Prenatal testing for Imprinting Disorders: A clinical perspective

Imprinting Disorders (ImpDis) are a group of congenital conditions caused by aberrant imprinting resulting in disturbed expression of parentally imprinted genes. ImpDis are rarely associated with major malformations, but pre- and/or postnatal growth and nutrition are often affected. In some ImpDis, behavioral, developmental, metabolic and neurological symptoms might present in the perinatal context or later in life, and in single ImpDis, there is a higher risk of tumors in childhood. Prognosis depends in part on the molecular cause of each ImpDis, but due to high clinical variability and (epi)genetic mosaicism, predicting the clinical outcome of a pregnancy solely based on the underlying molecular disturbance is difficult. Therefore, interdisciplinary care and treatment approaches play an important role in the management and decision making of affected pregnancies, especially taking into account fetal imaging in addition to genetic findings. Prenatal findings influence perinatal management, and thereby improve the prognosis of ImpDis associated with severe but sometimes transient clinical complications in the neonatal period. Therefore, prenatal diagnosis can be crucial for appropriate management not only to the pregnancy itself but might also have a life-long effect.     

Perinatal outcome after selective fetal reduction in monochorionic twin pregnancies: A comparison of techniques over a 20-year period

Objective

To assess the perinatal outcome after fetal reduction in complicated monochorionic (MC) twin pregnancies by comparing different techniques.

Methods

A retrospective cohort study at a national referral center comparing data between four techniques: interstitial laser coagulation, radiofrequency ablation (RFA), fetoscopic laser coagulation (FLC) and bipolar cord coagulation (BCC). The primary outcome was the mortality of the co-twins. Secondary outcomes were preterm pre-labor rupture of membranes (PPROM), gestational age at delivery and neonatal morbidity.

Results

259 MC twin pregnancies underwent selective fetal reduction: 29 IL, 64 RFA, 85 FLC and 81 BCC. The perinatal mortality rate was 29% and fetal demise of the co-twins occurred in 19%. The lowest mortality rate was seen after BCC (17%, p = 0.012). PPROM occurred in 18% patients without significant differences between techniques. The mean gestational age at delivery in liveborn children was 35 weeks and did not differ between techniques. Severe cerebral injury and neonatal morbidity were reported in 4% and 14%, respectively, without significant differences between techniques.

Conclusions

Selective fetal reductions in MC twins are precarious procedures with an increased risk of perinatal mortality of the co-twins. Our results show the lowest mortality rates after BCC. However, high PPROM rates were seen irrespective of the technique.     

Justification of maternal serum alphafetoprotein screening in a population with low incidence of neural tube defects

A prospective study of maternal serum alphafetoprotein (α-FP) screening of 9838 women in an area with low prevalence of neural tube defects and predominance of anencephalics revealed that an intervention point of single serum α-FP level above 2·8 times the median was appropriate for this population. Ninety per cent of anencephalics and all fetuses with anterior abdominal wall defects were detected. There was no spina bifida among the population screened. Two per cent of the population screened had serum α-FP level above this cut-off level. Thirty-two per cent of twin pregnancies, 7 per cent of small-for-gestational age infants and 9 per cent of pregnancies which ended in either abortion or perinatal death in the population screened also had one serum α-FP level above this intervention point. The false positive rate was 66 per cent. This false positive rate was only reduced to 63 per cent if instead of one, two serum α-FP level above this intervention point was considered abnormal. Using this strategy there was no significant reduction in the detection rate of fetal anomalies and other pregnancy complications. Because of the predominance of anencephalics in this population the diagnosis of fetal anomaly in women with abnormal serum a-FP level was made by ultrasound examination alone. The reason amniocentesis was not performed in these patients was to avoid unnecessary loss of normal pregnancies which may result from this procedure.     

Non-invasive prenatal testing in the management of twin pregnancies

Twin pregnancies are common and associated with pregnancy complications and adverse outcomes. Prenatal clinical management is intensive and has been hampered by inferior screening and less acceptable invasive testing. For aneuploidy screening, meta-analyses show that non-invasive prenatal testing (NIPT) through analysis of cell-free DNA (cf-DNA) is superior to serum and ultrasound-based tests. The positive predictive value for NIPT is driven strongly by the discriminatory power of the assay and only secondarily by the prior risk. Uncertainties in a priori risks for aneuploidies in twin pregnancies are therefore of lesser importance with NIPT. Additional information on zygosity can be obtained using NIPT. Establishing zygosity can be helpful when chorionicity was not reliably established early in pregnancy or where the there is a concern for one versus two affected fetuses. In dizygotic twin pregnancies, individual fetal fractions can be measured to ensure that both values are satisfactory. Vanishing twins can be identified by NIPT. Although clinical utility of routinely detecting vanishing twins has not yet been demonstrated, there are individual cases where cf-DNA analysis could be helpful in explaining unusual clinical or laboratory observations. We conclude that cf-DNA analysis and ultrasound have synergistic roles in the management of multiple gestational pregnancies.     

Outcome of fetal echogenic bowel: A systematic review and meta-analysis

The main aim of this systematic review was to explore the outcome of fetuses with isolated echogenic bowel (EB) on antenatal ultrasound. Inclusion criteria were singleton pregnancies with isolated EB no associated major structural anomalies at the time of diagnosis. The outcomes observed were: chromosomal anomalies, cystic fibrosis (CF), associated structural anomalies detected only at follow-up scans and at birth, regression during pregnancy, congenital infections, intra-uterine (IUD), neonatal (NND) and perinatal (PND) death. Twenty-five studies (12 971 fetuses) were included. Chromosomal anomalies occurred in 3.3% of the fetuses, mainly Trisomy 21 and aneuploidies involving the sex chromosomes. Cystic fibrosis occurred in 2.2%. Congenital infections affected 2.2%, mainly congenital Cytomegalovirus (CMV) infection. The majority of fetuses with EB experienced regression or disappearance of the EB at follow-up scans. Associated anomalies were detected at a follow-up scan in 1.8%. Associated anomalies were detected at birth and missed at ultrasound in 2.1% of cases. IUD occurred in 3.2% of cases while the corresponding figures for NND and PND were 0.4% and 3.1%. Fetuses with EB are at increased risk of adverse perinatal outcome, highlighting the need for a thorough antenatal management and postnatal follow-up. Assessment during pregnancy and after birth should be performed in order to look for signs of fetal aneuploidy, congenital infections and associated structural anomalies.     

Etiology and management of early pregnancy renal anhydramnios: Is there a place for serial amnioinfusions?

Early pregnancy renal anhydramios (EPRA) comprises congenital renal disease that results in fetal anhydramnios by 22 weeks of gestation. It occurs in over 1 in 2000 pregnancies and affects 1500 families in the US annually. EPRA was historically considered universally fatal due to associated pulmonary hypoplasia and neonatal respiratory failure. There are several etiologies of fetal renal failure that result in EPRA including bilateral renal agenesis, cystic kidney disease, and lower urinary tract obstruction. Appropriate sonographic evaluation is required to arrive at the appropriate urogenital diagnosis and to identify additional anomalies that allude to a specific genetic diagnosis. Genetic evaluation variably includes karyotype, microarray, targeted gene testing, panels, or whole exome sequencing depending on presentation. Patients receiving a fetal diagnosis of EPRA should be offered management options of pregnancy termination or perinatal palliative care, with the option of serial amnioinfusion therapy offered on a research basis. Preliminary data from case reports demonstrate an association between serial amnioinfusion therapy and short-term postnatal survival of EPRA, with excellent respiratory function in the neonatal period. A multicenter trial, the renal anhydramnios fetal therapy (RAFT) trial, is underway. We sought to review the initial diagnosis ultrasound findings, genetic etiologies, and current management options for EPRA.     

Managing twins discordant for fetal anomaly

An excess of structural anomalies is observed in twins compared to singletons. Approximately 1–2% of twin pregnancies may face the dilemma of expectant management versus selective termination following diagnosis of an anomaly affecting only one fetus. If the option of selective fetocide is considered, the main variable determining the technique to achieve this aim is chorionicity. In a dichorionic pregnancy, passage of substances from one twin into the circulation of the co-twin is unlikely due to the lack of placental anastomoses, hence KCl can be injected safely into the circulation of the affected twin to produce fetal asystole. In monochorionic twin pregnancies, selective termination needs to be performed by ensuring complete and permanent occlusion of both the arterial and venous flows in the umbilical cord of the affected twin, in order to avoid acute haemorrhage from the co-twin into the dying fetus, which may lead to death or organ damage. Bipolar cord coagulation under ultrasound guidance is associated with approximately 70–80% survival rates. Copyright © 2005 John Wiley & Sons, Ltd.     

Antepartum rupture of the intertwin-dividing membrane in monochorionic diamniotic twins: a case report and review of the literature

We report a case of monochorionic diamniotic twin gestation confirmed by ultrasound visualization of the thin intertwin-dividing membrane at 32 weeks' gestation. Ultrasound at 36 weeks failed to demonstrate the thin dividing membrane. The pregnancy ended a few days later with spontaneous vaginal delivery of the first twin. The second twin was in transverse lie with no membranes that could be felt around. Severe fetal heart rate deceleration developed, prompting delivery by emergency caesarean section. Cord entanglement was noted at the time of delivery, which resulted in severe perinatal morbidity of the second twin. The antepartum rupture of the dividing membrane must have happened some time between 32 and 36 weeks. The etiology for this intrauterine disruption is unknown. A review of the literature about the antepartum rupture of the intertwin-dividing membrane is described, along with its possible causes and complications. In addition, we discuss possible causes of incorrect amnionicity determination, and thus how to minimize these pitfalls. We conclude that antepartum disruption of the intertwin-dividing membrane is more common than previously thought. Moreover, prenatal ultrasonographic visualization of a dividing membrane in a diamniotic twin pregnancy does not rule out future change in this environment to a monoamniotic one, with all its perinatal morbidity and mortality complications, which result mainly from cord entanglement. This suggests a modification in the method and frequency of the prenatal fetal well-being follow-up, as well as the time and mode of delivery. Copyright © 2005 John Wiley & Sons, Ltd.     

Is placental mosaicism associated with poor perinatal outcome?

In 37 pregnancies with placental mosaicism detected at first-trimester chorionic villus sampling in 2000 pregnancies, two pregnancies (5.4 per cent) ended in a spontaneous abortion at 15 weeks (46,XX/47,XX, + 16) and in a perinatal loss in a term pregnancy (46,XY/ 47,XY, +10), respectively. The outcome of the other 35 pregnancies was normal. The total pregnancy loss rate before 28 weeks in the first 1000 pregnancies was previously reported to be 3.6 per cent.     

Preterm delivery rate and fetal outcome in structurally affected twin pregnancies: A retrospective matched control study

Data from 23 twin pregnancies with one structurally affected fetus were compared with data from 23 twin pregnancies with proven absence of structural fetal anomalies and matched for maternal age, parity, and year of delivery. The preterm delivery rate ( < 37 weeks) was high in both groups but not significantly different (57 vs. 48 per cent). Perinatal mortality was significantly higher in the structurally affected twin pregnancies (65 vs. 9 per cent). In the affected twins, birth weight of the anomalous fetus was significantly lower than that of the normal co-twin. Since there was no difference in the incidence of maternal disease (hypertensive disorders, diabetes), it was concluded that the higher perinatal mortality was determined mainly by the nature of the anomaly and not by the preterm delivery rate.     

Second-trimester echogenic small bowel: An increased risk for adverse perinatal outcome

2267 singleton fetuses who had one ultrasound examination between 15 and 21 weeks' gestation were prospectively evaluated for echogenic small bowel. Thirty-two cases of echogenic small bowel were detected—a prevalence of 1·4 per cent. Echogenic fetal small bowel was divided into two grades: grade 1, where the small bowel was more echogenic than the liver; and grade 2, where the small bowel had the echogenicity of bone. In contrast to 19/23 fetuses with grade 1 small bowel echogenicity, only 2/9 fetuses with grade 2 echogenic bowel had a normal pregnancy outcome (Fisher's exact test; P⩽0·01). Complications associated with second-trimester echogenic small bowel included in utero cytomegalovirus infection, second-trimester growth restriction, intrauterine fetal demise, and chromosomal abnormalities. Second-trimester fetal echogenic small bowel is associated with an increased risk of an adverse outcome. The prevalence of perinatal and neonatal complications is significantly greater when small bowel echogenicity approaches that of bone.     

Spontaneous cessation of umbilical blood flow in the acardiac fetus of a twin pregnancy

The acardiac fetus is a rare entity found only in monozygotic multiple pregnancy. Although the acardiac fetus is non-viable, the perinatal mortality rate for the normal fetus may be as high as 50 per cent, and is usually associated with fetal heart failure and hydrops fetalis, or as the result of prematurity. In this communication, we describe a case of spontaneous cessation of blood flow to an acardiac fetus and discuss the management of this condition with special reference to optimizing the outcome for the normal fetus.     

Enhanced twin pregnancy detection within an open neural tube defect and down syndrome screening protocol using free-beta hCG and AFP

We have applied our multimarker approach of maternal serum alpha-fetoprotein (AFP) and free-beta human chorionic gonadotropin (hCG) for Down syndrome screening to multiple gestations to assess its efficacy for improved detection of twin and triplet pregnancies. This study matched 225 cases of twin pregnancy and 39 cases of triplet pregnancy each with ten singleton pregnancies based on gestational week, race, time to receive sample, time of year of sample, and geographical area. The ratios of the MOM for each group at the tenth, 50th, and 90th percentiles were compared by the Wilcoxon test. Risks for twins were calculated using Bayes' rule, the age-related incidence of twins, and the levels of AFP and free-beta hCG. The tenth, 50th, and 90th percentiles of free-beta hCG MOMs in twin and triplet cases were 0.85, 1.99, and 4.51, and 1.38, 2.78, and 4.07, respectively. For AFP, the MOMs at these percentiles were 1.26, 1.91, and 2.99, and 2.02, 2.68, and 5.30, respectively. The twin and triplet distributions for each marker were statistically significantly different from the singleton distributions (P<0.0001) and from each other (P=0.0012). At a twin risk cut-off of 1 in 50, 77.4 per cent of all twin gestations can be detected in a second-trimester AFP and free-beta hCG screening protocol with 5.1 per cent of singleton pregnancies falsely identified as at risk for twins. Our dual marker protocol for mid-trimester pregnancy screening combining AFP and free-beta hCG can identify over 77 per cent of twin pregnancies in women less than 35 years of age. This benefit may contribute to an improved outcome of pregnancy by early detection of multiple gestation.     

Intermittent absent and reversed umbilical artery flows in appropriately grown monochorionic diamniotic twins in relation to proximate cord insertion: A harmful combination?

Objective

To compare the prevalence of intermittent absent or reversed end-diastolic flow (iAREDF) in the umbilical artery in appropriately grown monochorionic diamniotic (MCDA) pregnancies with and without proximate cord insertion (PCI), and to evaluate pregnancy outcome.

Methods

The prevalence of iAREDF in MCDA pregnancies with PCI (n = 11) was compared with a control group without PCI (n = 33). PCI was defined as a distance between the cord insertions below the fifth percentile. Placental sharing, number, and diameter of anastomoses were assessed by placental examination. Pregnancy outcome was evaluated.

Results

iAREDF was present in 7/11 PCI pregnancies, compared with 0/33 in the control group (P ≤ .01). All PCI pregnancies and 94% of controls had arterioarterial (AA)-anastomoses (P = .56), the diameter was larger in the PCI group, respectively 3.3 vs 2.1 mm (P = .03). Three cases with iAREDF had adverse outcome, two resulted in fetal death of which one with brain damage in the co-twin, another underwent early premature emergency section for fetal distress.

Conclusion

iAREDF occurs in a large proportion of MCDA pregnancies with PCI and is related to the diameter of the AA anastomosis. We hypothesize that iAREDF in appropriately grown MCDA twin pregnancies reflects an unstable hemodynamic balance with an increased risk for fetal deterioration. Whether outcome in these pregnancies can be improved by altered management requires further investigation.

     

Stage-based approach to the management of fetal growth restriction

Fetal growth restriction (FGR) is among the obstetrical entities with the greatest variation in clinical practice. The first clinically relevant step in the management of FGR is the distinction of ‘true’ FGR, associated with signs of abnormal feto-placental function and poorer perinatal outcome, from small for gestational age fetuses, which do not present abnormal Doppler and have near normal perinatal outcome. Such distinction should not be only relied on umbilical artery Doppler, as this parameter identifies only severe, early-onset, forms of placental insufficiency. Instead, FGR should be diagnosed in the presence of any of the factors associated with a poorer perinatal outcome, including Doppler cerebroplacental ratio and uterine artery Doppler, a growth centile below the third centile. Upon diagnosis, differentiating into early-onset and late-onset FGR is useful to distinguish two clear phenotypes, with differences in severity, association with preeclampsia, and sequence of fetal deterioration. Finally, management of FGR aims at an optimal balance between minimizing fetal injury or death versus the risks of iatrogenic preterm delivery. We propose a protocol that integrates current evidence to classify stages of fetal deterioration, and establishes follow-up intervals and optimal delivery timings, which may facilitate decision-making and minimize variability in the clinical management. © 2014 John Wiley & Sons, Ltd.     

A quantitative estimation of the effect of prenatal diagnosis in dizygotic twin pregnancies in women of advanced maternal age

Genetic counselling in a dizygotic twin pregnancy is complicated by the large number of possible pregnancy outcomes and by the conceivable differences in the parental valuation of these outcomes. We present the probability distributions of the pregnancy outcomes in dizygotic twin pregnancies for women from 35 to 45 years old without prenatal diagnosis and with transabdominal chorionic villus sampling (TA-CVS) or amniocentesis (AC), using data from the literature. TA-CVS always gives a higher probability of a favourable pregnancy outcome (the birth of one or two infants with a normal karyotype) than AC. For a 35-year-old woman, a 0·7 per cent risk of an unfavourable pregnancy outcome without prenatal diagnosis has to be weighed against the 2·1 per cent excess risk of loss of the entire pregnancy after TA-CVS. For a 45-year-old woman, a 10·2 per cent risk of an unfavourable pregnancy outcome without TA-CVS has to be balanced against a 4·4 per cent excess risk of pregnancy loss after TA-CVS. This study provides a quantitative tool for the support of individual parents with respect to the decision to undergo prenatal diagnosis in a dizygotic twin pregnancy.     

Intrauterine rescue transfusion in monochorionic multiple pregnancies with recent single intrauterine death

To assess the role of fetal blood sampling and intrauterine transfusion in monochorionic (MC) multiple pregnancy complicated by single intrauterine death (IUD), we reviewed ten cases over a 4-year period in a tertiary referral centre which underwent fetal blood sampling within 24 h of death of its MC co-twin. Intrauterine rescue transfusion was performed in all seven anaemic fetuses (hematocrit; Hct<30%) to raise the fetal Hct to ≥40%. The rationale was to prevent death and/or brain injury. Two fetuses, which were severely acidaemic at blood sampling, died in utero within 24 h of the procedure. In two cases, the surviving twins manifested abnormal sonographic findings of the fetal brain 2–5 weeks later and underwent late termination. In two cases, the pregnancies continued uneventfully until delivery at 35 and 40 weeks' gestation with good neonatal outcome. In one case the co-twin delivered 1 week later at 29 weeks but died within 12 h. Fetuses without anaemia were not transfused and had normal clinical outcomes. We suggest that intrauterine rescue transfusion before the development of severe acidaemia in anaemic surviving MC co-twins may prevent fetal death, but does not necessarily prevent brain injury. Until its role becomes clearer, we recommend that its use be restricted to situations in which the parents and the local jurisdiction allow late termination as an option if brain injury subsequently manifests on ultrasound. Copyright © 2001 John Wiley & Sons, Ltd.     

Maternal serum alpha fetoprotein in monozygotic and dizygotic twin pregnancies

Maternal serum α-fetoprotein (MSAFP) values in the second trimester have been related to pregnancy outcome for 100 normal twin pairs, 42 monozygous (MZ) and 58 dizygous (DZ), liveborn after 28 weeks gestation. The median MSAFP value was 1.9 multiples of the median value (MOM) for uncomplicated singleton pregnancies. Both very low and very high MSAFP values were associated with twins of low birthweight. MSAFP values were higher in MZ than DZ twin pregnancies particularly those with dizygotes of like-sex. This effect was even more marked when only dichorionic like-sex twin pairs were compared.     

Incidence of abortion after genetic amniocentesis in twin pregnancies

Fetal outcome after genetic amniocentesis (AC) in viable twin pregnancies was analysed in a retrospective study at three centres in order to estimate the rate of fetal loss after AC. The maternal age ranged from 33 to 45 years (mean 36.7 years). The gestational age varied between 15 and 20 weeks of gestation (mean 17.1). In 98 viable twin pregnancies with complete follow-up, spontaneous abortion of both fetuses occurred within 28 completed weeks of gestation in eight pregnancies and six women aborted within 20 completed weeks of gestation after AC, corresponding to a rate of fetal loss of 8.1 and 6.1 per cent, respectively (excluding the loss of five twins with viable outcome of the co-twin in five pregnancies).