N. J. Leschot

Reproductive outcome after PGD in couples with recurrent miscarriage carrying a structural chromosome abnormality: a systematic review

BACKGROUND Preimplantation genetic diagnosis (PGD) has been stated to improve live birth rates compared with natural conception in couples with recurrent miscarriage (RM) carrying a structural chromosome abnormality. It is unclear to what extent this claim can be substantiated by evidence. A systematic review of the literature was performed on the reproductive outcome of these couples after natural conception or after PGD. METHODS MEDLINE, EMBASE and the Cochrane database were searched until April 2009. Trials, patient series and case reports describing reproductive outcome in couples with RM carrying a structural chromosome abnormality after natural conception and/or after PGD were included. Since no randomized controlled trials or non-randomized comparative studies were found, separate searches for both groups were conducted. Primary outcome measure was live birth rate per couple. Secondary outcome measure was miscarriage rate per couple. RESULTS Four observational studies reporting on the reproductive outcome of 469 couples after natural conception and 21 studies reporting on the reproductive outcome of 126 couples after PGD were found. After natural conception, live birth rate per couple varied between 33 and 60% (median 55.5%) after parental chromosome analysis; miscarriage rate ranged from 21 to 40% (median 34%). After PGD, live birth rate per couple varied between 0 and 100% (median 31%) after parental chromosome analysis; miscarriage rate ranged from 0 to 50% (median 0%). CONCLUSIONS Currently, there are insufficient data indicating that PGD improves the live birth rate in couples with RM carrying a structural chromosome abnormality.

Risks of midtrimester amniocentesis; assessment in 3000 pregnancies

Summary. The obstetric outcome of 3000 pregnancies with midtrimester amniocentesis was followed in all but one patient. Thirty pregnancies ended in fetal death or abortion within 3 weeks after amniocentesis. Chronologically 23 of these occurred in the first series of 1500 pregnancies and the remaining seven fetal deaths/abortions within 3 weeks after amniocentesis occurred in the second series of 1500 pregnancies. Fetal loss within 3 weeks after amniocentesis was apparently related to the experience of the obstetrician and to the use of modern ultrasound guidance. It is concluded that the risk of fetal death after midtrimester amniocentesis is approximately 0.5%, if only experienced obstetricians using modern techniques are involved.

Cytogenetic findings in 1250 chorionic villus samples obtained in the first trimester with clinical follow-up of the first 1000 pregnancies

Summary. First‐trimester chorionic villus sampling (CVS) was performed in a series of 1250 pregnancies. The direct method of karyotyping was successful in 1205 (96.4%). Abnormal laboratory findings resulted in 60 terminations of pregnancy (4.8%). In addition, six unexpected balanced chromosome rearrangements were detected. False‐positive cytogenetic findings occurred in 2.3%, comprising 22 with mosaicism confined to the trophoblast, and a further six non‐mosaic false‐positive discrepancies were detected, four after termination of pregnancy. The outcome of the first 1000 pregnancies is known in all but one. There were no false‐negative findings. Of 947 pregnancies meant to be continued, 34 (3.6%) ended in pregnancy loss before 28 weeks gestation. However, obstetricians with an experience of over 150 procedures had a pregnancy loss of 1.3%.

Severe congenital skin defects in a newborn: Case report and relevance of several obstetrical parameters

The clinical, laboratory, histologic and autopsy findings are reported from a live-born male infant with severe congenital skin defects (CSD) who survived for 2 days. The family history revealed consanguinity of the (Turkish) parents. The patient was compared with 10 cases from the literature with the most severe form of CSD. The combination of severe CSD, parental consanguinity and gastrointestinal atresia was found in 3 of these 11 cases, including our own patient. Differentiation from an atypical form of epidermolysis bullosa, complicated by pyloric atresia, is difficult. The mechanism of the (prenatally detected) elevated amniotic fluid alpha 1-fetoprotein (AFP) level is discussed. The finding of a balanced 13q14q chromosome translocation in the infant and his mother is considered a coincidence.

Five familial cases with a trisomy 16p syndrome due to translocation

A clinical description is given of a syndrome present in three postnatally and two prenatal‐ly detected cases with partial trisomy 16p, caused by a familial translocation t(16;21) (pll;q22). The most consistent features of this syndrome are: low birth weight, small head circumference, low‐set ears, palato(gnatho)schisis, micrognathia, thumb‐agenesis or hypoplasia, hypertonia, overlapping fingers, single umbilical artery, and psychomotor retardation. The clinical picture was identical to that described by Roberts & Duckett (1978) for a single case.

MATERNAL UNIPARENTAL DISOMY FOR CHROMOSOME 22 IN A CHILD WITH GENERALIZED MOSAICISM FOR TRISOMY 22

We report on a case of generalized mosaicism for trisomy 22. At chorionic villus sampling (CVS) in the 37th week of pregnancy, a 47,XX,+22 karyotype was detected in all cells. The indication for CVS was severe unexplained symmetrical intrauterine growth retardation (IUGR) and a ventricular septal defect (VSD) was noted. In cultured cells from amniotic fluid taken simultaneously, only two out of ten clones were trisomic. At term, a growth‐retarded girl with mild dysmorphic features was born. Lymphocytes showed a normal 46,XX[50] karyotype; both chromosomes 22 were maternal in origin (maternal uniparental disomy). Investigation of the placenta post‐delivery using fluorescence in situ hybridization showed a low presence of trisomy 22 cells in only one out of 14 biopsies. In cultured fibroblasts of skin tissue, a mosaic 47,XX,+22[7]/46,XX[25] was observed. Clinical follow‐up is given up to 19 months.

The outcome of pregnancies with confined placental chromosome mosaicism in cytotrophoblast cells

Cytogenetic findings and outcome of pregnancy are reported in 108 cases in which confined placental mosaicism (CPM, n=101) or generalized mosaicism (n=7) was found at or after first‐trimester chorionic villus sampling. In all samples, a (semi)direct cytogenetic analysis of cytotrophoblast cells was performed. Two pregnancies with CPM ended in a spontaneous abortion before 28 weeks (1·9 per cent). In 15 cases the pregnancy was terminated: eight cases were shown to be examples of CPM; seven cases can be considered as examples of generalized mosaicism. A normal cytogenetic result was obtained after follow‐up amniocentesis in 88 of the remaining 91 cases. In three cases, no amniocentesis was performed but confirmation of a normal karyotype was obtained in other cells. One of the 91 pregnancies was nevertheless terminated for psychosocial reasons. One child died perinatally and another on the seventh day after birth. The birth weight is known for 89 children; the curve shows a normal distribution. In 11 of these children (12·3 per cent), the birth weight was found to be below the tenth centile. The outcome in a subgroup of eight pregnancies with CPM and involvement of chromosome 13, 16, or 22, however, revealed two fetal losses and four children with a birth weight below the tenth centile (75 per cent).

Consecutive or non-consecutive recurrent miscarriage: is there any difference in carrier status?

BACKGROUND Carrier status of a structural balanced chromosome abnormality is associated with recurrent miscarriage. There is, at present, no evidence of the impact of the sequence of preceding pregnancies on the probability of carrier status. The aim of our study was therefore to examine whether the history of consecutive versus non-consecutive miscarriages in couples with two or more miscarriages has any impact on the probability of carrying a chromosome abnormality. METHODS A nested case-control study was performed in six centres for clinical genetics in the Netherlands. Couples referred for chromosome analysis after two or more miscarriages were included: 279 couples with a carrier of a structural chromosomal abnormality and 428 non-carrier couples who served as controls. Univariable and multivariable logistic regression analyses, corrected for known risk factors for carrier status, were performed. The main outcome measure was the probability of carrier status. RESULTS Two hundred and fifty-six of 279 (92%) carrier couples and 381 of 428 (89%) non-carrier couples had experienced consecutive miscarriages (P = 0.21). A history of two or three consecutive miscarriages did not alter the probability of carrier status when compared with two [odds ratio (OR) 0.90, 95% confidence interval (CI) 0.48-1.7] or three (OR 0.71, 95% CI 0.39-1.3) non-consecutive miscarriages. CONCLUSIONS The sequence of preceding pregnancies is not a risk factor for carrier status. Therefore, couples with miscarriages interspersed with healthy child(ren) should be managed the same as couples with consecutive miscarriages regarding chromosome diagnosis.

AMNIOTIC FLUID ALPHA-FETOPROTEIN LEVELS AND THE PRENATAL DIAGNOSIS OF NEURAL TUBE DEFECTS: A COLLABORATIVE STUDY OF 2180 PREGNANCIES IN THE NETHERLANDS

Amniotic fluid alpha‐fetoprotein (AFP) concentrations were measured in 2180 patients at risk of fetal abnormality because of previous history, family history, advanced maternal age, suspected fetal growth retardation and hydramnios. In 12 patients investigated before 20 weeks gestation, pregnancy was terminated because of a raised amniotic fluid AFP‐level: 11 fetuses had neural tube defects (NTDs) and one had a congenital nephrosis. There were no false negative results in the 1927 patients tested before 20 weeks and with a pregnancy of known outcome. In patients tested after 20 weeks, the amniotic fluid AFP concentration was raised in 20 cases of anencephaly, in 9 fetuses with severe congenital malformations without NTD and in one apparently normal fetus. Of 428 patients with a previous offspring who had a NTD, only 8 (1.9 per cent) again had a fetus with a NTD.

Unusual pedigree patterns in seven families with spinal muscular atrophy; further evidence for the allelic model hypothesis

Clinical and genetic findings are presented in 18 patients, from 7 pedigrees with different types of spinal muscular atrophy (SMA). The SMA diagnosis was based on EMG and muscle biopsy findings. All 7 pedigrees show an unusual genetic pattern, not consistent with simple autosomal recessive inheritance. Furthermore, in 6 of the 7 pedigrees different types of SMA were present within each pedigree. Our findings can be explained by an extension of a multiple alleles hypothesis originally described by Becker in 1964.