimal cut point for dichotomizing the PAPP-A percentile predictor in order to discriminate the composite hypertension outcome was determined to be 30.00. In a subsequent adjusted analysis this result remained statistically significant (p <0.01, OR 2.65 95% CI 1.67-4.21). In this adjusted analysis, a low PAPP-A level was identified to be an independent risk factor for the defined CH outcome. Our findings highlight that even in the setting of NIPT being used primarily for aneuploidy screening, PAPP-A evaluation should be further studied and considered as an adjunct to NIPT to aid in maternal risk stratification.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

387 Hypoglycemia on oral glucose tolerance test during pregnancy and risk for the small neonate

Hypoglycemia in oral glucose tolerance test (OGTT) may indicate maternal hyperinsulinemia and abnormal glucose metabolism . We aimed to evaluate maternal characteristics and neonatal birthweight in pregnancies with hypoglycemia on 100 grams OGTT. A retrospective cohort analysis of all live-born deliveries in one medical center in 2018-2019 with available OGTT results and birth outcomes. Preterm deliveries (<34 weeks), multiple pregnancies and major anomalies were excluded. Hypoglycemia was defined as at least one glucose value lower than 60 mg/dl. Maternal characteristics and perinatal outcomes were compared between 3 groups: Hypoglycemia on OGTT, Normal OGTT and abnormal OGTT, defined as at least one abnormal value according to Carpenter & Coustan thresholds. Parturient with abnormal OGTT and any hypoglycemic value were considered in the abnormal GTT group. Univariate followed by multivariate analysis was utilized to control for confounders. Overall, 2,079 met inclusion criteria and entered analysis. Cohort included 216(10.4%) OGTT's with at least one hypoglycemic value, 1,072(51.6%) normal OGTT's and 719(34.6%) abnormal OGTT's (Fig1-Average values). In over 90% (198/216) of cases, hypoglycemic values appeared 3H following sugar load. Rates of nulliparity were lowest in the hypoglycemia group despite similar maternal age as the normoglycemic. hypoglycemia was associated with fetal male gender and abnormal OGTT was associated with lower PAPP-A levels. Absolute birthweight, low birth weight and small for gestational age differed between groups, however, there was no difference between groups in birth weight percentiles (60.1±26.8 vs. 63±26 vs. 60.9±27, p>0.05, local sex-specific curves). Also, following adjustment to confounders (maternal age, BMI, nulliparity, any hypertensive disorder) hypoglycemia did not appear to affect rates of low birth weight or small for gestational age (p<0.05). There were no other differences in birth outcomes between groups. According to our study, hypoglycemia in OGTT is not associated with maternal or neonatal adverse outcomes.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

IGFBP-4: A promising biomarker for lung cancer.

Background: Insulin-like growth factor binding protein-4 (IGFBP-4), a member of the insulin-like growth factor (IGF) family, transports, and regulates the activity of IGFs. The pregnancy-associated plasma protein-A (PAPP-A) has proteolytic activity towards IGFBP-4, and both proteins have been associated with a variety of cancers, including lung cancer. Thus, we aimed to evaluate the use of IGFBP-4 and PAPP-A as potential biomarkers for lung cancer. Methods: Eighty-three volunteers, including 60 patients with lung cancer and 23 healthy individuals, were included in this study. The patients with lung cancer were selected based on their treatment status, histological subgroup, and stage of the disease. Enzyme-linked immunosorbent assays were used to assess the serum levels of IGFBP-4 and PAPPA, whereas the IGF-1 levels were measured using a chemiluminescent immunometric assay. Results: The serum IGFBP-4 levels in all patient groups, regardless of the treatment status and histological differences, were significantly higher than those in the control group (p<0.005). However, the serum PAPP-A levels in the untreated patient group were found to be higher than those in the control group, but this difference was not statistically significant (p=0.086). Conclusions: The serum PAPP-A and IGFBP-4 levels are elevated in lung cancer. However, IGFBP-4 may have better potential than PAPP-A as a lung cancer biomarker.

Prediction of Adverse Obstetric Outcomes by First Trimester Screening with Free β-hCG and PAPP-A: A Prospective Study of 889 Singleton Pregnancies

Aim: We aimed to analyze the association of first-trimester screening biomarkers (PAPP-A and free β-hCG) that correspond specific percentile with adverse pregnancy outcomes, including preterm labor, preterm delivery, gestational diabetes mellitus (GDM), gestational hypertension, preeclampsia, low birth weight (LBW), small for gestational age (SGA), large for gestational age (LGA), intrauterine growth restriction (IUGR), macrosomia, and intrauterine exitus (IUEX). Materials and Method: This prospective study conducted between 1st May 2011 and 1st May 2012 at Gazi University Faculty of Medicine, Turkey. We recruited only singleton pregnancies. The first-trimester screening test was performed between 11-14 weeks of gestation. Results: Eight hundred eighty-nine of them met the inclusion criteria for our study. The median age was 29 (26-33) years. Median free β-hCG MoM and PAPP-A MoM were 1.0 (0.7 - 1.48) and 1.04 (0.73 - 1.46), respectively. The most common adverse obstetric outcomes were preterm labor 164 (18.4%), threatened abortion 95 (10.7%), and GDM 75 (8.4%). There was a linear trend with PAPP-A MoM and SGA, LBW, preterm delivery (p=&amp;lt;0.0000001, 0.033, and 0.03, respectively). When PAPP-A MoM results were categorized under three groups as ≤0.42 (5th percentile), &amp;gt;2.5 (95th percentile), and 0.73-1.47 (25th -75th), a significant difference between there groups were detected for SGA (&amp;lt;0.0000001), LBW (0.01), IUEX (0.00005), preterm labor (0.002), IUGR (0.006). Only preterm labor showed a significant linear trend for β-hCG MoM values (p =0.007). However, this significance was not detected when β-hCG MoM values were categorized as ≤0.40 (5th percentile), &amp;gt;2.9 (95th percentile), and 0.75-1.49 (25th -75th) (p=0.47). The correlation coefficient of birth weight and PAPP-A MoM was 0.133, which is negligible (p=0.0001). Conclusion: Our study suggested the possibility of predicting the women with the risk of adverse obstetric outcomes by using first-trimester screening biomarkers, namely maternal free β-hCG, and PAPP-A levels.

Гормональний моніторинг функції жовтого тіла, трофобласта і плаценти при одноплідній вагітності в жінок із різними видами безплідності в анамнезі

Purpose — to investigate hormonal monitoring of the function of the corpus luteum, trophoblast and placenta in pregnant women with a history of various types of infertility. Materials and methods. We have studied hormonal parameters from 8 to 14 weeks of pregnancy in 420 women. The study of hormonal parameters was carried out in three groups (six subgroups): Group I — pregnant women with a history of endocrine infertility: Ia — 50 patients after IVF, Ib — 50 patients who became pregnant on their own after conservative and surgical treatment of infertility, but without IVF; Group II — pregnant women with a history of inflammatory infertility: IIa — 100 patients after IVF, IIb — 100 patients who became pregnant independently after conservative and surgical treatment of inflammatory infertility, but without IVF; Group III — pregnant women with a history of combined infertility, inflammatory genesis with endocrine, IIIa — 30 patients after IVF, IIIb — 30 patients who became pregnant on their own after conservative and surgical treatment of combined infertility, but without IVF. A study of the content of placental hormones in the dynamics of pregnancy at 7–10 and 11–14 weeks was carried out: estradiol (E2), progesterone, human chorionic gonadotropin (β-hCG) and pregnancy-associated plasmoprotein (PAPP-A). Determination of E2, progesterone was carried out by the enzyme-linked immunosorbent assay using standard kits of the Delfia system on a 1420 Victor 2 analyzer from Perken Elmer (USA). β-hCG and PAPP-A were determined by the immunochemiluminescent method using test systems manufactured by Siemens. Results. We carried out hormonal monitoring of the corpus luteum and trophoblast function and analyzed the results of fetal biochemical markers in 276 pregnant women. The data obtained indicate that in the period of 7–10 weeks of pregnancy, the concentration of progesterone was significantly higher in women after IVF relative to the indicators of patients with natural conception. At this stage of pregnancy, the level of progesterone did not depend on the form of infertility. Similar changes were observed with respect to estradiol levels. So the level of estradiol in pregnant women of 7–10 weeks during natural pregnancy was ≈5.0 nmol/L, while the same level of estradiol in pregnant women with one fetus after IVF was 8.4±1.1 nmol/L. The progesterone/estradiol ratio was virtually the same across the groups. The level of estradiol and progesterone in the blood of women at 11–14 weeks of gestation also practically did not differ, and did not depend on the form of infertility and the method of conception. It should be especially noted that at 11–14 weeks there was a decrease in the progesterone/estradiol ratio, which represents a progressive pronounced relative progesterone deficiency and hyperestrogenism in women with infertility. The indicators were especially low in pregnant women of groups I and III, who had endocrine and combined infertility in the anamnesis. We also investigated the indicators of β-hCG and PAPP-A in pregnant women 11–14 weeks. by groups, as classic markers of screening for congenital malformations of the fetus and the risk of complications of pregnancy. So the level of PAPP-A in pregnant women did not significantly differ in groups, both from the method of conception and the type of infertility in the anamnesis. The level of β-hCG in pregnant women 11–14 weeks of singleton pregnancy after IVF is significantly higher than in women with natural conception. The highest rates were in the group after combined infertility. Conclusions. The level of hormones: estradiol and progesterone in pregnant women after IVF at 7–10 weeks was higher than in women with a history of infertility during natural conception. Already at 11–14 weeks, the same indicators in the same groups did not differ. After natural conception, the rate of increase in estradiol significantly outpaced the increase in progesterone levels in pregnant women with a history of infertility. The concentration of PAPP-A in the first trimester in pregnant women after IVF did not significantly differ from those in women with natural conception. The content of β-hCG at 11–14 weeks in groups of pregnant women after IVF was 1.5–2 times higher. The highest rates were in pregnant women with a history of concomitant infertility. The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of these Institutes. The informed consent of the patient was obtained for conducting the studies. No conflict of interest was declared by the authors. Key words: estradiol, progesterone, β-hCG, PAPP-A, pregnancy after infertility.

Association between blastocyst morphology and maternal first trimester serum markers in ongoing pregnancies obtained after single fresh blastocyst transfer

ObjectiveIs there an association between blastocyst morphology and maternal first trimester serum markers in In Vitro Fertilization (IVF) pregnancies obtained after fresh single blastocyst transfer? Study designThis bi-centric retrospective study was conducted between January 2012 and August 2018. We included 122 women aged from 18 to 43 years-old, whose pregnancy progressed at least beyond 13 weeks after a single blastocyst transfer and who participated in the first trimester combined screening test. Day 5 and day 6 blastocysts were evaluated according to Gardner and Schoolcraft classification. Patients were classified into three groups according to blastocysts morphological quality: excellent (≥ 3AA), good (3-6AB, 3-6BA, B2), and medium to poor (3-6BB, 3-6AC, 3-6CA, B1, 3-6CB, 3-6BC). First trimester serum markers were measured in maternal blood between 9 and 11 + 6 gestational weeks. Univariate and multivariate analyses were performed. ResultsFemale body mass index, smoking status, type of infertility, geographical origin, anti-mullerian hormone level, ovarian stimulation characteristics, pregnancy outcomes and obstetrical complications were comparable between the three groups. Patient’s age was not distributed evenly across groups, with women in group “Medium to Poor” appearing to be slightly younger than in other groups. There were no significant differences in mean first trimester serum markers between the three groups (PAPP-A: excellent: 1.23 ± 0.59 MoM; good: 1.45 ± 0.71 MoM; medium to poor: 1.22 ± 0.52 MoM; p = 0,20; free beta-HCG: excellent: 1.66 ± 1.38 MoM; good: 1.19 ± 0.76 MoM; medium to poor: 1.81 ± 1.34 MoM; p = 0,12). No significant difference was found either between mean first trimester serum markers and inner cell mass morphology (PAPP-A: grade A: 1.23 ± 0.58 MoM; grade B: 1.26 ± 0.60 MoM; medium to poor: 1.64 ± 0.87 MoM; p = 0,67 ; free beta-HCG: grade A: 1.66 ± 1.36 MoM; grade B: 1.52 ± 1.10 MoM; medium to poor: 1.57 ± 0.39 MoM p = 0,60), trophectoderm cells morphology (PAPP-A: grade A: 1.25 ± 0.63 MoM; grade B: 1.26 ± 0.51 MoM; medium to poor: not comparable; p = 0,66; free beta-HCG: grade A: 1.60 ± 1.34 MoM; grade B: 1.69 ± 1.14 MoM; medium to poor: not comparable; p = 0,25), or blastocoel expansion (PAPP-A: B1: 1.08 ± 0.51MoM; B2: 1.57 ± 0.70 MoM; B3: 1.26 ± 0.61 MoM; B4: 1.28 ± 0.62 MoM; B5: 1.04 ± 0.38 MoM; p = 0,22; free beta-HCG: B1: 2.01 ± 1.88 MoM; B2: 1.07 ± 0.49 MoM; B3: 1.43 ± 0.87 MoM; B4: 1.68 ± 1.28 MoM ; B5: 1.82 ± 2.03 MoM; p = 0,48).After adjustment on potential confounding factors (female age, type of gonadotropin, parity, number of oocytes retrieved and occurrence of ovarian hyperstimulation syndrome), we did not observe any association between PAPP-A or free beta-HCG levels and blastocyst morphology. ConclusionOur study concluded that first trimester serum markers were not associated with blastocyst morphological characteristics. Although this needs further confirmation, this suggests that blastocyst morphology would not have an impact on placentation. Therefore, these findings are reassuring for couples undergoing IVF and blastocyst transfer.

Evaluation of indications for amniocentesis in cases of normal fetal ultrasound results.

The objective of this study was to analyze indications for amniocentesis in cases of patients with normal fetal ultrasound results between 11+0 and 13+6 weeks of gestation. The results of first-trimester screening tests performed between 2014 and 2018 on 6,863 patients of the Prenatal Testing Outpatient Clinic at the Clinical Department of Obstetrics and Gynecology, Pomeranian Medical University, Szczecin, Poland, were analyzed. The inclusion criteria were a singleton pregnancy and normal results of fetal ultrasound between 11+0- and 13+6-weeks' gestation. Depending on the calculated risk of fetal trisomy 21, the patients were divided into three groups (group A = RS > 1:300, group B = RS 1:300 - 1:999, group C = RS ≤ 1:1000). Subsequently, values such as PAPP-A and fβ-hCG protein levels and maternal age were analyzed for each of the groups. The patients, 6,310 (91.94%) met the inclusion criteria. A high risk of fetal trisomy 21 was identified for 514 women (8.15%). Group B had 733 (11.62%) and group C 5,063 (80.23%) patients. In group A, an fβ-hCG level of ≥ 2.000 MoM was shown for 50.97% of the women. A PAPP-A level ranging from 0.001 to 0.499 MoM was observed for 38.72% of group A patients. The mean maternal age in groups A, B and C was 36.45, 36.08 and 31.64 years, respectively. In the first-trimester, patients with normal ultrasound results obtained during prenatal screening tests, the main cause of an increased risk of trisomy 21 was elevated PAPP-A and fβ-hCG concentrations. According to this paper's authors, in these cases extension of diagnosis to include other gestational complications, e.g. preeclampsia, should be considered.

Impact of Long-Term HFD Intake on the Peripheral and Central IGF System in Male and Female Mice.

The insulin-like growth factor (IGF) system is responsible for growth, but also affects metabolism and brain function throughout life. New IGF family members (i.e., pappalysins and stanniocalcins) control the availability/activity of IGFs and are implicated in growth. However, how diet and obesity modify this system has been poorly studied. We explored how intake of a high-fat diet (HFD) or commercial control diet (CCD) affects the IGF system in the circulation, visceral adipose tissue (VAT) and hypothalamus. Male and female C57/BL6J mice received HFD (60% fat, 5.1 kcal/g), CCD (10% fat, 3.7 kcal/g) or chow (3.1 % fat, 3.4 kcal/g) for 8 weeks. After 7 weeks of HFD intake, males had decreased glucose tolerance (p < 0.01) and at sacrifice increased plasma insulin (p < 0.05) and leptin (p < 0.01). Circulating free IGF1 (p < 0.001), total IGF1 (p < 0.001), IGF2 (p < 0.05) and IGFBP3 (p < 0.01) were higher after HFD in both sexes, with CCD increasing IGFBP2 in males (p < 0.001). In VAT, HFD reduced mRNA levels of IGF2 (p < 0.05), PAPP-A (p < 0.001) and stanniocalcin (STC)-1 (p < 0.001) in males. HFD increased hypothalamic IGF1 (p < 0.01), IGF2 (p < 0.05) and IGFBP5 (p < 0.01) mRNA levels, with these changes more apparent in females. Our results show that diet-induced changes in the IGF system are tissue-, sex- and diet-dependent.

The association between first trimester placental biomarkers and placental lesions of maternal vascular malperfusion

IntroductionAbnormal levels of first trimester placental biomarkers are associated with the development of placental syndrome (PS). However, prediction performance is moderate, possibly explained by the clinical heterogeneity of PS. Aim of this study is to investigate the association between first trimester biomarkers and the presence of maternal vascular malperfusion (MVM), as a marker for placental insufficiency. MethodsThis retrospective study included 195 women with available first trimester blood sample and placenta histological sections for examination at the Maastricht University Medical Centre. Women were divided into 4 groups, based on the presence of having MVM lesions and/or PS. Levels of PAPP-A, PlGF and sFlt-1 were measured and MVM lesions were classified according to the Amsterdam Placental Workshop Group Consensus Statement. ResultsMVM occurrence was observed in 32% of the uncomplicated pregnancies. Women with MVM (regardless of the PS) had lower levels of PAPP-A (p = 0.038) and sFLt-1 (p = 0.006), and a non-significant trend for lower PlGF and sFlt-1/PlGF ratio compared to women without MVM. Low PAPP-A levels individually and in combination with the presence of PS was significantly associated with MVM lesions (aOR = 3.0 and 6.1, respectively), as did the combination of low PlGF levels and PS (aOR = 4.6). In women with PS, having MVM increased the incidence of fetal growth restriction, small for gestational age neonates, lower birthweight and adverse neonatal outcome. DiscussionOur findings suggest that MVM lesions were found to be associated with increased obstetric risks due to early placental dysfunction that can potentially be predicted by the use of first trimester biomarkers.