336
387
MEDICAL SCIENCE
Ultrasound screening and perinatal mortality: controlled trial of systematic one-stage screening in pregnancy The Helsinki Ultrasound Trial
gestational age than does an estimate from the last period.! Ultrasound screening not only has the improved dating of pregnancies but also has decreased rate.2 postmaturity In a retrospective study, Belfrage et al3
During a 19-month period, 95% of all pregnant
assesses
women
in the greater Helsinki area, Finland, entered a study to compare one-stage ultrasonography screening with selective
menstrual
screening according to antenatal hospital use, obstetric procedures, and fetal outcomes. Of 9310 women who entered the trial, 4691 were randomly allocated to ultrasound screening between the 16th and 20th gestational weeks and 4619 to follow-up only. Screened and control groups
found that there were fewer labour inductions in women who had had ultrasound screening. In twin pregnancies, ultrasonography has reduced perinatal morbidity and mortality rates.4 Opinions differ about the advantages of routine ultrasound screening. In the early 1980s various workers did not find any benefits of routine screening;S-7 moreover, screened women were admitted to hospital more often than were unscreened women. By contrast, in the trial reported by Eik-Nes et al,8 there was a decrease in the rate of labour inductions in the screened group. In 1988, Waldenstrom and colleagues9 found that there were fewer labour inductions and that babies had a higher birthweight in screened women than in unscreened women. The lack of a statistically significant decrease in perinatal mortality in these randomised trials5-9 may have been due to their limited sample size. Thacker’O concluded that these studies had "failed to demonstrate the usefulness of ultrasound screening for all pregnant women", and he suggested that "increasing the sample size may reveal the differences of the two policies which remain undetected in trials using small sample sizes".
otherwise had the same antenatal care, which included ultrasonography according to usual practice. Screened women made fewer visits to the antenatal outpatient clinic than did women in the control group (2·3 vs 2·6). There were no differences in the number of labour inductions or mean birthweights in the two groups. Perinatal mortality was significantly lower in the screened than in the control group (4·6/1000 vs 9·0/1000); this 49·2% reduction was mainly due to improved early detection of major malformations which led to induced abortion. All twin pregnancies were detected before the 21st gestational week in the screening group compared with 76·3% in the control group; perinatal mortality in the small series of twins was 27·8/1000 vs 65·8/1000, respectively.
Introduction
Ultrasonography is regarded as an important aid in the dating of gestational age, monitoring of fetal growth, confirmation of site of placenta, and detection of twins and major fetal anomalies. The procedure more accurately
ADDRESSES: First and Second Departments of Obstetrics and Gynaecology, Helsinki University Central Hospital (A. SaariKemppainen, MD, O Karjalainen, MD, P Ylostalo, MD) and Department of Public Health, University of Helsinki, Finland (O. P. Heinonen, DSc) Correspondence to Dr A Saari-Kemppainen, First and Second Departments of Obstetrics and Gynaecology, Helsinki University Central Hospital, Haartmanink 2, SF-00290 Helsinki, Finland.
388
The Helsinki Ultrasound Trial was designed to evaluate the systematic ultrasound screening of all pregnancies compared with the current practice of ultrasonography for selected patients. We here report the main fmdingsnamely, antenatal use of medical services, rates of obstetric procedures, and fetal outcomes.
Subjects and methods Finland has a highly developed antenatal care system and the lowest perinatal mortality in the world (World Health Organisation, unpublished 1986 statistics). 99-8% of pregnant women over the entire country had antenatal visits in 1987 (National Board of Health [Finland], unpublished). With a few exceptions they attended the maternal health centres; 92 3% had their first visit by the 16th week of pregnancy. Ultrasonography is well-established in
antenatal
care
in Finland.
Subjects
uestatioriai
The source population for the trial consisted of women who attended 64 maternal health centres in the catchment area of Helsinki University Central Hospital. The ultrasound screening was carried out in two women’s hospitals. All women who visited a health centre early enough in pregnancy were eligible for the study, irrespective of whether ultrasonography had been done elsewhere
for any
size estimation called for about 10 000 participants. This number was a compromise between the need for versatile evaluation of ultrasound screening according to various endpoints and their importance, and the practical limitations in carrying out a trial. The geographical area and time span for recruitment were defmed according to this assessment. 9310 women were willing to take part in the trial, of whom 74-5% lived in Helsinki. According to assessments made by two methods, the study sample included about 95 % of pregnant women in the city of Helsinki. The participation rate in the remaining source population was estimated by one of these methods to be also about 95%. Recruitment (from April, 1986, to November, 1987) started simultaneously in all health centres. Women were randomly allocated either to ultrasound screening (screening group) or to follow-up only (control group) by sealed envelope method on their first visit to the health centres. No factor other than the health centre was considered in the randomisation. 4691 women were randomised into the screening group and 4619 into the control group (fig 1). Before screening began, 11women discovered that they were not pregnant, and 549 had a miscarriage (defined as a fetus less than 500 g in weight or born before the 22nd gestational week); reason.
Sample
Fig 1-Recruitment and randomisation
of
participants.
age
Fig 2-Distribution of gestational age at first ultrasonography. Gestational age was calculated from the last menstrual penod Difference between screening and control groups is significant
(p< 0-001). N= screening
group; D = control group
there were 47 induced abortions. Despite their stated willingness, 318 women did not attend ultrasound screening at the two study hospitals, although 88-7% went elsewhere for ultrasound examination. Since drop-outs between randomisation and delivery were equally distributed between the groups, they did not bias comparisons of the delivery series. Ultrasound screening was done as planned in the remaining 4073 participants (86-8%) of the screening group. 4 women were lost to follow-up because of incomplete identification or moving abroad. 6 women proved not to be pregnant. After the screening 20 women had a miscarriage and 11had an induced abortion as indicated by ultrasonography. Thus, there were 4353 deliveries in the screening group (4389 babies; 72 twins) and 4309 in the control group (4347 babies; 76 twins). 94-8% of the babies were born in Helsinki (57-3% City Maternity Hospital, 37-5% University Hospital). The babies were born between September, 1986, and July, 1988.
Methods Ultrasound screening for the screening group was done between the 16th and 20th gestational weeks at the City and University Hospitals. The examination included measurement of biparietal diameter, location of the placenta, and registration of the number of fetuses. The cross fetal anatomy and the amount of amniotic fluid were evaluated. The expected date of delivery was estimated from biparietal diameter with charts derived from a Finnish population." Special attention was given to the diagnosis of major malformations at the University Hospital, where there was more time allocated to the screening examination. Real-time equipment’Kretz Combison 320’, ’Hitachi EUB 400’, and ’Aloka SS 13-280’ were used. Repeat ultrasound examination, which was done if any of the indices could not be recorded, was necessary in 6-5% of women, mainly for placental localisation or re-evaluation of fetal anatomy. The data on the ultrasound findings were collected on a prestructured form. The screening and control groups otherwise had the same antenatal care, including ultrasonography according to usual practice. Between the time when study ultrasound screening was done and delivery, ultrasonography was allowed if indicated (as before the study screening); its indication, time, and results were recorded as accurately as possible. In 22-6% of the screening group ultrasonography had also been done before the study screening and in 35-6% after it. In 1-6% of the total screening group no ultrasonography at all was done (the women were randomised but did not attend screening or have ultrasonography earlier or later). Smoking habits were recorded on a structured questionnaire at the beginning and late in pregnancy. Data on pregnancy outcomes were collected manually from patient records. All data were computerised for analyses.
389
TABLE I-REASONS FOR FIRST EARLY ULTRASOUND EXAMINATION BEFORE 21 ST GESTATIONAL WEEK
Ultrasonography preceded study screening in 1096 participants, and occurred after the 20th week m 93 participants *tnformat!on missing in 95. tinformation missing in 102 tPnvate practice §Amniocenteses were done for genetic reasons
Statistics Statistical
analysis
was done on the original randomised groups the intention-to-treat principle:12 it was then repeated for relevant subgroups. The differences between comparison groups were evaluated by either Student’s t-test or Fisher’s exact test. Two-tailed p values are presented. Confidence interval estimation was based on independent binomials (approximate variance of log relative risk by delta method).
according to
Results In the control group 77-0% of women had ultrasonography during pregnancy. In the screening group most of first ultrasonographies were done within the 16th to 20th gestational weeks, whereas in the control group they were distributed more evenly throughout pregnancy (fig 2). First ultrasonography after the 20th gestational week was done in 2-1% of the screening group (mainly because of wrong timing according to the last menstrual period) and in 21 ’5%
of the control group. The mean number of ultrasound examinations during pregnancy was 2-1and 1-8 in the screening and control groups, respectively. Reasons for first ultrasonography before the 21st gestational week are shown in table I.
Women in both groups were broadly similar with respect to mean length of gestation from last menstrual period to spontaneous onset of labour. Correction of the expected date of delivery ( !! 10 days) in the screening group decreased the rate of post-maturity (> 42 gestational weeks) from 5-5% to 2-9% at spontaneous onset of labour. Twin pregnancies. Twin pregnancies (88/1000) were detected early in the screening. There were 2 additional cases of vanishing twins. All twin pregnancies in the study group were detected before the 21st gestational week compared with 76-3% in the control group (p=0005). Eventually, all the control group twin pregnancies were identified by ultrasonography, though detections were made until the 38th gestational week. Placenta praevia. Placenta praevia was noted by screening ultrasound in 11/1000 pregnancies and marginal placenta in 53/1000. Placenta praevia led to closer follow-up. In the screening group there were 4 cases of this condition at delivery, 1 of which had been missed at screening. In all cases caesarean section was necessary. The control group also included 4 women with placenta praevia at delivery, all of whom had haemorrhage; they were admitted to hospital and underwent caesarean section. Thus, the prevalence of placenta praevia at delivery in the entire cohort was 1/1000 deliveries. Hospital attendance. If the screening visit is discounted, there were fewer antenatal outpatient clinic visits (mean number of visits 2-34, 95% confidence interval [CI] 2-27-2-42) and fewer women attending (53%) from the screening group than from the control group (2-59,95% CI The mean number of 2-52-2-67, 56-8%) (p 22 weeks old or we!gh!ng within 7
"p500
g, and mfants
dying
390
2514 g in the control group; 40 8% of babies in the screening group weighed less than 2500 g compared with 42 1 % in the control group. Apgar score and neonatal hospitalisation. The mean Apgar score and the proportion of babies with scores of less than 7 at one minute were the same in both groups. There was no difference between the groups in the rate of infant admissions to the intensive care unit or to the prematurity ward for longer than five days (3-6% vs 3-1%). The main reasons
for
admission
were
prematurity (21-5%),
hyperbilirubinaemia (20-2%), infections (15-6%), and anomalies (55%). Among the twins of the screening group, 25-7% of infants were admitted to intensive care for longer than five days compared with 19-7% in the control group. Malformations. The rate of detection, by screening, of the major malformations observed at induced abortion or delivery was 36-0% in the City Hospital and 76-9% at the University Hospital. Major malformation was suspected in a total of 30 cases during ultrasound screening. In 11 cases (2-7/1000) this led to termination of pregnancy before the 25th gestational week. 4 malformed babies died perinatally, 3 were operated on postnatally,1 had hydronephrosis, and 1 had a minor anomaly. In 10 cases, the suspected abnormality had disappeared in the follow-up ultrasound examinations (before 20th-36th weeks)—1 case of a cyst in the choroid plexus (before 22nd week), 5 of apparent fetal hydronephrosis (20th-29th week), 1 of cystic changes in the thorax (36th week), 2 of hydroureter or cyst in the abdomen (33rd and 35th week), and 1 fetus with short femur for gestational age which became normal before the 23rd week. In the control group, none of the women had induced abortion after an ultrasound finding of congenital malformation. Perinatal mortality The perinatal mortality rate of singletons was significantly lower in the screening group than in the control group (table II). 18 singleton babies in the screening group died; of these, 11 were stillbom-1 with a serious anomaly whose mother refused an abortion, 2 cases of infection, and 8 cases of asphyxia. 7 infants died within 7 days because of major anomalies, 1 hydrops fetalis, 3 prematurity, 1 asphyxia, and 1 listeriosis. In the control group, 34 singletons died. There were 22 stillborn infants: 3 had major anomalies, 5 were due to placental abruption, 1 to traffic accident, and 13 had asphyxia. 12 infants died within seven days: 7 had major anomalies, 1 persistent fetal circulation, 1 asphyxia due to placental abruption, and 3 were premature. The perinatal mortality rate of twins was 278/ 1000 in the screening group compared with 65-8/1000 in the control group. 2 twin babies died in the screening group and 5 in the control group. In the screening group there was 1 anomalous baby (twin B acardicus amorficus) and another
died in utero because of feto-fetal transfusion. In the control group one twin pair was lost in utero because of feto-fetal transfusion (twin B acardicus amorficus). One pair of twins and another baby were lost in utero because of asphyxia. Overall perinatal mortality rate (singleton and twins combined) was significantly lower (p 0-013) in the group with ultrasound screening than in the control group, irrespective of the selected denominator (original randomised series or deliveries only) with or without women who did not attend the screening (table II). =
Discussion In some countries all pregnant women are routinely screened by ultrasound. In West Germany the "Mutterschafts-Richtlinien" of 1980 stated that every pregnant woman should be offered at least two ultrasound examinations during pregnancy,13 and in the UK a working party of the Royal College of Obstetricians and Gynaecologists also recommended screening. 14 By contrast, in the USA, a 1984 consensus conference of the National Institutes of Health concluded that "the data on clinical efficacy and safety do not allow a recommendation for routine screening at this time" .15 The aim of the Helsinki Ultrasound Trial was to test whether strictly timed, systematic screening of all pregnancies would reveal any benefits (or adverse effects) under circumstances in which one can neither prevent nor limit participants in a controlled clinical trial from having ultrasonography when desired. Customary use of ultrasound was so common among the trial participants that only a quarter of the control group had no ultrasound examination during pregnancy. Moreover, in a quarter of the screening group, ultrasonography had already been done before the screening ultrasound. Of the women randomly allocated to the screening group, 318 did not attend, although only 36 of these had no ultrasonography at all before they delivered. In such circumstances, the possibilities of revealing an effect in a controlled trial are less likely than when there is a sharper contrast between screening and selective use of ultrasound. Although the fmal sample size of the study was about 7% smaller than estimated, it did not affect our results. This study has shown that ultrasound screening improved the management of pregnancy and was beneficial to the children. Adverse effects were negligible. Early screening saved women from later outpatient hospital visits (one visit per 4 women screened) and decreased the antenatal use of hospital beds (one day per 5 screened). In twin pregnancies, screening improved early detection by a quarter (1/500 pregnancies) and found three-quarters of cases of placenta praevia (1/1300 preganancies). The most important finding, however, was that half the serious malformations were detected-a frequency of 1/200. Perinatal mortality decreased by about the same rate, mainly because of induced abortions as a result of the detected malformations. No serious disadvantages were recorded. A placenta found to be overlying the internal os during screening, but which migrated on follow-up could have caused unneccessary anxiety. The suspected anomalies that turned out to be normal and the rare cases of vanishing twins can also be regarded as negative effects. Otherwise, the ultrasound screening clearly reassured the women because they required fewer antenatal outpatient visits. The same trend was observed in antenatal hospital use, although the difference in mean number of days did not quite reach statistical significance. The trial did not have enough statistical power to distinguish between the outcomes of twin pregnancies in the two groups because of the small number in the series and because of the 76-3% detection rate already established in the control group at the 21st gestational week. In the small series of twins there were only 7 deaths, 2 of whom were in the screening group. Even these small numbers suggest a reduction of mortality among twins, which would support the findings in singletons and previous studies. The Malmö ultrasound study2 showed a decrease in the rate of pretenn
391
a reduction in the perinatal mortality and of twins. Bakketeig et aF and Eik-Nes et al8 found higher birthweights of twins in the screened group, whereas Waldenstrom et al9 found no difference in birth weight, premature deliveries, or hospital admissions. Thus, if twin pregnancies are detected early enough, good antenatal follow-up can prevent some premature deliveries and so influence perinatal morbidity and mortality. Like Wexler and Gottesfeld16 and Cochlin ’17 we found that marginal insertion or placenta praevia were common in second trimester ultrasound screening. In most of our cases diagnosed by ultrasound the placenta migrated and caused no trouble at delivery, whereas in the control group all cases of haemorrhaged placenta praevia led to hospital admission and caesarean section. More accurate dating of pregnancies by the screening ultrasound reduced the rate of postmaturity at the onset of spontaneous delivery but did not decrease the rate of labour inductions as in some other studies.3,8,9 The reason for this unexpected finding may be that there were no instructions from the trial reasearch team about how any changes in pregnancy-dating by ultrasound screening should be used, and thus clinical judgement varied considerably. Overall, we were very careful to leave prevailing clinical practice as it was, since bias is possible with active interference. Our evaluation of labour inductions calls for post hoc case analyses of all inductions according to preset criteria. Walderstrom and colleagues9 proposed that decreased smoking due to a mother’s ultrasound experience (seeing her fetus) could explain why there was a higher mean birthweight of babies among screened women. However, in our trial there was no difference in smoking habits in early or late pregnancy between the screening and control groups; the well-known difference in birthweight of babies between smoking and non-smoking mothers18,19 was clearly observed. In the present study, major anomalies in the control group vs induced abortions in the screening group because of major anomalies detected in the screening ultrasound examination accounted for half the decrease in perinatal mortality among the singletons. The difference between the groups loses statistical significance if the induced abortions are added into the data as dead babies. In twins the reduction was consistent with the singletons’ rate. However, since there were only a few deaths and no induced abortions, the effect of screening, if any, in reducing the mortality of twins remained unknown. Two-stage screening programmes7,zo have also been used to monitor growth retardation, final placental site, and anomalies detectable only late in pregnancy. We could not evaluate the benefits of two-stage screening in the present trial. With such a low perinatal mortality, the most important single cause of perinatal death in Finland is congenital anomalies. These can be detected with ultrasound screening; with well-organised genetic counselling as well as the option of induced abortion before the 25th gestational week, the proportion of anomalies which result in perinatal death can be decreased. The development of screening techniques for improved detection of malformations should be encouraged. In the current trial, for example, only half the serious malformations were revealed by ultrasound screening, though it is noteworthy that detection was much better (three-quarters vs one-third) in the hospital where special arrangements were made to improve it. Although no data on findings at ultrasonography in the control group were
twin births and
morbidity rates
available, the fact that no abortions were induced because of malformations points to a large false-negative detection rate, at least early in pregnancy. The decrease in perinatal mortality of about half in this trial can be explained mainly by the detection of major fetal anomalies by ultrasound screening and the subsequent termination of these pregnancies. We believe that our findings justify systematic one-stage ultrasound screening of all pregnancies for the detection of major congenital anomalies under circumstances in which their elimination by induced abortion is acceptable. This
study was supported by a grant from Helsinki University Central Hospital fund and the Academy of Finland. We thank Dr Tapani Luukkainen, head of Helsinki City Maternity Hospital, for providing facilities and support for the study, and the personnel of Helsinki City Maternity Hospital radiological department for doing part of the ultrasound screening. We thank all the health centre nurses for recruiting patients to the study; Ms P. Vantola, Ms H. Huhtaniemi, Ms M. Krogell, Ms S. Lund, Ms L. Oinonen, Ms M. Tammenpaa, and Mrs E. Valkonen-Rantala for technical assistance; and Mrs H. Rita and Ms Juni Palmgren for assistance in statistics and data processing.
REFERENCES 1.
Campbell AS, Warsof SL, Little D, Cooper DJ. Routine ultrasound screening for the prediction of gestational age. Obstet Gynecol 1985; 65:
613-20. 2. Persson PH, Kullander S. Long-term experience of general ultrasound screening in pregnancy. Am J Obstet Gynecol 1983; 146: 942-47. 3. Belfrage P, Fernström I, Hallenberg G. Routine or selective ultrasound examinations in early pregnancy. Obstet Gynecol 1987; 69: 747-50. 4. Grennert L, Persson PH, Gennser G. Benefits of ultrasonic screening of a pregnant population. Acta Obstet Gynaecol Scand 1978 (suppl 78): 5-14. 5. Bennett MJ, Little G, Dewhurst J, Chamberlain G. Predictive value of ultrasound measurements in early pregnancy: a randomised controlled trial. Br J Obstet Gynaecol 1982; 89: 338-41. 6. Neilson JP, Munjanja JP, Whitfield CR. Screening for small-for-dates fetuses: a controlled trial. Br Med J 1984; 289: 1179-82. 7. Bakketeig LS, Eik-Nes SH, Jacobsen G, et al. Randomised controlled trial of ultrasonographic screening in pregnancy. Lancet 1984; ii: 207-11. 8. Eik-Nes SH, Okland O, Aure JC, Ulstein M. Ultrasound screening in pregnancy: a randomised controlled trial. Lancet 1984; i: 1347. 9. Waldenström U, Axelsson O, Nilsson S, et al. Effects of routine one-stage ultrasound screening in pregnancy: a randomised controlled trial. Lancet 1988; ii: 585-88. 10. Thacker SB. Quality of controlled clinical trials. The case of imaging ultrasound in obstetrics: a review. Br J Obstet Gynaecol 1985; 92: 437-44. 11. Aantaa K, Forss M. Growth of the fetal biparietal diameter in different types of pregnancies. Radiology 1980; 137: 167-69. 12. Friedman LM, Furberg CD, De Mets DL. Fundamentals of clinical trials. 2nd ed. Littleton, Massachusetts; PSG Publishing, 1985: 241-65. 13. Hansmann M. Ultraschallscreening in der Schwangerschaft-Vorsicht vor übertriebenen Forderungen. Geburtsch Frauenheilk 1981; 41: 725-28. 14. Royal College of Obstetricians and Gynaecologists Working Party. Routine ultrasound examination in pregnancy. London: Royal College of Obstetricians and Gynaecologists, 1984. 15. Consensus Conference. The use of diagnostic ultrasound imaging during
pregnancy. JAMA 1984; 252: 669-72. 16. Wexler P, Gottesfeld KR. Second trimester placenta previa. An apparently normal placentation. Obstet Gynecol 1977; 50: 706-09. 17. Cochlin DL. Effects of two ultrasound regimens on the management of pregnancy. Br J Obstet Gynaecol 1984; 91: 885-90. 18. Persson PH, Grennert L, Gennser G, Kullander S. A study of smoking and pregnancy with special reference to fetal growth. Acta Obstet Gynaecol Scand 1978 (suppl 78): 33-39. 19. Peters TJ, Golding J, Butler NR, et al. Plus ça change: predictors of birthweight in two national studies. Br J Obstet Gynaecol 1983; 90: 1040-45. 20. Rosendahl H, Kivinen S. Routine ultrasound screening for early detection of small for gestational age fetuses. Obstet Gynecol 1988; 71: 518-21.
387
MEDICAL SCIENCE
Ultrasound screening and perinatal mortality: controlled trial of systematic one-stage screening in pregnancy The Helsinki Ultrasound Trial
gestational age than does an estimate from the last period.! Ultrasound screening not only has the improved dating of pregnancies but also has decreased rate.2 postmaturity In a retrospective study, Belfrage et al3
During a 19-month period, 95% of all pregnant
assesses
women
in the greater Helsinki area, Finland, entered a study to compare one-stage ultrasonography screening with selective
menstrual
screening according to antenatal hospital use, obstetric procedures, and fetal outcomes. Of 9310 women who entered the trial, 4691 were randomly allocated to ultrasound screening between the 16th and 20th gestational weeks and 4619 to follow-up only. Screened and control groups
found that there were fewer labour inductions in women who had had ultrasound screening. In twin pregnancies, ultrasonography has reduced perinatal morbidity and mortality rates.4 Opinions differ about the advantages of routine ultrasound screening. In the early 1980s various workers did not find any benefits of routine screening;S-7 moreover, screened women were admitted to hospital more often than were unscreened women. By contrast, in the trial reported by Eik-Nes et al,8 there was a decrease in the rate of labour inductions in the screened group. In 1988, Waldenstrom and colleagues9 found that there were fewer labour inductions and that babies had a higher birthweight in screened women than in unscreened women. The lack of a statistically significant decrease in perinatal mortality in these randomised trials5-9 may have been due to their limited sample size. Thacker’O concluded that these studies had "failed to demonstrate the usefulness of ultrasound screening for all pregnant women", and he suggested that "increasing the sample size may reveal the differences of the two policies which remain undetected in trials using small sample sizes".
otherwise had the same antenatal care, which included ultrasonography according to usual practice. Screened women made fewer visits to the antenatal outpatient clinic than did women in the control group (2·3 vs 2·6). There were no differences in the number of labour inductions or mean birthweights in the two groups. Perinatal mortality was significantly lower in the screened than in the control group (4·6/1000 vs 9·0/1000); this 49·2% reduction was mainly due to improved early detection of major malformations which led to induced abortion. All twin pregnancies were detected before the 21st gestational week in the screening group compared with 76·3% in the control group; perinatal mortality in the small series of twins was 27·8/1000 vs 65·8/1000, respectively.
Introduction
Ultrasonography is regarded as an important aid in the dating of gestational age, monitoring of fetal growth, confirmation of site of placenta, and detection of twins and major fetal anomalies. The procedure more accurately
ADDRESSES: First and Second Departments of Obstetrics and Gynaecology, Helsinki University Central Hospital (A. SaariKemppainen, MD, O Karjalainen, MD, P Ylostalo, MD) and Department of Public Health, University of Helsinki, Finland (O. P. Heinonen, DSc) Correspondence to Dr A Saari-Kemppainen, First and Second Departments of Obstetrics and Gynaecology, Helsinki University Central Hospital, Haartmanink 2, SF-00290 Helsinki, Finland.
388
The Helsinki Ultrasound Trial was designed to evaluate the systematic ultrasound screening of all pregnancies compared with the current practice of ultrasonography for selected patients. We here report the main fmdingsnamely, antenatal use of medical services, rates of obstetric procedures, and fetal outcomes.
Subjects and methods Finland has a highly developed antenatal care system and the lowest perinatal mortality in the world (World Health Organisation, unpublished 1986 statistics). 99-8% of pregnant women over the entire country had antenatal visits in 1987 (National Board of Health [Finland], unpublished). With a few exceptions they attended the maternal health centres; 92 3% had their first visit by the 16th week of pregnancy. Ultrasonography is well-established in
antenatal
care
in Finland.
Subjects
uestatioriai
The source population for the trial consisted of women who attended 64 maternal health centres in the catchment area of Helsinki University Central Hospital. The ultrasound screening was carried out in two women’s hospitals. All women who visited a health centre early enough in pregnancy were eligible for the study, irrespective of whether ultrasonography had been done elsewhere
for any
size estimation called for about 10 000 participants. This number was a compromise between the need for versatile evaluation of ultrasound screening according to various endpoints and their importance, and the practical limitations in carrying out a trial. The geographical area and time span for recruitment were defmed according to this assessment. 9310 women were willing to take part in the trial, of whom 74-5% lived in Helsinki. According to assessments made by two methods, the study sample included about 95 % of pregnant women in the city of Helsinki. The participation rate in the remaining source population was estimated by one of these methods to be also about 95%. Recruitment (from April, 1986, to November, 1987) started simultaneously in all health centres. Women were randomly allocated either to ultrasound screening (screening group) or to follow-up only (control group) by sealed envelope method on their first visit to the health centres. No factor other than the health centre was considered in the randomisation. 4691 women were randomised into the screening group and 4619 into the control group (fig 1). Before screening began, 11women discovered that they were not pregnant, and 549 had a miscarriage (defined as a fetus less than 500 g in weight or born before the 22nd gestational week); reason.
Sample
Fig 1-Recruitment and randomisation
of
participants.
age
Fig 2-Distribution of gestational age at first ultrasonography. Gestational age was calculated from the last menstrual penod Difference between screening and control groups is significant
(p< 0-001). N= screening
group; D = control group
there were 47 induced abortions. Despite their stated willingness, 318 women did not attend ultrasound screening at the two study hospitals, although 88-7% went elsewhere for ultrasound examination. Since drop-outs between randomisation and delivery were equally distributed between the groups, they did not bias comparisons of the delivery series. Ultrasound screening was done as planned in the remaining 4073 participants (86-8%) of the screening group. 4 women were lost to follow-up because of incomplete identification or moving abroad. 6 women proved not to be pregnant. After the screening 20 women had a miscarriage and 11had an induced abortion as indicated by ultrasonography. Thus, there were 4353 deliveries in the screening group (4389 babies; 72 twins) and 4309 in the control group (4347 babies; 76 twins). 94-8% of the babies were born in Helsinki (57-3% City Maternity Hospital, 37-5% University Hospital). The babies were born between September, 1986, and July, 1988.
Methods Ultrasound screening for the screening group was done between the 16th and 20th gestational weeks at the City and University Hospitals. The examination included measurement of biparietal diameter, location of the placenta, and registration of the number of fetuses. The cross fetal anatomy and the amount of amniotic fluid were evaluated. The expected date of delivery was estimated from biparietal diameter with charts derived from a Finnish population." Special attention was given to the diagnosis of major malformations at the University Hospital, where there was more time allocated to the screening examination. Real-time equipment’Kretz Combison 320’, ’Hitachi EUB 400’, and ’Aloka SS 13-280’ were used. Repeat ultrasound examination, which was done if any of the indices could not be recorded, was necessary in 6-5% of women, mainly for placental localisation or re-evaluation of fetal anatomy. The data on the ultrasound findings were collected on a prestructured form. The screening and control groups otherwise had the same antenatal care, including ultrasonography according to usual practice. Between the time when study ultrasound screening was done and delivery, ultrasonography was allowed if indicated (as before the study screening); its indication, time, and results were recorded as accurately as possible. In 22-6% of the screening group ultrasonography had also been done before the study screening and in 35-6% after it. In 1-6% of the total screening group no ultrasonography at all was done (the women were randomised but did not attend screening or have ultrasonography earlier or later). Smoking habits were recorded on a structured questionnaire at the beginning and late in pregnancy. Data on pregnancy outcomes were collected manually from patient records. All data were computerised for analyses.
389
TABLE I-REASONS FOR FIRST EARLY ULTRASOUND EXAMINATION BEFORE 21 ST GESTATIONAL WEEK
Ultrasonography preceded study screening in 1096 participants, and occurred after the 20th week m 93 participants *tnformat!on missing in 95. tinformation missing in 102 tPnvate practice §Amniocenteses were done for genetic reasons
Statistics Statistical
analysis
was done on the original randomised groups the intention-to-treat principle:12 it was then repeated for relevant subgroups. The differences between comparison groups were evaluated by either Student’s t-test or Fisher’s exact test. Two-tailed p values are presented. Confidence interval estimation was based on independent binomials (approximate variance of log relative risk by delta method).
according to
Results In the control group 77-0% of women had ultrasonography during pregnancy. In the screening group most of first ultrasonographies were done within the 16th to 20th gestational weeks, whereas in the control group they were distributed more evenly throughout pregnancy (fig 2). First ultrasonography after the 20th gestational week was done in 2-1% of the screening group (mainly because of wrong timing according to the last menstrual period) and in 21 ’5%
of the control group. The mean number of ultrasound examinations during pregnancy was 2-1and 1-8 in the screening and control groups, respectively. Reasons for first ultrasonography before the 21st gestational week are shown in table I.
Women in both groups were broadly similar with respect to mean length of gestation from last menstrual period to spontaneous onset of labour. Correction of the expected date of delivery ( !! 10 days) in the screening group decreased the rate of post-maturity (> 42 gestational weeks) from 5-5% to 2-9% at spontaneous onset of labour. Twin pregnancies. Twin pregnancies (88/1000) were detected early in the screening. There were 2 additional cases of vanishing twins. All twin pregnancies in the study group were detected before the 21st gestational week compared with 76-3% in the control group (p=0005). Eventually, all the control group twin pregnancies were identified by ultrasonography, though detections were made until the 38th gestational week. Placenta praevia. Placenta praevia was noted by screening ultrasound in 11/1000 pregnancies and marginal placenta in 53/1000. Placenta praevia led to closer follow-up. In the screening group there were 4 cases of this condition at delivery, 1 of which had been missed at screening. In all cases caesarean section was necessary. The control group also included 4 women with placenta praevia at delivery, all of whom had haemorrhage; they were admitted to hospital and underwent caesarean section. Thus, the prevalence of placenta praevia at delivery in the entire cohort was 1/1000 deliveries. Hospital attendance. If the screening visit is discounted, there were fewer antenatal outpatient clinic visits (mean number of visits 2-34, 95% confidence interval [CI] 2-27-2-42) and fewer women attending (53%) from the screening group than from the control group (2-59,95% CI The mean number of 2-52-2-67, 56-8%) (p 22 weeks old or we!gh!ng within 7
"p500
g, and mfants
dying
390
2514 g in the control group; 40 8% of babies in the screening group weighed less than 2500 g compared with 42 1 % in the control group. Apgar score and neonatal hospitalisation. The mean Apgar score and the proportion of babies with scores of less than 7 at one minute were the same in both groups. There was no difference between the groups in the rate of infant admissions to the intensive care unit or to the prematurity ward for longer than five days (3-6% vs 3-1%). The main reasons
for
admission
were
prematurity (21-5%),
hyperbilirubinaemia (20-2%), infections (15-6%), and anomalies (55%). Among the twins of the screening group, 25-7% of infants were admitted to intensive care for longer than five days compared with 19-7% in the control group. Malformations. The rate of detection, by screening, of the major malformations observed at induced abortion or delivery was 36-0% in the City Hospital and 76-9% at the University Hospital. Major malformation was suspected in a total of 30 cases during ultrasound screening. In 11 cases (2-7/1000) this led to termination of pregnancy before the 25th gestational week. 4 malformed babies died perinatally, 3 were operated on postnatally,1 had hydronephrosis, and 1 had a minor anomaly. In 10 cases, the suspected abnormality had disappeared in the follow-up ultrasound examinations (before 20th-36th weeks)—1 case of a cyst in the choroid plexus (before 22nd week), 5 of apparent fetal hydronephrosis (20th-29th week), 1 of cystic changes in the thorax (36th week), 2 of hydroureter or cyst in the abdomen (33rd and 35th week), and 1 fetus with short femur for gestational age which became normal before the 23rd week. In the control group, none of the women had induced abortion after an ultrasound finding of congenital malformation. Perinatal mortality The perinatal mortality rate of singletons was significantly lower in the screening group than in the control group (table II). 18 singleton babies in the screening group died; of these, 11 were stillbom-1 with a serious anomaly whose mother refused an abortion, 2 cases of infection, and 8 cases of asphyxia. 7 infants died within 7 days because of major anomalies, 1 hydrops fetalis, 3 prematurity, 1 asphyxia, and 1 listeriosis. In the control group, 34 singletons died. There were 22 stillborn infants: 3 had major anomalies, 5 were due to placental abruption, 1 to traffic accident, and 13 had asphyxia. 12 infants died within seven days: 7 had major anomalies, 1 persistent fetal circulation, 1 asphyxia due to placental abruption, and 3 were premature. The perinatal mortality rate of twins was 278/ 1000 in the screening group compared with 65-8/1000 in the control group. 2 twin babies died in the screening group and 5 in the control group. In the screening group there was 1 anomalous baby (twin B acardicus amorficus) and another
died in utero because of feto-fetal transfusion. In the control group one twin pair was lost in utero because of feto-fetal transfusion (twin B acardicus amorficus). One pair of twins and another baby were lost in utero because of asphyxia. Overall perinatal mortality rate (singleton and twins combined) was significantly lower (p 0-013) in the group with ultrasound screening than in the control group, irrespective of the selected denominator (original randomised series or deliveries only) with or without women who did not attend the screening (table II). =
Discussion In some countries all pregnant women are routinely screened by ultrasound. In West Germany the "Mutterschafts-Richtlinien" of 1980 stated that every pregnant woman should be offered at least two ultrasound examinations during pregnancy,13 and in the UK a working party of the Royal College of Obstetricians and Gynaecologists also recommended screening. 14 By contrast, in the USA, a 1984 consensus conference of the National Institutes of Health concluded that "the data on clinical efficacy and safety do not allow a recommendation for routine screening at this time" .15 The aim of the Helsinki Ultrasound Trial was to test whether strictly timed, systematic screening of all pregnancies would reveal any benefits (or adverse effects) under circumstances in which one can neither prevent nor limit participants in a controlled clinical trial from having ultrasonography when desired. Customary use of ultrasound was so common among the trial participants that only a quarter of the control group had no ultrasound examination during pregnancy. Moreover, in a quarter of the screening group, ultrasonography had already been done before the screening ultrasound. Of the women randomly allocated to the screening group, 318 did not attend, although only 36 of these had no ultrasonography at all before they delivered. In such circumstances, the possibilities of revealing an effect in a controlled trial are less likely than when there is a sharper contrast between screening and selective use of ultrasound. Although the fmal sample size of the study was about 7% smaller than estimated, it did not affect our results. This study has shown that ultrasound screening improved the management of pregnancy and was beneficial to the children. Adverse effects were negligible. Early screening saved women from later outpatient hospital visits (one visit per 4 women screened) and decreased the antenatal use of hospital beds (one day per 5 screened). In twin pregnancies, screening improved early detection by a quarter (1/500 pregnancies) and found three-quarters of cases of placenta praevia (1/1300 preganancies). The most important finding, however, was that half the serious malformations were detected-a frequency of 1/200. Perinatal mortality decreased by about the same rate, mainly because of induced abortions as a result of the detected malformations. No serious disadvantages were recorded. A placenta found to be overlying the internal os during screening, but which migrated on follow-up could have caused unneccessary anxiety. The suspected anomalies that turned out to be normal and the rare cases of vanishing twins can also be regarded as negative effects. Otherwise, the ultrasound screening clearly reassured the women because they required fewer antenatal outpatient visits. The same trend was observed in antenatal hospital use, although the difference in mean number of days did not quite reach statistical significance. The trial did not have enough statistical power to distinguish between the outcomes of twin pregnancies in the two groups because of the small number in the series and because of the 76-3% detection rate already established in the control group at the 21st gestational week. In the small series of twins there were only 7 deaths, 2 of whom were in the screening group. Even these small numbers suggest a reduction of mortality among twins, which would support the findings in singletons and previous studies. The Malmö ultrasound study2 showed a decrease in the rate of pretenn
391
a reduction in the perinatal mortality and of twins. Bakketeig et aF and Eik-Nes et al8 found higher birthweights of twins in the screened group, whereas Waldenstrom et al9 found no difference in birth weight, premature deliveries, or hospital admissions. Thus, if twin pregnancies are detected early enough, good antenatal follow-up can prevent some premature deliveries and so influence perinatal morbidity and mortality. Like Wexler and Gottesfeld16 and Cochlin ’17 we found that marginal insertion or placenta praevia were common in second trimester ultrasound screening. In most of our cases diagnosed by ultrasound the placenta migrated and caused no trouble at delivery, whereas in the control group all cases of haemorrhaged placenta praevia led to hospital admission and caesarean section. More accurate dating of pregnancies by the screening ultrasound reduced the rate of postmaturity at the onset of spontaneous delivery but did not decrease the rate of labour inductions as in some other studies.3,8,9 The reason for this unexpected finding may be that there were no instructions from the trial reasearch team about how any changes in pregnancy-dating by ultrasound screening should be used, and thus clinical judgement varied considerably. Overall, we were very careful to leave prevailing clinical practice as it was, since bias is possible with active interference. Our evaluation of labour inductions calls for post hoc case analyses of all inductions according to preset criteria. Walderstrom and colleagues9 proposed that decreased smoking due to a mother’s ultrasound experience (seeing her fetus) could explain why there was a higher mean birthweight of babies among screened women. However, in our trial there was no difference in smoking habits in early or late pregnancy between the screening and control groups; the well-known difference in birthweight of babies between smoking and non-smoking mothers18,19 was clearly observed. In the present study, major anomalies in the control group vs induced abortions in the screening group because of major anomalies detected in the screening ultrasound examination accounted for half the decrease in perinatal mortality among the singletons. The difference between the groups loses statistical significance if the induced abortions are added into the data as dead babies. In twins the reduction was consistent with the singletons’ rate. However, since there were only a few deaths and no induced abortions, the effect of screening, if any, in reducing the mortality of twins remained unknown. Two-stage screening programmes7,zo have also been used to monitor growth retardation, final placental site, and anomalies detectable only late in pregnancy. We could not evaluate the benefits of two-stage screening in the present trial. With such a low perinatal mortality, the most important single cause of perinatal death in Finland is congenital anomalies. These can be detected with ultrasound screening; with well-organised genetic counselling as well as the option of induced abortion before the 25th gestational week, the proportion of anomalies which result in perinatal death can be decreased. The development of screening techniques for improved detection of malformations should be encouraged. In the current trial, for example, only half the serious malformations were revealed by ultrasound screening, though it is noteworthy that detection was much better (three-quarters vs one-third) in the hospital where special arrangements were made to improve it. Although no data on findings at ultrasonography in the control group were
twin births and
morbidity rates
available, the fact that no abortions were induced because of malformations points to a large false-negative detection rate, at least early in pregnancy. The decrease in perinatal mortality of about half in this trial can be explained mainly by the detection of major fetal anomalies by ultrasound screening and the subsequent termination of these pregnancies. We believe that our findings justify systematic one-stage ultrasound screening of all pregnancies for the detection of major congenital anomalies under circumstances in which their elimination by induced abortion is acceptable. This
study was supported by a grant from Helsinki University Central Hospital fund and the Academy of Finland. We thank Dr Tapani Luukkainen, head of Helsinki City Maternity Hospital, for providing facilities and support for the study, and the personnel of Helsinki City Maternity Hospital radiological department for doing part of the ultrasound screening. We thank all the health centre nurses for recruiting patients to the study; Ms P. Vantola, Ms H. Huhtaniemi, Ms M. Krogell, Ms S. Lund, Ms L. Oinonen, Ms M. Tammenpaa, and Mrs E. Valkonen-Rantala for technical assistance; and Mrs H. Rita and Ms Juni Palmgren for assistance in statistics and data processing.
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