Prenatal progesterone II. Its role in the treatment of pre-eclamptic toxaemia and its effect on the offspring's intelligence: a reappraisal

Early Human Development, 1978, 214, 323-339 o Elsevier/North-Holland Biomedical Press

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Prenatal progesterone II. Its role in the treatment of pre-eclamptic toxaemia and its effect on the offspring’s intelligence: a reappraisal*

ANTHONY LYNCH and WASYL MYCHALKIW

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

Accepted for publication 11 July 1978

SUMMARY

Dalton’s results concerning the beneficial effect of progesterone supplementation in preventing pre-eclamptic toxaemia [ 161 and in enhancing intellectual potential [17,18] were reappraised. We could find no evidence in the data that progesterone supplementation was any better at preventing pre- eclamptic toxaemia than treating the disorder symptomatically. Nor could we find any convincing evidence that excess progesterone enhances development at 1 yr of age, academic attainment at 9-10 yr of age, or success in school leaving examinations and improves the chances of continuing further full-time education after leaving school.

pre-eclamptic toxaemia; development; prenatal progesterone; intelligence

INTRODUCTION

Pre-eclamptic toxaemia is still a major disorder of late pregnancy and remains one of the leading causes of maternal and perinatal death [29]. It has also been linked to abnormal development in the neonate [40] and to behavioural disorders in surviving children [2,6,37], the effects of toxaemia apparently being related to its severity and the length of stay of the fetus in the abnormal environment [8,27,28,34] . Therefore treatment is directed towards reducing the severity of the hypertension, maternal cortical and motor activi- ty and in an attempt to achieve maturity of the fetus before delivery. How- ever, despite its prevalence toxaemia still remains a disease of theories, and although good results may be obtained with suitable symptomatic measures a more logical basis for treatment is required. *This work was financed by the Medical Research Council and by grants from the Chase Charity and ‘The People’ newspaper.

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It has been suggested that the principal triggering factor in the pathogene- sis of toxaemia is uteroplacental ischemia which results in placental degene- ration with the liberation of thromboplastin, which in its turn results in the development of intravascular coagulation with resultant lesions in the kidney and possibly other sites. Then as a result of aberrations in the renin-angiotensin-aldosterone system and an increased vascular response to endogenous vasoconstrictors, the generalized vasospasm, hypertension, oedema and pro- teinuria characteristic of the disease develops [9] .

Of particular interest is the role that progesterone might play in the treatment and prevention of the disease. It has been found that aldosterone levels are low in the disease [ 221, and additionally that when progesterone is given to women it causes a marked rise in aldosterone concentration presumably due to the progesterone-induced naturesis [ 351. Therefore it is possible that prophylactic progesterone administered to patients with the disorder may alleviate some of the characteristic symptoms of the disease, possibly by affecting the renin-angiotensin-aldosterone system. Ragab et al. [ 381 found that administering the naturally occurring progestin, 17a-hydroxy- progesterone (from the 36th wk of pregnancy), to 36 women already showing all the symptoms of pre-eclamptic toxaemia, they could produce a decrease in blood pressure, body weight and oedema in over 80% of cases. Pro- teinuria persisted in all cases though at a reduced level. Possibly of more clinical importance are the claims of Dalton [15,16] that it is possible to identify women ,during the middle trimester who are likely to be at-risk to developing pre-eclamptic. toxaemia during the third trimester, and that it is possible to treat these at-risk women with prophylactic progesterone during the middle trimester and prevent pre-eclamptic toxaemia developing in the third trimester, thereby preventing the exposure of the fetus to an abnormal environment. However, what is more surprising and of greater clinical and scientific importance are Dalton’s claims [17,18] that early development can be accelerated and intellectual attainment enhanced by in utero exposure to extraneous progesterone.

However, in a previous paper [33] we failed to confirm Dalton’s earlier findings on enhanced intellectual development of progesterone-treated (P) children, and presented evidence against the idea that in utero exposure to excess steroids such as progesterone and androgens ,can enhance later intellectual development. The present paper re-examines the theoretical and factual basis for Dalton’s claims that progesterone is efficacious in preventing the development of toxaemia and in enhancing offspring intelligence and academic success.

METHOD

Dalton’s papers concerning the effects of progesterone on the incidence of pre-eclamptic toxaemia [ 15,161 and on intellectual development [9,17] and unpublished data (Dalton, personal communication) have been re-examined,

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and the results shown in the tables and figures re-analysed using the same type of statistical tests as that used by Dalton. Where it has been necessary to extract the data from figures, we have tried to corroborate our data with those in the text. Whenever there was uncertainty about the numbers in a particular group, the results were always biased in favour of the P subjects, thereby increasing the chances of finding significant differences between groups.

RESULTS

Effects of prenatal progesterone on the incidence of toxaemia of pregnancy

In an early paper, Dalton [38] looked at the progress of women identified as showing ‘toxaemic symptoms’ during the middle trimester of pregnancy (i.e. 16%2&h wk) with women not showing these ‘symptoms’. Briefly, Dalton [13,14] ascertains that women showing two or more ‘toxaemic symptoms’ namely nausea and vomiting, lethargy, backache, headache, vertigo, fainting, cramp/paraesthesia, depression/headache are more likely to go on to develop pre-eclamptic toxaemia than those who do not have these symptoms. Dalton examined the occurrence of pre-eclamptic toxaemia in both groups. Pre- eclamptic toxaemia was diagnosed if women previously free from hypertension, albuminuria or oedema developed these signs after the 28th wk of pregnancy on more than one occasion. Table I gives the relative incidence of pre- eclamptic toxaemia in both groups, and it appears that significantly more women with ‘toxaemic symptoms’ during the middle trimester do go on to develop toxaemia.

In a second paper, Dalton [ 161 compared the incidence of toxaemia after the 28th wk in two matched groups of women with ‘toxaemic symptoms’ during the second trimester, the subjects being matched for parity, age and the incidence of various ‘toxaemic symptoms’. One group was given prophylactic progesterone to relieve the symptoms, the second group was given symptomatic treatment for their symptoms, i.e. antihistamines, analgesics or

TABLE I

The differences in the incidences of toxaemia after the 28th wk of pregnancy between women that showed ‘toxaemic symptoms’ and those that ‘felt well’ between the 16th and 28th wk of pregnancy

Toxaemic (%) Normal x2 P

With symptoms in the middle trimester

Feeling well in the middle trimester

(adapted from Dalton, 1960 [ 151)

35 (25) 107 17.19 < 0.001

52 (11) 439

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TABLE II .

The difference in the incidence of various symptoms of pre-eclamptic toxaemia ih women treated with progesterone (P) and those whose symptoms were treated symptomatically (controls: C)

Symptom Present Absent Dalton’s P’ Reanalysed data

Toxaemia P C

2 7

Blood pressure3 (140/90 mm Hg) P 7

C 13

0edema3 P 3

C 11

Albuminuria P C

1 5

60 59

0.039 Fisher test? = 0.196

55

53

0.039 X 2 = 1.14 (df 1) 0.30-0.20

59

55

0.028 X * = 3.46 (df 1) 0.10-0.05

61 61

0.051 Fisher test’ = 0.238

(Adapted from Dalton, 1962 [ 161) ’ a-tailed tests. ZCorrected for even more extremes. 3 Expected cell frequencies greater than 5.

sedatives. A comparison was made between the actual numbers that developed pre-eclamptic toxaemia in both groups (Table II). Dalton states that,

“incidences of toxaemia between progesterone and control groups is statistically significant . . . . . as is the lowered incidence of raised blood pressure, and oedema and albuminuria.”

The reworking of the data using both the Fisher Exact Probability Test or chi-square test with Yates’ correction does not support this statement. It appears that progesterone treatment is no better or worse in reducing the incidence of pre-eclamptic toxaemia than treating symptomatically.

Effects of prenatal progesterone on offspring intelligence

In 1968, Dalton published her paper on the development of the offspring of mothers used in the earlier progesterone trials [ 163 . Doctors and Health Visi- tors were asked to complete a questionnaire on the P and control children’s development at 1 yr of age. Dalton states that,

“significantly more progesterone children were able to stand unaided and walk unaided than controls, and more progesterone children were breast-fed until 6 months”.

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TABLE III

Development follow-up: The number of progesterone-treated children (P) and control children (C) being breast-fed. at 6 mth, and the number standing and walking alone at 1 yr of age

% x* (df 1) P’

Breast feeding Fed Not fed

P (32) 9 20 1.93 NS C (14) 4 27

Standing alone Standing Not standing

P (93) 27 2 4.54 <0.05 C (67) 21 10

Walking alone Walking Not walking

P (62) 18 11 3.24 NS C (35) 11 20

(adapted from Dalton, 1968 [ 17 J) I %-tailed test.

Table III shows the results derived from Dalton’s Figure 1, which showed that a significantly greater proportion of P children stood unaided at 1 yr of age than controls, but that the proportion walking unaided and those who had been breast-fed were not significant.

In the second part of the 1968 paper, Dalton looked at the educational attainments, at 9-10 yr of age, of children who had been included in earlier trials on the prophylactic use of progesterone in toxaemia [ 141. Each P child ,born during these trials was included in the study along with the next- born child in the labour ward register, whose mother had had a normal pregnancy (normal controls = NC), and the next child born to a mother who had developed toxaemia (toxaemic controls = TC). In this study, questionnaires were sent to the child’s head teacher who was asked to grade the child as below average, average or above average standard in verbal reasoning, Eng- lish, arithmetic, craft and P.E. Dalton states that

“... progesterone children received significantly more above average grades than either the normal or toxaemic controls. The better grades obtained by progesterone children exceeded that of the controls by 10% in all subjects, 14% in academic subjects, 13% verbal reasoning, 11% English, 14% arithmetic and 10% craftwork . . . These results are significant as shown by the chi-square test with one degree of freedom on two-tailed tests in respect of all subjects, academic subjects and arithmetic”.

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TABLE IV

Educational follow-up at 9-10 yr: children were graded by head teachers as below average, average or above average in a variety of subjects

% Above average Average or below x2 df P

All subjects P= NC TC

Academic subjects P’ NC TC

Verbal reasoning P3 NC TC

English P NC TC

Arithmetic P NC TC

Craftwork PJ NC TC

(37) 10 (29) 6 (24) 7

(43) 12 16 (29) 6 15 (24) 7 22

(46) 13 (29) 6 (31) 9

(48) 14 (38) 8 (31) 9

(35) 10 19 (25) 5 16 (17) 5 24

(43) 12 16 (30) 6 15 (28) 8 21

17 15 22

15 15 20

15 13 20

1.14

(0.57

2.45

(1.48

2.14

(0.85

1.82

(1.15

2.32

(1.44

1.79

(0.87

2 NS

1 NS)’

2 NS

1 NS)’

2 NS

1 NS)’

2 NS

1 NS)’

2 NS

1 NS)’

2 NS

1 NS)’

(adapted from Dalton, 1968 [ 17 ] ) ’ A comparison of the most extreme control group and progesterone group. ’ 2 progesterone subjects not assessed. 3 1 progesterone subject not assessed for verbal reasoning, another for craftwork. P = progesterone; NC = normal controls; TC = toxaemic controls.

Table IV is derived from Dalton’s Figure 2, and gives the proportion of children obtaining above average grades. It is not certain from the text how the percentage differences in achievement between P and control groups were determined. However, the percentage differences between the P group and the nearest control group in our derived figures are comparable to those quoted by Dalton. A reworking of the data using a 3 X 2 chi-square test, which is a more appropriate test in this situation since all expected frequencies are greater than 5, does not support Dalton’s statement, nor does a comparison of the P and worst control group.

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Dalton then examined the effect of progesterone dosage on a child’s grad- ing. Dalton’s Figure 3 claims to show a progressive decrease in attainment from the high dosage group to the controls in both development at 1 yr and academic achievement. Table V shows that the only significant difference at 1 yr of age is that more high ‘dosage P children are standing unaided at 1 yr than controls, while Table VI shows that there were in fact no significant differences between the high dosage group and combined controls in academic achievement.

Finally, Dalton examined the relationship between the time of administration of progesterone and academic achievement (Dalton’s Fig. 4) and claims that

“A significant improvement in educational performance was demonstrated among children who received progesterone before the 16th week of pregnancy”.

A reanalysis of this data is given in Table VII, and the results show that the early progesterone-treated children only obtain significantly more above average grades than combined controls in arithmetic. However, if the combined controls are divided into normal and toxaemic controls, which is a legitimate action since Dalton acknowledges that toxaemia has an adverse effect on development, then the differences in arithmetic appear to be due to differences between the early progesterone-treated group and toxaemic controls (Table VIII).

In the most recent paper in the series Dalton [16] examined the Ordinary (‘0’) and Advanced (‘A’) level General Certificate of Education (G.C.E.)

TABLE V

Progesterone dosage: effect on breast feeding at 6 mth of age and development at 1 yr of age

Breast feeding HP

Standing unaided Standing Not standing HP 18 0 Fisher test 0.011 C 21 10 LP 9 2 Fisher test 0.635 C 21 10

Walking unaided Walking Not walking HP 11 7 X o ‘L 2.08 (df 1) NS C 11 20

Fed 6 4

P’ Not fed 12 ’ X ’ = 1.80(df 1) NS 27

-

(adapted from Dalton, 1968 [ 171) 1 a-tailed test. HP = high progesterone dosage, i.e. > 8 g; LP = low progesterone dosage, i.e. < 8 g; C = control.

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TABLE VI

Progesterone dosage: effect on educational follow-up at 9-10 yr of age

Above average Average and below x2 (df 1) P’

All subjects HP3 C

Academic subjects HP C

Verbal reasoning HP C

English HP C

Arithmetic HP C

Craftwork HP3 C

4 13

5 5 1.2gz NS 13 37

6 4 2.112 NS 15 35

5 5 0.36’ NS 17 33

5 5 2.56= NS 10 40

4 5 0.35’ NS 14 36

5 o.532 NS 37

(adapted from Dalton, 1968 [ 171) ’ a-tailed test. * A Fisher Exact Probability test would have been more appropriate in all cases: however, like Dalton we have used a x’ test since with such a large number of subjects x* test ap- proximates to P values obtained by a Fisher test. 3 1 high-dosage progesterone child was not assessed for craftwork. HP = high progesterone dosage; C = combined normal and toxaemic controls.

success of the children who were assessed at 9-10 yr of age and also the proportion of them entering university. Table IX is reproduced from Dalton’s paper and shows numbers of ‘0’ and ‘A’ level G.C.E.s obtained by the various groups. While a chi-square contingency table of ‘0’ level G.C.E.s was not significant, Dalton does claim that the number of ‘0’ and ‘A’ levels per child are significantly different on a chi-square test. However, the two chi-square values concerning ‘0’ and ‘A’ level G.C.E. results have been calculated on a completely inappropriate basis. It appears that these values have been erro- neously calculated as follows: the expected number of passes in the three groups has been calculated by assuming the same average number of passes per person over all groups, and then by multiplying this by the number of persons in the three groups. The observed numbers of passes have then been

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compared with the above expected numbers using the usual chi-square pro- cedure. This approach is not valid.

Finally, it would appear that Dalton’s [ 181 claim that more P children go to university than controls is apparently correct. Unfortunately, from an unpublished paper (Dalton, personal communication) which gives more details of the groups, it appears that the results have been baised in favour of the P group (Table X). In the first place, there is a greater proportion of females in the control group and, in the second place, no account is taken of children entering other forms of non-university full-time education. These factors are related and when some account is taken of them, the difference between the groups is not significant. The importance of these factors in the interpreta- tion of Dalton’s results is shown in Table XI. Of subjects sitting ‘A’ level G.C.E.s, which are the common university entrance examinations, proportionally more males get the minimum university entrance requirements of 2

TABLE VII

Time of progesterone administration: a comparison of academic achievement between children started on progesterone before the 16th wk of pregnancy and controls

Above average Average and below x2 (df 1) P’

All subjects EP3 C

Academic subjects EP4 C

Verbal reasoning EP4 C

English EP C

Arithmetic EP C

Craftwork EP4 C

4 13

5 4 1.902 NS 13 37

6 3 3.022 NS 15 35

5 5 0.36’ NS 17 33

6 4 4.932 <0.05 10 40

3 6 0.011 NS 14 36

4 0.93’ NS 37

(adapted from Dalton, 1968 [ 171) ’ a-tailed test. * See note 2 at bottom of Table VI. ’ 2 progesterone subjects not assessed. 4 1 progesterone subject not assessed for verbal reasoning and another for craftwork. BP = early progesterone group, i.e. 16th wk; C = combined toxaemic and normal controls.

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TABLE VIII

The timing of progesterone administration: a comparison between the progesterone- treated group's assessment and the two control groups’ assessments in arithmetic

Above average Average and below x’ df P

Arithmetic EP NC TC

6 4 1.01 2 <0.05 5 16 5 24

EP&NC 2.46l 1 NS EP & TC 4.77’ 1 <0.05

(Adapted from Dalton, 1968 [ 17 ] ) ’ See note 2 at bottom of Table VI. EP = early progesterone group; NC = normal controls; TC = toxaemic controls.

TABLE IX

Educational attainment of progesterone and control children

Progesterone Normal Toxaemic xa (df 2) control control

P’

No. of children 34 31 12 ‘0’ levels per child

none 5 9 5 l-4 8 11 4

I NS NS

5 or more 21 17 3

Total ‘0’ levels 196 201 43 8.18 <0.02 ‘O’s per child 5.7 5.4 3.6

Total ‘A’ levels 44 34 6 6.1 <0.05 ‘A’s child per 1.3 0.9 0.5

(adapted from Dalton, 1976 [ 181) 1 a-tailed test

‘A’ level G.C.E.s. In addition, of those of both sexes passing ‘A’ level G.C.E.s, proportionally more males go on to further forms of training than females, and of those continuing further full-time education more than twice as many males are admitted for degree courses than females [42] .

Therefore, on the whole, it appears that Dalton’s claims for progesterone, regarding its efficacious effects in preventing pre-eclamptic toxaemia and on intellectual and academic achievement, are unsubstantiated even by her own data.

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TABLE X

Number of progesterone and control children entering further full-time education after leaving school

Progesterone-treated Control X2 df P’ group (n=34) group (n=49’)

Sex : males 21 23 1.23 1 NS females 13 26

Numbers entering university* entering not entering

11 3 6.67 1 <O.Ol 18 33

Numbers entering college and other non-university full-time education%

entering not entering

7 22

12 24

0.29 1 NS

Numbers entering any form of further full-time education’

entering not entering

18 15 1.92 1 NS 11 21

(adapted from Dalton, unpublished paper) ’ a-tailed test. ’ 5 progesterone children and 13 control children were still at school and had not yet made a decision regarding their further education.

TABLE XI

Percentage of males and females taking ‘A’ level examinations, and the proportion of the sexes entering further full-time education

Males Females Ratio (%) (%) (males/females)

Numbers leaving with 2 or more ‘A’ levels of the total school population

Destiny of those leaving with ‘A’ levels degree courses (universities and polytechnics) teacher training

further education

other

4.65 3.64 1.3:1

48 21 2.3:1 5 17 0.3:1

31 15 2.1:1

15 11 1.4:1

Total having further training 99 64 1.5:l

(adapted from Statistics of Education, 1974 [42] )

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DISCUSSION

It appears that there is no factual evidence to support Dalton’s hypothesis that progesterone prevents the development of pre-eclamptic toxaemia, and very little factual evidence to support the claim that progesterone enhances intellectual and academic ability [17,18,33,45]. It is appreciated that with such a small sample size, there is always a possibility of committing a Type II error [ 241, that is, accepting the Null Hypothesis when with a larger sample size it might be rejected. However, even were Dalton’s claims to have some statistical validity, it would still be necessary to explain what is the mode of action of progesterone in preventing pre-eclamptic toxaemia and in enhancing intellectual potential.

Dalton [ 161 suggests that, while pre-eclamptic toxaemia is not caused by a simple progesterone deficiency, it is possible that prolonged progesterone deficiency from mid-pregnancy onwards can ultimately cause secondary changes in progesterone metabolism which are manifested by toxaemic signs in the last trimester. One possible way in which alterations in progesterone concentration could act is through changes in the renin-angiotensin- aldosterone system [9], and/or in sodium retention. Evidence suggests that the mean total exchangeable sodium in women who develop preeclamptic toxaemia shows an excessive increase until the 26th wk of pregnancy which falls as soon as toxaemic symptoms appear [ 191. However, a direct link between progesterone deficiency during mid-pregnancy and changes in either the renin-angiotensin-aldosterone system and/or in sodium metabolism has not yet been demonstrated. Moreover, there are other problems in trying to implicate progesterone deficiency in pre-eclamptic toxaemia. Firstly, there is apparently no consistent relationship between maternal progesterone concentration and pregnancy disorders [31]. Secondly, we know nothing about the fate or physiological effects of the extraneous progesterone, its rate of absorption, its distribution in the various anatomical compartments, or its effects on endogenous progesterone levels. Thirdly, little is known regarding the metabolic clearance rate of progesterone, although recent work suggests that its half-life disappearance from maternal plasma is only 19 min [30] . Therefore, before we can even begin to postulate a mechanism for the mode of action of progesterone in relieving the symptoms of toxaemia these points need to be clarified.

Another theoretical problem is to envisage a mechanism whereby a deficit or an excess of progesterone can respectively retard and enhance intellectual potential, since Dalton (personal communication) hypothesizes that a deficiency of progesterone causes malnutrition which damages the brain of a child of a toxaemic pregnancy whereas the administration of excess progesterone causes overnutrition resulting in an increased number of brain neu- rons. Since body weight is a good indicator of malnutrition one would ex- pect toxaemic babies to be small-for-date; however, the relationship between pre-eclamptic toxaemia and birthweight are not consistent. Fitzgerald and Clift [ 251 and Chakravorty [lo] claim that birthweight is reduced in infants

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of toxaemic mothers, whereas other authors failed to find significant differences in birthweight, head size or placental weight between toxaemic and non-toxaemic groups [4,20]. However, these negative findings and incon- sistencies between studies are probably a result of differences in the treatment of the mothers, of a lack of suitable controls and of whether the pregnancies were allowed to go to term or not. It has been suggested that reduced birthweight occurs only when the mother has severe toxaemia [8]. There is nothing to suggest that the offspring of Dalton’s toxaemic mothers were undernourished. We, therefore, conclude that the evidence for the tenet of the hypothesis that low progesterone during mid-term in pre-eclamptic toxaemia produces intrauterine growth retardation and reduced intellectual potential is, at best, equivocal. Albeit possible that progesterone deficiency could affect brain development it is extremely difficult to envisage a mechanism whereby progesterone could increase neuronal numbers, even assuming this were an index of intellectual capacity.

The exact roles of progesterone in pregnancy are still to a large extent un- known. Progesterone is known to be necessary to maintain pregnancy and in the fetus it acts as a precursor for other steroids [41]. However, it is still not clear why the placenta produces such a large amount of progesterone, a sizeable proportion of which is excreted in the maternal urine as pregnanediol, nor is the role of progesterone in fetal development, especially in the development of the CNS, clearly understood. Progesterone production in mid-pregnancy is approximately 75 mg/day, 70% of which is placental in origin, the remaining 30% coming from extraplacental sources, mainly the ovaries [ 231. During the last trimester, the production rate of the placenta in- creases to 200-300 mg/day, the major portion of which is secreted into the uterine venous blood where the concentration of progesterone is a third to twice as high as in the perinatal circulation [32] . The remainder of the placental progesterone production, approximately 75 mg/day, passes into the fetal circulation, 40% of which is taken up by fetal tissues, the remainder returning to the placenta [41]. Experiments with previable fetuses have shown that the progesterone produced by the placenta is mainly metabolized by the fetal adrenal glands to form corticosteroids, and the fetal liver to form pregnanediol and pregnanetriol [21] . Examination of the distribution of tritiated pregnanediol in the previable fetus shows that, after the liver, the brain and spinal cord are the areas which show the highest concentrations of pregnanediol [ 111, previous studies having shown a similar uptake of progesterone in these areas [ 5,441 . Moreover, in animal experiments it has been demonstrated that progesterone, pregnanediol and 3a-hydroxy-5p-pregnan-20- one, a fetal metabolite of both pregnanediol and progesterone [7], have anaesthetic properties [36] . It remains to be shown whether these steroids have a physiological effect on the fetal nervous system. While it is conceiv- able that progesterone and/or a metabolite such as pregnanediol could affect development, present evidence suggests otherwise, since there is virtually no conjugation or metabolism of these steroids in nervous tissue [ 111.

Our difficulty in envisaging a mechanism whereby extraneous progeste-

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rone might enhance the development of the central nervous system is com- pounded if we consider how, in principle, the extraneous progesterone could reach the fetus. It seems extremely unlikely that the progesterone administered to the mother, and which is rapidly metabolized in maternal blood, would have much effect on fetal progesterone concentrations since high doses of progesterone have been given to pregnant women in the past without any obvious effects (Little, personal communication). Even in the event of extraneous progesterone crossing the placenta which is already producing large quantities of progesterone, it seems unlikely that this would affect the level of progesterone in fetal tissues. Evidence suggests that fetal tissues are saturated with progesterone and that they do not have the capacity for a higher progesterone uptake [39]. Moreover, there is little experimental evidence that progesterone supplementation has any effect on placental and fetal development either in man [43] or in experimental animals [ 11. In a recent study, Bartholomeusz and Bruce [3] examined the effect of daily progesterone supplementation at various stages of pregnancy on the fetal and placental development of rats. The results showed that progesterone at five times the normal daily endogenous levels had no apparent effect on maternal weight gain, nor on myometrial, fetal or placental weights. Further- more, there is no evidence that the prenatal administration of progesterone to pregnant rats affects the biochemical and histological development of their brains, their physical development, reflex ontogeny or behavioural development [ 121 (also: Croskerry and Howarth, in preparation). Thus the weight of experimental evidence suggests that prenatal administration does not have any effect upon brain development.

A recent survey of articles published in a medical journal has shown that in a large number of them erroneous conclusions have been drawn because the statistics were unsound; especially common were errors involving the chi- square test [ 261. We suggest that this also true of Dalton’s papers on the prophylactic use of progesterone in preventing pre-eclamptic toxaemia and on the intellectual development of children exposed prenatally to progesterone. We found no differences in the incidence of pre-eclamptic toxaemia between women given progesterone and those who were treated symptomatically [ 161. Similarly, of the 21 parameters measured by Dalton [ 171 in the 9-lo-yr-olds, in only 1 case was there a statistically reliable difference between the controls and treated subjects, namely the more above average grades obtained by the early progesterone-treated group compared to the combined toxaemic and normal controls. Since 1 in 20 of the tests would be expected by chance to be significant at the 5% level, we suggest that this result is probably a chance finding. The only other significant finding was that more children in the progesterone group appeared to be standing unaided at 1 yr of age than controls; it seems probable that this too is a chance finding or is due to an unrecognized sampling bias. Finally, the results concerning the apparently greater success of the progesterone group in school- leaving examinations and in entering university are open to question. Not only are the statistics of the ‘0’ and ‘A’ level G.C.E. results invalid, but two

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highly pertinent factors in assessing further academic success, namely sex and other forms of higher education, have been ignored.

In conclusion, it has to be stated that there is little theoretical or factual support for either of Dalton’s two hypotheses: namely, that progesterone prevents the development of pre-eclamptic toxaemia, or, more importantly, that it enhances intellectual potential.

ACKNOWLEDGEMENTS

Thanks are due to Mrs. P. Lovie, Department of Mathematics, University of Keele for statistical advice.

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Documents

Prenatal progesterone II. Its role in the treatment of pre-eclamptic toxaemia and its effect on the offspring's intelligence: a reappraisal