Risk of amniocentesis in women screened positive for Down syndrome with second trimester maternal serum markers

In routine obstetrical practice, prior to offering invasive prenatal diagnosis, it is crucial to weigh the risks attendant on amniocentesis against the individual's risk of aneuploidy. We took advantage of a policy of follow-up of patients undergoing Down syndrome maternal serum screening to compare the rates of fetal loss before 24 weeks and of early premature delivery at 24–28 weeks between women who underwent amniocentesis and women who did not. A total of 54 902 patients entered the study, of whom 4039 (7.35%) were lost to follow-up and 387 were excluded because of a severe fetal abnormality. Of the 50 476 remaining patients, 3472 had an amniocentesis whereas 47 004 had not and served as controls. In the amniocentesis group, the fetal loss rate before 24 weeks was 1.12% (95% CI=1.08–1.15) and the 24–28 weeks premature delivery rate was 0.40% (95% CI=0.39–0.41) which was significantly higher than in controls (0.42% with 95% CI 0.41–0.43 and 0.24% with 95% CI 0.23–0.25, respectively). The 0.86% difference in adverse outcome rates between the amniocentesis and control groups may be attributable to amniocentesis and compares favourably with the positive predictive value of maternal serum markers (1.70%) observed in the present study. Copyright © 2002 John Wiley & Sons, Ltd.     

Persistently elevated AFP and AChE in amniotic fluid from a normal fetus following demise of its twin

Intrauterine fetal demise (IUFD) in one of twins at 12 weeks of gestation was accompanied by markedly elevated maternal serum alpha-fetoprotein (AFP) at 17 and 18 weeks. Amniotic fluid AFP from the healthy surviving twin's sac at 18·5 and 23 weeks was also greatly increased along with a positive acetylcholinesterase (AChE) band. Persistently elevated AFP and positive AChE so long after fetal demise–-6·5 and 11 weeks post IUFD–-has not, to our knowledge, been previously described. In similar cases, high level ultrasound and careful placental examination at birth should be utilized to search for fetal abnormalities or multiple pregnancy with IUFD.     

Performance of comprehensive first trimester fetal anatomy assessment

Objective

Ultrasound assessment of the fetal anatomy and fetal echocardiography are feasible in the first trimester of pregnancy. This study was designed to assess the performance of a comprehensive fetal anatomy assessment in a high-risk population at a tertiary fetal medicine unit.

Methods

A retrospective review of high-risk patients undergoing comprehensive fetal anatomy ultrasound assessment between 11 weeks and 13 + 6 weeks of gestation was conducted. Findings of the early anatomy ultrasound scan were compared with those of the second trimester anatomy scan, and birth outcomes or post-mortem results.

Results

Early anatomy ultrasounds were performed in 765 patients. The sensitivity of the scan for detecting fetal anomalies compared to the birth outcome was 80.5% (95% CI 73.5–86.3) and specificity was 93.1% (95%CI 90.6–95.2). Positive and negative predictive values were 78.5% (95% CI 71.4–84.6) and 93.9% (95% CI 91.4–95.8), respectively. The most missed and overdiagnosed abnormalities were ventricular septal defects. The second trimester ultrasound had sensitivity of 69.0% (95% CI 55.5–80.5) and specificity of 87.5% (95% CI 84.3–90.2).

Conclusions

In a high-risk population, early assessments had similar performance metrics as the second trimester anatomy ultrasound. We advocate for a comprehensive fetal assessment in the care of high-risk pregnancies.     

Perinatal outcomes and genomic characteristics of fetal copy number variants: An individual record linkage study of 713 pregnancies

Objective

To determine the perinatal outcomes of fetuses diagnosed with a pathogenic copy number variant (CNV) or variant of uncertain significance (VUS); and to characterize these variants in terms of testing indication, genomic location, size, and inheritance.

Methods

Retrospective study of singleton pregnancies with a pathogenic CNV or VUS from a single laboratory during 2012–2018. Probabilistic record linkage between the prenatal diagnosis dataset and perinatal outcome data for births from 20 weeks gestation was performed. If no birth record was found, this implied a pregnancy loss <20 weeks.

Results

We included 6945 prenatal microarray results; a pathogenic CNV was detected in 230 (3.3%, 95% CI: 2.9%–3.8%) and a VUS in 483 (7.0%, 95% CI: 6.4%–7.6%). Of pregnancies with a pathogenic CNV, 20.0% (95% CI: 15.3%–25.6%) had a live birth, 3.0% (95% CI: 1.5%–6.2%) had a perinatal death (stillbirth or neonatal death), and 77% (95% CI: 71.1%–81.9%) had no birth record. Of those with a VUS, 64.4% (95% CI: 60.0%–68.5%) had a live birth, 1.8% (95% CI: 1.0%–3.5%) had a perinatal death, and no birth record was found for 33.7% (95% CI: 29.7%–38.1%). Most pathogenic CNVs (61.1%) were <7 Mb in size. The most common microdeletion syndromes were DiGeorge, Wolf-Hirschhorn, and Cri-du-chat syndromes.

Conclusion

This study provides an overview of perinatal outcomes and frequency of recurrent CNVs observed in the prenatal microarray era.     

Neonatal outcomes of congenital diaphragmatic hernia in full term versus early term deliveries: A systematic review and meta-analysis

This systematic review and meta-analysis aimed to review the optimal timing of delivery at term for neonates with prenatally diagnosed congenital diaphragmatic hernia (CDH). We reviewed the literature up to December 19, 2022 using MEDLINE and the Cochrane Library databases. The inclusion criteria were original articles, comparative studies of CDH neonates delivered at an early term (37–38 weeks of gestation) and at full term (39 weeks of gestation or later), and comparative studies investigating outcomes of CDH neonates. Six studies met the inclusion criteria, including 985 neonates delivered at an early term and 629 delivered at full term. The cumulative rate of survival to discharge showed no significant difference between CDH neonates delivered at an early term (395/515; 76.7%) or at full term (345/467; 73.9%) (risk ratio [RR] 1.01; 95% confidence interval [CI], 0.89–1.16; p = 0.85). Furthermore, the number of neonates requiring oxygen therapy at discharge was not significantly different between CDH neonates delivered at an early term (32/370; 8.6%) and at full term (14/154; 9.1%) (RR, 0.99; 95% CI, 0.36–2.70; p = 0.99). Therefore, the optimal timing of delivery at term for neonates with CDH remains unclear.     

Genetic amniocentesis at 7–14 weeks of gestation

Genetic amniocentesis performed at 7–14 weeks of gestation was studied in a series of 138 patients of whom 50 wanted termination of pregnancy (⩽ 12 weeks). The material for analysis consisted of 132 samples due to two sampling failures and four samples being handled incorrectly. Forty-eight samples (36 per cent) were taken at 7–12 weeks of gestation, mainly transvaginally (36/48:75 per cent). The success rate of culture and karyotyping increased with the duration of pregnancy, but was only satisfactory from week 11 onwards. The time until harvest was then 14–15 days. The transvaginal approach is easy to perform and was accepted by the women, but we experienced bacterial or fungal overgrowth in 17 per cent of these samples, whereas no infection occurred in the samples taken transabdominally (n = 96). We conclude that genetic amniocentesis is feasible from week 11, but further studies concerning side effects, especially focusing on the procedure-related abortion risk, should be carried out before early amniocentesis is routinely applied.     

Mid-trimester amniocentesis and antibiotic prophylaxis

Objectives and Methods Assuming that the rate of fetal loss after amniocentesis may be reduced in patients receiving antibiotic prophylaxis, we conducted a retrospective study on untreated versus treated patients receiving prophylactic antibiotics (amoxicillin/clavulanic-acid or azithromycin) and evaluated the fetal loss rate within the 22nd week of gestation, also with respect to the risk of spontaneous abortion, both preexisting and related to mid-trimester amniocentesis. Results Spontaneous abortion occurred in 22 cases out of 1744 (1.26%). The incidence of spontaneous abortion was 1.3% among patients treated with antibiotic prophylaxis and 1.2% among untreated patients. Between patients with risk factors that predated amniocentesis, the spontaneous fetal loss rate was 9.2% in untreated patients versus 2.3% in patients treated (p = 0.10). In patients with procedure-related risk factors at amniocentesis, the spontaneous abortion rate was, respectively, 2.2 and 1.2% (p = 0.72). Conclusion Our data demonstrate that antibiotic prophylaxis does not reduce the risk of spontaneous abortion within the 22nd week of gestation. Compared with untreated patients, patients treated with amoxicillin showed the lower fetal loss rate (1.16 vs 0.31%), but the difference was not statistically significant (odds ratio (OR) = 3.68, p = 0.32). The same was true for patients with preexisting risks (OR = 4.25, p = 0.10). Copyright © 2007 John Wiley & Sons, Ltd.     

Re-evaluation of the colorimetric assay for cytidine deaminase activity

This study re-evaluated the colorimetric assay for cytidine deaminase (CTD), and showed that the optimum conditions were pH 7·5, 37°C, and up to 24 h. In addition, this method was found to require protein precipitation. Following these modifications, intra-assay and inter-assay coefficients of variation were below 5 per cent, indicating that the assay was highly reliable. CTD activity was determined in 282 serum samples from 206 normal pregnant women by the incubation of 100 μl of serum and 400 μl of 1·4 mmol/l cytidine substrate for 16 h at 37°C. Following protein precipitation, the ammonia liberated during conversion was measured by a colorimetric procedure. The mean (±SD) CTD activity was 7·31 ± 2·50 U at 3–12 weeks of gestation, 8·70 ± 2·12 U at 13–24 weeks, 7·59 ± 2·25 U at 25–36 weeks, and 7·29 ± 2·16 U at 37–42 weeks. High levels of CTD activity were found in patients with abruptio placentae and amnionitis associated with intrauterine fetal death (IUFD). The increase in CTD activity was noted from 3 days to 1 week before the confirmation of IUFD. The placenta contains extremely high levels of CTD, but cord serum does not. Thus, the excessive elevation of CTD activity was probably derived from progressive placental damage. This modified CTD assay was concluded to be simple and reliable, and may perhaps be useful in detecting pregnancy disorders.     

Association of amnioinfusion volume at the time of surgery for twin-twin transfusion syndrome and latency to delivery

Objective

To evaluate the impact of amnioinfusion and other peri-operative factors on pregnancy outcomes in the setting of Twin-twin transfusion syndrome (TTTS) treated via fetoscopic laser photocoagulation (FLP).

Methods

Retrospective study of TTTS treated via FLP from 2010 to 2019. Pregnancies were grouped by amnioinfusion volume during FLP (<1 L vs. ≥1 L). The primary outcome was latency from surgery to delivery. An amnioinfusion statistic (AIstat) was created for each surgery based on the volume of fluid infused and removed and the preoperative deepest vertical pocket. Regression analysis was planned to assess the association of AIstat with latency.

Results

Patients with amnioinfusion of ≥1 L at the time of FLP had decreased latency from surgery to delivery (61 ± 29.4 vs. 73 ± 28.8 days with amnioinfusion <1 L, p < 0.001) and increased preterm prelabor rupture of membranes (PPROM) <34 weeks (44.7% vs. 33.5%, p = 0.042). Amnioinfusion ≥1 L was associated with an increased risk of delivery <32 weeks (aRR 2.6, 95% CI 1.5–4.5), 30 weeks (aRR 2.4, 95% CI 1.5–3.8), and 28 weeks (aRR 1.9, 95% CI 1.1–2.3). Cox-proportional regression revealed that AIstat was inversely associated with latency (HR 1.1, 95% CI 1.1–1.2).

Conclusion

Amnioinfusion ≥1 L during FLP was associated with decreased latency after surgery and increased PPROM <34 weeks.     

Low-dose aspirin for prevention of adverse outcomes related to abnormal placentation

Meta-analysis of randomized studies on the use of low-dose aspirin in women at high risk of preeclampsia (PE) has demonstrated that if treatment is initiated at ≤16 weeks' gestation, there is significant reduction in the risk of PE [relative risk (RR) 0.47, 95% confidence interval (CI) 0.36–0.62], fetal growth restriction (RR 0.46, 95% CI 0.33–0.64), preterm birth (RR 0.35, 95% CI 0.22–0.57) and perinatal death (RR 0.41, 95% CI 0.19–0.92), whereas the effect of treatment after 16 weeks is substantially less (RR 0.78, 95% CI 0.61–0.99; RR 0.98, 95% CI 0.88–1.08; RR 0.90, 95% CI 0.83–0.97; and RR 0.93, 95% CI 0.73–1.19, respectively). Moreover, the decrease in the risk of PE from early onset treatment seems to be related to the dose of aspirin, and a dose of >80 mg daily should be considered for optimal benefits. © 2014 John Wiley & Sons, Ltd.     

Down syndrome maternal serum marker screening after 18 weeks' gestation

Women having access to prenatal care late in pregnancy may still wish to benefit from maternal serum screening for Down syndrome. Therefore, we established reference values for α-feto protein (AFP) and free β-human chorionic gonadotrophin (β-hCG), and assessed the diagnostic value of maternal serum marker screening at 18–35 weeks' gestation based upon a series of 4072 sera from unaffected pregnancies and 118 sera from pregnant women with fetuses affected by Down syndrome. Using a 1/250 risk cut-off, a detection rate of 72.9% (95% CI = 71.5–74.3%) was achieved with a false-positive rate of 7.51% (95% CI = 6.71–8.3%). This was not significantly different from the percentages observed in our 14–17 weeks routine screening (50 596 patients): 71.9% (95% CI = 71.5–72.3%) and 6.48% (95% CI = 6.28–6.68%), respectively. Detection and screen-positive rates were, respectively, 51.3% (95% CI = 35.6–67.0%) and 5.95% (95% CI = 5.12–6.68%) in women aunder 35 years of age, and 84.8% (95% CI = 76.9–92.7%) and 24% (95% CI = 20.7–27.3%) in women aged 35 years and over. In conclusion, maternal serum marker screening is feasible at 18 weeks' gestation and later, which may be of interest in selected cases. Copyright © 2002 John Wiley & Sons, Ltd.     

Solomon versus selective fetoscopic laser photocoagulation for twin-twin transfusion syndrome: A systematic review and meta-analysis

This meta-analysis aims to compare the perinatal outcome of twin-twin transfusion syndrome (TTTS) pregnancies undergoing selective versus vascular equator (Solomon) fetoscopic laser photocoagulation (FLP). We performed a systematic search in PubMed and Web of Science from inception up to 25 July 2021. Studies comparing the Solomon and selective techniques of FLP for treatment of TTTS pregnancies were eligible. Random-effects or fixed-effect models were used to pool standardized mean differences (SMD) and log odds ratio. Seven studies with a total of 1664 TTTS pregnancies (n = 671 undergoing Solomon and n = 993 selective techniques) were included. As compared to the selective FLP, Solomon was associated with a lower risk of recurrent TTTS compared to the selective technique (Log odds ratio [OR]: −1.167; 95% credible interval [CrI]: −2.01, −0.33; p = 0.021; I²: 67%). In addition, Solomon was significantly associated with a higher risk of placental abruption than the selective technique (Log [OR]: 1.44; 95% CrI: 0.45, 2.47; p = 0.012; I²: 0.0%). Furthermore, a trend for the higher risk of preterm premature rupture of membranes was observed among those undergoing Solomon (Log [OR]: 0.581; 95% CrI: −0.43, 1.49; p = 0.131; I²: 17%). As compared to selective FLP, the Solomon technique for TTTS pregnancies is associated with a significantly lower recurrence of TTTS; however, it significantly increases the risk of placental abruption.     

The value of echocardiography and Doppler in the prediction of fetal demise after laser coagulation for TTTS: A systematic review and meta-analysis

This study aimed to investigate the value of echocardiography and Doppler before fetoscopic laser coagulation for twin-twin transfusion syndrome (TTTS) in the prediction of intrauterine fetal demise (IUFD). We performed a systematic review and meta-analysis to compare preoperative parameters between fetuses with and without demise after laser surgery. Eighteen studies were included. Recipient twins have an increased risk of demise in case of preoperative absent/reversed flow (A/REDF) in the umbilical artery (odds ratio [OR] 2.76, 95% confidence interval [CI], 1.78-4.28), absent or reversed a-wave in the ductus venosus (OR 2.32, 95% CI, 1.70-3.16), or a middle cerebral artery peak systolic velocity > 1.5 multiples of the median (MoM) (OR 7.59, 95% CI, 2.56-22.46). In donors, only A/REDF in the umbilical artery (OR 3.40, 95% CI, 2.68-4.32) and absent or reversed a-wave in the ductus venosus (OR 1.66, 95% CI, 1.12-2.47) were associated with IUFD. No association was found between donor-IUFD and preoperative myocardial performance index (MPI). Two studies found an association between abnormal MPI and recipient demise. With this study, we have identified a set of preoperative Doppler parameters predictive of fetal demise after laser surgery. More research is needed to assess the utility of preoperative echocardiographic parameters such as the MPI in predicting IUFD.     

The effect of fetal gender on nuchal translucency at 10–14 weeks of gestation

Recent data have suggested that fetal nuchal translucency (NT) is affected by fetal gender. We investigated the size of this effect in 12 189 unselected pregnancies with known normal outcomes that had undergone NT measurements between 10 and 14 weeks of gestation. NT increased with gestation and was converted to multiples of the median (MoM) for the gestational day. The median NT MoM (95% CI) for female fetuses was 0.98 (0.97–0.99). This was significantly lower than that of the male fetuses (1.03; range1.02–1.04) (p<0.0005; Wilcoxon rank-sum test). The gender difference was not observed at 10 weeks but was observed from 11 weeks onwards. There is no obvious explanation for the above findings. Copyright © 2001 John Wiley & Sons, Ltd.     

Fetoscopic laser photocoagulation versus expectant management for stage I twin-to-twin transfusion syndrome: A systematic review and meta-analysis

To investigate the outcomes of asymptomatic stage I twin-to-twin transfusion syndrome (stage I TTTS) among patients treated with fetoscopic laser photocoagulation (FLP) versus expectant management. Databases such as PubMed, Web of Science and Scopus were systematically searched from inception up to March 1st, 2022. The primary outcome was at least one fetal survival at birth and secondary outcomes included gestational age at delivery, preterm premature rupture of membranes < 32 weeks, preterm birth < 32 weeks, and single and dual fetal survival. Five studies were included in the meta-analysis. There was no significant difference in terms of at least one survival (odds ratio (OR) = 1.40, 95%CI= (0.26, 7.43), P = 0.70), single survival (OR = 0.87, 95%CI= (0.51, 1.48), P = 0.60) and dual survival (OR = 1.63, 95%CI= (0.74, 3.62), P = 0.23) among FLP and expectant groups. Gestational age at delivery (mean difference = 1.19, 95%CI= (−0.25, 2.63), P = 0.10), the risk of PTB<32 weeks (OR = 0.88, 95%CI= (0.50, 1.54), P = 0.65), and pPROM<32 weeks (OR = 1.80, 95% CI= (0.41, 7.98), P = 0.44) were also comparable between the groups. Routine FLP of the placental anastomoses before 26 weeks of gestation is unlikely to be beneficial among asymptomatic stable stage I TTTS patients without cervical shortening as the procedure does not offer a survival advantage compared with expectant management.     

Spontaneous abortion after amniocentesis in women with a history of spontaneous abortion

The incidence of spontaneous abortion after amniocentesis (19 to 28 weeks gestation) in women who have had previous spontaneous abortions is compared with the rate in women who have not had previous spontaneous abortions. The outcome of the pregnancy after amniocentesis and the previous history of spontaneous abortion is reported for 691 pregnancies. The rate of spontaneous abortion after amniocentesis was found to be significantly higher in women who had one or more previous spontaneous abortions, 12/238 (5 per cent), than in women who did not, 6/453 (1.3 per cent). In women who reported two or more previous spontaneous abortions, the rate was 7/81 (8.6 per cent). No statistically significant effect of maternal age or gravidity was detected. The incidence of spontaneous abortion after amniocentesis was greater in the three weeks following the procedure (three for each of the three weeks) than in the subsequent seven weeks (nine for seven weeks).     

Social and geographical inequalities in prenatal care in Italy

The purpose of this study was to find out possible differences in prenatal diagnosis (PD) by amniocentesis or chorionic villus sampling and ultrasound examination before 16 weeks' gestation (early ultrasound examination, EUE), according to area of residence and level of education of the mothers. Data come from a multicentre study in Italy involving 43 maternity hospitals (Mercurio project) and were collected through structured interviews a few days after delivery. Study subjects were 1541 mothers of single non-malformed infants born between April 1992 and March 1994. Overall, the incidence of PD and EUE was 5.8 and 80 per cent, respectively. After adjustment for maternal age and other possible confounders, the odds ratios for PD were 2.19 (95 per cent confidence interval (CI)=1.26–3.81) when women residing in the northern regions were compared with those residing in the southern regions, and 2.06 (95 per cent CI=1.12–3.79) and 4.08 (95 per cent CI=1.97–8.42) when women with medium and high levels of education were compared with those with low level. For EUE, the odds ratios were 1.77 (95 per cent CI=1.32–2.36) and 2.88 (95 per cent CI=1.56–5.29) when comparing women with medium and high levels of education with those with low level. No relationship was found between area of residence and EUE. These geographical and social inequalities in prenatal care in Italy should be taken into account for the organization, delivery, and evaluation of pregnancy services in the coming years.     

Prognostic accuracy of factors associated with poor outcome in prenatally diagnosed sacrococcygeal teratoma: A systematic review and meta-analysis

Several factors associated with poor outcome in patients with prenatally diagnosed sacrococcygeal teratoma (SCT) have been found. However, the prognostic accuracy of these factors has not been well established. Therefore, we aimed to systematically review the prognostic accuracy of factors associated with poor outcome in these patients. We queried Search Premier, COCHRANE Library, EMCARE, EMBASE, PubMed, ScienceDirect, and Web of Science databases to identify studies regarding patients with prenatally diagnosed SCT. Poor outcome was defined as termination of pregnancy (TOP), intrauterine fetal death (IUFD), or perinatal death. We estimated the odds ratio of factors associated with poor outcome. Eleven studies (447 patients) were included. Overall mortality, including TOP, was 34.9%. Factors associated with poor outcome in fetuses with prenatally diagnosed SCT were cardiomegaly, hypervascular tumor, solid tumor morphology, fetal hydrops, and placentomegaly. A tumor volume to fetal weight ratio (TFR) of >0.12 before a gestational age of 24 weeks is predictive of poor outcome. The prognostic accuracy of factors associated with poor outcome in fetuses prenatally diagnosed with SCT seems promising. Factors associated with cardiac failure such as cardiomegaly, hypervascular tumor, solid tumor morphology, fetal hydrops, placentomegaly, and TFR >0.12 were found to be predictive of poor outcome.     

Prenatal diagnosis for women aged 37 years and over: to have or not to have

Forty percent of pregnant women aged 37 years and over do not have prenatal diagnosis despite being eligible for a free test. The present study aimed to determine how often, and which, untested women were making a choice about this, how many declined an offer and why. A questionnaire was given to untested women, aged 37 years and over, at no less than 24 weeks gestation. A total of 375 (81.5%) women declined, 72 (16%) were not offered a test and 13 presented too late antenatally. There was a three-fold increased likelihood (OR 3.10 95% CI 1.44, 6.65) of no offer for urban non-English speaking background women, compared with the reference group (metropolitan, English speaking). Unpartnered women were also significantly less likely to receive an offer (OR 3.18, 95% CI 1.19, 8.46). Risk to the baby was the main reason for declining. When offered non-invasive prenatal screening, most decliners of prenatal diagnosis accepted, even those who declined because they were opposed to abortion. We estimate that overall 33% of older pregnant women were being offered and declining amniocentesis and/or chorion villus sampling (CVS). Only 6% were not offered a test, but this small proportion is over-represented by minority groups who must be given equal opportunity to make this choice. Copyright © 2001 John Wiley & Sons, Ltd.