Roberto Fogliani

Haematological indices at fetal blood sampling in monochorionic pregnancies complicated by feto-fetal transfusion syndrome

36 MCDA twin pregnancies with FFTS investigated by fetal blood sampling (FBS) were studied over a 10‐year period (1988–1997). The haematological data obtained at FBS were compared between the donor and recipient fetuses. It was shown that the donor fetus had a significantly lower haematocrit (35·7 per cent versus 47·2 per cent; p<0·001), haemoglobin (12·2 gs/dl versus 15·8 g/dl; p<0·001), and red blood cell count (2·9×1012/l versus 3·8×1012/l; p=0·006) compared with the recipient fetus. A haematocrit discordancy of >15 per cent, however, was found in only 25 per cent of twin pairs. There were no significant inter twin differences in the remaining indices. The study concluded that although there are significant differences in haematocrit and red cell mass between the donor and recipient fetuses, only a minority of fetuses will have degrees of discordancy suggested in the literature to be diagnostic. We suggest that FBS does not have a role in establishing the diagnosis of FFTS, although its role in determining the degree of haematocrit discordancy to assist in timing of delivery remains to be evaluated.

Confined placental mosaicism at chorionic villous sampling: risk factors and pregnancy outcome

This study aims to investigate the clinical relevance of confined placental mosaicism (CPM) detected at chorionic villous sampling (CVS) and to identify risk factors for this condition.

Discordant Prenatal Phenotype and Karyotype of Monozygotic Twins Characterized by the Unequal Distribution of Two Cell Lines Investigated by Different Methods: A Review

We present the case of a monozygotic twin pregnancy discordant for phenotype and karyotype. A chorionic villus sample was performed at the 11th week of gestation in a primigravida because of cystic hygroma detected by ultrasound in one twin of a monochorionic, biamniotic pregnancy. Rapid testing by means of quantitative fluorescence polymerase chain reaction and conventional karyotyping, obtained by both short- and long-term culture, revealed a homogeneous monosomy X (45,X). Amniocentesis was performed separately for both twins before termination and showed an homogeneous monosomy X in one sample and a 46,X,del(X)(p11.1) karyotype in the other one. Postmortem fetal tissues culture confirmed the discordant karyotype between the two embryos. Placental samples obtained after termination revealed the cell line which was not detected at chorionic villus sampling. Based on this and previous reports, we suggest that in cases of a phenotypic discordance detected at ultrasound in the first trimester, it is advisable to perform a karyotype analysis on amniocytes because it better reflects fetal constitution rather than chorionic villi or lymphocytes in case of heterokaryotipic monosomy X monochorionic twins.

Selective termination by intrahepatic vein alcohol injection of a monochorionic twin pregnancy discordant for fetal abnormality

A 33 year old woman was referred with a twin pregnancy discordant for fetal abnormality. Initial ultrasound at 17 weeks of gestation confirmed, in one of the twins, a lumbo-sacral myelomeningocoele associated with an absent cerebellum, a lemon shaped head, and bilateral talipes. The other twin appeared normal. The ultrasound appearances of concordant external genitalia, indeterminate septa1 thickness (1.7 mm), and absent ‘twin peak’ sign, were suggestive of monochorionic placentation. Placental vascular anastomoses between the twins, and therefore monochorionic placentation, were confirmed by injecting donor adult red cells into the intrahepatic vein of the normal twin, and then demonstrating their substantial intertwin passage on Kleihauer testing of fetal blood sampled from the abnormal twin ( 1 6% adult cells) after a delay of 30 min. The parents received detailed counselling but remained adamant that they would not consider continuing the pregnancy. In the absence of alternative options, they requested that both twins be terminated. After discussing this at length, they consented to experimental selective fetocide which was performed at 18 weeks of gestation. One millilitre 100% alcohol (Martindale Pharmaceuticals, Essex UK) was injected under ultrasound control into the lumen of the abnormal twin’s intrahepatic vein, resulting in immediate asystole. In the healthy twin, umbilical and cerebral arterial Doppler waveforms showed no evidence of haemodynamic instability on continuous monitoring over the first 15 min, intermittent monitoring over the next 90 min, and then again 24 h later. The pregnancy progressed without incident, with

Prenatal ultrasound predictors of postnatal major cerebral abnormalities in fetuses with apparently isolated mild ventriculomegaly.

We aim to examine the incidence of major cerebral abnormalities on postnatal imaging in cases with isolated mild ventriculomegaly on fetal sonography and to evaluate the relationship between the presence or absence of such defects and prenatal ultrasound factors.

Neurofibromatosis type 1 and pregnancy: Maternal complications and attitudes about prenatal diagnosis

Neurofibromatosis type 1 (NF1) is one of the most commoninherited genetic disorders with an incidence of 1/2,500 to 1/3,300 live births. The disease is caused by a mutation in NF1,atumorsuppressorgeneon17q11.2codingforneurofibromin,orbyamicrodeletioninvolvingtheNF1anditssurroundingregion.NF1is an autosomal dominant condition with complete penetranceafter childhood. Almost half the cases result from a de novomutation,whiletheothersinheritthealteredgenefromanaffectedparent.Thediseaseismarkedbypoorgenotype–phenotypecorre-lation and high inter- and intra-familial variability. Thereforegenetic counseling for affected individuals is hampered by thedifficulty in forecasting the clinical outcome for future offspring.Prenatal testing can be carried out if the parental mutation isknown, or if there are multiple affected family members, andlinkagehasbeenestablishedwithinthefamily;suchtestingisusefulfor establishing the presence of the parental mutation in the fetalDNA, but, as noted, cannot make any prediction about diseaseseverity [Origone et al., 2000; Terzi et al., 2009].Pregnancyhasalwaysbeenconsideredacriticaltimeforwomenwith NF1 because of reports of increased complications duringgestationarisingfrompre-eclampsia,pretermlabor,IUGR,hyper-tension, oligohydramnios, and spontaneous abortion and/or still-birth [Blickstein and Lancet, 1987; Sharma et al.,1991;Segalet al.,1999].Furthermore,casereportsdescribedtheassociationbetweenpregnancy and HELLP syndrome [Hagymasy et al., 1998; Agarwaletal.,2003],diagnosisofmalignantperipheralnervesheathtumor(MPNST)[Posmaaetal.,2003;KelloggandWatson,2010;Nelsonet al., 2010] and the occurrence of pheochromocytoma [Liu et al.,1996]. Although Dugoff and Sujansky [1996] presented a largestudy of pregnancy in 105 women, including data from 247gestations and noted a greater cesarean rate than in thegeneral population, they did not find an increased incidence ofany of these complications. However they did describe thegrowth of new neurofibromas and the enlargement ofexistingneurofibromasinmorethanthehalf.Althoughthemajor-ity of NF1 pregnant women did not report complications, someinvestigators proposed special monitoring in specific situations[Chetty et al., 2011].Here we describe our experience in the management of preg-nancies in women with NF1, and their attitude towards prenataldiagnosis. We included 43 women with a total of 79 pregnancies.Eightofthewomen(18.6%)werereferredforcareduringtheentiregestationalperiod,whiletheother35womenhadtheirpregnanciesdetected before joining our program; for them we obtained datafrom a review of their medical records and through personalinterviews. Among these 79 pregnancies, 65 were carried to termwhile the other 14 resulted in five first trimester spontaneousabortions, seven elective terminations (not related to concernsaboutNF1),andtwotherapeuticabortionsafterprenataldiagnosisthrough chorionic villus sampling (CVS). Two of the 65 full termpregnancies were twins, for a total of 67 live births.Forwomenvisitingourcenterbeforeandduringtheirpregnan-cies, we set up a model based on a set of preconceptional multi-specializedevaluationsthatwefeltwereaprerequisiteforaproperpersonalized management of pregnancy in women with NF1. The

Fetal Behavioral States

Main points: historical survey, sleep in children and premature infants, fetal micro-awakenings are not wakefulness, fetal ocular motions building blocks of the visual system, development of behavioral states, and differences and similarities with neonatal states

Prenatal and postnatal findings in five cases of Fryns syndrome

It is characterized by a variety of congenitalanomalies, such as diaphragmatic hernia, facial dysmorphisms(coarse face, hypertelorism, broad and flat nasal bridge withthick nasal tip, long philtrum, tented upper lip, wide mouth,micrognathia, low-set and poorly formed ears), distal digitalhypoplasia, and others (cerebral, ocular, cardiovascular,genitourinary).

Unusual prenatal presentation of rubinstein-taybi syndrome: A case report

Rubinstein–Taybi syndrome (RTS) is a rare multiple congenital anomalies‐intellectual disability syndrome. The diagnosis is made after birth and based on the detection of signs such as growth and developmental delay, minor facial anomalies, and broad thumbs and halluces. It is rare to suspect RTS during the prenatal period. We report here the approach to a patient with RTS whose pregnancy was complicated by multiple congenital anomalies. However, in the presence of the broad thumb and facial anomalies, we were able to suggest the correct diagnosis. The RTS was confirmed at birth and the molecular analysis of the major causative gene revealed a previously unreported heterozygous truncating mutation of CREBBP. This report provides new knowledge of the fetal phenotype of RTS.

Author's reply regarding “Confined placental mosaicism at chorionic villous sampling: risk factors and pregnancy outcome”

We highly appreciated the comment of Toutain et al. regarding our study on obstetrical and neonatal outcome in women with confined placental mosaicism (CPM) at chorionic villous sampling. These authors suggest that only mosaicism of meiotic origin (type III) may impact on obstetrical outcome. This is biologically plausible, and the authors support their view reporting their own data on 20 women with type III CPM, of whom four (20%) had unfavorable obstetrical outcome. These results do not contrast with our data. We also detected a higher frequency of pregnancy-induced hypertension in women carrying pregnancies with type III CPM (20%, p=0.03 when compared with controls). This result was already mentioned in the last paragraph of the results section. In contrast, we failed to detect other statistically significant differences when comparing pregnancy outcomes inwomenwith type III CPMwith thosewith a normal karyotype at chorionic villous sampling. These results were not reported in details in our original manuscript. They are now thoroughly illustrated in Table 1. The data refer to ten women with type III CPM rather than the original 13 women, because one had a spontaneous abortion before 20weeks of gestation and two decided for induced abortion as they were concerned about the diagnosis of CPM. In contrast to Toutain et al., we did not investigate neonatal growth restriction because this outcome is a transient condition and a debatable outcome. Overall, our data are not incompatible with a worse pregnancy outcome inwomen carrying type III CPMpregnancies. However, our study was definitely underpowered to draw meaningful conclusions. For this reason, we deemed it scientifically inappropriate to emphasize the results emerging from subgroup analyses in our original study. The low number of cases per group and the use of multiple comparisons expose these analyses to a significant risk of types I and II errors. These limits of our study are clearly stated in the discussion. Much larger series are warranted to perform reliable subgroup analyses. For this reason, we disagree with the definite tone used by Toutain et al. The question on obstetrical outcome in women with pregnancies complicated by CPM remains open and requires additional investigation. Controlled studies, that is, cohort studies using women who were diagnosed with a normal fetal karyotype at CPM as controls, are as yet very rare. Most available evidence has not reported on the long-term outcome of affected children. No study at present can draw robust subgroup analyses Table 1 Pregnancy outcome in gestations lasting more than 20weeks in women carrying type III confined placental mosaicisms and controls