Association between fetal fraction of cell-free DNA and adverse pregnancy outcomes.

PURPOSE: To determine the association between fetal fraction (FF) levels in cell-free fetal DNA (cffDNA) testing and adverse pregnancy outcomes. METHODS: This retrospective cohort study, conducted at a single center, involved 2063 pregnant women with normal 1st and 2nd trimester non-invasive prenatal test (NIPT) results between 2016 and 2021. Pregnancy outcomes were examined by determining the < 4% and < 5th percentile (3.6%) cut-off values for low fetal fraction (LFF). Pregnancy outcomes were also examined by dividing the FF into population-based quartiles. Adverse pregnancy outcomes were pregnancy-induced hypertensive diseases (PIHD), gestational diabetes mellitus (GDM), spontaneous preterm birth (PTB), intrahepatic cholestasis of pregnancy (ICP), small for gestational age (SGA), large for gestational age (LGA), low birth weight (LBW), macrosomia, and 1st and 5th minutes low APGAR scores (< 7). RESULTS: PIHD was significantly higher in LFF (< 4% and < 5th percentile) cases (p = 0.015 and p < 0.001, respectively). However, in population-based quartiles of FF, PIHD did not differ significantly between groups. Composite adverse maternal outcomes were significantly higher in the FF < 4% group (p = 0.042). When analyzes were adjusted for maternal age, BMI, and gestational age at NIPT, significance was maintained at < 4%, < 5th percentile LFF for PIHD, and < 4% LFF for composite adverse maternal outcomes. However, there was no significant relationship between LFF with GDM, ICP and PTB. Additionally, there was no significant association between low APGAR scores, SGA, LGA, LBW, macrosomia, and LFF concerning neonatal outcomes. CONCLUSION: Our study showed that LFF in pregnant women with normal NIPT results may be a predictor of subsequent PIHD.

Association of increased fetal epicardial fat thickness with maternal pregestational and gestational diabetes.

OBJECTIVE: To evaluate the changes of fetal epicardial fat thickness (EFT) in pregnancies with pregestational diabetes mellitus (PGDM) and gestational diabetes mellitus (GDM) and to identify the diagnostic effectiveness of fetal EFT in differentiating PGDM and GDM from normal pregnancies. METHODS: The study was conducted with pregnant women who admitted to perinatology department between October 2020 and August 2021. Patients were grouped as PGDM (n = 110), GDM (n = 110), and control (n = 110) for comparison of fetal EFT. EFT was measured in all three groups at 29 weeks of gestation. Demographic characteristics and ultrasonographic findings were recorded and compared. RESULTS: The mean fetal EFT was significantly higher in PGDM (1.47 ± 0.083 mm, p < .001) and GDM (1.40 ± 0.082 mm, p < .001) groups compared to control group (1.19 ± 0.049 mm) and was also significantly higher in PGDM group than GDM group (p < .001). Fetal EFT was significantly positively correlated with maternal age, fasting, 1st hour, 2nd hour glucose values, HbA1c, fetal abdominal circumference, and deepest vertical pocket of amniotic fluid (p < .001). Fetal EFT value of 1.3 mm diagnosed PGDM patients with a sensitivity of 97.3% and a specificity of 98.2%. Fetal EFT value of 1.27 mm diagnosed GDM patients with a sensitivity of 94% and a specificity of 95%. CONCLUSIONS: Fetal EFT is greater in pregnancies with diabetes than in normal pregnancies, and also greater in PGDM than in GDM. In addition, fetal EFT is strongly correlated with maternal blood glucose levels in diabetic pregnancies.

Expected Versus Unexpected Delivery for Placenta Accreta Spectrum (PAS) Disorders with Same Team in Single Tertiary Center.

OBJECTIVES: To evaluate the maternal and neonatal outcomes of expected and unexpected pathologically proven placenta accreta spectrum (PAS) cases in a single multidisciplinary center. MATERIAL AND METHODS: This was a retrospective cohort study of 92 PAS cases from January 2011 until September 2021. Only cases with histopathologically invasive placentation were included in the study. The cases diagnosed at the time of delivery were defined as unexpected PAS (uPAS) and those diagnosed antenatally as expected PAS (ePAS). Maternal and neonatal outcomes of both groups were compared. RESULTS: Thirty-five (38%) of 92 cases were in the uPAS group. Placenta previa and high-grade PAS (percreata) were significantly higher in the ePAS group (p=0.028, p<0.001; respectively). The mean packed red blood cell transfusion was significantly higher in the uPAS group (p=0.030) but transfusions of other blood products were similar in the two groups. There was no significant difference in intraoperative complication rates between the two groups. Preterm delivery (<37 weeks) was significantly higher in the ePAS group (p<0.001), but there was no significant difference between the two groups in terms of adverse neonatal outcomes. CONCLUSIONS: Our single center data show that although ePAS cases include more highly invasive PAS cases, maternal hemorrhagic morbidity is lower than uPAS cases. Reducing maternal morbidity in PAS cases can be achieved by increasing antenatal diagnosis.

Contribution of fetal magnetic resonance imaging in the evaluation of neurosonographically detected cases of isolated mild and moderate cerebral ventriculomegaly.

AIM: This study aimed to present the contribution of prenatal magnetic resonance imaging (MRI) in the diagnosis of fetuses that were previously identified as isolated mild and moderate cerebral ventriculomegaly (VM) by ultrasound (US). METHODS: The data between February 2013 and August 2020 were collected for women who were diagnosed with isolated mild or moderate fetal VM by US and subsequently underwent a fetal MRI. RESULTS: Among 321 women, 21 (6.5%) had a clinically important additional finding after MRI. Twelve of 276 (4.3%) fetuses with mild VM and 9 of 45 (20%) with moderate VM had turned out to have additional central nervous system abnormalities. Additional findings were detected more in fetuses with moderate VM, mothers with an anterior-located placenta, and mothers with higher body mass indexes (BMIs) with statistical significance (p = 0.001, p = 0.013, p = 0.036, respectively). The most common additional MRI finding was grade 3 or 4 germinal matrix hemorrhage, which was detected in 11 of 21 fetuses (52.3%). CONCLUSIONS: Considering the countries' health policies, prenatal MRI would contribute mostly to the diagnosis of fetuses with moderate VM, pregnancies with anterior-located placenta, and mothers with high BMIs. According to our data, we believe that MRI will be valuable, especially in the diagnosis of grade 3 and 4 intracranial hemorrhage group.

Can sonographic imaging of the fetal pancreas predict perinatal outcomes in gestational diabetes mellitus?

OBJECTIVES: To evaluate whether fetal pancreatic echogenicity and its measurements are associated with gestational diabetes mellitus (GDM) and perinatal outcomes. METHODS: A prospective cohort study was conducted with 150 pregnant women with a singleton pregnancy. The study included pregnant women between 30 and 41 weeks with or without GDM. Fetal pancreatic circumference was measured using the free-hand tracking function. The echogenicity of the fetal pancreas was compared with the echogenicity of the liver and bone (ribs, spine) and classified as Grades 1, 2 and 3. The relationship between maternal characteristics and perinatal outcomes with fetal pancreas measurements and echogenicity was evaluated. RESULTS: Pregnant women with 75 GDM and 75 without GDM were included in the study. Mean fetal pancreas circumference measurements were significantly higher in pregnant women with GDM than in those without GDM (p=0.001). Hyperechogenic (Grade 3) fetal pancreas was significantly higher in pregnant women with GDM than in pregnant women without GDM, and there was a positive correlation between pancreatic echogenicity and HbA1c levels in pregnant women with GDM (r=0.631, p<0.01). There was a significant relationship between pancreatic echogenicity, measurements and adverse neonatal outcomes in pregnant women with GDM, and pancreas measurements were significantly higher in pregnant women with cesarean delivery. CONCLUSIONS: Fetal pancreatic echogenicity and measurements in pregnant women with GDM can give an idea about glucose regulation and adverse perinatal outcomes.

Can the Cell-free DNA Test Predict Placenta Accreta Spectrum or Placenta Previa Totalis?

BACKGROUND: Following the discovery that fetal DNA originates from the trophoblastic cells of the placenta, the contribution of the cell-free DNA test in placenta-related obstetric complications has begun to be investigated. Compared to uncomplicated pregnancies, higher fetal fractions were detected in placenta accreta spectrum and placenta previa, which are among placenta-related obstetric complications. However, this data applies only to advanced gestational weeks. AIM: To investigate the possible predictive value of fetal fraction in cell-free DNA tests in pregnancies with placenta previa and placenta accreta spectrum in early gestational ages. MATERIALS AND METHODS: This study was conducted in women who were screened via cell-free DNA tests for common aneuploidies in the first and second trimester and subsequently diagnosed with placenta previa or placenta accreta spectrum. After the diagnosis was confirmed with a C-section, fetal fractions were retrospectively compared to a control group with a history of an uncomplicated C-section who were also previously screened by cell-free DNA test. RESULTS: The median and interquartile range (IQR) of fetal fractions for placenta previa (n=19), placenta accreta spectrum (n=7), and control groups (n=85) were 8.1 (6-10), 6.8 (6.7-10.7), and 7.1 (4.7-9.65), respectively. No statistically significant difference was observed among the three groups in terms of fetal fractions (p=0.587). CONCLUSIONS: According to our data, we did not observe any relationship between placental invasion abnormalities vs. control group or placenta previa vs. control group using the fetal fractions of the cell-free DNA test. Furthermore, we could not confirm a predictive role and/or any additional clinical contribution. We believe that future studies focusing on placental mRNA might be more helpful than cell-free fetal DNA testing.

How COVID-19 pandemic is changing the practice of prenatal screening and diagnosis?

OBJECTIVES: To evaluate the impact of the COVID-19 pandemic on prenatal screening and diagnostic tests. METHODS: We conducted a retrospective study with pregnant women attending to the perinatology department of a tertiary referral center. The pre-COVID-19 period between 11 March 2019 and 10 March 2020 and COVID-19 period between 11 March 2020 and 10 March 2021 were evaluated. Both periods were compared in terms of outpatient visits, ultrasound examinations, prenatal screening and diagnostic tests. The correlation of deaths related to COVID-19 pandemic on these parameters was also assessed. RESULTS: A total of 38,918 patients were examined and 28,452 ultrasound examinations, 26,672 prenatal screening tests and 1,471 prenatal diagnostic tests were performed over two years. During COVID-19 pandemic, number of outpatient visits decreased by 25.2%, ultrasound examinations decreased by 44.2%, prenatal screening tests decreased by 36.2% and prenatal diagnostic tests decreased by 30.7%. Statistically significant correlation was not observed between deaths related to COVID-19 and outpatient visits (p=0.210), ultrasound examinations (p=0.265), prenatal screening (p=0.781) and diagnostic tests (p=0.158). Among indications of prenatal diagnostic tests, maternal anxiety was significantly higher in COVID-19 period (p=0.023). There was significant decrease in the detection of fetuses with trisomy 21 (p=0.047) and a significant increase in the detection of fetuses with Turner syndrome (p=0.017) during COVID-19 period. CONCLUSIONS: The COVID-19 pandemic has severely impacted antenatal care. Prenatal fetal screening and diagnosis was adversely affected by the pandemic in terms of detecting genetic and structural anomalies.

Termination of pregnancy following a Down Syndrome diagnosis: decision-making process and influential factors in a Muslim but secular country, Turkey.

OBJECTIVES: This study aims to present the termination of pregnancy (TOP) rates and elucidate the decision-making process following a prenatal diagnosis of Trisomy 21 in Turkey. METHODS: This retrospective single-center study was conducted with 146 pregnant women between January 2016 and December 2019 in a tertiary hospital. Data on maternal characteristics, sonographic findings, indications for chromosome analysis, and educational, religious, and economic factors that can influence the parental decision process were collected. RESULTS: The TOP rate of Down syndrome (DS) in our center was 78.8%. We concluded that maternal age, earlier diagnosis, indication for chromosome analysis, and previous pregnancies had no effect on the TOP decision. On the other hand, not having a minor or a major sonographic sign, employed mothers, middle- and high-income families, and families having a secondary or higher education tended to terminate the pregnancy affected by DS at statistically higher rates. CONCLUSIONS: There are many studies worldwide investigating the TOP preferences for DS. However, there is limited data about TOP rates and influential factors affecting the decision-making process in Muslim countries. This study contributes by clarifying the factors in the decision-making process and elucidating perspectives about TOP in a Muslim country with a unique status: Turkey.

Assessment of renal volume by 3D VOCAL Ultrasonography method in late-onset growth-restricted fetuses with normal amniotic fluid index.

OBJECTIVES: The aim of this study was to study renal volumetric alterations and renal artery doppler changes in late-onset fetal growth restricted (FGR) fetuses with normal amniotic fluid compared to healthy pregnancies. MATERIAL AND METHODS: This prospective study was composed of pregnant women with late-onset FGR and a control group of uncomplicated pregnancies within 32-37 weeks of gestation. Following the assessment of umbilical, bilateral uterine, middle cerebral using Doppler Ultrasonography (US), three dimensional (3D) US Virtual Organ Computer-aided Analysis (VOCAL) was executed to calculate bilateral renal volumes. RESULTS: A total of 76 fetuses with FGR and 51 healthy fetuses (control group) were evaluated. Umbilical artery Doppler systole/diastole and Pulsatility index values were found to be significantly different between the two groups (p = 0.001 and p = 0.001, respectively). Middle cerebral, bilateral uterine, and bilateral renal arteries' Doppler indices revealed no difference between the two groups. Right, left, and mean renal volume of the fetuses with FGR were smaller than the control group, and the differences were statistically significant (p = 0.025, p = 0.004, p = 0.004, respectively). Left renal volume was significantly greater than the right renal volume in the control group (p = 0.009). CONCLUSION: Although not accompanied by oligohydramnios, and having similar renal vascular resistance as the control group, renal volumes of fetuses with late-onset FGR were still observed lower than the control group. This difference was explained by not decreased blood flow via redistribution but other mechanisms like glomeruli reduction and glomerular apoptosis.

Can fetal fractions in the cell-free DNA test predict the onset of fetal growth restriction?

Objective To investigate the possible predictive value of fetal fraction in the cell-free DNA (cfDNA) test in pregnancies with early- and late-onset fetal growth restriction (FGR). Methods This retrospective study comprised 247 women who were screened using the cfDNA test for aneuploidies during the first or second trimester and had deliveries at our institution from January 2016 to December 2019. The fetal fractions of women with early- (n = 14) and late-onset (n = 83) FGR and those with uncomplicated pregnancies (n = 150) were compared. Results The median fetal fractions for the early-onset FGR, late-onset FGR, and control groups were 5.7 [interquartile range (IQR) 2.65], 7 (IQR 5), and 7.35 (IQR 3.65), respectively. The fetal fractions were significantly lower in the early-onset FGR group than in the late-onset FGR and control groups (P = 0.047 and P = 0.037, respectively). There was no difference in fetal fractions between the late-onset FGR and control groups (P = 1.00). Conclusion As a placenta-related disease, early-onset FGR had lower fetal fractions in the cfDNA test than uncomplicated pregnancies. For clinical use, lower fetal fractions can contribute as a biomarker for screening asymptomatic women for possible placenta-related diseases, such as early-onset FGR. However, more studies are needed to define the "lower" limit.

Could high levels of cell-free DNA in maternal blood be associated with maternal health and perinatal outcomes?

The aim of this study was to evaluate the maternal and foetal factors affect higher cell-free DNA (cfDNA) levels and to investigate a possible relationship between high cfDNA levels and adverse perinatal outcomes. From a total of 4594 women who underwent non-invasive prenatal testing from January 2016 to March 2018 in our hospital, 112 women had high levels of cfDNA, which was not appropriate for testing. Maternal characteristics and perinatal outcomes were compared between patients with high levels of cfDNA and normal levels of cfDNA. Patients with high levels of cfDNA had greater risks than patients with normal cfDNA levels of pregnancy complications but no statistically significant difference was found. Patients with high cfDNA levels had higher foetal death rates with a statistically significant difference (9.8% versus 1.8%, p = .024). An increase in foetal death could be expected in patients with increased cfDNA levels; therefore, these patients should be carefully followed up during pregnancy.IMPACT STATEMENTWhat's already known about this topic? Most studies about cfDNA levels are focussed on the foetal fraction. There are new arguments about maternal health and cfDNA. It is known that autoimmune diseases as systemic lupus erythematosus (SLE) and maternal obesity increase cell turnover. There are also clinical studies suggesting a relationship between low molecular weight heparin therapy and the amount of cfDNA.What do the results of this study add? This is the first study evaluating the maternal and foetal biological factors affecting cfDNA concentrations and investigating the possible relationship between high cfDNA levels and adverse perinatal outcomes in patients with high levels of cfDNA compared to patients with normal levels of cfDNA. In the present study, it was found that an increase in foetal death could be expected in patients with higher cfDNA levels.What are the implications of these findings for clinical practice and/or further research? If potential effects and underlying causes of increased cfDNA could be explained, cfDNA might be used as a biomarker for adverse perinatal outcomes.