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The ratio of second to fourth digit lengths: a marker of impaired fetal growth?
Early Human Development 68 (2002) 21 – 26 www.elsevier.com/locate/earlhumdev
The ratio of second to fourth digit lengths: a marker of impaired fetal growth? G. Ronalds a, D.I.W. Phillips a,*, K.M. Godfrey a, J.T. Manning b a
MRC Environmental Epidemiology Unit, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK b School of Biological Sciences, University of Liverpool, Liverpool L693BX, UK
Received 2 October 2001; received in revised form 10 January 2002; accepted 10 January 2002
Abstract Background: Epidemiological studies showing that impaired fetal growth has long-term adverse health consequences have depended on crude measures of fetal growth such as overall weight or length. For future studies, there is a need to develop improved morphological markers of fetal growth which persist into adult life. Recent studies have suggested that the ratio of the length of the second finger relative to the length of the fourth finger (2D:4D ratio) is determined during fetal life and may be such a marker. Aims: To determine whether the 2D:4D ratio is associated with size at birth. Design: Cohort study. Subjects: 139 men and women born in Preston, Lancashire between 1935 and 1943. Outcome measures: Measurements of the 2D:4D ratio in palm prints. Results: Men who had an above average placental weight and a shorter neonatal crown-heel length had higher 2D:4D ratios in adult life. Conclusions: These preliminary findings lend support to the hypothesis that the 2D:4D ratio is determined during fetal life. D 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: 2D:4D; Impaired fetal growth; Morphological marker
1. Introduction There is increasing epidemiological evidence that impaired fetal growth has long term effects on the body’s morphology and physiology which in turn are associated with adverse health consequences in adult life [1]. These studies have depended on showing
*
Corresponding author. Tel.: +44-2380-777624, fax: +44-2380-704021. E-mail address: [email protected] (D.I.W. Phillips).
0378-3782/02/$ - see front matter D 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 3 7 8 - 3 7 8 2 ( 0 2 ) 0 0 0 0 9 - 9
22
G. Ronalds et al. / Early Human Development 68 (2002) 21–26
correlations between crude indices of fetal growth such as overall weight or length at birth and adult health outcomes. There is a need to develop improved morphological markers of impaired fetal growth and in particular to identify markers which persist into adult life. The ratio between the length of the second and fourth digits (2D:4D ratio) may be one such marker. This ratio is sexually dimorphic [2,3]; the tendency of men to have a longer fourth digit compared to the second digit (lower 2D:4D ratio) has been described in several populations [3]. The ratio does not change at puberty [4] and is probably determined during prenatal differentiation of the digits as bone-to-bone ratios in the terminal phalanges are thought to be established by the end of the 13th week of gestation [5]. During adult life, a greater 2D:4D ratio on the right hand is associated with higher oestrogen and luteinising hormone concentrations in men and women and, in men, with lower testosterone levels [4]. Alterations in the endocrine milieu of the fetus are known to ‘programme’ hormone levels in adults and it is suggested that prenatal gonadal hormone levels influence the relative lengths of fingers by modulating the actions of Homeobox or Hox genes regulating the differentiation of the digits [10]. There is also substantial evidence that gonadal steroids influence the rate of fetal development. Exposure to increased prenatal androgens, for example, is associated with an inhibition of lung development [6] and a variety of neurodevelopmental disorders [7]. The possibility that the 2D:4D ratio could act as an indicator of fetal growth is supported by data showing that the structure and shape of the hand and fingers are related to impaired fetal growth. The palmar ‘atd’ angle which reflects the breadth of the palm relative to its length and finger print whorls were found to be associated with two different patterns of fetal growth [8]. In a long-term follow-up study of men and women who were born in Preston, Lancashire, those who had below-median placental weights and were thin at birth, as indicated by a low ponderal index, tended to have more whorls on their finger tips. In contrast, those who had an above-median placental weight and were short at birth in relation to their head size, tended to have palms which were long relative to their breadth and a narrow atd angle [8]. In this study, we have used the hand prints of these men and women born in Preston to examine whether fetal growth is related to the 2D:4D ratio.
2. Subjects and methods The unusually complete and detailed labour ward records which were kept on all babies delivered at Sharoe Green Hospital in Preston from 1934 onwards have been described previously [8]. The record included the date of the mother’s last menstrual period and the baby’s birthweight, placental weight, crown-heel length, and head circumference. Weights were measured in pounds (1 lb = 454 g) and length and head circumference in inches (1 in. = 2.54 cm). Measurements were often rounded, and we therefore preserved the original units. The NHS central register was used to trace the 1298 singleton infants born in the hospital during 1935 –1943. A total of 503 were found to be living in Lancashire at addresses known to their general practitioner. Of these, 402 people had already participated in two studies, and so it was not considered appropriate to ask them to be involved in this study. We therefore approached the 47 people who had not been asked to take part in
G. Ronalds et al. / Early Human Development 68 (2002) 21–26
23
the second study because they lived too far from Preston and 131 others who had been traced only recently and had not taken part in the previous studies. A total of 10 of the 178 people could not be contacted at their last known address and 29 declined to participate, leaving 139 who took part. Ethical approval was obtained from the Preston District Hospital Ethics Committee and each subject gave informed consent. Each person was visited at home by a single fieldworker, who had not seen the obstetric records. Prints of the fingers and full hand were obtained by placing the palm and digits on an inked plate and then rolling them on to a record form. Fingerprint ink was used in order to obtain high quality prints. Impressions were obtained from both hands. For the current study, a dial caliper (Moore and Wright, measuring to 0.1 mm) was used to measure the length of the second (index) and fourth (ring) fingers from the archival prints. Digit length was measured from the crease proximal to the palm to the tip of the finger [3,4]. In two prints on the left hand and one on the right, the 2D:4D ratio could not be ascertained. To assess reproducibility, a second observer who was unaware of the original values repeated the measurements in 20 hands.
3. Results Repeatability or intra-class correlation coefficient (r1) of the 2D:4D ratio was calculated by means of a repeated measures ANOVA test. The r1 value (0.79) was high and the F ratio (ratio between the real differences between subjects and the measurement error) was significant ( F = 8.52, p = 0.0001). We concluded that the 2D:4D ratios reflected real differences between participants. As in previous studies [3,4], mean 2D:4D ratio was significantly higher in women than in men, for both the right hand ( p < 0.05) and left hand ( p < 0.001), as shown in Table 1. In men, mean 2D:4D ratio was similar in both hands but in the women the ratio was somewhat but not significantly higher in the left hand. As the proportionate relations of birth weight, length, head circumference and placental weight differ in babies born prematurely we followed the procedure of our previous studies of birth measurements [8] and restricted analyses with birth measurements to the 123 men and women born after 38 completed weeks (266 days) of gestation. Neither birth weight, placental weight, length and head circumference at birth, nor the ratios of these measurements, were significantly associated with 2D:4D ratio on either hand. As in the previous studies [8], we examined for associations with neonatal ponderal index in Table 1 2D:4D ratio (mm/mm 1000) on the left and right hands of men and women aged 47 – 56 who were born in Preston
Men Women All
Right hand 2D:4D ratio
Left hand 2D:4D ratio
957 (72) 977 (66) 966 (138)
954 (71) 994 (66) 974 (137)
Number of subjects measured are in parentheses. Overall SD = 57.5.
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G. Ronalds et al. / Early Human Development 68 (2002) 21–26
Table 2 Mean 2D:4D ratio (mm/mm 1000) on men and women aged 47 – 56 born after 38 completed weeks of gestation according to placental weight and head circumference to length ratio at birth, for the left and right hands
(a) Men Right Left
(b) Women Right Left
Placental weight (lb)
Head circumference to length ratio
V 1.25 > 1.25 V 1.25 > 1.25
967 933 932 949
(6) (5) (6) (4)
971 917 962 959
(9) (4) (9) (4)
946 954 946 943
V 1.25 > 1.25 V 1.25 > 1.25
969 981 988 965
(7) (7) (7) (7)
998 965 1009 1001
(7) (3) (7) (3)
959 960 1004 992
< 0.65
0.675
0.7
z 0.7
All
(7) (6) (6) (6)
968 968 961 967
(11) (15) (11) (16)
964 952 953 959
(33) (30) (32) (30)
(9) (7) (9) (7)
978 976 987 998
(11) (7) (11) (7)
975 971 996 987
(34) (24) (34) (24)
Number of subjects are in parentheses.
subjects with a placental weight below the median and for associations with neonatal head circumference to length ratio in subjects with a placental weight above the median. We then examined for associations with the other birth measurements within each of the two placental weight groups. Among those whose placental weight was 1.25 lb or less, the 2D:4D ratio of either hand was not significantly related to either neonatal ponderal index or to any of the other birth measurements for either men or women. Among subjects whose placental weight was over 1.25 lb, significant associations were found in men but not in women. For men with a placental weight over 1.25 lb, right hand 2D:4D ratio correlated significantly with head circumference to length ratio ( p = 0.02); a weak positive trend with left hand 2D:4D ratio was not significant. Table 2 shows that right hand 2D:4D ratio increased from 0.933 to 0.968 between men with a head circumference to length ratio of less than 0.65 and those Table 3 Mean 2D:4D ratio (mm/mm 1000) on men and women aged 47 – 56 born after 38 completed weeks of gestation according to placental weight and length at birth, for the left and right hands Placental weight (lb) (a) Men Right Left
(b) Women Right Left
Length at birth (in.) < 20
V 1.25 > 1.25 V 1.25 > 1.25
949 1065 951 992
(6) (1) (6) (1)
V 1.25 > 1.25 V 1.25 > 1.25
987 919 997 981
(13) (3) (13) (3)
Number of subjects are in parentheses.
20 970 956 957 963
21
>21
All
(17) (19) (17) (19)
975 946 958 948
(6) (7) (5) (7)
946 904 958 948
(4) (3) (4) (3)
964 952 953 959
(33) (30) (32) (30)
974 (12) 974 (11) 1006 (12) 989 (11)
959 986 982 989
(9) (6) (9) (6)
(0) 981 (4) (0) 982 (4)
975 971 996 987
(34) (24) (34) (24)
G. Ronalds et al. / Early Human Development 68 (2002) 21–26
25
with a ratio above 0.7. Further analyses in subjects with a placental weight above the median showed that men who were short at birth had a higher 2D:4D ratio on the right hand, indicating that they had a shorter fourth digit relative to their second. Table 3 shows that right hand 2D:4D ratio rose progressively from 0.904 to 1.065 between men who were over 21 in. to those who were less than 20 in. long at birth. Regression analysis showed that 2D:4D ratio for the right hand rose by 0.03 for every 1 in. decrease in length at birth ( p = 0.02). Length was also negatively related to 2D:4D ratio for the left hand but this was not significant ( p = 0.4).
4. Discussion We have shown that the ratio of second to fourth digit length is associated with body size and proportion at birth in men. Men who had longer second digits relative to their fourth digit and a high 2D:4D ratio were shorter at birth and had greater head size relative to their length. These associations existed in people whose placental weight was above the median, and were stronger for the right hand than for the left. Our previous studies have shown that males who have above median placental weight and were short at birth and/or had high head circumference in relation to length tend to develop high blood pressure in later life [9]. Furthermore, men with a higher 2D:4D ratio tend to have an earlier presentation of cardiovascular disease than men with a low 2D:4D ratio [10]. These findings suggest that a high 2D:4D ratio in men could act as a marker both of impaired fetal growth and cardiovascular disease [11]. We did not find a relationship between 2D:4D and body size or proportion at birth in women. This may be because testosterone has sex-dependent effects on fetal growth and adult-onset heart disease. Men with a high 2D:4D ratio are less likely to report high attainment in sports such as running [15] and testosterone has a protective effect against heart disease in men but not in women [11]. In addition measures of body size at birth are less predictive of heart disease in females compared to males [12]. Prenatal testosterone level may not be an important predictor of fetal growth of females or their predisposition to adult-onset heart disease. The people we studied were born in hospital in Preston and currently living in or around the town. However, as our analyses are based on internal comparisons, it is unlikely that the selection of the sample had biased relationships between fetal growth and the 2D:4D ratio. In this study, we used fingerprint ink rolled onto the palm of the hand to obtain palm prints. A problem with this method is that it is sometimes difficult to ascertain the skin creases used to define finger lengths. Nevertheless, a repeatability study suggested close agreement between two different observers and that the differences between subjects were high in comparison with measurement error. These relationships add to our previous findings showing links between fetal growth and the morphology of the hand in adult life. In this study, we found that a pattern of fetal growth resulting in shortness relative to head size at birth, in people with a placental weight above the median was associated with a narrow palmar ‘‘atd’’ angle. Hands with a narrow ‘‘atd’’ angle are long relative to their breadth. The findings in this paper suggest that they are also characterised by relative shortness of the fourth finger. They suggest that
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G. Ronalds et al. / Early Human Development 68 (2002) 21–26
a pattern of fetal development that leads, in men, to shortness and a large head relative to length is associated with low circulating levels of testosterone and high levels of oestrogens prenatally. An explanation for our findings may lie in the action of the Hox gene family, which has already been implicated in the association between 2D:4D and testosterone levels. The posterior-most Hoxa and Hoxd genes have shared importance in the control of digit formation and formation of the urogenital system, including the gonads [13]. In mice raised with mutations in Hoxd, progressive reduction in gene function led to reductions in size of both the digits and genital bud. In humans also, the hand –foot – genital syndrome, characterised by mild defects in the digits and genitals, is caused by a mutation within Hoxa-13 [14]. Production of testosterone in males begins around the eighth week of gestation. Therefore, variation in the expression of these genes (prior to fixation of the bone-to-bone ratios in the phalanges at the end of the 13th week) could affect gonad development and sex hormone production, while simultaneously influencing 2D:4D ratio and the palmar atd angle Alternatively, levels of the hormones themselves may influence formation of the digits and 2D:4D ratio.
References [1] Barker DJP. Mothers, babies and health in later life. Edinburgh: Livingstone; 1998. [2] Phelps VR. Relative index finger length as a sex-influenced trait in man. Am J Hum Genet 1952;4:72 – 89. [3] Manning JT, Barley L, Lewis-Jones I, et al. The 2nd to 4th digit ratio, sexual dimorphism, population differences and reproductive success: evidence for sexually antagonistic genes. Evol Hum Behav 2000;21: 163 – 83. [4] Manning JT, Scutt D, Wilson J, Lewis-Jones DI. The ratio of 2nd to 4th digit length: a predictor of sperm numbers and levels of testosterone, LH and oestrogen. Hum Reprod 1998;13:3000 – 4. [5] Garn SM, Burdi AR, Babler WJ, Stinson S. Early prenatal attainment of adult metacarpal-phalangeal rankings and proportions. Am J Phys Anthropol 2001;43:327 – 32. [6] Klein JM, Nielsen HC. Androgen regulation of epidermal growth factor receptor binding activity during fetal rabbit lung development. J Clin Invest 1993;91:425 – 31. [7] Geschwind N, Galaburda AM. Cerebral lateralisation. Biological mechanisms, associations and pathology: I. A hypothesis and a program for research. Arch Neurol 1985;42:428 – 59. [8] Godfrey KM, Barker DJP, Peace J, Cloke J, Osmond C. Relation of fingerprints and shape of the palm to fetal growth and adult blood pressure. Br Med J 1993;307:405 – 9. [9] Barker DJP, Godfrey KM, Osmond C, Bull A. The relation of fetal length, ponderal index, and head circumference to blood pressure and the risk of hypertension in adult life. Paediatr Perinat Epidemiol 1992;6:35 – 44. [10] Manning JT, Blundred P. The ratio of the 2nd to 4th digit length: a new predictor of disease predisposition? Med Hypotheses 2000;54:855 – 7. [11] Manning JT, Blundred P. The 2nd to 4th digit ratio and age at first myocardial infarction in men: evidence for a link with prenatal testosterone? Br J Cardiol 2001;8:720 – 3. [12] Barker DJP. Fetal origins of coronary heart disease. Br Med J 1995;311:171 – 4. [13] Kondo T, Zakany J, Innis JW, Duboule D. Of fingers, toes and penises. Nature 1997;390:29. [14] Mortlock DP, Innis JW. Mutation of HOXA 13 in hand – foot – genital syndrome. Nat Genet 1997;15:179 – 80. [15] Manning JT, Taylor RP. 2nd to 4th digit ratios and male ability in sport. Implications for sexual selection in humans. Evol Hum Behav 2001;22:61 – 9.
The ratio of second to fourth digit lengths: a marker of impaired fetal growth? G. Ronalds a, D.I.W. Phillips a,*, K.M. Godfrey a, J.T. Manning b a
MRC Environmental Epidemiology Unit, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK b School of Biological Sciences, University of Liverpool, Liverpool L693BX, UK
Received 2 October 2001; received in revised form 10 January 2002; accepted 10 January 2002
Abstract Background: Epidemiological studies showing that impaired fetal growth has long-term adverse health consequences have depended on crude measures of fetal growth such as overall weight or length. For future studies, there is a need to develop improved morphological markers of fetal growth which persist into adult life. Recent studies have suggested that the ratio of the length of the second finger relative to the length of the fourth finger (2D:4D ratio) is determined during fetal life and may be such a marker. Aims: To determine whether the 2D:4D ratio is associated with size at birth. Design: Cohort study. Subjects: 139 men and women born in Preston, Lancashire between 1935 and 1943. Outcome measures: Measurements of the 2D:4D ratio in palm prints. Results: Men who had an above average placental weight and a shorter neonatal crown-heel length had higher 2D:4D ratios in adult life. Conclusions: These preliminary findings lend support to the hypothesis that the 2D:4D ratio is determined during fetal life. D 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: 2D:4D; Impaired fetal growth; Morphological marker
1. Introduction There is increasing epidemiological evidence that impaired fetal growth has long term effects on the body’s morphology and physiology which in turn are associated with adverse health consequences in adult life [1]. These studies have depended on showing
*
Corresponding author. Tel.: +44-2380-777624, fax: +44-2380-704021. E-mail address: [email protected] (D.I.W. Phillips).
0378-3782/02/$ - see front matter D 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 3 7 8 - 3 7 8 2 ( 0 2 ) 0 0 0 0 9 - 9
22
G. Ronalds et al. / Early Human Development 68 (2002) 21–26
correlations between crude indices of fetal growth such as overall weight or length at birth and adult health outcomes. There is a need to develop improved morphological markers of impaired fetal growth and in particular to identify markers which persist into adult life. The ratio between the length of the second and fourth digits (2D:4D ratio) may be one such marker. This ratio is sexually dimorphic [2,3]; the tendency of men to have a longer fourth digit compared to the second digit (lower 2D:4D ratio) has been described in several populations [3]. The ratio does not change at puberty [4] and is probably determined during prenatal differentiation of the digits as bone-to-bone ratios in the terminal phalanges are thought to be established by the end of the 13th week of gestation [5]. During adult life, a greater 2D:4D ratio on the right hand is associated with higher oestrogen and luteinising hormone concentrations in men and women and, in men, with lower testosterone levels [4]. Alterations in the endocrine milieu of the fetus are known to ‘programme’ hormone levels in adults and it is suggested that prenatal gonadal hormone levels influence the relative lengths of fingers by modulating the actions of Homeobox or Hox genes regulating the differentiation of the digits [10]. There is also substantial evidence that gonadal steroids influence the rate of fetal development. Exposure to increased prenatal androgens, for example, is associated with an inhibition of lung development [6] and a variety of neurodevelopmental disorders [7]. The possibility that the 2D:4D ratio could act as an indicator of fetal growth is supported by data showing that the structure and shape of the hand and fingers are related to impaired fetal growth. The palmar ‘atd’ angle which reflects the breadth of the palm relative to its length and finger print whorls were found to be associated with two different patterns of fetal growth [8]. In a long-term follow-up study of men and women who were born in Preston, Lancashire, those who had below-median placental weights and were thin at birth, as indicated by a low ponderal index, tended to have more whorls on their finger tips. In contrast, those who had an above-median placental weight and were short at birth in relation to their head size, tended to have palms which were long relative to their breadth and a narrow atd angle [8]. In this study, we have used the hand prints of these men and women born in Preston to examine whether fetal growth is related to the 2D:4D ratio.
2. Subjects and methods The unusually complete and detailed labour ward records which were kept on all babies delivered at Sharoe Green Hospital in Preston from 1934 onwards have been described previously [8]. The record included the date of the mother’s last menstrual period and the baby’s birthweight, placental weight, crown-heel length, and head circumference. Weights were measured in pounds (1 lb = 454 g) and length and head circumference in inches (1 in. = 2.54 cm). Measurements were often rounded, and we therefore preserved the original units. The NHS central register was used to trace the 1298 singleton infants born in the hospital during 1935 –1943. A total of 503 were found to be living in Lancashire at addresses known to their general practitioner. Of these, 402 people had already participated in two studies, and so it was not considered appropriate to ask them to be involved in this study. We therefore approached the 47 people who had not been asked to take part in
G. Ronalds et al. / Early Human Development 68 (2002) 21–26
23
the second study because they lived too far from Preston and 131 others who had been traced only recently and had not taken part in the previous studies. A total of 10 of the 178 people could not be contacted at their last known address and 29 declined to participate, leaving 139 who took part. Ethical approval was obtained from the Preston District Hospital Ethics Committee and each subject gave informed consent. Each person was visited at home by a single fieldworker, who had not seen the obstetric records. Prints of the fingers and full hand were obtained by placing the palm and digits on an inked plate and then rolling them on to a record form. Fingerprint ink was used in order to obtain high quality prints. Impressions were obtained from both hands. For the current study, a dial caliper (Moore and Wright, measuring to 0.1 mm) was used to measure the length of the second (index) and fourth (ring) fingers from the archival prints. Digit length was measured from the crease proximal to the palm to the tip of the finger [3,4]. In two prints on the left hand and one on the right, the 2D:4D ratio could not be ascertained. To assess reproducibility, a second observer who was unaware of the original values repeated the measurements in 20 hands.
3. Results Repeatability or intra-class correlation coefficient (r1) of the 2D:4D ratio was calculated by means of a repeated measures ANOVA test. The r1 value (0.79) was high and the F ratio (ratio between the real differences between subjects and the measurement error) was significant ( F = 8.52, p = 0.0001). We concluded that the 2D:4D ratios reflected real differences between participants. As in previous studies [3,4], mean 2D:4D ratio was significantly higher in women than in men, for both the right hand ( p < 0.05) and left hand ( p < 0.001), as shown in Table 1. In men, mean 2D:4D ratio was similar in both hands but in the women the ratio was somewhat but not significantly higher in the left hand. As the proportionate relations of birth weight, length, head circumference and placental weight differ in babies born prematurely we followed the procedure of our previous studies of birth measurements [8] and restricted analyses with birth measurements to the 123 men and women born after 38 completed weeks (266 days) of gestation. Neither birth weight, placental weight, length and head circumference at birth, nor the ratios of these measurements, were significantly associated with 2D:4D ratio on either hand. As in the previous studies [8], we examined for associations with neonatal ponderal index in Table 1 2D:4D ratio (mm/mm 1000) on the left and right hands of men and women aged 47 – 56 who were born in Preston
Men Women All
Right hand 2D:4D ratio
Left hand 2D:4D ratio
957 (72) 977 (66) 966 (138)
954 (71) 994 (66) 974 (137)
Number of subjects measured are in parentheses. Overall SD = 57.5.
24
G. Ronalds et al. / Early Human Development 68 (2002) 21–26
Table 2 Mean 2D:4D ratio (mm/mm 1000) on men and women aged 47 – 56 born after 38 completed weeks of gestation according to placental weight and head circumference to length ratio at birth, for the left and right hands
(a) Men Right Left
(b) Women Right Left
Placental weight (lb)
Head circumference to length ratio
V 1.25 > 1.25 V 1.25 > 1.25
967 933 932 949
(6) (5) (6) (4)
971 917 962 959
(9) (4) (9) (4)
946 954 946 943
V 1.25 > 1.25 V 1.25 > 1.25
969 981 988 965
(7) (7) (7) (7)
998 965 1009 1001
(7) (3) (7) (3)
959 960 1004 992
< 0.65
0.675
0.7
z 0.7
All
(7) (6) (6) (6)
968 968 961 967
(11) (15) (11) (16)
964 952 953 959
(33) (30) (32) (30)
(9) (7) (9) (7)
978 976 987 998
(11) (7) (11) (7)
975 971 996 987
(34) (24) (34) (24)
Number of subjects are in parentheses.
subjects with a placental weight below the median and for associations with neonatal head circumference to length ratio in subjects with a placental weight above the median. We then examined for associations with the other birth measurements within each of the two placental weight groups. Among those whose placental weight was 1.25 lb or less, the 2D:4D ratio of either hand was not significantly related to either neonatal ponderal index or to any of the other birth measurements for either men or women. Among subjects whose placental weight was over 1.25 lb, significant associations were found in men but not in women. For men with a placental weight over 1.25 lb, right hand 2D:4D ratio correlated significantly with head circumference to length ratio ( p = 0.02); a weak positive trend with left hand 2D:4D ratio was not significant. Table 2 shows that right hand 2D:4D ratio increased from 0.933 to 0.968 between men with a head circumference to length ratio of less than 0.65 and those Table 3 Mean 2D:4D ratio (mm/mm 1000) on men and women aged 47 – 56 born after 38 completed weeks of gestation according to placental weight and length at birth, for the left and right hands Placental weight (lb) (a) Men Right Left
(b) Women Right Left
Length at birth (in.) < 20
V 1.25 > 1.25 V 1.25 > 1.25
949 1065 951 992
(6) (1) (6) (1)
V 1.25 > 1.25 V 1.25 > 1.25
987 919 997 981
(13) (3) (13) (3)
Number of subjects are in parentheses.
20 970 956 957 963
21
>21
All
(17) (19) (17) (19)
975 946 958 948
(6) (7) (5) (7)
946 904 958 948
(4) (3) (4) (3)
964 952 953 959
(33) (30) (32) (30)
974 (12) 974 (11) 1006 (12) 989 (11)
959 986 982 989
(9) (6) (9) (6)
(0) 981 (4) (0) 982 (4)
975 971 996 987
(34) (24) (34) (24)
G. Ronalds et al. / Early Human Development 68 (2002) 21–26
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with a ratio above 0.7. Further analyses in subjects with a placental weight above the median showed that men who were short at birth had a higher 2D:4D ratio on the right hand, indicating that they had a shorter fourth digit relative to their second. Table 3 shows that right hand 2D:4D ratio rose progressively from 0.904 to 1.065 between men who were over 21 in. to those who were less than 20 in. long at birth. Regression analysis showed that 2D:4D ratio for the right hand rose by 0.03 for every 1 in. decrease in length at birth ( p = 0.02). Length was also negatively related to 2D:4D ratio for the left hand but this was not significant ( p = 0.4).
4. Discussion We have shown that the ratio of second to fourth digit length is associated with body size and proportion at birth in men. Men who had longer second digits relative to their fourth digit and a high 2D:4D ratio were shorter at birth and had greater head size relative to their length. These associations existed in people whose placental weight was above the median, and were stronger for the right hand than for the left. Our previous studies have shown that males who have above median placental weight and were short at birth and/or had high head circumference in relation to length tend to develop high blood pressure in later life [9]. Furthermore, men with a higher 2D:4D ratio tend to have an earlier presentation of cardiovascular disease than men with a low 2D:4D ratio [10]. These findings suggest that a high 2D:4D ratio in men could act as a marker both of impaired fetal growth and cardiovascular disease [11]. We did not find a relationship between 2D:4D and body size or proportion at birth in women. This may be because testosterone has sex-dependent effects on fetal growth and adult-onset heart disease. Men with a high 2D:4D ratio are less likely to report high attainment in sports such as running [15] and testosterone has a protective effect against heart disease in men but not in women [11]. In addition measures of body size at birth are less predictive of heart disease in females compared to males [12]. Prenatal testosterone level may not be an important predictor of fetal growth of females or their predisposition to adult-onset heart disease. The people we studied were born in hospital in Preston and currently living in or around the town. However, as our analyses are based on internal comparisons, it is unlikely that the selection of the sample had biased relationships between fetal growth and the 2D:4D ratio. In this study, we used fingerprint ink rolled onto the palm of the hand to obtain palm prints. A problem with this method is that it is sometimes difficult to ascertain the skin creases used to define finger lengths. Nevertheless, a repeatability study suggested close agreement between two different observers and that the differences between subjects were high in comparison with measurement error. These relationships add to our previous findings showing links between fetal growth and the morphology of the hand in adult life. In this study, we found that a pattern of fetal growth resulting in shortness relative to head size at birth, in people with a placental weight above the median was associated with a narrow palmar ‘‘atd’’ angle. Hands with a narrow ‘‘atd’’ angle are long relative to their breadth. The findings in this paper suggest that they are also characterised by relative shortness of the fourth finger. They suggest that
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a pattern of fetal development that leads, in men, to shortness and a large head relative to length is associated with low circulating levels of testosterone and high levels of oestrogens prenatally. An explanation for our findings may lie in the action of the Hox gene family, which has already been implicated in the association between 2D:4D and testosterone levels. The posterior-most Hoxa and Hoxd genes have shared importance in the control of digit formation and formation of the urogenital system, including the gonads [13]. In mice raised with mutations in Hoxd, progressive reduction in gene function led to reductions in size of both the digits and genital bud. In humans also, the hand –foot – genital syndrome, characterised by mild defects in the digits and genitals, is caused by a mutation within Hoxa-13 [14]. Production of testosterone in males begins around the eighth week of gestation. Therefore, variation in the expression of these genes (prior to fixation of the bone-to-bone ratios in the phalanges at the end of the 13th week) could affect gonad development and sex hormone production, while simultaneously influencing 2D:4D ratio and the palmar atd angle Alternatively, levels of the hormones themselves may influence formation of the digits and 2D:4D ratio.
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