Increased risk of preterm delivery and pre-eclampsia in women with polycystic ovary syndrome and hyperandrogenaemia.

OBJECTIVE: To study the risk of adverse pregnancy outcomes in women with polycystic ovary syndrome (PCOS), and to examine the role of hyperandrogenaemia. DESIGN: Cohort study. SETTING: Singleton pregnancies in women with PCOS identified at a private fertility clinic during 1997-2010 and a background population including all singleton deliveries at Hvidovre Hospital, Denmark, in 2005. POPULATION: A cohort of 459 women with PCOS and a background population of 5409 women. METHODS: Obstetric outcomes were extracted from national Danish registries and odds ratios (ORs) were calculated by multiple logistic regression analysis, adjusting for age, parity, and body mass index. MAIN OUTCOME MEASURES: Risk of pre-eclampsia, preterm delivery, and small for gestational age offspring in the entire PCOS population and in a subsample with hyperandrogenaemia. RESULTS: Women with PCOS had an increased risk of preterm delivery <37 weeks of gestation (OR 2.28; 95% confidence interval, 95% CI, 1.51-3.45; P < 0.0001). The elevated risk was confined to hyperandrogenic women with PCOS: preterm delivery before 37 weeks of gestation (OR 2.78; 95% CI 1.62-4.77; P < 0.0001), and was not seen in normoandrogenic women with PCOS (OR 1.35; 95% CI 0.54-3.39; P = 0.52). The overall risk of pre-eclampsia was not elevated (OR 1.69; 95% CI 0.99-2.88; P = 0.05) compared with the background population, but was significantly increased in the hyperandrogenic subsample (OR 2.41; 95% CI 1.26-4.58; P < 0.001). The risk of small for gestational age offspring was similar in all groups. CONCLUSION: Women with PCOS had an increased risk of preterm delivery compared with the background population. The increased risk was confined to hyperandrogenic women with PCOS who had a two-fold increased risk of preterm delivery and pre-eclampsia.

First trimester Down syndrome screening: distribution of markers and comparison of assays for quantification of pregnancy-associated plasma protein-A.

OBJECTIVE: First trimester screening for fetal chromosomal disease is now possible using the maternal serological markers pregnancy-associated plasma protein-A (PAPP-A) and the free ss-form of human chorionic gonadotrophin (sshCG) in combination with the ultrasound marker nuchal translucency (NT) thickness. The availability of well-defined analytical methods and reference ranges for the involved parameters, and knowledge of the correlation between markers and clinical parameters, e.g. maternal weight, parity and age, are important for the design of efficient screening programs. MATERIAL AND METHODS: Women (n = 2702), with singleton pregnancies, participating in the Copenhagen First Trimester Screening Study had PAPP-A and sshCG values determined and NT measured at a gestational age of 11 to 14 weeks, as determined from crown rump length (CRL). The distribution of gestational age-independent multiples of the median (MoM) of the parameters was defined and reference intervals established. Three methods for determination of PAPP-A, one manual in-house poly-monoclonal ELISA and two commercial semi-automatic double-monoclonal methods, i.e. PAPP-A for the AutoDelfia platform and PAPP-A for the Kryptor platform, were compared in 260 women. RESULTS: All markers had log-normally distributed MoMs. Gestational age independent reference intervals were established. Maternal weight should be included in risk algorithms. The semi-automated PAPP-A assays (AutoDelfia and Kryptor) gave similar values, mean difference 10.5 %, whereas the manual assay gave higher values, mean differences 50.4 % and 41.0 %, respectively, CONCLUSIONS: This calls for better standardization and a uniform quality control scheme that is focused on discriminatory ability rather than adherence to mean values from a large number of laboratories.

Improved first-trimester Down syndrome screening performance by lowering the false-positive rate: a prospective study of 9941 low-risk women.

OBJECTIVE: To determine the performance of screening for Down syndrome (DS) and other major chromosomal abnormalities using nuchal translucency (NT), free beta-human chorionic gonadotropin (beta-hCG) and pregnancy-associated plasma protein-A (PAPP-A) in a prospective study of a non-selected population. METHODS: Of 9941 women with an early ultrasound examination, NT was measured in 8622 singleton pregnancies with a gestational age between 10 + 3 and 13 + 6 weeks. beta-hCG and PAPP-A were analyzed in 6441 cases. Detection rates (DR) and false-positive rates (FPR) for the NT screening, the double test (beta-hCG and PAPP-A) and the combined test (NT and the double test) were calculated using a 1 : 250 cut-off. RESULTS: NT could be measured in 97.5% of cases. The DR for DS with NT screening alone was 75% with a FPR of only 1.8%. The double test detected 73% and the combined test 91%, for FPRs of 8.8% and 2.1%, respectively. We detected 80% of fetuses with other major chromosomal abnormalities with a combination of NT screening and other ultrasound findings. Low beta-hCG and PAPP-A values (below 0.4 MoM) were observed in 0.5% of the women including all cases of triploidy and trisomy 18 and 13. CONCLUSIONS: The performance of a screening strategy for DS using a combination of NT and the double test was superior to that using either NT or the double test alone due to a very low FPR and a higher DR.

Screening for Down's syndrome in early and late first and second trimester using six maternal serum markers.

The efficiency of six maternal serum markers for Down's syndrome (DS), alpha fetoprotein (AFP), human chorionic gonadotropin (hCG), free beta-hCG, pregnancy-associated plasma protein-A (PAPP-A), the proform of eosinophil major basic protein (ProMBP), pregnancy-specific-beta-1-glycoprotein (SP(1)), and combinations thereof, was examined. Discriminant analysis in 156 DS pregnancies and 546 controls defined three effective combinations of serum marker logMoMs (multiples of the median in control samples) in three gestational age windows, i.e. Index I (weeks 7-9) = 0.52 logMoM ProMBP + 0.28 logMoM PAPP-A - logMoM SP(1); Index II (weeks 10-12) = 1.94 logMoM free beta-hCG - logMoM SP(1), and Index III (weeks 15-19) = 0.78 logMoM free beta-hCG + 1.12 logMoM ProMBP - logMoM AFP. The estimated detection rates of indices and age for a false-positive rate (FPR) of 5% were 73% for Index I, 69% for Index II, and 60% for Index III. Including the ultrasound marker nuchal translucency, using a DS at term risk of 1 : 400 as cut-off, the detection rates of the indices increased to 86, 83, and 82% for FPRs of 4.3, 4.1, and 5.8%, respectively. The indices are promising markers for screening for DS.

Expected, prenatally discovered, and born cases of Down syndrome in Denmark during the period 1980-1998.

In order to elucidate the consistency between generally used age-dependent risk values for Down syndrome (DS) and estimates of the probability of miscarriage in Down pregnancies we have compared expected numbers with estimated numbers of births with DS in Denmark had no intervention at all been carried out. The expected numbers were calculated from the distribution of newborn children according to maternal age combined with the age-related risk of DS. The estimated numbers of children that actually would have been born without any intervention were estimated from observed numbers of cases of DS, i.e. the cases born plus - with corrections because of the high probability of miscarriage in DS pregnancies - a proportion of those cases discovered prenatally. The analysis was carried out separately for mothers aged 35 years or older and for younger mothers. We found a high degree of compatibility between expected and estimated numbers, probably with a minor underestimation of the expected values for the older mothers. The performance of DS screening in Denmark in the period under consideration (1980-1998) is discussed in relation to the figures presented. Despite the fact that 11.8% of all pregnancies were subjected to an invasive diagnostic procedure, only about 38% of all births with DS were prevented. This means that in the period 1990-1998, reluctance to accept serological screening has indirectly resulted in the birth of almost 300 cases of DS in Denmark and at the same time the miscarriage of an unreasonable high number of normal fetuses.

First trimester screening for Down syndrome and assisted reproduction: no basis for concern.

In pregnancies obtained after assisted reproduction the false-positive rate of second trimester Down syndrome (DS) screening is increased by 1.5-3-fold. This may cause an increase in the number of amniocenteses and the fetal loss rate. The present study for the first time examined whether assisted reproductive technologies affect the results of first trimester screening. The markers PAPP-A, free beta-hCG and the nuchal translucency (NT) thickness were examined at 12-14 weeks' gestation. Screening markers in 47 in vitro fertilisation (IVF), 63 ovulation induction (OI) and 3026 spontaneously conceived singleton pregnancies were compared. The MoM (multiples of the median) value in the IVF pregnancies was 1.02 (95% CI: 0.85-1.22) for PAPP-A, 1.14 (95% CI: 0.95-1.37) for beta-hCG and 0.97 (95% CI: 0.89-1.05) for NT; the MoM value in the OI pregnancies was 0.89 (95% CI: 0.76-1.05) for PAPP-A, 1.08 (95% CI: 0.93-1.25) for beta-hCG and 1.02 (95% CI: 0.95-1.11) for NT. The first trimester marker values in assisted reproductive pregnancies and spontaneously conceived pregnancies were not significantly different. Estimated false-positive rates for a risk cut-off of 1:400 varied from 4.7% in IVF pregnancies to 5.1% in OI pregnancies. Therefore the false-positive rate in Down syndrome screening should be independent of the method of conception.

Precision of risk in multidimensional likelihood ratio based screening with first trimester screening for Down's syndrome as a special case.

OBJECTIVES: The development of computer programs for the calculation of risks and Monte Carlo estimation of the precision of such risks in likelihood ratio based screening with multiple gaussian distributed risk markers and a priori risks. A quantitative study of the variation of risk estimates in first trimester screening for Down's syndrome as a function of the variation of markers, and comparison of the results with published information on the variation of risk estimates in quality control schemes. METHODS: Algorithms for calculations in the multidimensional normal distribution and procedures for Monte Carlo simulation of risk distributions were implemented in the S-PLUS programming language and used to construct programs producing risk estimates and risk distributions. Parameters of risk marker distributions and correlations were obtained from the scientific literature. RESULTS: In screening for Down's syndrome during the first trimester the variation in risk estimates increased with increasing variation of biochemical and biometric markers, and the a posteriori risk may vary with at least a factor of 2-4. CONCLUSIONS: Risk estimates are not reasonable parameters in quality control systems. Instead, screening programmes should be controlled through careful monitoring of the distribution of risk estimates, in particular the screen positive rate, and control of the quality of the biochemical and biometric data. Furthermore, the correct classification of samples submitted for proficiency testing into screen positive and screen negative cases should be checked.

Diagnostic assessment of haemorrhagic rash and fever.

AIMS: To establish criteria for early distinction between meningococcal disease and other conditions with similar clinical features, and to identify other causes for haemorrhagic rashes accompanied by fever. METHODS: In a prospective study, 264 infants and children hospitalised with fever and skin haemorrhages were studied. RESULTS: We identified an aetiological agent in 28%: 15% had meningococcal disease, 2% another invasive bacterial infection, 7% enterovirus infection, and 4% adenovirus infection. Five clinical variables distinguished between meningococcal disease and other conditions on admission: (1) skin haemorrhages of characteristic appearance; (2) universal distribution of skin haemorrhages; (3) maximum diameter of one or more skin haemorrhages greater than 2 mm; (4) poor general condition (using a standardised observation scheme); and (5) nuchal rigidity. If any two or more of these clinical variables were present, the probability of identifying a patient with meningococcal disease was 97% and the false positive rate was only 12%. This diagnostic algorithm did not identify children in whom septicaemia was caused by other bacterial species.

Quality assessment in prospective nuchal translucency screening for Down syndrome.

OBJECTIVES: To develop and apply a quality control system in a Down syndrome screening study using nuchal translucency as an interventional marker. METHODS: In a prospective Down syndrome screening study fetal nuchal translucency thickness was measured in 9236 of the 10 045 examined pregnancies. For quality assessment two models were introduced: firstly, image-scoring evaluation of the nuchal translucency thickness measurements and secondly, establishment of the distributions of nuchal translucency multiples of the median over time and the influence of intervention. RESULTS: The observer variability in the image-scoring evaluation was high with a kappa value of 0.48 in the overall validation. A revised model showed better interobserver agreement with a kappa value of 0.58; however, comparing the individual criteria the differences were still unsatisfactory, i.e. we found highly significant differences in the criteria "position of the fetus" (P = 0.0026) and "magnification of the image" (P = 0.0001). Regarding the distributions of the nuchal translucency multiples of the median, the median stabilized after a short learning phase representing the practical part of the sonographer's certification to nuchal translucency screening. In groups of medians of 50 nuchal translucency multiples of the median the intergroup standard deviation decreased from 0.100-0.060 after the learning phase to 0.046 after intervention. CONCLUSIONS: When well-trained certified examiners perform nuchal translucency screening, continuous evaluation of the distribution of the nuchal translucency multiples of the median seems to be a good method to assess the quality for a center and may also be used to identify individual examiners deviating from the mean performance. The image-scoring methods we introduced cannot be recommended for quality control in a nuchal translucency screening program.

Different patterns of Helicobacter pylori adherence to gastric mucosa cells in children and adults. An ultrastructural study.

BACKGROUND: Infection with Helicobacter pylori in childhood may be the initiation of a lifelong coexistence between microorganisms and epithelial cells resulting in chronic inflammation. The adhesion pattern of H. pylori found in antral biopsies from a group of H. pylori-infected children with recurrent abdominal pain was compared with a group of H. pylori-infected adults suffering from dyspepsia, in an attempt to reveal differences in the type of adhesion. METHODS: The histology of antrum biopsies and the ultrastructure of adherent H. pylori in biopsies from 26 children (median age, 10.1 years) were compared with organisms in biopsies from 19 adults (median age, 54.4 years). RESULTS: More than 1000 adherent H. pylori were studied and divided into four types of adhesion: 1) contact to microvilli; 2) connection to the plasma membrane via filamentous material; 3) adhesive pedestal formation; and 4) abutting or making a depression in the plasma membrane. Contact to microvilli was significantly higher (69% versus 39%; P = 0.002) in children compared with adults and comprised two-thirds of all adherent organisms in children. The more intimate adhesion types as abutting or adhesive pedestals dominated in adults. CONCLUSIONS: These results indicate a change in contact types between H. pylori and gastric epithelial cells in adults compared with children and this may be a natural development in the lifelong infection of humans.

Reported side effects to chloroquine, chloroquine plus proguanil, and mefloquine as chemoprophylaxis against malaria in Danish travelers.

BACKGROUND: The aim of the study was to provide data on the relative frequency of reported symptoms in travelers using chloroquine, chloroquine plus proguanil, and mefloquine. METHOD: The study was an open, nonrandomized study recording self-reported events in travelers recruited consecutively from two travel clinics in Copenhagen, Denmark. The main outcome measures were the relative proportion of travelers reporting particular symptoms in the three prophylaxis groups, compliance, hospitalization and premature termination of the travel. RESULTS: From May 1996 to April 1998 5, 446 travelers were included and 4,158 questionnaires (76.3%) returned. Compliance was significantly better in mefloquine users with 83.3% of short term travelers compared to 76.3% in chloroquine plus proguanil users. Also, 84.8%, 59.3% and 69.5% using chloroquine, chloroquine plus proguanil, and mefloquine respectively reported no symptoms and 0.6%, 1.1% and 2.8% reported "unacceptable" symptoms. Compared to chloroquine, mefloquine users had a significantly higher risk of reporting depression, RR 5.06 (95% CI 2.71 - 9.45), "strange thoughts," RR 6.36 (95% CI 2.52 - 16.05) and altered spatial perception, RR 3.00 (95% CI 1.41 - 6.41). CONCLUSION: Overall mefloquine is tolerated at least as well as chloroquine plus proguanil and shows better compliance, however, symptoms related to the central nervous system are more prevalent in mefloquine users and when symptoms develop, they are perceived as more severe.

Infant BCG vaccination study in Lithuania.

SETTING: Infants identified in maternity hospitals in Vilnius, Lithuania. OBJECTIVES: To test the capacity of the BCG vaccine, Danish strain 1331 (Danish vaccine), to induce tuberculin reactivity and scar formation in neonates compared to the WHO International Reference Preparation of BCG (IRP vaccine), and to study the effect of dose and of age at vaccination. DESIGN: A randomized four-armed study: 1) normal dose, 0.05 ml Danish vaccine given to neonates at birth, 2) half the normal dose of Danish vaccine given at birth, 3) IRP vaccine given at birth at normal infant dose, and 4) the normal infant dose of Danish vaccine given at 3 months of age. RESULTS: Larger tuberculin reactions, as well as an increased frequency and larger scars, were seen when Danish vaccine was given at 3 months of age in comparison to neonatal vaccination. Halving the dose resulted in smaller reactions, but the difference was not significant. The IRP vaccine resulted in borderline significantly larger reactions in comparison to the Danish vaccine. The number of infants receiving very early vaccination (0-2 days) was not evenly distributed in all groups, however, which is believed to explain the observed difference.

The proform of eosinophil major basic protein: a new maternal serum marker for Down syndrome.

The proform of eosinophil major basic protein (proMBP), the most abundant protein in the eosinophil specific granule, is synthesized by the placenta and secreted into the maternal circulation, where it is found complex-bound to pregnancy-associated plasma protein-A (PAPP-A) and other proteins. We examined the potential of proMBP as a maternal serum marker for fetal Down syndrome (DS) by determining its maternal serum concentration (MSpMBP) in 25 Down syndrome (DS) pregnancies and 152 control pregnancies in the first trimester, and in 105 DS pregnancies and 156 control pregnancies in the second trimester. The median (95 per cent confidence interval) MSpMBP MoM in DS pregnancies (n=15) was 0.66 (0.49-0.79) in gestational weeks 5-9; 1.06 (0.71-1.97) in weeks 10-12 (n=10) and 1.62 (1.18-1.98) in weeks 14-20 (n=105). Using parameterized receiver operator characteristics analysis for proMBP as a single marker for DS, detection rates (DRs) of 22 per cent and 38 per cent, for false-positive rates (FPRs) of 5 per cent, were found in weeks 5-9 (using MSpMBP/=cut-off), respectively. When age and MSpMBP were used as markers in combination, a DR of 36.8 per cent for an FPR of 5.5 per cent was obtained in weeks 5-9 using a risk cut-off of 1:250. In weeks 14-20 the DR was 48.4 per cent for an FPR of 5.3 per cent using the same risk cut-off. This makes proMBP a marker comparable in diagnostic efficiency to human chorionic gonadotrophin (hCG), and exceeding that of alpha-fetoprotein (AFP) and unconjugated oestriol (uE3), in the second trimester.

Feasibility of neonatal screening for toxoplasma infection in the absence of prenatal treatment. Danish Congenital Toxoplasmosis Study Group .

BACKGROUND: The best method for prevention and control of congenital toxoplasma infection is uncertain. Prenatal screening is done in Austria and France, but the effect of treatment during pregnancy is not well documented. The aim of our study was to find out the maternofetal transmission rate and outcome in infants born to mothers who were not treated during pregnancy. METHODS: We analysed 89873 eluates from phenylketonuria (PKU) cards from neonates and paired first-trimester serum samples from the mothers for specific IgG antibodies to Toxoplasma gondii. Children born to mothers who seroconverted during pregnancy were followed-up clinically and serologically to 12 months of age. In addition, 21144 PKU cards were analysed for toxoplasma-specific IgM antibodies during the last 12 months of the study. FINDINGS: In 24989 (27.8%) cases both the PKU eluate and the first-trimester samples were IgG positive, which indicates previous maternal infection. 139 of the 64884 seronegative women acquired toxoplasma infection during pregnancy and gave birth to 141 infants (two sets of twins). 27 of these children were diagnosed with congenital toxoplasma infection. The transmission rate was 19.4% (95% CI 13.2-27.0). Clinical signs and symptoms were found in four (15%) of the 27 children. The additional analysis for toxoplasma-specific IgM antibodies from the PKU card identified seven of nine children with congenital toxoplasma infection. The false-positive rate for the IgM test was 0.19 per 1000, and no false-negatives were found. INTERPRETATION: The risks of transmission of infection and of disease in the infant are low in an area with a low risk of toxoplasma infection. A neonatal screening programme based on detection of toxoplasma-specific IgM antibodies alone will identify between 70% and 80% of cases of congenital toxoplasmosis.

Immunogenicity and safety of a tetravalent diphtheria-tetanus-acellular pertussis-inactivated poliovirus vaccine.

The objective of this study was to investigate whether a tetravalent vaccine containing diphtheria, tetanus, monocomponent acellular pertussis and inactivated poliovirus (DTaP-IPV) was immunogenic and safe compared with the vaccination regime used in Denmark at the time of the study. The study was performed as an open controlled study in which 270 Danish children were enrolled at their 5 weeks' routine examination. The children were allocated to receive either (i) DTaP-IPV (12.5 Lf, 7 Lf, 40 microg, 40, 8, 32 DU) at 3, 5 and 12 months of age (n = 186) or (ii) DT-IPV (50 Lf, 12.5 Lf, 40, 8, 32 DU) at 5, 6 and 15 months of age plus whole-cell pertussis vaccine (> or = 4 IU) at 5 and 9 weeks and at 10 months of age (n = 84). No hypotonic hyporesponsive episodes or other vaccine-related serious adverse events were seen. Local reactions, febrile and crying episodes with the investigational vaccine (DTaP-IPV) were similar to the reactions seen with the existing DT-IPV vaccine. One month after completing the vaccination schedule, all children had antibodies above the defined protective antibody concentrations to polio, tetanus and diphtheria. For pertussis toxin, there was a significantly better response in the investigational vaccine group. We therefore conclude that, when used according to the schedule tested, the tetravalent DTaP-IPV vaccine is safe and immunogenic. In addition, the number of visits and the number of injections necessary are reduced with this vaccine and vaccination schedule.

Antibodies to urinary tract pathogens in patients with spinal cord lesions.

Chronic or recurrent urinary tract infection (UTI) is a significant problem or patients with spinal cord lesions (SCL). UTIs are thought to be a major factor in the development of reduced renal function. To investigate the pathogenesis 151 patients with SCL were included in this study during a 7 year period. Results of intravenous pyelography and isotope renography were recorded as well as the bladder emptying methods. One to seven blood samples were obtained from each patient and tested for plasma creatinine, and the presence of precipitating antibodies against Escherichia coli, Klebsiella pneumonia, Klebsiella ozaenae, Proteus mirabilis, Enterococcus faecalis and Pseudomonas aeruginosa. We found significant correlation between duration of SCL and precipitating antibodies against urinary tract pathogens (PAU) (r = 0.23, P < 0.005), between plasma creatinine and PAU in patients with spina bifida (r = 0.64, P < 0.01), between PAU and the number of positive urine cultures (r = 0.17; P < 0.05) and a relation between abnormal urological findings and PAU. In addition, the PAU was significantly higher in patients with indwelling urethral catheters (P < 0.001). Thus it seems that PAU can be of prognostic value in SCL patients, and PAU might be an indicator for intensified treatment of recurrent UTI.

Inclusion of serum marker measurements from a previous pregnancy improves Down syndrome screening performance.

A predisposition for high or low levels of serum marker concentrations in second trimester Down syndrome screening reflecting itself in consecutive pregnancies in the same woman has been demonstrated, but hitherto the possible effect of including previous marker results in a current risk evaluation has been considered negligible. Using published data on correlations between the markers AFP, hCG and uE3 in different normal pregnancies in the same women and age-related a priori probabilities we found, that in triple marker screening the inclusion of results from a previous pregnancy in a likelihood ratio based risk calculation could increase the detection rate for women having had an earlier pregnancy from 68.0 per cent to 70.2 per cent at a risk cut-off = 1:250. The screen positive rate for normals for the same population of women, being on average older than the total population, fell from 7.1 per cent to 6.8 per cent. These figures, that are based on an assumption of the same correlations between one normal and one Down syndrome pregnancy as between two normal pregnancies, corresponds to an expected reduction, in the population considered, of the number of children born with Down syndrome of 6.7 per cent and of the number of screen positive normals of 4.7 per cent. Considering that this can be achieved at no extra cost, it is concluded that implementation of a procedure for taking information from previous pregnancies into account in second trimester screening should be considered at centres that can handle the software problems involved in doing so. However, better data on the correlations between a normal and a subsequent Down syndrome pregnancy in the same woman should probably be awaited before this is done.

Calculation of roc curves in multidimensional likelihood ratio based screening with Down's syndrome as a special case.

OBJECTIVES: The development of algorithms and computer programs for the analysis of screening performance in situations with multiple normally (Gaussian) distributed selection markers and a priori risks depending on a stratification of the population. METHODS: The S-PLUS programming language was used to construct programs producing distributions of log likelihood ratios based on the Monte Carlo simulation. These distributions were used to construct programs for the calculation of roc curves, including a possible stratification of the population. RESULTS: S-PLUS programs for the analysis of screening performance are listed and described. The programs can be used without any special knowledge of S-PLUS. An example of the use of the programs is given.

Chromosomal abnormalities in secondary MDS and AML. Relationship to drugs and radiation with specific emphasis on the balanced rearrangements.

BACKGROUND AND OBJECTIVE: In therapy-related myelodysplasia (t-MDS) or acute myeloid leukemia (t-AML) balanced chromosome aberrations to bands 11q23 and 21q22 have been significantly related to previous chemotherapy with DNA topoisomerase II inhibitors. The purpose of the present study was to evaluate to what extent other balanced chromosome aberrations show the same association, and to evaluate a possible relationship to patient age and subgroups of drugs. DESIGN AND METHODS: All previously published cases of t-MDS and t-AML with any type of balanced aberration identified from Felix Mitelman's Catalog of Chromosome Aberrations in Cancer were analyzed for age and type of previous therapy, and the results were evaluated in univariate and multivariate analyses. RESULTS: A total of 422 cases were recorded, 328 had previously received well specified types of chemotherapy; 254 presented one out of five characteristic balanced aberrations, whereas 168 cases presented different uncharacteristic balanced aberrations. In univariate analysis cases with translocations to 11q23 had most often received DNA topoisomerase II inhibitors, whereas patients with the uncharacteristic balanced rearrangements most often had received alkylating agents (p < 0.00000001). Inv(16), t(15;17), and t(9;22) were likewise significantly associated with previous therapy with DNA topoisomerase II inhibitors and to almost the same extent as translocations to 21q22. Patients with translocations to 11q23 were significantly younger as compared to all other groups of patients. Translocations to 11q23 predominated following therapy with epipodophyllotoxins, whereas patients with translocations to 21q22, inv(16), t(15;17), and t(9;22) most often had received anthracyclines. In a multivariate analysis taking age into consideration, however, these drug-specific associations were no longer significant. INTERPRETATION AND CONCLUSIONS: Specific balanced chromosome aberrations in t-MDS and t-AML involving chromosome bands 11q23 and 21q22, inv(16), t(15;17), and t(9;22) are all significantly associated with previous therapy with DNA topoisomerase II inhibitors, as compared to the uncharacteristic balanced aberrations most commonly observed after therapy with alkylating agents. Younger age and not a specific type of DNA topoisomerase II inhibitor seems to predispose specifically to development of t-MDS and t-AML with translocations to chromosome band 11q23.