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Sinistrality—a side-effect of prenatal sonography: A comparative study of young men

Kieler, Helle1; Cnattingius, Sven2; Haglund, Bengt1,3; Palmgren, Juni2,4; Axelsson, Ove1

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Although ultrasound during pregnancy is used extensively, there is little published on adverse fetal effects. We undertook a cohort study including men born in Sweden from 1973 to 1978 who enrolled for military service. We estimated relative risks for being born left-handed according to ultrasound exposure in fetal life using logistic regression analysis. Eligible for the study were 6,858 men born at a hospital that included ultrasound scanning in standard antenatal care (exposed) and 172,537 men born in hospitals without ultrasound scanning programs (unexposed). During the introduction phase (1973 to 1975) there was no difference in left-handedness between ultrasound exposed and unexposed (odds ratio = 1.03, 95% confidence interval (CI) = 0.91 to 1.17). When ultrasonography was offered more widely (1976 to 1978), the risk of left-handedness was higher among those exposed to ultrasound compared with those unexposed (odds ratio = 1.32, 95% CI = 1.16 to 1.51). We conclude that ultrasound exposure in fetal life increases the risk of left-handedness in men, suggesting that prenatal ultrasound affects the fetal brain.

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From the 1Department of Women’s and Children’s Health, Obstetrics and Gynecology, Uppsala University, Uppsala, Sweden;

2Department of Medical Epidemiology Karolinska Institutet, Stockholm, Sweden;

3The Center for Epidemiology, National Board of Health and Welfare, Stockholm, Sweden; and

4Department of Mathematics Stockholm University, Stockholm, Sweden.

Address correspondence to: Helle Kieler, MD, PhD, Department of Medical Epidemiology, Karolinska Institutet, PO Box 281, SE-171 77, Stockholm, Sweden.

This work was supported by the Research Council of Dalarna; the Foundation of Astrid Karlsson, Uppsala University and the Foundation of Medical Research and Evaluation in Dalarna in co-operation with Uppsala University.

Submitted November 17, 2000; final version accepted February 9, 2001.

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Ultrasound scanning in pregnancy is widely used throughout the developed world. An extended number of scans, longer and more advanced examinations, higher output levels, and weaker regulations for ultrasound machines contribute to increased fetal ultrasound exposure during recent decades. 1–3 Although it has been shown that ultrasound is capable of damaging tissue, 2,4 few epidemiologic studies have addressed possible adverse effects of ultrasound. 5 Nevertheless, an association between prenatal ultrasound exposure and non right-handedness among boys has been reported in two randomized, controlled trials. 6,7

Non right-handedness includes left-handedness and ambidexterity. 8 Left-handedness, which runs in families, 9 occurs in about 8% to 9% of the population. 9 The prevalence of left-handedness varies between different populations, 9 and is influenced by the methods used for determining handedness. Lesions to the left side of the brain before the age of 6 years have been found to cause a shift to non right-handedness in genotypic right-handed children, a condition described as “pathological non right-handedness.”10

In contrast to other organs, which are formed before 12 weeks of pregnancy, the brain continues to develop throughout fetal life. From the 6th to the 32nd week of gestation, neurons migrate from the neural tube towards their final destinations in the cerebral cortex. 8 A disturbance of migration of neurons to cortical regions on one side should favor growth of regions on the opposite side. The left hemisphere is the more vulnerable of the two hemispheres, as it develops more slowly than the right. 8 Moreover, random unilateral brain damage would increase the prevalence of non right-handedness, 11 because of the high prevalence of right-handedness in a normal population. The male brain matures later than that of the female, which makes it more susceptible to environmental effects. 8

This cohort study was undertaken to evaluate the association between ultrasound exposure in fetal life and left-handedness among young men enrolling for military service.

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Subjects and Methods

The Swedish Medical Birth Register, established in 1973, contains prospectively collected information on more than 99% of all births in Sweden. 12 Eligible for inclusion in the study population were all male singletons born between 1973 and 1978 at hospitals with reliable information about ultrasound scanning during the 1970s.

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Definition of Exposure to Fetal Ultrasound

Exposed Group

The Department of Obstetrics and Gynecology at the University Hospital in Malmö was the first department to introduce ultrasound scanning as part of the standard antenatal care. The use of ultrasound in Malmö from this period is well documented. 13 Since October 1972, all pregnant women who were seen for antenatal care in Malmö were offered an ultrasound scan, and 90% were scanned. 13 The ultrasound examination was initially performed at about 28 weeks of gestation, but was gradually changed to the 19th week during 1974–1975. From October 1976, two examinations at the 19th and 32nd week were performed, and from April 1978, the first examination was performed at the 17th week. Real-time ultrasound machines (Kretz-Technic 4100 MGS and Combison II echoscope, Germany, Philips Diagnost B, The Netherlands and ADR-Kranzbühler, Germany) with a sound velocity of 1540 m/s were used. 13 Each examination was scheduled for 15 minutes.

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Unexposed Group

The year of introduction of obstetric ultrasound in Sweden was determined in 1994 through a questionnaire sent to all hospitals with departments of Obstetrics and Gynecology. 14 As some of this information was incomplete or inconsistent with information from other sources, we contacted physicians and midwives involved in the introduction of prenatal ultrasound scanning. Besides the University Hospital of Malmö, 11 hospitals introduced ultrasound scanning before 1980. As none of these hospitals had reliable documentation on the ultrasound program from the study period, they were excluded from this study. We also excluded 37 hospitals where information on the introduction of ultrasound was missing. The remaining 48 hospitals that did not practice ultrasound scanning (routine or selective) before 1980 were included in the unexposed group.

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Definition of Left-Handedness

In Sweden, all males are enrolled to be tested for military service, generally at the age of 18. At enrollment, a thorough physical examination is performed as well as specific tests to evaluate the capability of the enrollees. Until 1998, as certain guns used in the Swedish army required right-handed shooters, a majority of the enrollees were tested as to whether they shoot right- or left-handed. Preferred hand was determined by handing a replica rifle to the enrollee, who was then asked to take up alert position (the rifle is placed at the shoulder but not aimed at a target). Only enrollees who shoot left-handed were registered as such. Those not registered are either right-handed or not tested. As in previous studies, 15,16 the test with the replica rifle is used to determine laterality by classifying the men as right- or left-handers. The National Service Register was used to obtain data on enrollment center, year of enrollment, and left-handed marksmen. It was possible to obtain data until April 1997. Individual record linkage between the Birth Register and the National Service Register was made possible by using the unique National Registration Number, assigned to each Swedish resident at birth.

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Study Population

The men included in the study were born as singletons, from 1973 through 1978. Of the study population (Table 1), 99% were examined at one of the six enrollment centers before reaching 21 years of age. The majority were enrolled from 1991 to 1996.

Table 1

Table 1

We assumed that women registered as citizens in Malmö and giving birth at the University Hospital in Malmö had attended antenatal care in Malmö, and thereby participated in the ultrasound-scanning program. Thus, males born at the University Hospital in Malmö to mothers registered as citizens in Malmö were included as exposed to ultrasound.

We also assumed that women giving birth at one of the 48 hospitals without ultrasound scanning before 1980 and not living in Malmö or its surrounding municipalities were not scanned during pregnancy. Thus, males born at one of the hospitals without ultrasound scanning to mothers not registered as citizens of Malmö were included as unexposed to ultrasound.

Of the entire birth cohort of 306,995 singleton, live-born males, 7,999 men fulfilled the criteria for inclusion in the exposed group and 197,829 men fulfilled the criteria for inclusion in the unexposed group. For various reasons approximately 26,000 men were excluded, leaving 6,858 exposed and 172,537 unexposed men, respectively (Table 1).

As other factors related to place of birth may affect the prevalence of left-handedness, we also analyzed left-handedness before the introduction of ultrasound scanning. We studied left-handedness among 188,370 male singletons born from 1969 through 1972 and enrolled from 1987 through 1990. Information on place of birth was obtained through record linkage between the National Service Register and Statistics Sweden’s Birth Register. It was not possible to obtain the hospital of birth before the establishment of the Swedish Medical Birth Register in 1973.

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Statistical Analyses

All comparisons of left-handedness between groups were analyzed and expressed as odds ratios with 95% confidence intervals (CI), estimated from logistic regression. Owing to the varying frequency of a positive left-handedness test by year and enrollment center, we analysed the southern enrollment center separately after controlling for year of enrollment. Most of the exposed men were enrolled in the southern enrollment center. For analyses of the total population we adjusted for center and year of enrollment.

We assessed the risk for left-handedness after dividing the enrollees into two sub-cohorts born 1973 to 1975 and 1976 to 1978, respectively. These two time periods coincide approximately with the introduction phase and full-scale phase of the ultrasound-scanning program in Malmö.

Maternal age, preterm birth, low birth weight, and birth stress have been found to correlate with an increased risk of left-handedness. 17,18 Maternal age, parity, gestational age, intrauterine growth (calculated as the ratio between birth weight and expected birth weight for the gestational age), and neonatal asphyxia (Apgar score <7 at 5 minutes) were therefore considered possible confounders and were controlled for in logistic regression analyses.

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Results

Maternal and infant characteristics, as well as the proportion of registered left-handers among enrollees at the southern enrollment center, are shown in Table 2. Primiparity, pre- and postterm birth, and intrauterine growth restriction were more common among births at Malmö University Hospital than other hospitals. Of all maternal and infant characteristics, a low birth weight ratio seems to have the strongest association with left-handedness. The proportion of left-handed enrollees was slightly higher among men born at Malmö University Hospital compared with those born at other hospitals (10.9% vs. 9.6%).

Table 2

Table 2

For men born between 1973 to 1975 and enrolled at the southern enrollment center, there was practically no difference in left-handedness (odds ratio = 1.04, 95% CI = 0.91–1.18) between men prenatally exposed to ultrasound and unexposed men (Table 3, model I). For men born 1976 to 1978, however, those exposed to ultrasound had a higher risk for left-handedness (odds ratio = 1.32, 95% CI = 1.16–1.51). Controlling for possible confounders did not change these estimates (Table 3, model II).

Table 3

Table 3

To see if this increased risk of left-handedness was biased by type of hospital or municipality, we expanded the model to include enrollees at all enrollment centers (Table 4). Thus, the total study population was analyzed with control for enrollment center. The relative risk of left-handedness by prenatal ultrasound exposure was, however, essentially the same as when only enrollees from the southern enrollment center were included (Table 4, model I). When we also included dichotomous variables for other university and/or larger city hospitals, the relative risk for left-handedness in Malmö was practically unchanged (Table 4, model II), and none of the other university hospitals deviated from the standard risk of left-handedness.

Table 4

Table 4

Although we found an association between the full-scale ultrasound program and the risk for left-handedness, it is possible that men from Malmö normally have a higher prevalence of left-handedness. We therefore also analyzed left-handedness before the start of ultrasound scanning, but found essentially no difference in risk of left-handedness between men from Malmö, the other two major Swedish cities, and the rest of Sweden (Table 5).

Table 5

Table 5

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Discussion

In this study we found an increased risk of left-handedness in young men exposed to ultrasound in fetal life, suggesting that prenatal ultrasound influences the development of the fetal brain.

Two trials 6,7 have previously reported an association between prenatal ultrasound exposure and increased risk of non right-handedness among boys aged 8 to 9 years. These trials were criticized for not using objective tests for handedness, and for finding an excess only in non right-handedness and not in left-handedness. 19 In the present investigation, the preferred hand was determined objectively by handing a replica rifle to the enrollee, and an excess in left-handedness among men exposed to prenatal ultrasound was found.

We were not able to trace ultrasound exposure for each individual. More than 90% of women attending antenatal care in Malmö had prenatal ultrasound scans from 1973 and onwards. Thus, we considered men born in Malmö to Malmö citizens as prenatally exposed to ultrasound, and men born in hospitals with no ultrasound practice were considered as unexposed. Some women whom we considered as exposed did not have ultrasound, however, and some of those considered as unexposed may have had antenatal care, including prenatal ultrasound in another part of Sweden. If anything, this error should produce an underestimation of the association between ultrasound exposure and risk of left-handedness.

The prevalence of left-handedness among unexposed men born between 1973 and 1978 and enrolled at the southern enrollment center was 9.6%, which is in agreement with the expected prevalence of about 8% to 9%. 9 Although we, in accordance with previous studies, 17,18 found that low birth weight was associated with left-handedness, adjusting for low birth weight for gestational age did not change the relative risk of left-handedness among men exposed to ultrasound. Another possible confounding factor could be differences in test procedure for handedness at the enrollment centers. The majority of men born and living in Malmö were enrolled at the same center in the south of Sweden, which performed the test for handedness more frequently than other centers. However, the relative risk of left-handedness among ultrasound exposed men was almost identical whether analyses included all enrollment centers or were restricted to the southern enrollment center. Moreover, before the start of ultrasound scanning, there was practically no difference in left-handedness according to birthplace. That the rise in prevalence of left-handedness during the study period was found only in Malmö and not among males born in other university/regional level hospitals without ultrasound scanning indicates that sociodemographic factors had negligible effects on results. Previously, and presumably nowadays in certain countries, attempts have been made to force left-handed children to use their right hands. Since the 1960s, Swedish schools have abandoned that policy, however. We are unaware of any possible unmeasured confounder that substantially would have affected the results and to our knowledge no other major event occurred in Malmö during the study period that could have affected handedness in the male cohort.

During the study period, there was a gradual change in ultrasound exposure for women attending the maternity units in Malmö. 13 During the first study period, 1973 to 1975, the scanning was performed at 28 weeks of gestation and no differences in left-handedness between ultrasound exposed and unexposed were found. In the second study period, 1976 to 1978, when a second trimester scan had been introduced as well as a second scan at 32 weeks, we found a higher prevalence of left-handedness among those exposed to ultrasound. We may only speculate whether the increased prevalence of left-handedness, if causal, was an effect of the second trimester scan, the two-scan regime, or the postponed third trimester scan. In the second trimester, the fetal brain is presumably more susceptible to external effects because of the high developmental activity that includes completion of the early migration stages, proliferation, and connectivity of the cortex. 20 In a previous study, 7 ultrasound exposure after 19 weeks of gestation did not additionally increase the prevalence of non right-handedness among boys exposed to ultrasound earlier in fetal life. It is therefore conceivable that the increase in left-handedness was caused by the second trimester scan.

In a “meta-analysis”21 of the two controlled trials, 6,7 it was concluded that “left-handers are no different from right-handers” and that “a positive association between ultrasound during pregnancy and sinistrality among boys should not lead to the conclusion that ultrasound causes harm to the developing brain in male fetuses”. It has also been argued 19 that the previous findings of an association between prenatal ultrasound exposure and non right-handedness were weak and of uncertain public health or clinical significance. There are, however, many indications that pathological left- or non right-handedness exists. 8,10,22 We believe that a positive association between prenatal ultrasound scanning and left-handedness, if it is causal, could result from lesions to the left or to both hemispheres. Such lesions may not necessarily imply interference with other developmental processes, but highlights the importance of also investigating other possible effects of ultrasound.

It has been suggested 21 that a follow-up of the Finnish 23 and the RADIUS trial 24 might clarify whether ultrasound exposure causes non right-handedness. Of the women allocated to the control groups in these trials, 23,24 however, 77% and 45% were exposed to ultrasound, respectively. The high prevalence of exposure among controls clearly demonstrates the problems encountered when evaluating the risk of ultrasound exposure and analyzing according to randomization. If ultrasound induces left- or non right-handedness, the differences in handedness between the randomized groups would be expected to be small because of the small difference in ultrasound exposure between the groups. In the randomized trial from South Africa, 25 only 25% of the women in the control group were examined by ultrasound. Although this South African study is relatively small, 988 women were included in comparison with several thousands in the Finnish 23 and the RADIUS trial, 24 it might be more useful when studying adverse effects of ultrasound because of less contamination by crossovers in the groups.

Left-handedness is reported to occur in about 8% to 9% of the population. 9 Today, second trimester ultrasound scanning is generally performed in many countries. The present results suggest a 30% increase in risk of left-handedness among boys prenatally exposed to ultrasound. If this association reflects a brain injury, this means that as many as 1 in 50 male fetuses prenatally exposed to ultrasound are affected.

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Keywords:

ultrasound scanning; adverse effects; left-handedness; males; pregnancy; diagnostic tests

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