prenatal progesterone i. its effect on development and on intellectual and academic achievement

Early Human Development, 1978,214, 305-322 0 Elsevier/North-Holland Biomedical Press

305

Prenatal progesterone I. Its effect on development and on intellectual and academic achievement*

&NTHONY LYNCH, WASYL MYCHALKIW and S. JOHN HUTT

department of Psychology, University of Keele, Keele, Staffordshire ST5 5BG, United Kingdom

iccepted for publication 11 July 1978

XJMMARY

Ihe development of two groups of children whose mothers had been given lrogesterone supplements during pregnancy to relieve symptoms of toxae- nia was assessed, one group at 2 yr of age and the other at 16 yr of age. ‘here was no evidence that progesterone supplements accelerated develop- rent in the 2-yr-old age group or enhanced intellectual and academic attain- lent in the 16-yr-old age group. In addition, the evidence regarding the sported beneficial effects on intellectual attainment of in utero exposure to xcess sex steroids is discussed.

yenatal progesterone; toxaemia; intelligence

4TRODUCTION

Nuring the last 20 yr an extensive literature has grown up showing that some ?netica.lly based characteristics of an organism can be extensively modified y both pre- and postnatal factors. It has been shown that various intrinsic id extrinsic factors can have a marked effect on brain growth and develop- ent and on subsequent behavioural development [lo]. There is now in- #easing evidence that sex steroids influence the development and function- g of the central nervous system during fetal and neonatal life, and that ese hormones act on the sexually undifferentiated brain to establish its ale or female pattern of functioning [ 151. Of particular interest is the evidence which suggests that hormones with

androgenic side-effect and progesterone circulating in excess during a rtain critical period of human fetal development can enhance the subse-

‘his research was financed by the Medical Research Council.

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quent intellectual development of the child. Evidence for these claims comes from a number of sources.

Firstly, Money and Lewis [18] studied the intellectual development of a group of patients with the adrenogenital syndrome (AGS). This genetically recessive disorder causes an excessive production of adrenal androgens due to an enzymatic defect in the synthesis of cortisol during both fetal and postnatal life, and in the genetic female it causes fetal masculinization of the external genitalia. They found that the mean IQ of a large sample of AGS patients was significantly above that of the normal population. Analysis of the data, with respect to various variables such as sex and age, found that the only correlation was between high IQ and excessive androgen production that is characteristic of the syndrome. The fact that there were no differences in IQ between the AGS group who were treated early to rectify the excess androgen production and the AGS group who were allowed to go untreated until adulthood would appear to indicate that the excess androgens during fetal and/or early postnatal life, i.e. during the brain’s growth spurt [9], may be responsible for the elevation in IQ. Lewis et al. [16] also examined the subtest scaled scores on the Wechsler Intelligence Tests of a sample of 44 of the AGS patients to determine if there was any asymmetric development in verbal or performance IQs or whether the high IQ was a result of a general elevation, since it was hypothesized that prenatal androgenization might be expected to differentially affect ‘male superior skills’, i.e. non-verbal scores, rather than ‘female superior skills’. However, there was no evidence of any asymmetric development and it was concluded that the elevation in IQ was the result of a general elevation in intellectual ability, although recent work questions the validity of these findings [l, 201. However, Ehrhardt et al. [12] did find evidence of a selective effect of androgens on the behaviour of females. When they compared the sexually dimorphic behavioural characteristics of the AGS females with that of a matched group of control females, they found that the AGS females showed significantly more masculine traits, i.e. tomboyish behaviours, _and fewer feminine traits than the normal female, and the authors suggest that these masculine traits are possibly a result of the masculinization of the female brain in utero by excessive androgens.

Additional evidence supporting the view that high levels of androgenic-like substances may significantly augment intelligence and alter the female’s psychosexual identity came from a study of offspring of mothers administered synthetic progestins to prevent threatened miscarriage [ 111. These progesterone-like substances resulted in some women giving birth to partially mascul- inized genetic females who required corrective surgery on their external genitalia. Although the females apparently developed normally, a subsequent test of the IQ and sex-role preference of 10 of these progestin-females revealed that, like the AGS group, progestin-females had a higher than normal IQ, though not significantly so, and 9 of the 10 could be classified as tomboys.

The second series of papers concerning the role of sex steroids in intellec-

tual development come from Dalton [ 7, 81. Dalton [ 51, whilst treating preg- nant women with progesterone to relieve the symptoms of toxaemia, made the incidental discovery that the offspring of these progesterone-treated mothers apparently attained their milestones of development earlier than the offspring of women with normal pregnancies. A subsequent follow-up study of the progesterone-treated (P) children [7] revealed that they attained more of their milestones of development at 1 yr than normal controls. Moreover, a significantly greater proportion of them was graded as above average in a variety of academic subjects by their teachers at 9-10 yr of age than controls. Additionally, it appeared that the extent of the enhanced intellectual development was positively related to both the dosage and timing of prenatal progesterone treatment. More recently, Dalton [8] claimed that P children passed significantly more school leaving examinations at 16 and 18 yr of age than controls, and that a significantly greater proportion of the P children went on to university.

The primary aim of the present study was to attempt to confirm Dalton’s earlier findings using more objective and quantitative techniques: more speci- fically, whether the reported advanced development of P children seen at 1 yr of age [ 71 was still evident in their intellectual and academic performance at 16 yr of age, and whether the reported accelerated development seen at 1 yr of age in P children was evident in another group of P children at 2 yr of age.

METHODS

Subjects

Information on both groups was supplied by Dalton.

2-yr-old group All the children in this group were born between July 1973 and January 1975 at the City of London Maternity Hospital, where progesterone was regularly given by pessary or suppository to mothers who showed ‘toxaemic symptoms’ [6] . The mothers of both groups came from the controlled trials into the value of progesterone suppositories in the prophylaxis of toxaemia and on entry into the trial, the mothers (between the 16th and 28th wk of pregnancy) were allocated at random to either the progesterone-treated or the control symptomatic group. There were 164 children (90 males and 74 females) half of whom were progesterone-treated children. Children’s parents were contacted initially by letter using the last address given in the hospital admissions book. Of those contacted only 37 replied, 33 agreeing to take part in the study and 4 refusing. Two further attempts to contact parents uiho did not reply were made by post, and personal calls at the last known address failed to trace any more children.

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16-yr-old group The subjects for this part of the study were born between 1959 and 1961 at the Chase Farm Hospital, Enfield, and are the same group of children whose development was examined by Dalton [7] at 1 yr of age, and whose mothers had been included in the trials on the prophylactic use of progesterone in the prevention of pre-eclamptic toxaemia [6] . (This group is distinct from the group whose intellectual attainment has been previously reported [8, 231.) Briefly, in these trials, women who were found to be suffering from two or more ‘toxaemic symptoms’ between the 16th and 28th wk of pregnancy were allocated at random to the progesterone or control group. The control group’s symptoms were treated symptomatically while the progesterone group were given i.m. injections of progesterone to alleviate the toxaemic symptoms. Dosages of progesterone varied from 300 mg daily to 50 mg on alternate days. In a third of the progesterone group it was possible to stop injections by the 34th wk of pregnancy, whereas the remainder required injections until term.

Children were traced through their National Health Service numbers by the Medical Statistics Unit of the Office of Population, Consensuses and Sur- veys, which provided a list of the last known Family Practitioners Commit- tee (FPC) with whom the child was registered. Of the original 134 names sent to the Statistics Unit, 3 were not traceable and 12 were lost through emigration or adoption. Contact was then made with the local FPCs to obtain the last known addresses of the remaining 118 children or their doctor’s address. The majority of the local FPCs co-operated with our requests for addresses, except for the local FPCs of Middlesex (but excluding Enfield). As a result of this negative attitude, we were not able to contact 32 of the subjects. Of the remaining 86 children, 60 were not seen because: the family doctor refused to reveal the address of the patient (6), or did not know the patient’s current address (13); or because the parents refused permission (6) or defaulted on their appointments (8). The remainder did not reply to the letter setting out details of the study and asking parental permission for the child to take part (27). Two further attempts were made to contact those who did not reply, but did not yield any further subjects. Therefore, the complete test battery was given to only 26 of the 118 traceable children, i.e. 22% which compares to 46% when Dalton tested them at 1 yr of age.

Selection of tests

2-yr-old group To obtain a quantitative measure of the child’s current state of motor and mental development the Bayley Scales of Infant Development (BSID) were used [2]. The interviewers, blind to the child’s treatment, arranged and con- ducted the testing at the child’s home. The testing lasted 30-45 min and included: (1) a brief interview with the mother about the child’s development,

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home background and the composition of the household; and (2) the Motor and Mental Scales of the BSID.

16-yr-old group The choice of tests was made with a view to testing the hypotheses:

a. that it was not only necessary to assess the subjects’ present level of functioning, i.e. full IQ, but also to examine a wide variety of cognitive abilities in order to establish whether: (1) the original pattern of enhanced intellectual and academic development of P children reported by Dalton [73 had been maintained into adolescence; and (2) the reported superiority of P children was generalized as in the AGS children or specific to some skills only;

b. that the reported differences between the P and control children may be due in part to personality differences, the P children being more disposed to stay at home and study; and

c. that there may be differential changes in the development of the P girls in view of Ehrhardt and Money [ 111 and Money and Lewis’s [ 181 findings that girls with AGS and those exposed in utero to synthetic progestins develop masculine traits.

To test overall functioning, and whether any increased intelligence was generalized or specific to some skills, the Wechsler Adult Intelligence Scale (WAIS) was chosen*. Not only does this test give an overall IQ score, it makes it easier to determine whether the P subjects have any areas of special ability. The Gottschaldt Embedded Figures Test was given as a measure of perceptual functioning since it involves the ability to extract information amid distracting and confusing detail. In addition, part of the ‘Coltheart Test’ was given [4]. Briefly the authors claim that most tests of verbal and visuospatial ability are too involved; to overcome these problems they use tests which they consider purely verbal and visuospatial in origin and are extremely simple to administer. In the Verbal Task, subjects are asked to proceed verbally through the alphabet from A to Z counting the number of letters containing the sound “ee”, i.e. B, C, D, E, G, P, T, V, without the use of external aids such as speaking or writing. In the Visual Task, subjects are asked to proceed through the alphabet mentally counting the number of letters containing a curve in their upper case, i.e. B, C, D, G, J, 0, P, Q, R, S, U. They claim that women are quicker on the verbal task than men and make significantly fewer errors; whilst men are quicker on the visual task and make fewer errors. Therefore, not only was this test included as a test of verbal and visuospatial ability, but also as a means of assessing whether there was any differential changes in the male or female P subjects.

Finally to determine if there were personality differences between the

*The WAIS was given to all subjects even though half were under 16 years of age (range 14.9-17.1 yr), even though the WISC would have been more appropriate. This enabled us to make a direct comparison between all the subjects, and is a valid procedure since no comparisons were being made with reported population ‘norms’.

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groups, the Eysenck Personality lnventory (EPI) was administered and a slightly modified version of the Mf interest scale of the Minnesota Multi- phasic Personality Inventory (MMPI). The latter scale purports to measure the tendency towards masculinity or femininity of interest patterns, and was included to see if there were any masculine traits in the P females.

The testing was carried out in the subject’s home by interviewers blind to the subject’s treatment. The testing lasted l-l% h and included a short interview to collect demographic details.

Prior to testing, the subject’s school was contacted and asked to complete a questionnaire on the subject’s school performance during the previous year. A school questionnaire was included in the survey, despite the inherent problems present in using such a questionnaire, since Dalton based her original claims for the greater intellectual and educational attainment of the 9- to lo-yr-old P group on the results of a similar questionnaire sent to the children’s schools. Teachers were asked to rate the subject’s academic performance in relation to his or to her peers on a five-point scale ranging from poor through to excellent in:

1. English attainment 2. Verbal reasoning 3. Mathematics 4. Craftwork 5. Physical education 6. Physical sciences, i.e. physics and chemistry 7. Natural or biological sciences 8. Arts, i.e. history, geography, etc. 9. Foreign languages.

Statistics

Because of the small number of subjects, unequal cell sizes and the non-gaus- sian distribution of some of the data, non-parametric analyses were consider- ed more appropriate than parametric analyses. Individual group comparisons were made with a 2-tailed Mann-Whitney U-test, and where the P group data was dichotomized on the basis of progesterone dosage, duration and time of administration and compared to the controls, a Kruskal-Wallis one-way analysis of variance was used to test for a treatment effect [22]. Where the chi- squared (x2 ) test was used Yates’ correction was applied.

RESULTS

The relationship between progesterone treatment and the various develop- mental, intellectual and academic parameters were examined as well as the relationship between these parameters and progesterone dosage, duration of treatment and time of administration of progesterone.

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2-yr-old group

Of the 33 children tested, 20 were progesterone-treated and 13 were controls*. A summary of the demographic details of the two groups is given in Table 1. The results show that the groups were comparable as regards maternal age, parity and family size. Approximately two-thirds of the children were working class, and a third of the children’s parents were immigrants, mainly from Cyprus (6) and the Indian sub-continent (3); except for 1 parent all could speak English. There was a tendency, though not significant, for more of the controls to be firstborn and to come from immigrant fami- lies. Table II shows that the groups were comparable as regards gestational age and birthweight and although there was a greater proportion of males in the P group this difference in sex ratio was not significant. Table II also shows the characteristics of the P group as regards progesterone dosage, duration and time of onset of treatment.

TABLE I

Demographic characteristics of the 2-yr-old progesterone-treated control group

Progesterone- Control P - -treated group group (n=19) (n=13)

Maternal age’ (yr) 25.8 + 6.1 25.7 i 5.4 NS

Parity 1 7 7 x2=O.35 (df 1) NS 22 12 6

Family size 1 5 6 Fisher test 0.1555 22 14 7

Social class3 middle (I, II & IIINM) 7 5 Fisher test 0.2875 working (IIIM, IV & V) 12 8

Parent’s country of origin British Isles4 14 8 Fisher test 0.232s Other 5 5

’ Mean f SD. * a-tailed Mann-Whitney U-test. 3 Registrar General’s classification of occupations. 4 Includes Republic of Ireland. 5 Not corrected for even more extreme deviations. NS = not significant.

*One male progesterone child’s results were subsequently excluded from the analyses. This child’s mother, unlike the rest of the progesterone group, had been given progesterone intramuscularly from the first week of pregnancy. Originally, Dr. Dalton stated that this child should have been included in the trials, but later insisted that he be excluded.

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TABLE II

Prenatal and postnatal details of the 2-yr-old progesterone-treated group and control group, and age at testing

Progesterone Control group P group

Length of gestation’ (wk)

Birthweight’ (kg)

Sex ratio: males females

Progesterone dosage (g) median range

Duration of treatment (wk) median range

39.7 + 2.0 39.9 +- 2.3 NS1

3.327 ?r 0.621 3.213 i 0.640 NS*

11 6 x2 =0.09 (df 1) NS 8 7

5.6 0.4-117.6

2.5 l-22

-

-

Time of onset of progesterone treatment (wk of pregnancy) median 20.5 range 16-28

Age at testing’ (mth) 25.2 ? 1.3 25.5 -I 1.1 NS2

1 Mean ? SD. * a-tailed Mann-Whitney U-test.

Bayley Scales of Infant Development There were no significant effects of social class, sex and country of origin on either the Mental Development Index (MDI) or the Motor Development In- dex (PDI); therefore, for the purpose of further analysis these factors were not taken into account. Table III gives the mean scores on the Bayley MD1 and PDI of the control and P groups and of the P group when dichotomized at the median as regards progesterone dosage, duration and time of onset of treatment. There was no evidence of any significant acceleration in the development of the P group as a whole or in the high dosage, long duration or early treatment sub-categories. Nor was there any significant correlation between scores on the MD1 or PDI and progesterone dosage (Spearman Rank Correlation Coefficient, rs = - 0.027 and - 0.074), duration (rs = - 0.41 and +0.143) or time of onset of administration (rs = +0.17 and +0.06).

16-yr-old group

The characteristics of the control and P groups are given in Table IV, and the

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TABLE III

Mean (t SD) Mental Development Index (MDI) and Motor Development Index (PDI) on the Bayley Scales of Infant Development of the control group and progesterone-treated group, and the scores of the various subcategories of the progesterone-treated group

Group n MD1 P PDI P

Controls 13 105.9 f 16.2 NS’ 99.3 * 14.8 NS’ Progesterone 19 114.8 + 16.3 107.9 + 14.2

Progesterone sub-categories

High vs low dosage (median dosage 5.6 g) >median: high dosage 9 115.4 * 16.9 NS2 106.1 ?: 13.7 NS’ <median: low dosage 10 114.2 ?: 16.7 109.5 * 15.2

Long vs short duration (median duration 2.5 wk) > median: long duration 10 113.8 f 16.4 NS2 108.8 i 11.2 NS’ <median: short duration 9 114.6 ?: 17.7 109.6 * 16.2

Early vs late administration (median period of pregnancy 20.5 wk) <median : early 10 119.2 + 18.2 NS* 109.3 * 15.9 NS* z median : late 9 109.9 * 13.3 106.3 ? 12.9

1 a-tailed Mann-Whitney U-test. * Kruskal-Wallis Analysis of Variance: controls vs the 2 progesterone subgroups.

TABLE IV

Demographic characteristics of the 16-yr-old progesterone-treated group and control group

-

Progesterone- Control P’ -treated group group (n=15) (n=ll)

Age at testing (yr)’ 15.8.k 0.5 16.1 * 0.8 NS3

Sex ratio : males 2 4 Fisher 0.323 females 13 7

Parity: 1 12 5 x2=1.99 (df 1) NS 22 3 6

Family size: < 2 8 5 xa =O.OO (df 1) NS >2 7 6

Social class4 middle (Groups I, II & IIINM) 6 5 x2=0.02 (df 1) NS working (Groups IIIM, IV & V) 9 6

- ’ a-tailed test. ’ Mean t SD. 3 Mann-Whitney U-test. ’ Registrar General’s classification of occupations.

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hormone characteristics of the P group in Table V. Groups were comparable as regards age at testing, social class and family size. However, a greater proportion of the P children were firstborn (12 compared to 5 in controls) and females (13 compared to 7 controls).

TABLE V

A summary of the hormone treatment of the 16-yr-old progesterone-treated group

Dosage Duration (g) (wk)

Time of first administration (wk of pregnancy)

Characteristics of whole group median 10.1 15 23 range 0.3-29.8 l-24 16-28

Characteristics of sub-groups (mean + SD) high 15.27 + 6.41 long 19.7 * 2.5 early 18.6 * 2.4 low 7.13 f 3.46 short 11.9 * 4.7 late 25.5 f 2.0

Psychological assessment Despite the fact that there were no significant differences in sex ratio and social class ratio between the groups there is a priori evidence that these might be important factors that could be acting independently of treatment in certain of the tests [ 181. Therefore, these factors as well as treatment were taken into account in the analyses.

WAIS Table VI gives the effect of social class and sex on full scale, verbal and performance IQs. Whilst there was no difference in the IQs of males and females, there were significant social class differences, middle class subjects

TABLE VI

Scores on the Wechsler Adult Intelligence Scale (mean f SD) when subjects are divided by social class and sex

n Full scale IQ P’ Verbal IQ P’ Performance IQ P’

Social class middle working

11 113.0 * 6.4 <0.02 115.3 f 8.2 <0.02 107.7 f 5.2 <O.lO 15 104.7 f 9.4 105.7 f 12.9 102.9 * 7.4

Sex males females

6 109.3 t 8.2 NS 110.2 f 10.8 NS 105.8 t 7.8 NS 20 107.6 ?; 9.7 109.7 2 12.5 104.4 f 6.8

I 2-tailed Mann-Whitney U-test.

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obtained better scores than working class subjects. A comparison of the full scale, verbal and performance IQs of the control and P groups (Table VII) failed to find any significant differences between the groups. However, when the treatment groups were divided by social class, there were no significant differences between the IQ scores of the working class P and control subjects, but middle class control subjects obtained significantly better full scale and verbal IQs than P subjects, which is contrary to expectations.

TABLE VII

IQ scores on the Wechsler Adult Intelligence Scale (mean + SD) of the control and progesterone-treated groups

_._._- n Full scale IQ P’ Verbal IQ P’ Performance IQ P’

Social classes combined: progesterone 15 107.1 f 8.9 NS 108.9 ?: 12.7 NS 103.7 f 6.6 NS controls 11 109.6 f 9.7 111.0 f 12.0 106.5 + 7.4

Social classes separate: Middle class

progesterone 6 108.7 f 2.9 0.03 110.2 f 7.0 0.018 105.0 f 3.2 0.066 controls 5 118.2 f 5.6 121.4 ? 5.5 111.0 f 5.6

Working class progesterone 9 106.1 f 11.4 NS 108.0 f 15.3 NS 102.9 f 8.3 NS controls 6 102.5 f 5.4 102.3 * 8.2 102.8 f 6.9

1 a-tailed Mann-Whitney U-test.

Perceptual and spatial tests Table VIII shows the time to complete the Embedded Figures Test and the Verbal and Visual Tasks of the ‘Coltheart Test’. There were no significant differences between the control and P groups on any of these parameters, nor were the predictions that there are sex differences on these tests substanti- ated. There were no significant effects of social class in either test.

Personality tests The results are shown in Table IX. There were no significant differences between control and P groups, although the P group tended to score higher on the N scale and lower on the E scale of the EPI. However, there were significant sex differences, males scoring significantly higher on the EPI E scale than females. A comparison of just female scores revealed that P females appeared to get significantly lower E scores, that is are more introverted than the controls, and although they scored higher on the N scale these differences were not significant. There were no significant differences between males.

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TABLE VIII

Mean (+ SD) times taken to complete the Embedded Figures Test and Coltheart Teat

n Embedded Figures Coltheart (set) P’ Verbal P’ Visual P’

(set) (see)

Hormone treatment progesterone 15 31.7 + 10.6 NS 38.3 f 18.6 NS 41.0 * 15.8 NS controls 11 31.7 f 9.9 32.6 -f 11.9 43.2 + 14.7

Sex males 6 34.0 f 12.2 NS 42.8 * 18.8 NS 41.2 f 9.3 NS females 20 31.1 + 9.4 33.9 f 15.4 42.2 f 16.4

’ a-tailed Mann-Whitney U-test.

TABLE IX

Personality scores (mean f SD) on the Eysenck Personality Inventory (EPI) and Minnesota Multiphasic Personality Inventory (MMPI)

n EPI MMPI Mf Scale N-scale P’ E-scale P’ T scores P’

A_

Sex males females

6 7.7 i 4.2 NS 15.3 * 1.5 <0.02 45.0 f: 11.3 NS 20 11.0 f 4.1 13.0 * 3.1 60.6 f 13.0

Hormone treatment

Females only progesterone controls

13 11.9 f 4.5 <O.lO 11.8 + 2.7 <0.05 59.4 f 14.2 NS 7 9.1 zt 2.3 15.1 * 2.7 61.7 f 12.0

Combined sexes progesterone controls

15 11.3 t 4.4 <O.lO 12.4 + 2.7 NS 57.3 + 13.8 NS 11 8.6 f 3.4 15.1 i 2.4 56.9 + 11.1

1 a-tailed Mann-Whitney U-test.

There were no significant differences in T scores between the males and females on the MMPI Mf scale, both males and females showed interest patterns supposedly appropriate to their sex. A comparison of scores of the control and P groups revealed no significant deviation in interest patterns between the groups, nor was there any significant deviation between the control and P groups when only the females’ and males’ interest patterns were examined. Therefore, the results suggest that, unlike androgens and synthetic

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progestins, progesterone does not affect psychosexual identity. To determine if progesterone dosage, duration and time of administration

were important variables, the P group was dichotomized at the appropriate median (Table V) into high and low dosage, long and short duration, or early and late administration. The median dosage is greater than the 8 g used by Dalton [7] and the 3 g chosen by Zussman et al. [23] as the cut-off point for dividing high from low dosage groups. In fact 12 of the present group could be classified as high dosage according to Dalton’s criterion and 14 as high dosage according to the Zussmans’ criterion. In addition, 14 of the present group could be classified as having been exposed to progesterone for a long duration using the Zussmans’ criterion of 8 wk exposure rather than the present criterion of 15 wk. However, our early progesterone group was not comparable to Dalton’s early progesterone group since the latter group were children exposed to progesterone before the 16th wk of pregnancy, whereas in our group treatment only started at the 16th wk of pregnancy.

Both Dalton [ 7, 81 and Zussman et al. [23] claim that high dosage, long duration of treatment and early administration are important positive factors in the enhancement of intellectual ability. A Kruskal-Wallis one-way analysis of variance failed to reveal any significant effect of high dosage, long duration or early administration on any of the test parameters, therefore the results have not been presented.

Academic perfor??zance (Table X) There were no significant differences in the proportion of P subjects and control subjects who got ‘above average’ grades in any of the school subjects. The results are also negative when the P group was divided into high dosage, long duration and early dosage.

DISCUSSION

The present study sought to determine whether extraneous progesterone administered during pregnancy enhanced development, later intellectual and academic attainment and personality development, and whether this enhancement was general or specific to certain skills.

Dalton [7] claims that a greater proportion of P children are walking and standing unaided at 1 yr than matched controls, and that they have an intellectual advantage over controls at 9-10 yr of age in ‘academic subjects’ and arithmetic. In addition, she claims that the enhanced development and academic achievement are positively related to progesterone dosage and timing of its administration. More recently, Dalton [8] analysed the performance of the 9- to lo-yr-olds reported in the previous study in their school leaving examinations, namely ordinary (0) level General Certificate of Education (GCE) at 16 yr of age, and the advanced (A) level GCE examinations at 18 yr of age. She claims to have found a higher level of’achievement among the P subjects compared to the controls in both examinations.

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TABLE X

Teacher assessment of the child’s academic abilities

Academic assessment Below average Above average

P’

1.

2.

3.

4.

5.

6.

7.

8.

9.

English attainment progesterone controls

Verbal reasoning2 progesterone controls

Arithmetic progesterone controls

Craftwork progesterone controls

Physical education2 progesterone controls

Physical sciences’ progesterone controls

Natural sciences’ progesterone controls

Arts2 progesterone controls

Foreign languages* progesterone controls

11 8 11 4

10 6 10 5

10 11

12 5 5 8

14 3 7 6

8 5

6 3 6 4

10 6 8 3

5 6 5 1

9 4

4 4

x* =0.329 (df 1) NS

x2 =0.018 (df 1) NS

x2=O.771 (df 1) NS

x2 =1.926 (df 1) NS

Fisher test3 0.163

Fisher test’ 0.163

Fisher test3 0.700

Fisher test” 0.564

Fisher test? 0.285

I a-tailed probability test. z Not all children were assessed on all subjects. ’ Not corrected for even more extreme events.

In addition, it appears that five times as many P children are likely to go to university (32%) compared to controls (6%).

Our results do not substantiate Dalton’s claims. We failed to find any positive significant effect of progesterone on development at 2 yr of age. Proges- terone treatment was not associated with enhanced intellectual and academic achievement at 16 yr of age; in fact there was evidence that P subjects had

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poorer full scale and verbal IQs than comparable control subjects. It is not certain how much emphasis should be placed on this finding. It seems prob- able that the result is either a chance finding or due to unknown sampling bias.

However, there did appear to be significant personality differences between groups, the P females appear to be more introverted than controls, the typical introvert being somebody who is quiet and retiring, introspective and fond of books rather than people, likes a well-ordered life and seldom be- haves aggressively [ 141. Whilst this too could be a chance finding or due to sampling bias, similar conclusions about P subjects were reported in another study [23]. In this study, the authors investigated the effects of prenatal progesterone in postpubertal subjects in a variety of intellectual, psychological and maturational areas. They report that P subjects aged 16-19 yr were less orientated towards intense social activity than controls. They reported that at age 5-10 yr, they engaged in less active play and had less influence on peers than controls. In addition, P females received less discipline in school and showed a decreased likelihood of having been tomboys between 5 and 10 yr of age than controls. This latter finding is in contrast to the tomboyish behaviour amongst AGS and synthetic progestin exposed females [12, 181. Further recent work on the effects of synthetic progestins on personality [ 211 suggests that subjects exposed to prenatal synthetic progestins are more independent, individualistic, self-assured and self-sufficient, traits that are commonly associated with males. Therefore, there appears to be a certain amount of evidence to suggest that prenatal exposure to excess androgens and possibly progesterone may have some long-term effect on personality and/or behaviour, although the physiological mechanism is not known.

It is arguable that because of the low returns in both studies, the small number of subjects, the problems associated with any long-term retrospec- tive study and the suitability of the controls, our ability to interpret and extrapolate from our results to Dalton’s are limited, and that we could be guilty of committing a Type II error, namely accepting the Null Hypothesis when, in fact, with a very much larger sample size one might reject it. How- ever, some of these arguments about sample size and suitability of controls also apply to some extent to Dalton’s studies. In addition there are a number of studies which lend indirect support to our argument that progesterone does not enhance intellectual development.

Undoubtedly, the studies which have supported Dalton’s hypothesis that excess steroids enhance intellectual development are those of Money and his associates [19] on the IQ of AGS children and those exposed to synthetic progestins. However, recent studies have called their evidence of elevated IQs into question. In a study of AGS children [l] a fresh attempt was made to elucidate the factors that might have contributed to their reported higher IQs. Towards this end, the performance of parents and the unaffected siblings of the probands were tested at the same time as the probands. The results confirm the findings of elevated IQ in the AGS children but also show

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that the IQs of parents and nonaffected siblings is also significantly above the norm. Thus it appears that the enhancement of IQ cannot be attributed solely to the hormonal aspects of the syndrome, although the sexually dimorphic behaviour of the AGS female does appear to be due to the hormonal dysfunction [13] . In another study of AGS children, Perlman [20] found that the overall level of intellectual functioning is again above the normal in these children, but it is comparable to the scores of carefully matched normal controls on the Wechsler Scales, Goodenough-Harris Drawing Test and selected problems from the Stanford-Binet Intelligence Scales. It is suggested that the apparent overall high intellectual functioning of AGS children is apparently due to variables involved in their selection. Similar conclusions were arrived at by Reinisch [ 201 concerning the elevation in IQ of girls exposed in utero to synthetic progestins. The intellectual development of offspring of mothers given synthetic progestins for the maintenance of at-risk pregnancies was compared with that of their unexposed siblings. The IQ scores of both the exposed and unexposed subjects were 20 points higher than the expected norm, and of a similar order of magnitude to the results of Ehrhardt and Money [II] in their study of progestin-exposed females. It is suggested that the elevated scores probably reflect the better socio- economic status of the family who undertook the expensive and timecon- suming treatment to support an at-risk pregnancy.

Further support for our hypothesis that progesterone does not enhance intellectual development comes from a consideration of our own work. Firstly, in the 16-yr-old group, the majority of the P group could be classified as a high dosage group according to previously used criteria [7,8, 231. According to Dalton’s hypothesis both of these factors are positively related to intellectual and academic attainment, therefore one would expect that the chance of finding enhancement would be heavily weighted in favour of our P group. This does not appear to be the case. Secondly, unlike Dalton’s [7] earlier study, the testing of the children’s development and intellectual attainment were carried out using well-standardized tests by the same interviewers, so the results should be more objective and quantitative. The Bayley Scales of Infant Development give a direct measure of the child’s current level of functioning, whereas Dalton relied on clinic doctors and health visitors to complete a maternal questionnaire. Similarly in the educational follow-up at 9-10 yr of age, Dalton required teachers to complete a prepared questionnaire, whereas in the present study intellectual functioning was assessed using standardized tests. Another problem in the interpretation of the 9- to lo-yr-old’s results is that mothers of the P group tended to be older and of higher parity and had experienced a significantly greater number of previous miscarriages than the control group. Thus one cannot exclude the possibility that factors other than prenatal hormonal history may have af- fected intellectual and academic achievement.

The only other objective and quantitative study on P children was that of Zussman et al. 1231. The subjects, aged 16-19 yr, were the same group whose academic performance had been assessed at 9-10 yr of age. Subjects

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were given problems from the Differential Aptitude Test, namely, verbal and abstract reasoning, and mechanical, spatial and numerical ability. They found several marginally positive significant relationships between progesterone treatment and mechanical and spatial ability, and a negative relationship between progesterone treatment and abstract reasoning in boys. How- ever, the only highly positive significant difference between the P group and controls was on the numerical ability sub-test, the advantage was significantly related to progesterone dosage and length of treatment. Nevertheless, the authors state that there were some complications in the direct comparison between the P and control groups due to a differential drop-out rate. On the basis of previous information on the subjects, namely, their academic achievement at 9-10 yr, it appears that it was the intellectually less able subjects who were likely to drop out. Therefore, whilst this result on numerical ability is at variance with out own results on intellectual performance, the rest of the results do not unequivocally support Dalton’s claims 17, 81 that P children are better intellectually and academically than controls. Zussman et al. [23] also raise the question as to whether the result might be better explain- ed by the fact that P children are more studious and less socially interactive than controls rather than postulating that progesterone somehow affects motor and cognitive development.

Therefore, at the moment, it appears that the weight of evidence is now against the idea that excess androgenic-like substances and progesterone administered during fetal life can enhance later intellectual attainment. Moreover, although the present psychological findings are open to dispute, it has become apparent that there are serious anomalies in Dalton’s own papers, the evidence for which is presented in the companion paper [ 171.

ACKNOWLEDGEMENTS

Thanks are due to the parents and children who took part in the study, to Dr. K. Dalton who supplied the names of the children, to the Chase Farm Hospital, Enfield and the City of London Maternity Hospital for access to the patients’ records, and the FPCs and family doctors who allowed us to contact their patients.

REFERENCES

1 Baker, S.W. and Ehrhardt, A.A. (1974): Prenatal androgen, intelligence and cognitive sex differences. In: Sex Differences and Behaviour, pp. 53-76. Editors: R.C. Fried- man, R.M. Richart and R.L. Vande Wiele. Wiley, New York, NY.

2 Bayley, N. (1969): Bayley Scales of Infant Development. The Psychological Corpora- tion, New York, NY.

3 Belmont, L., Stein, Z.A. and Wittes, J.T. (1976): Birth order, family size and school failure. Dev. Med. Child Neurol., l&421--430.

4 Coltheart, M., Hull, E. and Slater, D. (1975): Sex differences in imagery and reading. Nature, 253,439-441.

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Dalton, K. (1957): Toxaemia of pregnancy treated with progesterone during the symptomatic stage. Brit. Med. J., 2, 378-381. Dalton, K. (1962): Controlled trials in the prophylactic value of progesterone in the treatment of pre-eclamptic toxaemia. J. Obstet. Gynaec. Br. Commonw., 69, 463- 468. Dalton, K. (1968): Antenatal progesterone and intelligence. Br. J. Psychiat., 114, 1377-1382. Dalton, K. (1976): Prenatal progesterone and educational attainment. Br. J. Psy- chiat., 129,438-442. Dobbing, J. and Sands, J. (1973): Quantitative growth and development of human brain. Arch. Dis. Child., 48,757-767. Dobbing, J. and Smart, J.L. (1974): Vulnerability of developing brain and behaviour. Br. Med. Bull., 30,164-168. Ehrhardt, A.A. and Money, J. (1967): Progestin-induced hermaphroditism: IQ and psychosexual identity in a study of ten girls. J. Sex. Res., 3,83-100. Ehrhardt, A.A., Epstein, R. and Money, J. (1968): Fetal androgens and female gender identity in the early-treated androgenital syndrome. Johns Hopkins Med. J., 122, 160-167. Ehrhardt, A.A. and Baker, SW. (1974): Fetal androgens, human central nervous system differentiation and behaviour sex differences. In: Sex Differences and Be- haviour, pp. 33-51. Editors: R.C. Friedman, R.M. Richart and R.L. Vande Wiele. Wiley, New York, NY. Eysenck, H.J. and Eysenck, S.B.G. (1963): The validity of questionnaires and rating assessments of extraversion and neuroticism and their factorial validity. Br. J. Psy- chol., 54,51-62. Hutt, C. (1972): Neuroendocrinological, behavioural and intellectual aspects of sexual differentiation in human development. In: Gender Differences: their Onto- geny and Significance, pp. 73-122. Editors: G. Ounsted and D.C. Taylor. Churchill- Livingston, London. Lewis, V.G., Money, J. and Epstein, R. (1968): Concordance of verbal and nonverbal ability in the androgenital syndrome. Johns Hopkins Med. J., 122, 192-195. Lynch, A and Mychalkiw, W. (1978): Prenatal progesterone II. Its role in the treatment of pre-eclamptic toxaemia and its effect on the offspring’s intelligence: a re- appraisal. Early Hum. Dev., 2, 323-339. Money, J. and Lewis, V.G. (1966): IQ, genetics and accelerated growth: Andro- genital Syndrome. Bull. Johns Hopkins Hosp., 118, 365-373. Money, J. and Ehrhardt, A.A. (1972): Man and Woman, Boy and Girl. Johns Hop- kins University Press, Baltimore, MD. Perlman, S.M. (1973): Cognitive abilities of children with hormone abnormalities: screening by psychoeducational tests. J. Learn. Disabil., 6, 26-34. Reinisch, J.M. (1977): Prenatal exposure of human foetuses to synthetic progestin and oestrogen affects personality. Nature, 266, 561-562. Siegel, S. (1956): Nonparametric Statistics for the Behavioural Sciences. McGraw- Hill, New York, NY. Zussman, J.U., Zussman, P.P. and Dalton, K. (1975): Postpubertal effects of prenatal administration of progesterone. Proceedings of the Society for Research in Child Development. Denver, April, 1975.

prenatal progesterone i. its effect on development and on intellectual and academic achievement

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