The proportions of Down's syndrome pregnancies detected prenatally in England and Wales from 1989 to 2004.

OBJECTIVES: The proportion of Down's syndrome pregnancies detected prenatally in England and Wales is lower in younger mothers than in older mothers. This paper examines the reasons for this apparent age inequality. METHODS: We used data from the National Down Syndrome Cytogenetic Register (NDSCR) to examine the time trend of the proportion of Down's syndrome pregnancies diagnosed prenatally according to maternal age over the years 1989-2004 in England and Wales. RESULTS: A lower proportion of younger mothers had their Down's syndrome pregnancy detected prenatally than older mothers; however, this gap has been closing over time. For example, for mothers under 25 years of age only 13% of Down's syndrome pregnancies were detected prenatally from 1989 to 1992, with this figure rising to 34% in 2001-2004, compared with proportions of 74% in both periods for mothers over 44 years of age. A lower uptake of screening among younger women could not explain these differences. The differences in detection rates of the screening methods according to maternal age, particularly of the older screening tests, could account for these differences. CONCLUSIONS: The closing gap between the proportions of younger and older women having their affected pregnancy prenatally diagnosed is a confirmation of the improvement of screening methods over time.

Recurrences of free trisomy 21: analysis of data from the National Down Syndrome Cytogenetic Register.

OBJECTIVES: To determine the recurrence risk of a free trisomy 21 pregnancy. METHODS: Data from the National Down Syndrome Cytogenetic Register (NDSCR), which contains information on nearly all cases of Down syndrome between 1989 and 2001 in England and Wales were used. Among 11 281 women with a Down syndrome pregnancy who had had at least one previous pregnancy there were 95 women who had had a previous Down syndrome pregnancy. RESULTS: Women who have had a previous Down syndrome pregnancy have a constant absolute excess risk above their maternal age-related risk of having a subsequent affected pregnancy. This absolute excess risk is determined by the age at which the affected pregnancy occurred and is higher for younger than for older women. For example, after a Down syndrome pregnancy at age 20, this excess is 0.62% (95% CI: 0.24 to 1.15%) at early second trimester, and, after one at age 40, it is 0.04% (95% CI: 0.01 to 0.07%). CONCLUSION: More precise risk estimates by single year of maternal age for use in genetic counselling are provided, but they need validation from other studies before they are incorporated in the risk estimation routines used in Down syndrome screening programmes.

Risk of a Down syndrome live birth in women 45 years of age and older.

OBJECTIVES: To determine the risk of a Down syndrome (DS) live birth for women 45 years of age and over. METHODS: A meta-analysis of data from five published articles, 13 EUROCAT congenital anomaly population registers and two unpublished sources. RESULTS: Information was available on the number of DS live births occurring amongst 13,745 live births to women 45 years of age and over. Information was also available on DS pregnancies diagnosed prenatally that were subsequently terminated. These pregnancies were adjusted for expected fetal loss to estimate the number of live births that would have occurred in the absence of prenatal diagnoses, when a total of 471 DS live births were estimated to have occurred. The risk of a DS birth did not increase for women 45 years of age and over. The average risk was 34 per 1000 births (95% CI: 31-37). CONCLUSION: The risk of a DS live birth for women 45 years of age and over is considerably lower than has often been previously assumed. The most likely explanation is that women of this age are more likely to miscarry DS pregnancies than younger mothers.

Comparison of models of maternal age-specific risk for Down syndrome live births.

OBJECTIVES: To display and compare the different published formulae that specify the association between maternal age and the risk of a Down syndrome live birth. METHODS: Papers published since 1987 on the prevalence of Down syndrome live births in relation to maternal age were located using MEDLINE and the references given in other papers. The data series and the models fitted to them were plotted to obtain a visual idea of their similarities and differences. RESULTS: The observed and modelled age-specific rates for Down syndrome births were remarkably similar in all published series of data for women up to the age of 35, were reasonably similar for women aged 35 to 45, but differed for women older than 45. CONCLUSION: In practice, the overall small differences in age-related risk between the different studies did not materially affect the performance of antenatal screening for Down syndrome. If a choice is to be made, the analysis based on the National Down Syndrome Cytogenetic Register (NDSCR) has marginal advantages since it is based on the largest data set and the corresponding model fits the data well. More data is needed to clarify the pattern of risk with maternal age among women over 45 years of age.

Revised estimates of the maternal age specific live birth prevalence of Down's syndrome.

OBJECTIVES: To revise the estimates of maternal age specific live birth prevalence of Down's syndrome in the absence of antenatal screening and selective termination using newly available data. SETTING AND DESIGN: Data were used from the National Down Syndrome Cytogenetic Register (NDSCR), which contains information on nearly all antenatally or postnatally diagnosed cases of Down's syndrome in which a karyotype was confirmed between 1989 and 1998 in England and Wales. It is the largest single series of data on the prevalence of Down's syndrome. RESULTS AND CONCLUSION: The prevalence does not continue increasing at an increasing rate with age above age 45 as has been previously assumed. Above this age the rate of increase declines with increasing age. The overall age pattern is sigmoidal. A new logit logistic model is proposed which fits the data well. The risk of a Down's syndrome live birth is given by: risk=1/(1+exp(7.330-4.211/(1+exp(-0.282x(age-37.23))))).

Peak and kinetic cardiorespiratory responses during arm and leg exercise in patients with spinal cord injury.

STUDY DESIGN: A paired comparison of the peak and submaximal responses of oxygen uptake and heart rate in patients with spinal cord injury (SCI) performing voluntary arm cycle exercise and functional electrical stimulation (FES) leg cycling exercise. OBJECTIVES: To test if the blunted heart rate response and slower rate of adjustment of oxygen uptake seen in patients with SCI performing FES leg cycle exercise are also characteristic of arm exercise in these patients. METHODS: Eight paraplegics performed incremental and constant work rate (CWR) exercise with the legs and arms. Mean response times (MRT) for Vo2 during exercise (on) and in recovery (off) were calculated from the breath-by-breath Vo2 profile. RESULTS: Peak heart rate was higher during incremental arm exercise, and uncorrelated with that observed during incremental FES leg cycling. For the same increase in Vo2, constant work rate arm exercise was associated with faster (and normal) Vo2 kinetics, greater increase in heart rate, and lower end-exercise blood lactate, compared to FES leg cycling. CONCLUSIONS: The consistently higher peak heart rate and Vo2, and faster Vo2 kinetics, for voluntary arm compared to FES leg cycle exercise suggest no intrinsic dysfunction of heart rate control in these paraplegics. Rather, these data suggest that during FES leg cycling the changes seen are due to some characteristic specific to the injury, such as reduced muscle mass and/or deconditioning of the remaining muscle. SPONSORSHIP: This research was supported by The Department of Veterans Affairs, Rehabilitation Research and Development Project #B603-RA. Spinal Cord (2000) 38, 340 - 345.

Female predominance (low sex ratio) in 47,+21 mosaics.

Data from the New York State Chromosome Registry on over 10,000 cases of Down syndrome reported from 1977 to 1996 confirm findings in the England and Wales Cytogenetic Register that in mosaic 46/47,+21 cases of Down syndrome the male/female ratio (as inferred from XY and XY karyotypes respectively) is less than 1.0 as opposed to the ratio in nonmosaic 47,+21 cases in which the ratio is close to 1.2, or in the general background population with ratio of about 1.05. These results may reflect in part differential pairing in 47,+21 somatic cells of X and Y chromosomes with a 21 chromosome and/or in in-utero selection.

Is there evidence of clustering in Down syndrome?

BACKGROUND: Associations between environmental hazards and the occurrence of congenital anomalies may be detectable by seeking evidence of non-random occurrence of cases (clusters). There have been a number of anecdotal reports of occurrences of clusters of Down syndrome (DS). METHODS: Data from a national register of cytogenetic diagnoses of Down syndrome births and legal terminations occurring between 1989 and 1995 were used to examine the possibility of clustering. Space-time clustering at Regional Health Authority (RHA) level was examined by comparing the expected monthly number of DS pregnancies given the maternal age distribution, with the observed numbers. Knox's method was used to determine if any clustering of RHA of unexpectedly high prevalence had occurred. Seasonality was also investigated by comparing monthly expected and observed numbers of DS pregnancies. Time clustering was examined by using the scan statistic to determine whether a statistically significant excess of pregnancies in any 3-month period occurred in any individual or adjacent groups of District Health Authority (DHA). RESULTS: The numbers of DS pregnancies were no higher than expected (P < 0.05) in the same RHA over consecutive months. There was no evidence of any seasonality of DS pregnancies (P > 0.5). Only two individual DHA and three pairs of adjacent DHA had significantly high scan statistics (P < 0.03), but as over 400 statistical tests had been completed 12 clusters would be expected to have occurred due to chance alone. CONCLUSION: There was no evidence of any space-time clustering in DS at DHA level.

Physiologic responses during functional electrical stimulation leg cycling and hybrid exercise in spinal cord injured subjects.

OBJECTIVES: (1) To determine if a hybrid exercise (leg plus arm) training program performed immediately after functional electrical stimulation (FES) leg cycle exercise (LCE) training would further improve aerobic capacity when compared with FES leg cycle training alone, and (2) to compare the submaximal responses occurring during both FES-LCE alone and hybrid exercise in the same SCI subjects. DESIGN: Nonrandomized control trial whereby subjects act as their own control. SETTING: Outpatient rehabilitation in a primary care hospital. PATIENTS: A volunteer sample (n = 11) of men 20 to 50 years old with complete spinal cord injury, free from cardiovascular and metabolic disease with spasticity. INTERVENTIONS: Three phases of exercise training: phase I, progressive FES-LCE to 30 minutes of exercise (n = 11); phase II, 35.2 +/- 16.2 sessions of FES-LCE (n = 11); phase III, 41.4 +/- 17.7 30-minute sessions of hybrid exercise (n = 8). MAIN OUTCOME MEASURES: (1) Aerobic capacity-a further increase after hybrid exercise when compared with FES-LCE alone; (2) submaximal physiologic parameters (oxygen uptake [VO2], heart rate [HR], blood lactate [BLa-])-measurement of these during constant work rate exercise and a training effect. RESULTS: VO2 (the body's ability to utilize oxygen) significantly improved (p < .05) after both FES-LCE and then further after hybrid training. Hybrid exercise training resulted in significantly (p < .05) greater work rates and VO2 values than both FES-LCE at baseline and training work rates. CONCLUSION: These subjects demonstrated that hybrid exercise performed twice a week provided sufficient intensity to improve aerobic capacity and provide a medium whereby patients with SCI can burn more calories than via FES-LCE alone. This has important implications for improving the health and fitness levels of individuals with SCI and may ultimately reduce their risk of cardiovascular disease.

Reliability of statistics on Down's syndrome notifications.

OBJECTIVES: To evaluate the completeness of notifications of Down's syndrome live births and terminations to the Office for National Statistics (ONS) using data from the National Down Syndrome Cytogenetic Register (NDSCR). To examine the agreement of observed birth prevalence of Down's syndrome with the expected birth prevalence derived from published maternal age specific rates. METHODS: The number of live births (adjusted to allow for the estimated underascertainment) and the number of terminations due to fetal Down's syndrome from NDSCR were compared with those figures reported to the ONS. Subsequently, using the NDSCR figures, the live birth prevalence of Down's syndrome that would have occurred in the absence of antenatal diagnosis and selective termination was calculated in England and Wales in the years 1990-1993. These figures were compared with those derived by applying published age specific prevalences to the maternal age distribution in England and Wales. RESULTS: It is estimated that only 48% and 46% respectively of Down's syndrome live births and terminations of pregnancy were notified to ONS between 1990 and 1993. The annual expected birth prevalences of Down's syndrome obtained by applying maternal age specific prevalences to the maternal age distribution were in close agreement with observed rates from NDSCR. CONCLUSIONS: There is considerable underreporting of Down's syndrome births and terminations to ONS. The NDSCR data are more complete and therefore the effects of screening should be monitored using data from this source, or using estimates derived from the age specific rates of Down's syndrome.

Changes in gas exchange kinetics with training in patients with spinal cord injury.

We examined the ability of patients with spinal cord injury to undergo adaptations to chronic exercise training (cycle ergometry) invoked by functional electrical stimulation (FES) of the legs. Nine such patients performed incremental and constant work rate exercise before and after exercise training. Exercise sessions averaged 2.1 +/- 0.4/wk, and consisted of 30 min/session of continuous FES recumbent cycling with increasing work rate as tolerated. Peak VO2 and peak work rate significantly improved with training. Peak VO2 was significantly correlated with peak heart rate both before and after training (r = 0.97 pre and 0.85 post, P < 0.01 for both). The time course of the VO2, VCO2 and VE responses to constant-load exercise (unloaded cycling) and in recovery (mean response time MRT) were very long prior to training, and became significantly faster following training. However, there was no correlation between percentage improvement in either MRTon or MRToff for VO2 and the percentage increase in peak VO2. Exercise tolerance in these patients with spinal cord injury appears to be a direct function of the ability to increase heart rate. Further, exercise training can elicit significant improvements in both exercise tolerance and in gas exchange kinetics, even when performed only twice per week. However, these improvements may be accomplished by different mechanisms.

Cytogenetic and epidemiological findings in Down syndrome, England and Wales 1989 to 1993. National Down Syndrome Cytogenetic Register and the Association of Clinical Cytogeneticists.

Data from the National Down Syndrome Cytogenetic Register is used to describe the cytogenetics and epidemiology of registered cases. The register comprises notifications from cytogenetics laboratories in England and Wales. This report is of 5737 cases registered between 1989 and 1993: 2169 prenatal and 3436 postnatal diagnoses, and 132 spontaneous abortions. Eighty eight registrations were from multiple pregnancies. Ninety five percent had regular trisomy 21. In 4% there was a translocation, mostly Robertsonian t(14;21) or t(21;21). One percent were mosaics with one normal cell line. Mean maternal age was raised in free trisomy 21, but not in translocations. Where families had been investigated, about a third of translocations were inherited, six to seven times more often from the mother than the father. Associations between free trisomy 21 and structural chromosomal defects in the births were no more common than expected from newborn series. The overall sex ratio was raised (male to female: 1.23 to 1), and there was an excess of associated male sex chromosomal aneuploidy. However, in mosaics with one normal cell line the male to female ratio was 0.8 to 1, and in twins discordant for trisomy 21 there was also a female excess.

Peak and submaximal physiologic responses following electrical stimulation leg cycle ergometer training.

Eight males with spinal cord injury (SCI) participated in an exercise training program using neuromuscular electrical stimulation (NMES) leg cycle ergometry. Each subject completed a minimum of 24 (mean +/- SD = 38.1 +/- 17.2) 30-minute training sessions over a 19-week period. The initial work rate (WR) of 0 watts (W) of unloaded cycling was increased when appropriate with subjects exercising at 11.4 +/- 3.7 W (range = 6.1 W-18.3 W) at the end of the training program. Randomized block repeated measures ANOVA was used to compare pretraining and posttraining peak physiologic responses during graded NMES leg cycle tests and subpeak physiologic responses during 10 minutes of NMES leg cycle exercise at an absolute WR (0 W). A significant (P < or = 0.05) increase was observed for peak VO2; (+10%, 1.29 +/- 0.30 to 1.42 +/- 0.39 1.min-1). No other statistically significant differences were noted for any other peak variable (VCO2, VO2 ml.kg-1 min-1, VE, WR, HR, RER) pre- to posttraining. During submaximal NMES leg cycle testing, a significant decrease was noted for RER (-9.2%, 1.19 +/- 0.14 to 1.08 +/- 0.09). No other submaximal variable (VO2 1.min-1, ml.kg-1.min-1, VCO2, HR, VE) showed significant changes as a result of the training. Although the improvement in peak VO2 was not as dramatic as those reported in previous studies, it appears that NMES leg cycle training performed two times per week can significantly enhance cardiorespiratory fitness.

The natural history of Down syndrome conceptuses diagnosed prenatally that are not electively terminated.

The pregnancy outcomes on cases of Down syndrome diagnosed prenatally in which the mother did not elect termination were evaluated in data reported to a comprehensive Register of Down syndrome for England and Wales for 1989-94. In the 168 cases in which placental biopsy was not used, the overall rate of spontaneous loss was 35%, but this figure masks considerable heterogeneity by gestational stage at ascertainment. Data on ages at diagnostic procedure and on pregnancy termination enabled a more precise survival analysis. The loss rates were approximately 50% for those fetuses ascertained at 15-17 completed wk, 43% at 18 wk, 31% at 19 wk, 25% at 20 wk, and then a leveling off at approximately 20%-25% for fetuses ascertained at 21-28 completed wk. For fetuses ascertained prior to 18 wk, there was no evidence that maternal age was associated with fetal loss, consistent with earlier reports. At 18 wk and after, however, maternal age was on the average approximately 3 years greater in fetuses that were lost. Comparison of successive gestational birth cohorts provided no evidence in these 168 cases that the diagnostic procedure itself had any effect on loss or that selective ascertainment of mothers in risk of loss had any effect on the results. In contrast, in the 21 cases in which placental biopsy had been undertaken, the overall loss rates were not only higher when appropriate comparisons could be made, but there was some evidence for selective ascertainment and/or procedure-associated losses.(ABSTRACT TRUNCATED AT 250 WORDS)

Gas exchange kinetics during functional electrical stimulation in subjects with spinal cord injury.

We examined the kinetics of VO2, VCO2, and VE following the onset of unloaded leg cycling, and in recovery, in six patients with spinal cord injury (SCI). Exercise was produced by functional electrical stimulation (FES) of the quadriceps, hamstrings, and gluteal muscles. End-exercise VO2 (1.03 +/- 0.16 l.min-1), VCO2 (1.20 +/- 0.22 l.min-1) and VE (41 +/- 10 l.min-1) were elevated compared to values typically seen in healthy ambulatory subjects performing similar unloaded cycling. Mean response times for the on transients (MRTon) were both long and variable across subjects for VO2 (165 +/- 62 s), VCO2 (173 +/- 58 s), and VE (202 +/- 61 s). Recovery kinetics showed much less intersubject variability, and for five of six subjects were faster than the equivalent exercise MRT for all three variables (MRToff for VO2 of 103 +/- 28 s, VCO2 136 +/- 20 s, and VE 144 +/- 34 s), but P > 0.05 for all three. Size of the O2 deficit (1.96 +/- 0.90 l) and end-exercise lactate (7.05 +/- 1.65 mmol.l-1) were similar to values reported for healthy sedentary subjects performing maximal voluntary exercise, but the end-exercise heart rate (102 +/- 16 bpm) was lower than expected for this intensity of exercise. In conclusion, FES-induced unloaded cycling leads to exaggerated responses of pulmonary gas exchange and long time constants in patients with SCI. The delayed kinetics may be due in part to a blunted increase in heart rate in addition to severe deconditioning.

Down's syndrome births and pregnancy terminations in 1989 to 1993: preliminary findings.

OBJECTIVE: To investigate changes in the numbers of Down's syndrome births and terminations of pregnancies from 1989 to 1993. DESIGN: Data from a national register of cytogenetic diagnoses of karyotypes associated with Down's syndrome were analysed to obtain observed numbers of births and terminations of pregnancies known to be affected. Allowance was made for those cases diagnosed prenatally for whom the eventual outcome of the pregnancies had not yet been ascertained. RESULTS: There has been an increase over the study years in the number of cytogenetic diagnoses of Down's syndrome from 1063 in 1989 to 1137 in 1993, despite an overall fall in births in England and Wales. This is largely due to the increase in antenatal screening and diagnosis, but in part also due to the rise in numbers of pregnancies at increased maternal ages. The rise in prenatally diagnosed cases, of which 92% end in termination, has been accompanied by a fall in both the estimated numbers of affected live births, from 764 in 1989 to 615 in 1993, and the rate per 1000 total live births in the same years from 1.1 to 0.9. CONCLUSIONS: Better and speedier information on the outcome of prenatally diagnosed cases of congenital anomalies such as Down's syndrome would improve the quality of information available for those auditing genetic services or those planning for the care of survivors.

Monitoring trends in prenatal diagnosis of Down's syndrome in England and Wales, 1989-92.

The national register of chromosomal anomalies that lead to Down's syndrome has enabled the monitoring of change in prenatal diagnosis for this condition, and the factors which affect the change. The proportion of cases of cytogenetically diagnosed Down's syndrome in England and Wales detected prenatally rose to 46% in 1991-2 from 31% in 1988-9, a 1.5-fold increase (95% confidence interval 1.3 to 1.7). The increase was confined to mothers under 40 years and was due to the introduction of screening by maternal serum analysis and ultrasound. Over a quarter of affected pregnancies in women aged 25-29 were detected prenatally in 1991-2 compared with less than 10% in 1988-9. Analysis of the data showed regional differences in prenatal diagnosis rates, and in the length of time elapsing between the diagnostic test and termination of an affected pregnancy. An inexplicable finding was that this period varied with the sex of the fetus, being on average a day longer for females than for males.

Effect of run vs combined cycle/run training on VO2max and running performance.

The effects of 5 wk of equivalent intensity, 85-90% maximum heart rate (MHR), run-only (N = 6) vs cycle/run (N = 5) training were evaluated in moderately fit runners, mean VO2max of 55.2 ml.kg-1.min-1, 19-35 yr old, on maximal treadmill (TM) and cycle ergometer (CE) testing, 5000-m and 1609-m run performances, and submaximal measures while treadmill running. Subjects participated in either 4 d.wk-1 of run-only or alternating run and cycle training. Both groups significantly improved TM VO2max (P < 0.05), CE VO2peak (P < 0.01), and 5000-m (P < 0.01) and 1609-m (P < 0.05) run times with no significant differences between the groups. The TM VO2max pre/post values were 55.3 +/- 3.0 to 58.2 +/- 3.0 and 55.6 +/- 3.8 to 58.9 +/- 2.4 ml.kg-1.min-1 for the run group and cross-trained group, respectively. Posttraining submaximal treadmill running showed statistically significant pace increases of 18.7 (run) and 16.1 (cycle/run) m.min-1 with similar heart rate, blood lactate, and RQ values as pretraining. Results indicate that 5 wk of either mode of training can significantly improve aerobic capacity and run performance.