Extremely large nuchal translucency measurement predicts adverse pregnancy outcome.

A prospective study was conducted to determine the outcome of pregnancies with 1st trimester nuchal translucency measurement of ≥ 6.5 mm. The risk of fetal abnormalities increases with enlarging nuchal translucency, being around 45% with a measurement of ≥ 6.5 mm. A total of 27,144 women with singleton pregnancies participated in the combined Down syndrome screening within the public healthcare system in Northern Finland. The study period was 1 May 2002 to 31 May 2009. The nuchal translucency measurement was ≥ 6.5 mm in 16 cases (0.06%). Pregnancy outcome was normal in one case (6.3%). The risk of abnormality was higher in our study than reported in the literature. According to our study, immediate diagnostic tests should be offered after an nuchal translucency measurement of ≥ 6.5 mm. We should also consider analysis of fetal micro-deletions associated with certain syndromes.

The secretion of PAPP-A, ADAM12, and PP13 correlates with the size of the placenta for the first month of pregnancy.

OBJECTIVES: Pregnancy Associated Protein A (PAPP-A), A Disintegrin and Metalloproteinase 12 (ADAM12) and Placental Protein 13 (PP13) are secreted from the placental trophoblastic tissue and are involved in normal implantation and placental development. The aim of the study was to assess the connection between the secretion of these proteins and the growth of the gestational sac and the placenta. STUDY DESIGN: In an observational longitudinal study at Oulu University Hospital, women with naturally conceived pregnancies were followed-up weekly to pregnancy week 11. MAIN OUTCOME MEASURES: PAPP-A, ADAM12 and PP13 serum concentrations and their correlation with the volumes of the gestational sac and the placenta were assessed using three-dimensional ultrasonography. RESULTS: The study group consisted of 41 women. The PAPP-A, ADAM12 and PP13 serum concentrations increased continuously from pregnancy week 4 to week 11 and correlated closely with each other. The serum concentrations of PAPP-A, ADAM12 and PP13 also correlated with the volumes of the gestational sac and the placenta up to pregnancy week 8. CONCLUSIONS: The secretion of PAPP-A, ADAM12 and PP13 is closely related to the size of the placenta in the beginning of pregnancy. After 8 weeks of pregnancy, which is the time for luteoplacental shift, the correlation disappears, possibly reflecting the morphologic transformation in the placenta.

Cord compression may rapidly influence the expression of placental angiogenic genes in pre-eclampsia.

Gene expression studies have demonstrated the altered expression level of placental angiogenesis related genes in severe pre-eclampsia (PE). In cord compression, the transportation of oxygen from the placenta to the fetus is blocked, and it is speculated that during blockade the originally hypoxic placenta may become hyperoxic. We compared the placental gene expression profiles of one pre-eclamptic patient with cord compression (the index patient) to the profiles of patients with PE and those of normal pregnancy controls (including one woman with cord compression). The gene expression of the cord compression PE patient resembled that observed in the normal pregnancies. We hypothesize that umbilical blockade may in a short period of time lead to placental hyperoxia, which in turn has an effect on angiogenic gene expression profile.

Screening for BRCA1 and BRCA2 mutations in Eastern Finnish breast/ovarian cancer families.

Familial aggregation is thought to account for 5-10% of all breast cancer cases, and high penetrance breast and ovarian cancer susceptibility genes BRCA1 and BRCA2 explain < or =20% of these. Hundreds of mutations among breast/ovarian cancer families have been found in these two genes. The mutation spectrum and prevalence, however, varies widely among populations. Thirty-six breast/ovarian cancer families were identified from a population sample of breast and ovarian cancer cases among a relatively isolated population in Eastern Finland, and the frequency of BRCA1/BRCA2 germline mutations were screened using heteroduplex analysis, protein truncation test and sequencing. Five different mutations were detected in seven families (19.4%). Two mutations were found in BRCA1 and three in BRCA2. One of the mutations (BRCA2 4088insA) has not been detected elsewhere in Finland while the other four, 4216-2nt A-->G and 5370 C-->T in BRCA1 and 999del5 and 6503delTT in BRCA2, are recurrent Finnish founder mutations. These results add to the evidence of the geographical differences in distribution of Finnish BRCA1/BRCA2 mutations. This screen also provides further evidence for the presumption that the majority of Finnish BRCA1/BRCA2 founder mutations have been found and that the proportion of BRCA1/BRCA2 mutations in Finnish breast/ovarian cancer families is around 20%.

Evaluation of factor V Leiden, prothrombin and methylenetetrahydrofolate reductase gene mutations in patients with severe pregnancy complications in northern Finland.

BACKGROUND: Thrombosis in placenta may lead to severe pregnancy complications. Most important inherited thrombophilias are factor V Leiden mutation, prothrombin mutation, and methylenetetrahydrofolate reductase mutation. The aim of our research was to evaluate the prevalence of inherited thrombophilias in severe pregnancy complications and in normal pregnancies. MATERIAL AND METHODS: The study subjects with severe preeclampsia, intrauterine growth restriction, placental abruption or fetal death were collected during the period 1999-2004 from Oulu University Hospital. We also collected during the same period voluntary parturients with normal pregnancy outcome as the control group. FVL, FII, and MTHFR gene mutations of the patients and controls were analyzed. RESULTS: We found a significant difference in the prevalence of FVL mutation between the groups. There were 9.5% FVL mutations in the study group compared to 1.8% in the control group; the observed difference between prevalences was 7.7% (95% CI 2.0-13.4). No statistical difference was found in the FII or MTHFR mutations between the groups. All FV and FII mutations were heterozygous and all the MTHFR mutations homozygous. CONCLUSION: Women with thrombophilia have a risk for severe pregnancy complications. Randomized controlled trials are needed to assess the influence of low-molecular-weight heparin in pregnant women with thrombophilia.

Maternal serum beta-HCG and alpha-fetoprotein concentrations in singleton pregnancies following assisted reproduction.

BACKGROUND: The reason for the elevated levels of HCG in assisted reproduction pregnancies remains unknown. Our hypothesis was that this increase is caused by the ovarian superovulation therapy. METHODS: We compared the beta-HCG and alpha-fetoprotein (AFP) multiples of the median (MoM) in singleton pregnancies after IVF or ICSI with those achieved by frozen embryo transfer (FET) in spontaneous cycles. RESULTS: The HCG and AFP MoMs (plus minus SEMs) of 59 FET pregnancies were compared with 144 IVF (including 48 ICSI) pregnancies. The maternal HCG of pregnancies following ovarian stimulation was 1.31 plus minus 0.08 MoM compared with 1.35 plus minus 0.12 MoM in the unstimulated ones. The values for AFP were 1.06 plus minus 0.05 versus 1.11 plus minus 0.05 respectively. No significant differences could be observed between pregnancies following stimulated IVF/ICSI and unstimulated FET cycles. CONCLUSIONS: Our results show that second trimester maternal serum HCG is also elevated in singleton pregnancies following spontaneous FET cycles. The increased maternal serum HCG in IVF pregnancies is thus not related to superovulation therapy. Because of the elevated maternal serum HCG levels, serum screening cannot be performed reliably in pregnancies following assisted reproduction technology. Ultrasonographic detection of the nuchal translucency is unaffected and should be used for this group of women undergoing assisted reproduction.

Genome-wide linkage disequilibrium mapping of late-onset Alzheimer's disease in Finland.

BACKGROUND: AD is a complex neurodegenerative disorder comprising several disease-associated chromosome loci. To find novel susceptibility genes for late-onset AD, a population-based genome-wide search using linkage disequilibrium (LD) mapping approach has been performed. METHOD: Forty-seven patients with late-onset AD and 51 age-matched control subjects were carefully chosen from the same geographic area in eastern Finland, where the population is descended mainly from a small group of original founders. These subjects were initially genotyped with 366 polymorphic microsatellite markers, and a follow-up analysis was performed with additional microsatellite markers for those chromosome loci found to be associated with AD. RESULTS: Initial genome-wide screening revealed 21 chromosomal loci significantly associated with AD in addition to the 13q12 locus described previously. Subsequent comparison of single-allele frequencies of the microsatellite markers in the AD and control groups indicated the presence both of possible risk alleles (odds ratio [OR] > 1) and of possible protective alleles (OR < 1). Screening of the LD regions with additional microsatellite markers revealed seven chromosomal loci where more than one microsatellite marker was associated with AD (1p36.12, 2p22.2, 3q28, 4p13, 10p13, 18q12.1, and 19p13.3) in addition to the 13q12 locus. CONCLUSIONS: These genome-wide LD screening data suggest that several AD-associated chromosomal loci exist, which may encompass novel susceptibility genes for late-onset AD. Therefore, extensive screening of the genes located in the vicinity of these LD regions is necessary to elucidate their role in AD.

Evaluation of first trimester maternal serum and ultrasound screening for Down's syndrome in Eastern and Northern Finland.

The current trend in prenatal diagnosis is that trisomy screening is being moved to the first trimester and ultrasonographic nuchal translucency measurement is included in risk calculation. It is likely that biochemical screening in the second trimester will gradually be given up. In Eastern and Northern Finland, during the year 1999 we offered first-trimester ultrasonographic and serum screening for trisomy 21, with measurements of maternal serum PAPP-A and beta-hCG. A total of 2515 pregnant women participated in the screening, yielding the detection of eight foetuses with Down's syndrome. Six affected foetuses (75%) were detected by means of first-trimester serum screening. Since we were in the phase of collecting data for the Finnish medians for PAPP-A and beta-hCG, the women were not given the estimates of risk for trisomy 21. Only 1602 of the 2515 enrolled women had the combination of first-trimester ultrasonographic and serum screening performed, and in that group there were five foetuses with Down's syndrome. The combination ultrasonographic and serum approach yielded a Down's syndrome detection rate of 80% (four out of five) with a 5% false positive rate, whereas in nuchal translucency based-screening the detection rate was 60%, with a 5% false positive rate.

Antenatal gene tests in low-risk pregnancies: molecular screening for aspartylglucosaminuria (AGU) and infantile neuronal ceroid lipofuscinosis (INCL) in Finland.

Approximately one in five subjects in Finland carries some gene defect associated with 30 diseases belonging to the Finnish disease heritage, and about one in 500 children born is affected. Almost all carriers, women and men, are unaware of their condition. Recent advances in molecular medicine have offered the possibility of population-based carrier screening for recessive disorders. We studied acceptance and attitudes to antenatal screening for aspartylglucosaminuria (AGU) and infantile neuronal ceroid lipofuscinosis (INCL). From January 1995 until December 1996 carrier tests were offered at Kuopio City Health Center, free of charge to all pregnant women attending maternity care units. Women found to be carriers of AGU (n = 47) or INCL (n = 14) underwent detailed genetic counseling, and their male partners were also offered the test. If both partners appeared to be carriers we offered prenatal testing (n = 1). No affected fetuses were detected. Attitudes towards the gene test were elicited by means of a questionnaire. Altogether 87% of pregnant women elected to undertake the gene tests. Antenatal screening for gene defects was feasible and well accepted, and it provided an effective way to find carriers of genetic diseases and to incorporate prenatal testing into this process.

Wide scope prenatal diagnosis at Kuopio University Hospital 1997-1998: integration of gene tests and fetal karyotyping.

OBJECTIVE: To investigate the applicability of carrier screening in women undergoing invasive prenatal diagnosis. DESIGN: Prospective study. SETTING: University-based clinic. PARTICIPANTS: Two hundred and fifty-six pregnant women. METHODS: Gene tests were offered for fragile X syndrome, aspartylglycosaminuria and infantile neuronal ceroid lipofuscinosis at the time of invasive prenatal testing. RESULTS: The overall uptake of the tests was 92%. Previously unrecognised carriership was found in 10 women: aspartylglycosaminuria (7); infantile neuronal ceroid lipofuscinosis (2) and fragile X (1). Fetal genotyping was carried out in one carrier of aspartylglycosaminuria whose partner was also a carrier, and in one woman who was found to have fragile X premutation. Both fetuses were unaffected. CONCLUSION: Carrier screening for single-gene disorders is feasible and well accepted among pregnant women undergoing invasive prenatal testing. The major benefit is that there is no need to consider extra invasive tests when carriership is detected. Incorporation of genetic testing into fetal karyotyping gives more security to future parents.

Antenatal genetic screening for congenital nephrosis.

This study was undertaken to study the applicability of genetic antenatal screening for the Finnish type of congenital nephrosis (CNF), which is a recessive disorder leading to nephrotic syndrome from birth. At Kuopio University Hospital, a total of 1303 pregnant women were offered carrier screening for CNF at the time of first trimester nuchal fold translucency measurement when fetally derived alpha-fetoprotein is still produced by the yolk sac. Two mutations of the nephrin (NPHS 1) gene, accounting for approximately 95% of affected alleles, were tested by two PCR tests. Uptake of the gene test was 91.0% (n=1183). Altogether 38 female carriers were found; a population carrier frequency of 1 in 31. Their partners were tested and two of them were also found to be carriers. In these two pregnancies invasive prenatal diagnosis was offered and accepted, and the results indicated one carrier and one affected fetus. Carrier screening is an effective and well-accepted method for antenatal screening for fetal CNF. Direct mutation analysis involves markedly less invasive procedures compared with serum alpha-fetoprotein (AFP) screening, and the diagnosis was clear-cut. The results indicate that in single-gene disorders genetic testing is suitable for antenatal screening.

Multiple founder effects and geographical clustering of BRCA1 and BRCA2 families in Finland.

In the Finnish breast and ovarian cancer families six BRCA1 and five BRCA2 mutations have been found recurrently. Some of these recurrent mutations have also been seen elsewhere in the world, while others are exclusively of Finnish origin. A haplotype analysis of 26 Finnish families carrying a BRCA1 mutation and 20 families with a BRCA2 mutation indicated that the carriers of each recurrent mutation have common ancestors. The common ancestors were estimated to trace back to 7-36 generations (150-800 years). The time estimates and the geographical clustering of these founder mutations in Finland are in concordance with the population history of this country. Analysis of the cancer phenotypes showed differential ovarian cancer expression in families carrying mutations in the 5' and 3' ends of the BRCA1 gene, and earlier age of ovarian cancer onset in families with BRCA1 mutations compared with families with BRCA2 mutations. The identification of prominent and regional BRCA1 and BRCA2 founder mutations in Finland will have significant impact on diagnostics in Finnish breast and ovarian cancer families. An isolated population with known history and multiple local founder effects in multigenic disease may offer distinct advantages also for mapping novel predisposing genes.

Prenatal diagnosis of fragile X syndrome and the risk of expansion of a premutation.

The aim of the present study was to evaluate prospectively the dynamics of the FMR1 gene. The risk of full mutation among pregnant women and the carriers, and the risk of expansion of a premutation allele to a full mutation were estimated. We identified 89 pregnant women with an expanded FMR1 gene seeking prenatal diagnosis. Amniocentesis or chorion villus sampling (CVS) was offered and a DNA test of the FMR1 gene was carried out in such pregnancies. The overall risk of full mutation among women (N = 21) with a repeat size between 60 and 80 was 4.8% (one fetus with mosaicism), and the risk of expansion of the premutation allele to a full mutation was 14% in those offspring to whom the premutation allele was transmitted. The risk of full mutation among the carriers (N = 13) with a repeat size between 81 and 100 was 61.5% (8/13), and the risk of expansion of a premutation allele to a full mutation was 89%. Only one case fell into the category of 101-200 repeats, and expansion to a full mutation was recorded. Fetuses of full mutation mothers inherited the larger allele in 64% (14/22) of the cases. The range of 40-59 repeats was safe: there were no fetal full mutations. The risk of full mutation was also low among the subjects with a repeat size between 60 and 80, whereas the risk increased significantly after 80 repeats. Maternal premutation size was positively correlated with the risk of having a full mutation offspring.

Pregnancy outcome in carriers of fragile X.

OBJECTIVE: To evaluate pregnancy outcome in women who are carriers of fragile X. DESIGN: Cross-sectional case-control study. SETTING: Department of Obstetrics and Gynaecology, Kuopio University Hospital, Finland. SAMPLE: Sixty-three singleton pregnancies in carriers of fragile X who were referred for genetic counselling and prenatal diagnosis to Kuopio University Hospital. METHODS: Logistic regression analysis was used to compare pregnancy outcome in women who are fragile X carrier with outcome of the general obstetric population. RESULTS: Carriers of fragile X often experienced more bleeding in late pregnancy than did the reference group. Otherwise, the course and outcome of pregnancy were comparable in both groups. CONCLUSION: Pregnancy outcome in women who are carriers of fragile X is favourable. There is no need to initiate special fetal monitoring because of the fragile X status of the woman.

Does apolipoprotein E genotype relate to BMD and bone markers in postmenopausal women?

OBJECTIVES: Bone mineral density (BMD) and development of osteoporosis are partly determined by genetic factors. The associations between one of suggested candidate, apolipoprotein E (apo E) genotype to bone mineral density (BMD) and bone biochemical markers was studied in 464 subjects recruited from a population-based group of early postmenopausal women (n = 13100). Additionally, the influence of apo E genotype on BMD changes during a 5-year follow-up with or without hormone replacement therapy (HRT) was investigated. METHODS: Participants were randomized into two treatment groups: HRT group: Sequential combination of 2 mg estradiol valerate and 1 mg cyproterone acetate with or without vitamin D3, 100-300 IU/day + calcium lactate, 500 mg/day (n = 232), and the non-HRT group: Calcium lactate, 500 mg/day alone or in combination with vitamin D3, 100-300 IU/day (n = 232). BMD was measured from the lumbar spine and proximal femur at baseline and after 5 years of treatment (n = 352). In a subgroup (n = 59), the serum concentrations of bone biochemical markers (intact osteocalcin (OC), bone-specific alkaline phosphatase (BAP) and type I collagen carboxy-terminal telopeptide (ICTP)) were measured at baseline and after 1 year of follow-up. RESULTS: At baseline, the BMDs were similar between the five apo E genotype groups (2/3, 2/4, 3/3, 3/4, 4/4). No significant differences in lumbar or femoral neck BMDs of women with the apo E4 allele were found compared with those without it. There was a statistically significant difference in 5-year BMD changes between the HRT and non-HRT groups. After 5 years, the BMD of the femoral neck had remained constant and the mean lumbar spine BMD had increased by 1.5% in the HRT group, whereas both BMDs had decreased by 4-5% in the non-HRT group. However, the apo E genotype did not modify the changes in BMD in either group. Additionally, the baseline concentrations of bone metabolic markers and their 1-year changes showed no genotype-related associations. CONCLUSIONS: The results of our population-based study indicate that apo E genotype does not modify lumbar or femoral neck BMDs or serum bone biochemical markers or their response to HRT in early postmenopausal Caucasian women.

Is the presenilin-1 E318G missense mutation a risk factor for Alzheimer's disease?

Nearly all of the presenilin-1 (PSEN-1) mutations are missense mutations leading to Alzheimer's disease (AD). The role of the mutation E318G (a substitution of glutamic acid to glycine) in the PSEN-1 is controversial. It has been found both in AD patients and in non-demented control individuals. Using the polymerase chain reaction and the restriction fragment length polymorphism method, we screened for E318G mutation in a total of 16 familial (FAD) cases, in 64 sporadic neuropathologically confirmed AD cases and in 270 non-demented controls including 35 neuropathologically confirmed individuals. We detected the E318G mutation in four FAD cases, seven sporadic AD cases and 10 control individuals with highly varying onset-ages. Odds ratios for carrying the mutation were 7.6 and 3 in FAD and sporadic AD cases, respectively. Our results suggest that this mutation could be a risk factor in the Finnish FAD and sporadic AD population. It may be in linkage disequilibrium with a pathogenic change somewhere else in the PSEN-1 gene or in close proximity to the PSEN-1 gene.

Etiology and outcome of second trimester non-immunologic fetal hydrops.

BACKGROUND: This investigation was undertaken to study the conditions resulting in midtrimester fetal hydrops and to evaluate its overall prognosis as regards counseling purposes. MATERIAL AND METHODS: The etiology of midtrimester non-immune fetal hydrops was retrospectively evaluated as regards cases detected in singleton pregnancies (n=58) from January 1987 through December 1996. The condition was diagnosed by way of routine biochemical and ultrasonographic screening of a pregnant population. RESULTS: The rate of diagnosed midtrimester fetal hydrops was 1 in 1700 pregnancies and the overall survival rate in this usually unexpected condition was less than 10%. Various chromosomal and fetal structural abnormalities dominated as a cause of fetal hydrops, representing 44.8% and 43.1% of the cases, respectively. Infection caused only 6.9%. The underlying etiology remained unknown in only three cases. However, in 78% the diagnosis was already known prenatally. DISCUSSION: Although the overall prognosis is poor, knowledge of the primary etiology is important to determine a rational therapeutic strategy. If the results of routine investigations rule out malformation and abnormal chromosomes, follow-up serial ultrasonographic assessment may indicate that the hydropic state is transient, carrying a somewhat better prognosis.