Fetal magnetic resonance imaging in the confirmation of congenital anomalies found on routine mid-trimester ultrasound.

OBJECTIVE: To determine the added value of fetal magnetic resonance imaging (MRI) when clarifying a suspected anomaly detected by mid-trimester scan. METHODS: Women attending two centers of fetal medicine between January 2017 and December 2021 were identified. The centers carried out routine mid-trimester ultrasound scans to detect fetal anomalies. Those with a suspected anomaly which required further clarification were referred for fetal magnetic resonance imaging (MRI). The medical records of all referred women were examined to determine the anomalies found at scan, MRI and termination of pregnancy or delivery. A total of 9571 women had a routine mid-trimester scan and an anomaly was either diagnosed or suspected in 449 (4.7%); an MRI examination was made in 76 cases (0.79%). RESULTS: MRI confirmed the presence of an abnormality in 61 referrals (80%) and failed to yield a result in one case. Outcome information was available for 69 cases: the MRI confirmation rate was 89% (48/54) in those with abnormal outcome and 40% (6/15) if the outcome was normal, P<0.0001. Among defects in the most common anatomical systems identified at ultrasound, the highest confirmation rates were for urinary tract abnormalities (94%, 15/16) and facial abnormalities (100%, 8/8). Results in other systems varied according to the specific defect but the confirmation rate was high for ventriculomegaly (86%, 6/7) and neural tube defects (83%, 5/6). CONCLUSIONS: We have shown that in women with suspected anomaly scan results, requiring further clarification, MRI confirmed ultrasound at a high rate, particularly for urinary tract and facial anomalies.

Antenatal screening for thyroid dysfunction: pre-term birth, low birth-weight, and growth restriction.

OBJECTIVE: To assess pre-term birth, low birth-weight and growth restriction according to maternal thyroid screening results and subsequent treatment. METHODS: This is a nonintervention nested case-control study derived from 10,052 asymptomatic women previously screened during the first trimester marker with anti-thyroid peroxidase antibodies, serum thyroid stimulating hormone, and free thyroxine. Screening results had been classified as positive with one or more markers outside the normal range and referred to an endocrinologist. Cases were 512 women with positive results and information on recommended treatment: 204 thyroxine, propylthiouracil or surgery, and 308 no treatment or only iodine. Controls were a sequential sample of 1292 women with negative results. All cases and controls had information on gestation at delivery or birth-weight. Outcome measures were pre-term birth (<37 weeks), low birth-weight (<2.5 kg) and, for singletons, small for gestational age (SGA; <10th percentile). RESULTS: Among singleton pregnancies, there was a higher prevalence of both pre-term birth (risk ratio (RR) 1.69, 95% confidence interval (CI) 1.21-2.36, p < .002) and low birth-weight (RR 1.72, 95% CI 1.13-2.62, p < .02) in cases compared with controls. An increase in low birth-weight was also present in term pregnancies, but not significant (RR 1.80, 95% CI 0.78-4.14, p = .16), and there was no difference in SGA prevalence (1.24, 95% CI 0.93-1.65, p = .14). Among cases there was no significant difference in these rates according to treatment even after logistic regression, allowing for the individual screening marker levels and maternal weight. CONCLUSIONS: Women with positive thyroid screening results are at increased risk of pre-term birth regardless of thyroid dysfunction or subsequent treatment. An association with low birth-weight is probably secondary to early delivery.

Overview of Noninvasive Prenatal Testing (NIPT) for the Detection of Fetal Chromosome Abnormalities; Differences in Laboratory Methods and Scope of Testing.

Although nearly all noninvasive prenatal testing is currently based on analyzing circulating maternal cell-free DNA, the technical methods usedvary considerably. We review the different methods. Based on validation trials and clinical experience, there are mostly relatively small differences in screening performance for trisomies 21, 18, and 13 in singleton pregnancies. Recent reports show low no-call rates for all methods, diminishing its importance when choosing a laboratory. However, method can be an important consideration for twin pregnancies, screening for sex chromosome abnormalities, microdeletion syndromes, triploidy, molar pregnancies, rare autosomal trisomies, and segmental imbalances, and detecting maternal chromosome abnormalities.

Maternal Plasma RNA in First Trimester Nullipara for the Prediction of Spontaneous Preterm Birth ≤ 32 Weeks: Validation Study.

The first-trimester prediction of spontaneous preterm birth (sPTB) has been elusive, and current screening is heavily dependent on obstetric history. However, nullipara lack a relevant history and are at higher risk for spontaneous (s)PTB ≤ 32 weeks compared to multipara. No available objective first-trimester screening test has proven a fair predictor of sPTB ≤ 32 weeks. We questioned whether a panel of maternal plasma cell-free (PCF) RNAs (PSME2, NAMPT, APOA1, APOA4, and Hsa-Let-7g) previously validated at 16-20 weeks for the prediction of sPTB ≤ 32 weeks might be useful in first-trimester nullipara. Sixty (60) nulliparous women (40 with sPTB ≤ 32 weeks) who were free of comorbidities were randomly selected from the King's College Fetal Medicine Research Institute biobank. Total PCF RNA was extracted and the expression of panel RNAs was quantitated by qRT-PCR. The analysis employed, primarily, multiple regression with the main outcome being the prediction of subsequent sPTB ≤ 32 weeks. The test performance was judged by the area under the curve (AUC) using a single threshold cut point with observed detection rates (DRs) at three fixed false positive rates (FPR). The mean gestation was 12.9 ± 0.5 weeks (range 12.0-14.1 weeks). Two RNAs were differentially expressed in women destined for sPTB ≤ 32 weeks: APOA1 (p < 0.001) and PSME2 (p = 0.05). APOA1 testing at 11-14 weeks predicted sPTB ≤ 32 weeks with fair to good accuracy. The best predictive model generated an AUC of 0.79 (95% CI 0.66-0.91) with observed DRs of 41%, 61%, and 79% for FPRs of 10%, 20%, and 30%, including crown-rump length, maternal weight, race, tobacco use, and age.

Cholelithiasis is an additional pre-pregnancy clinical risk factor for preeclampsia.

PURPOSE: To investigate additional potential clinical risk factors for preeclampsia. METHODS: This is a nested case-control study of preeclampsia and unaffected pregnancies. Cases were either from a prenatal screening database or from a national network of clinicians, and controls were from the same prenatal source. Preeclampsia was defined by international criteria which were endorsed by the Ukraine Ministry of Health. Questionnaires were used to record a range of pregnancy related factors, personal history of health conditions and family history, followed by a telephone interview to collect more details. RESULTS: There were 103 cases, 56 from the prenatal database and 47 from the clinicians, and 480 controls from the database. The two types of case did not differ in terms of age, weight, BMI or parity. Known risk factors were more common in cases than controls. In addition there was a 17-fold higher prevalence of cholelithiasis in cases compared with controls (29.1% versus 1.7%), a highly statistically significant difference (P < 0.0001). There was also an 8.8-fold increase among the mothers of cases and controls (P < 0.0001), and if either the patient or her mother had the disease the increase was 6.4-fold (P < 0.0001). Including the father or sibling did not increase the relative risk. CONCLUSION: Cholelithiasis is a clinical risk factor for preeclampsia which has not previously been reported. If confirmed by additional studies it may have utility in routine prenatal screening and provide insight into the pathogenesis of preeclampsia.

Evaluation of a Maternal Plasma RNA Panel Predicting Spontaneous Preterm Birth and Its Expansion to the Prediction of Preeclampsia.

Preterm birth is the principal contributor to neonatal death and morbidity worldwide. We previously described a plasma cell-free RNA panel that between 16 and 20 weeks of pregnancy had potential to predict spontaneous preterm birth (sPTB) ≤ 32 weeks caused by preterm labor (PTL) or preterm premature rupture of membranes (PPROM). The present study had three objectives: (1) estimate the RNA panel prognostic accuracy for PTL/PPROM ≤ 32 weeks in a larger series; (2) improve accuracy by adding clinical characteristics to the predictive model; and (3) examine the association of the RNA panel with preeclampsia. We studied 289 women from Memphis TN prospectively sampled 16.0-20.7 weeks and found: (1) PSME2 and Hsa-Let 7g were differentially expressed in cases of PTL/PPROM ≤ 32 weeks and together provided fair predictive accuracy with AUC of 0.76; (2) combining the two RNAs with clinical characteristics improved good predictive accuracy for PTL/PPROM ≤ 32 weeks (AUC 0.83); (3) NAMPT and APOA1 were differentially expressed in women with 'early-onset preeclampsia' (EOP) and together provided good predictive accuracy with AUC of 0.89; and (4) combining the two RNAs with clinical characteristics provided excellent predictive accuracy (AUC 0.96). Our findings suggest an underlying common pathophysiological relationship between PTL/PPROM ≤ 32 weeks and EOP and open inroads for the prognostication of high-risk pregnancies.

Modified multiple marker aneuploidy screening as a primary screening test for preeclampsia.

BACKGROUND: Abnormal levels of maternal biochemical markers used in multiple marker aneuploidy screening have been associated with adverse pregnancy outcomes. This study aims to assess if a combination of maternal characteristics and biochemical markers in the first and second trimesters can be used to screen for preeclampsia (PE). The secondary aim was to assess this combination in identifying pregnancies at risk for gestational hypertension and preterm birth. METHODS: This case-control study used information on maternal characteristics and residual blood samples from pregnant women who have undergone multiple marker aneuploidy screening. The median multiple of the median (MoM) of first and second trimester biochemical markers in cases (women with PE, gestational hypertension and preterm birth) and controls were compared. Biochemical markers included pregnancy-associated plasma protein A (PAPP-A), placental growth factor (PlGF), human chorionic gonadotropin (hCG), alpha feto-protein (AFP), unconjugated estriol (uE3) and Inhibin A. Logistic regression analysis was used to estimate screening performance using different marker combinations. Screening performance was defined as detection rate (DR) and false positive rate (FPR). Preterm and early-onset preeclampsia PE were defined as women with PE who delivered at < 37 and < 34 weeks of gestation, respectively. RESULTS: There were 147 pregnancies with PE (81 term, 49 preterm and 17 early-onset), 295 with gestational hypertension, and 166 preterm birth. Compared to controls, PE cases had significantly lower median MoM of PAPP-A (0.77 vs 1.10, p < 0.0001), PlGF (0.76 vs 1.01, p < 0.0001) and free-ß hCG (0.81 vs. 0.98, p < 0.001) in the first trimester along with PAPP-A (0.82 vs 0.99, p < 0.01) and PlGF (0.75 vs 1.02, p < 0.0001) in the second trimester. The lowest first trimester PAPP-A, PlGF and free ß-hCG were seen in those with preterm and early-onset PE. At a 20% FPR, 67% of preterm and 76% of early-onset PE cases can be predicted using a combination of maternal characteristics with PAPP-A and PlGF in the first trimester. The corresponding DR was 58% for gestational hypertension and 36% for preterm birth cases. CONCLUSIONS: Maternal characteristics with first trimester PAPP-A and PlGF measured for aneuploidy screening provided reasonable accuracy in identifying women at risk of developing early onset PE, allowing triage of high-risk women for further investigation and risk-reducing therapy. This combination was less accurate in predicting women who have gestational hypertension or preterm birth.

Consequences of imprecision in fetal fraction estimation on performance of cell-free DNA screening for Down syndrome.

BACKGROUND: There is a significant variability in reported fetal fraction (FF), a common cause for no-calls in cell-free (cf)DNA based non-invasive prenatal screening. We examine the effect of imprecision in FF measurement on the performance of cfDNA screening for Down syndrome, when low FF samples are classified as no-calls. METHODS: A model for the reported FF was constructed from the FF measurement precision and the underlying true FF. The model was used to predict singleton Down syndrome detection rates (DRs) for various FF cut-offs and underlying discriminatory powers of the test. RESULTS: Increasing the FF cut-off led to slightly increased apparent DR, when no-calls are excluded, and an associated larger decrease in effective DR, when no-calls are included. These effects were smaller for tests with higher discriminatory power and larger as maternal weight increased. CONCLUSIONS: Most no-calls due to a low reported FF have a true FF above the cut-off. The discriminatory power of a test limits its effective DR and FF precision determines the tradeoff between apparent and effective DR when low FF is used to discard samples. Tests with high discriminatory power do not benefit from current FF measurements.

Maternal weight as an additional first trimester spina bifida screening marker.

OBJECTIVE: To evaluate first trimester maternal weight as a spina bifida screening marker. METHODS: Case-control study of spina bifida and unaffected pregnancies; cases were from national records and controls from women referred to prenatal screening centers in the Ukraine. The median and inter-quartile range of weight, body mass index (BMI) and the obesity rate (BMI ≥ 30 kg/m2) were compared. Discriminatory power was assessed by logistic regression. Gaussian modeling was used to predict the additional spina bifida detection when weight was included as a screening marker risk in addition to first trimester biparietal diameter (BPD) and serum α-fetoprotein (AFP). RESULTS: There were 97 cases and 274 controls. The distribution of maternal weight was increased in cases by 3 kg, on average, about 5% (p < .05); BMI was increased about 8% (p < .005). Some 15% of cases were obese compared with 6.9% of controls (p < .02). In logistic regression including BMI and maternal age, 29% cases and 9.8% controls had high risk of spina bifida. Modeling predicted that incorporating weight would increase the detection rate compared with BPD and AFP alone by 3% and BMI would increase it by 4%. CONCLUSION: Incorporating maternal weight into first trimester spina bifida screening protocols will increase detection.

Oligohydramnios: how severe is severe?

OBJECTIVE: To investigate whether the severity of isolated oligohydramnios at term is associated with increased rates of adverse perinatal outcome. STUDY DESIGN: A retrospective study conducted in a single medical center from 2017 to 2019. All low-risk pregnancies with incidental isolated oligohydramnios at term were included. The degree of oligohydramnios was arbitrarily classified into mild (AFI = 41-50 mm), moderate (AFI = 21-40 mm) and severe (AFI = 0-20 mm). RESULT: A total of 610 women were included: 202 with a mild (33.1%), 287 moderate (47.0%), and 121 severe oligohydramnios (19.8%). Non-reassuring monitor requiring immediate delivery and worse composite neonatal outcome were more common among severe than mild or moderate oligohydramnios (14.0% and 6.4%, 7.3% respectively; p = .039 and 19.8%, 10.9% and 11.8%, respectively; p = .048). CONCLUSION: Low-risk pregnancies with isolated severe oligohydramnios at term have a higher tendency toward non-reassuring fetal monitoring requiring prompt delivery and adverse neonatal outcomes, this calls for close intrapartum surveillance.

Cost of providing cell-free DNA screening for Down syndrome in Finland using different strategies.

OBJECTIVES: A financial analysis is carried out to assess costs and benefits of providing cell-free DNA screening in Finland, using different strategies. METHODS: Three cell-free DNA screening strategies are considered: Primary, all women; Secondary, those with positive Combined test; and Contingent, the 10-30% with the highest Combined test risks. Three costs are estimated: additional cost for 10,000 pregnancies compared with the Combined test; 'marginal' cost of avoiding a Down syndrome birth which occurs in a pregnancy that would have been false-negative using the Combined test; and marginal cost of preventing the iatrogenic loss of a non-Down syndrome birth which occurs in a pregnancy that would have been false-positive. RESULTS: Primary cell-free DNA will require additional funds of €250,000. The marginal cost per Down syndrome birth avoided is considerably less than the lifetime medical and indirect cost; the marginal cost per unaffected iatrogenic fetal loss prevented is higher than one benefit measure but lower than another. If the ultrasound component of the Combined test is retained, as would be in Finland, the additional funds required rise to €992,000. Secondary cell-free DNA is cost-saving as is a Contingent strategy with 10% selected but whilst when 20-30% costs rise they are much less than for the Primary strategy and are cost-beneficial. CONCLUSIONS: When considering the place of cell-free DNA screening it is important to make explicit the additional and marginal costs of different screening strategies and the associated benefits. Under most assumptions the balance is favorable for Contingent screening.

Cell-free DNA screening for fetal aneuploidy using the rolling circle method: A step towards non invasive prenatal testing simplification.

OBJECTIVE: To assess the efficacy of cell-free (cf)DNA screening for aneuploidy using the automated system based on rolling circle replication. METHODS: A prospective study among women referred for invasive prenatal diagnosis between July 2018 and December 2019. The plasma fraction was extracted within 5 days from blood collection, stored at -20°C and cfDNA measured between January and December 2019. RESULTS: A total of 805 women were recruited; 778 with singleton pregnancies and 27 twins. There were 48 Down syndrome, 25 Edwards syndrome and 3 Patau syndrome cases. Overall, the no-call rate was 2.6% (95% confidence interval 1.6%-3.9%) which reduced from 4.7% to 1.1% after relocation of the system (p < 0.002) to ensure a constant ambient temperature below 25°C. In singletons the Down syndrome detection rate (DR) was 100% (93%-100%) and false-positive rate (FPR) 0.14% (0.00%-0.79%). The Edwards syndrome DR was 96% (80%-100%) and FPR 0.78% (0.29%-1.7%). One false-positive had a confined placental trisomy 18 and the remaining five a z-score requiring sample repetition; all the false-positives occurred before system relocation (p < 0.005). Patau syndrome DR and FPR were 67% (9.4%-99%) and 0.26% (0.03%-0.95%). CONCLUSION: The cfDNA rolling circle method yields similar results to other methods provided that room temperature is adequately controlled.

The origins of aneuploidy research consortium.

The presence of high levels of aneuploidy in oocytes and early embryos and their fate is of considerable scientific and clinical importance. The Origins of Aneuploidy Research Consortium (OARC) was established to promote interdisciplinary communication and collaborative research into this topic. Under the umbrella of OARC, a series of papers has now been published in this Special Issue of Prenatal Diagnosis. Recent studies have transformed the view that aneuploidy is usually attributable to meiotic non-disjunction. The molecular basis for the association between meiotic error and maternal age is becoming understood. The clinical significance of mitotic instability in the earliest cells divisions of the embryo is also becoming clearer. An error in the segregation of one or more whole chromosomes from a parent does not invariably result in a non-viable pregnancy or an abnormal outcome. Epidemiologic data allows an assessment of in utero viability, the effect of maternal age, and secondary factors that may affect aneuploidy prevalence. We advocate careful use of nomenclature and revision of educational materials to more accurately explain the complex and often nuanced mechanisms. OARC plans to hold additional workshops, promote additional publications and offer educational resources.

Increase rate of ruptured tubal ectopic pregnancy during the COVID-19 pandemic.

OBJECTIVE: During the 2020 COVID-19 pandemic there was a decrease in emergency room arrivals. There is limited evidence about the effect of this change in behavior on women's health. We aimed to evaluate the impact of the COVID-19 pandemic on the diagnosis, treatment and complications of women presenting with a tubal Ectopic Pregnancy (EP). STUDY DESIGN: This is a single centre retrospective cohort study. We compared the clinical presentation, treatment modalities and complications of all women presenting in our institution with a tubal EP during the COVID-19 pandemic between 15 March and 15 June 2020, with women who were treated in our institution with the same diagnosis in the corresponding period for the years 2018-2019. RESULTS: The study group included 19 cases of EP (N = 19) that were treated between the 15 March 2020 and 15 June 2020. The control group included 30 cases of EP (N = 30) that were admitted to in the corresponding period during 2018 and 2019. Maternal age, parity, gravity and mode of conception (natural vs. assisted) were similar between the two groups. There was no difference in the mean gestational age (GA) according to the last menstrual period. In the study group more women presented with sonographic evaluation of high fluid volume in the abdomen than in the control group (53 % vs 17 %, P value 0.01). This finding is correlated with a more advanced disease status. In the study group there was a highly statistically significant 3-fold increase in rupture among cases (P < 0.005) and a 4-fold larger volume of blood in the entrance to the abdomen (P < 0.002). We found that there were no cases of ruptured EP in the group of women who were pregnant after assisted reproduction. CONCLUSION: We found a higher rate of ruptured ectopic pregnancies in our institution during the COVID-19 pandemic. Health care providers should be alerted to this collateral damage in the non-infected population during the COVID-19 pandemic.

Maternal age in the epidemiology of common autosomal trisomies.

The birth prevalence rate of each common autosomal trisomy generally increases with advancing maternal age and there is a substantial fetal loss rate between late first trimester and term. The literature is reviewed in order to provide the best estimates of these rates, taking account where possible of biases due to prenatal diagnosis and selective termination of pregnancy. There is an almost exponential increase in Down syndrome birth prevalence between ages 15 and 45 but at older ages the curve flattens. There is no evidence of the claimed relatively high birth prevalence at extremely low ages. Gestation-specific intra-uterine fetal loss rates are estimated by follow-up of women declining termination of pregnancy after prenatal diagnosis, comparison of observed rates with those expected from birth prevalence and comparison of age-specific curves developed for prenatal diagnosis and birth. Down syndrome fetal loss rates reduce with gestation and increase with maternal age. Edwards and Patau syndrome birth prevalence is approximately 1/8 and 1/13 that of Down syndrome overall, although the ratio differs according to maternal age, particularly for Patau syndrome where it reduces steadily from 1/9 to 1/19. Fetal loss rates are higher for Edwards and Patau syndromes than for Down syndrome.

Review of epidemiological factors (other than maternal age) that determine the prevalence of common autosomal trisomies.

The birth prevalence of each common autosomal trisomy (21, 18 and 13) increases with advancing maternal age and this is the most important epidemiological risk factor. Prevalence during pregnancy is also dependent on gestational age. Other factors claimed to influence prevalence include paternal age, ethnicity, family history, premature reproductive aging, parity, twinning, smoking, environmental exposures, maternal medical conditions, and predispositions. We review the evidence for these associations since they may provide insights into causal mechanisms. When investigating potential co-factors it is important to adequately allow for maternal age and minimize its confounding contribution. This is well illustrated by reports of an inverse paternal age effect where there is strong correlation between parental ages. Gestational age at diagnosis, availability of prenatal screening, diagnostic testing, and elective termination of affected pregnancies and healthcare disparities also confound the studies on ethnicity, medical conditions, and predispositions or environmental factors. Data from twin zygosity studies demonstrate the importance of differences in fetal viability for affected pregnancies. We conclude that existing epidemiological evidence for most of the co-factors discussed should currently be considered tenuous; history of Down syndrome, albeit biased, may be an exception. The co-factors may yet provide clues to hitherto poorly understood causal pathways.

Impact of the COVID-19 Pandemic on Excess Perinatal Mortality and Morbidity in Israel.

OBJECTIVE: The 2020 COVID-19 pandemic has been associated with excess mortality and morbidity in adults and teenagers over 14 years of age, but there is still limited evidence on the direct and indirect impact of the pandemic on pregnancy. We aimed to evaluate the effect of the first wave of the COVID-19 pandemic on obstetrical emergency attendance in a low-risk population and the corresponding perinatal outcomes. STUDY DESIGN: This is a single center retrospective cohort study of all singleton births between February 21 and April 30. Prenatal emergency labor ward admission numbers and obstetric outcomes during the peak of the first COVID-19 pandemic of 2020 in Israel were compared with the combined corresponding periods for the years 2017 to 2019. RESULTS: During the 2020 COVID-19 pandemic, the mean number of prenatal emergency labor ward admissions was lower, both by daily count and per woman, in comparison to the combined matching periods in 2017, 2018, and 2019 (48.6 ± 12.2 vs. 57.8 ± 14.4, p < 0.0001 and 1.74 ± 1.1 vs. 1.92 ± 1.2, p < 0.0001, respectively). A significantly (p = 0.0370) higher rate of stillbirth was noted in the study group (0.4%) compared with the control group (0.1%). All study group patients were negative for COVID-19. Gestational age at delivery, rates of premature delivery at <28, 34, and 37 weeks, pregnancy complications, postdate delivery at >40 and 41 weeks, mode of delivery, and numbers of emergency cesarean deliveries were similar in both groups. There was no difference in the intrapartum fetal death rate between the groups. CONCLUSION: The COVID-19 pandemic stay-at-home policy combined with patient fear of contracting the disease in hospital could explain the associated higher rate of stillbirth. This collateral perinatal damage follows a decreased in prenatal emergency labor ward admissions during the first wave of COVID-19 in Israel. KEY POINTS: · Less obstetrical ER attendance is observed during the pandemic.. · There is a parallel increase in stillbirth rate.. · Stillbirth cases tested negative for COVID-19.. · Lockdown and pandemic panic are possible causes..