Patient acceptance of oral contraceptives

Patient acceptance of oral contraceptives II. The private

patient

EDWARD

E.

WALLACH,

FRANCIS

M.

WATSON,

CELSO-RAMON Philadelphia,

M.D. JR.,

GARCIA,

M.D.” M.D.

Pennsylvania

Oral contraceptives were employed in a private practice for a total of 2,594 cycles over a 9% year interval. Only 40 of 126 patients discontinued medication for various reasons during the course of study. Population characteristics were compared with those of an indigent group previously studied for factors considered relevant to acceptability. Liver function studies performed serially in those patients sampled at random revealed no significant alterations of hepatic function. One patient was studied with endocrinologic assays for assessment of ovulatory parameters through her last two medicated cycles and during her first cycle after stopping medication. The safety of any new drug is confirmed through long-term usage. The reported experiences further support the safety of these progestogen-estrogen combkations. Oral contraceptives were readily acceptable and provided an effective method of family planning in a private patient practice.

of oral estrogen-progestogen combinations in the control of fertility is well documented. Variations in the degree of acceptability of these preparations have been reported among different population groups1 f The question has been raised as to whether such preparations should be prescribed for private patient populations, which in the main are able to use the “more conventional methods” of contraception effectively.“’ ’ These latter methods, however, are recognized to have lower levels of effectiveness. The matter of safety of oral preparations has deterred some individuals, both patient and physician, from their use since a cause and effect relationship between the use of oral contraceptives and the occurrence of possible serious adverse reactions cannot be ruled out with certainty. Nonetheless, it is very significant to point out that pronouncements of various official agencies state ‘I‘HE

that, to date, no cause and effect relationship can be established between use of oral contraception and serious adverse experiences.’ In a previous publication we attempted to demonstrate the acceptability of oral contraceptives among a group of American Indians, which consisted largely of an illiterate, nonEnglish speaking, indigent population in a deprived area of the United States.” The present study was undertaken to review experience with oral contraceptives in a group of private patients. Acceptability of the method and associated reactions were primarily investigated. An attempt was also made to ascertain whether the administration of these drugs imposed any threat to the patients’ health during a reasonably long course of follow-up study. Factors involved in the administration of oral contraceptives to a middle-income population were contrasted with those encountered in other population groups. No attempt is implied in stating any statistical significance because of the small size of the sampling. However, the long-term aspects are of considerable interest in this particular group in which some of

EFFICACY

From the Department Gynecology. University School of Medicine. “Present Hospital,

address: Atlanta,

of Obstetrics and of Pennsylvania

Grady Memorial Georgia.

1071

1072

Wallach,

Watson,

and

Garcia Am.

the individuals experience.

have had up to 83 cycles of

Methods

All the women included in this study consisted of private patients of one of us (C-R. G.) during a 9vz year period (March, 1956, to August, 1965). Initially, the patients received periodic clinical follow-up care, but as the group increased in size and the numbers with long-term follow-up increased, these women began to participate voluntarily in evaluations of various parameters (for example, Donayre and Pincus’ sampled the group for coagulation studies). Information initially obtained included the patient’s age, medical, gynecologic, and obstetric histories, and the date of termination and outcome of the most recent pregnancy. Oral estrogen-progestogen combinations were given primarily for fertility control and in some instances for correction of hypermenorrhea or dysmenorrhea. Medication was provided without cost, and participation required only the keeping of accurate records. Such records included for each cycle the days on which medication was taken; dates, duration, and quantity of menstrual flow; coital frequency; periodic recordings of body weight; and any associated reactions. A standard medication form was used, on which no leading qurstions appeared. Instead, associated reactions could be listed in a column simply labeled “Remarks.“ At the time medication was initiated, each patient was informed that the common associated reactions were most nausea and breakthrough bleeding and weight gain. At the initial visit and all subrxaminasequent visits, a general physical tion, including pelvic examination and Papanicolaou smear, was performed. Blood was collected for liver function and hematologic studies at periodic intervals at random. Medications used, supplied by Dr. William Stewart of G. D. Searle Pr Company, were as follows: Enovid 2.5 mg.,* Enovid 5 mg.,? “Norethynod%cl esttadiot J-methyl Company. tNorethynodrel Searle s( Company.

2.5 m.~. with cthel (mestranol), 5.0 mg.

with

0.075

0.10 G. mg.

mg. oi ethinyl D. Searle &

mestranol,

G.

D.

August 15. 1967 J. Obst. & Gyner.

Enovid 10 mg.,* Ovulen 0.5 mg.,t and Ovulen 1.0 mg.$ Each formulation was administered cyclically from day 5 through day 21 of the menstrual cycle. Sufficient medication and records for two or three cycles were given to each patient initially, and additional medication and records were distributed at the office, or in some instances by mail. Patients were encouraged to phone the office with regard to advice in the event of difficulties with the medication or development of associated reactions. All patients \vcrc advised that they would be excluded frorn the study if they failed to cooperate in record-keeping. With all dropouts, an attempt was made to determine the reasons for discontinuing medication. Results

Over the course of the study 126 patients received oral contraceptives for a total of “Norctbynodrrl Sea,lr & Company. G.

tEthyrrodin1 D. Searlr

G.

SEthynodiol D. Sea&

Table

9.85

mg.

diacetate & company. diacetate & Company.

with

0.15

mg.

mcstranol,

(Z. D.

0.5

ms.

with

mestranot

0.1

111s..

1.0

mg.

with

mestranol

0.1

ms..

I. Age distribution Years

No.

< 20

3 39 37 17 10 7

20-24 25-29 30-34 35-39 > 39 Average Range Unknown

Table

II. Past obstetric

Gravidity 0 1 2 3 4 >: Not recorded Average

No. of patients 43 11 13 23 11 5 3 17 1.83

27.4 18-51 13

experience Parity 0 1 2 3 4 >5 Not recorded IAverage

No. of patients 46 15 ‘1‘I ii 19 3 0 17 1.45

Volume Number

98 8

Acceptance

2,594 cycles. Patients ranged in age from 18 to 51 years, with a mean age of 27.4 years (Table I). The number of previous pregnancies per patient averaged 1.83 and the mean number of living children per patient was 1.45 (Table II). There were 43 nulliparas (34 per cent) in the series. The number of cycles per patient averaged 20.6 with a range of 1 to 84 cycles (Table III). Twenty

Table III. Distribution of patients number of cycles completed No.

cycles

of

completed

No.

(

Total

Table

by

18 26 14 19 22 9 8 7 1 1 1 126

2,594

IV. Reasons

for discontinuing

Relevant to the method Objective changes Weight gain Headache Breakthrough bleeding Abdominal pain Mastalgia Subjective Desired “Tired

feelings IUCD of taking

Not revelant to the method Changed physician Moved Desired pregnancy Husband going away

3.

No

12

given

Totals *Seven

continued

tOne

continued

SThree

resumed

medication. medication. medication

after

of dropouts

%

of

dropouts

% of total

30

9.5

50

15.9

pill”

2.

reason

1073

oral contraceptives No.

1.

contraceptives

patients began medication within the first 2 postpartum months, and 32 within the first 6 months following pregnancy. Only one woman nursed her infant, but continued to do so without difficulty for 8 months while on medication. During the 9yz year period of study, 40 women (31.7 per cent) discontinued medication. In most instances the reasons for discontinuing were not considered relevant to the method itself. Five women discontinued medication in order to establish pregnancy, 7 patients moved to a different area; 7 patients transferred to the care of another physician; and in one instance the patient’s husband left for a protracted period of time. Twelve of those individuals leaving the study discontinued for reasons deemed relevant to the method, and 8 women discontinued but were unable to provide a reason for doing so (Table IV). Breakthrough bleeding and nausea comprised the most common associated reactions. The former occurred in 77 patients (61.1 per cent) during 370 cycles; however, 24 of

of patients

l-5 6- 10 11-15 16 - 20 21- 30 31-40 41- 50 51 -60 61 -70 71 -80 > 80

of oral

completion

of pregnancy.

8

20

40

100

6.3 _.. 31.7

1074

Wallach,

Watson,

and

Garcia

these women experienced breakthrough bleeding only once, and 64 of these episodes occurred during the first two cycles of therapy. Breakthrough bleeding was given as a reason for discontinuing medication only once. A history of nausea was elicited in -1-O

Table V. Weight oral contraceptives

change

among

patients

1-4 5-9 10 - 19 > 19 Total

29 21 12 -_____ 3 65

16 9 3 3

26.8 195 11.1 2.8 .---~__

14.8

31

60.2

28.7

‘Awage gain amtln~ patients gaininq punds; avCl age loac among patirnts Iminx pounds; awl-age wright change per patient, change,

12

patients;

insufficient

Table VI. Associated oral contraceptives

data.

Pntients /

Breakthrolrgh bleeding Nausea Mastalgia Amenorrhra Dysmenorrhea Headache Edema

Table VII. Hemoglobin contraceptives Cycle

(No.

370 85 56 21 53 50 14 2' 8 2 6

Hemoglobin of determinations)

13-24 25 -36 37-48 49-60 61-72

16 11 7 1 2* same

patients.

on

and hematocrit

19 24

on

8.3 2.8 2.8

Cycles

Control l-12

determinations

18

patient.

in

one

wornan

who

gained

34

pounds. Seven patients experiencing weight gain also developed demonstrahle edema which undoubtedly contributed to the inocmcnt in weight. Three women discontinued medication. All associated reactions are included and tabulated for incidence in ‘l’able VI. No significant alterations were noted in either hemoglobin or hematocrit values during the course of follow-up (Table VII 1. Furthermore, thymol turbidity, alkaline phosphatase. and SGOT values carried out at \.arying intervals through 81 cycles at random indicated no significant alteration in these liver function studies (Table VIII j durin,g the course of follow-up. There we~.e slight increases in the mean SGOT values with duration of Enovid administration. These changes. however, were nrither statistically significant nor in the abnormal range. One patient receiving Ovulen had an SGOT value of 105 units after 2J/2 months of treatment, hut hoth thymol turbidity and alkaline phosphatase levels were within normal

% ----x77--% 61.1 31.7 15.1 9.9 7.2 5.6 5.6 4.0 1.6 1.6 1.6

Bloating Nervousness Dizziness Irritability

occurred

wright. ti.5 weight, 6.2 +?.7 pound\.

effects while

No.

*Both

on

Percentage No. of @tient.r+ _______-of fiatients .___-___ Gaining \ Losing Gaining 1 Losing

Weight range* (pounds)

*No

of the 126 patients during 85 cycles and occurred during the first cycle in 30 instances. Nausea was not a reason for discontinuing oral contraceptives in this group of women. Weight change was tabulated in 5 pound increments or decrements. Twclvc women i 11.1 per cent) csperienced no weight change, while 65 (60.2 per cent i patients gained weight, and 31 I 28.7 per cent) women lost weight. Average weight change per patient was t2.7 pounds (Table VI. The most extreme degree of weight gain

14.3 3.3 2.2 0.8 2.0 1.9 0.5 0.8 0.3 0.08 0.2

values

in patients

Le7tel (chC%*)

(No.

receiving

oral

Hematocrit of determinations)

I

Level (G)

13.4

15

39.3

13.6 13.5 13.3 13.0 13.0 12.7

24 16 10 7 3 2*

40.2 40.2 40.3 40.3 39.7 41.0

Volume Numhc~

98 8

Acceptance

limits (0.7 MacLagen units and 2.6 sigma units, respectively). Alkaline phosphatase levels of 1.1 sigma units in one woman during her sixth cycle of Ovulen and 1.2 sigma units in another after 42 cycles of Enovid were reported. There was no other indication of hepatic impairment in either of these women, and in both patients the alkaline phosphatase levels returned to normal when the test was repeated, All other values for alkaline phosphatase and all thymol turbidity results fell within the range of normal. All Papanicolaou smears were reported as normal (Class I or Class II) during the period of observation. Of considerable interest in the present series is the course of several patients whose medical problems antedated initiation of contraceptive administration. One woman with known multiple sclerosis displayed no apparent effect on the course of her disease either in the form of progression, exacerbation, or amelioration. Diabetes mellitus was detected in one obese patient with a strong family history during an interval that she discontinued medication. There had been no indication of glycosuria during her last fullterm pregnancy 2 years earlier, but she experienced two spontaneous abortions after

Table VIII.

Liver

function

studies

during

of

oral

contraceptives

1075

medication had been suspended and during which time the diagnosis of diabetes was confirmed by an abnormal glucose tolerance test. She resumed medication and the diabetes was readily controlled with a combination of diet and oral hypoglycemic agents without any detectable effect on the diabetes. A 51-year-old woman who had a history of varicose veins and two episodes of thrombophlebitis ( 1949, 1960) was begun on Enovid for hypermenorrhea secondary to a mild cndometrial hyperplasia confirmed by biopsy and curettage. Thrombophlebitis recurred after 2 months of medication. Following suspension of Enovid administration, she was treated with venous ligation and a course of anticoagulant therapy. Four months after the episode had subsided she resumed Enovid with no concomitant ill effects. One of the long-term users in the study provided a unique opportunity for the investigation of ovulatory suppression during oral contraception and prompt return of ovulation on suspension of treatment. Twenty-four hour ur!ne specimens were collected and vaginal smears were performed daily. Daily basal body temperatures were recorded by the patient during her last two cycles of Enovid 5 mg. (cycles No. 7 1 and

long-term

administration

of oral

contraceptives Thymol

Cycle NO.

No.

Control

25

Enovid l13 25 37 49 61 73

12 -2-t - 36 -48 - 60 - 72 - 84

6 6 8 6

Ovulen l-6 7- 12 13-24 25 - 36

turbidity*

1 Range

SGOTf

IMean

S.D.

0.3 - 4.0

0.8

0.73

0.2 0.5 0.3 0.5

0.9 0.6 1.0 0.7

0.9 0.2 0.6 0.2

-

2.9 1.0 2.9 1.0

1

0.5

0.5

8 4 7 2

0.2 - 1.6 0.5 - 1.5 0.5 - 2.7 0.5

0.7 0.8 1.3 0.5

“Normal

values

are

0.4

tNrxma1

values

are

10 to 40

to 4.0

Katmen

$Nc~zmal

valurs

are

1 to

Sinma

3.5

1 No.

0.4 0.4 0.8

Machqan

units units

unit<

per per

per

S.D.

1 No

6 - 44

16.7

7.5

48

7 6 8 6 2

4-32 10 - 26 10 - 38 8 - 38 18 - 37

16.9 15.3 21.2 21.7 27.5

7.2 4.9 10.2 10.5 9.5

2

14-37

25.5

9 9 5 2

8 10 412 -

25.9 24.2 16.8 15.0

millilitr~.

miIlilitt~r. milliliter.

Alkaline ) Mean/

48

1 Range

105 38 28 18

phosphatase$

I Range

IMean

S.D.-

0.7 - 3.8

1.6

0.7

7 7 0 6 2

0.6 0.6 0.5 1.0 1 .o

2.2 2.2 2.4 4.2 2.4

1.4 1.4 1.8 3.3 1.7

0.5 0.5 0.5 1.1 0.7

9.5

2

1.2 - 1.5

1.4

0.2

28.5 7.6 7.1 3.0

9 9 9 2

0.5 0.8 0.8 1.5

1.9 1.3 1.6 1.6

0.9 0.2 0.5 0.1

-

-

4.1 1.6 2.5 1.7

1076

Wallach,

Watson,

and

Garcia Am

No. 72) and during her first postmedication cycles (Fig. 1). During medicated cycles No. 71 and No. 72, estrogen and pregnanediol excretion levels were diminished, the basal body temperature graph was monophasic, and no peak in superficial vaginal cells could be noted. It is noteworthy that estradiol and estriol were frequently undetectable in the urine during the two medicated cycles stud-

August 15, 1967 J. Obst. & Cynrc.

ied. During her first cycle off medication in over 5 years, the indirect indices of ovulatory activity indicated an increase in urinary estrogens, a significant elevation in pregnanediol excretion, a peak in superficial cells, and a suggestive thermal shift in the basal body temperature pattern. Of the 5 women who discontinued medication in order to establish a pregnancy, 4

Day of Inv,estLgatLon Fig. 1. Endocrine evaluation second cycles of medication those days on which Enovid

of a long-term Enovid user during the seventy-first and during the first postmedication cycle. The shaded was taken.

and seventyareas define

Volume Number

98 8

Table No.

Acceptance

IX.

Coital

of

exposures

exposure

per month 1-4 5-9 IO- 15 > 15 No record or none

Total

per month No. of patients 18 48 16 1 43 126

conceived within 4 months. Three of the patients were delivered of normal full-term infants, while the fourth is the previously discussed patient with diabetes mellitus. Follow-up information is lacking in the fifth woman in this group who has changed her residence without leaving a forwarding address. No pregnancies occurred in any patient while receiving oral contraceptives. Frequency of coital exposure of these patients did not appear unusual (Table IX). Comment In the past decade estrogen-progestogen combinations for oral contraception have achieved widespread use. Effectiveness of oral agents in the prevention of conception has proved to be manyfold greater than that of methods frequently employed prior to their advent. The most prominent factors leading to contraceptive failure with the oral agents at present seem to be limited to the level of motivation and degree of acceptability of the patient involved. Skepticism as to long-term effects of these agents among some physicians and the public has also limited the extent of their usage. It has been suggested that oral contraceptives, although of exceedingly high effectiveness, should be deferred for the more conventional methods among certain groups of people, specifically those individuals sophisticated enough to be able to attain the maximum degree of reliability with local methods3. 1 Experiences in the present study dealing with oral contraception among private patients compare with the previously published series based largely upon observations with a clinic or indigent population. All of these

of oral

contraceptives

1077

women had completed high school, and most had attained a minimum of one year’s college education. Although the average age of the present group is similar to that reported in of nulother studies,‘, s, D a high proportion liparas (36.5 per cent) is included in this series. As a result, the over-all average of previous pregnancies per patient (1.83) contrasts with our earlier report concerning the American Indian6 in which was cited a figure of 5.9 previous pregnancies per patient as well as with other studies in which this figure ranged from 3.8 to 5.3.‘~ I”, 11, I” Proved fertility may have been a prerequisite for participation in some earlier investigations which were concerned mainly with contraceptive effectiveness,‘, ‘-Ii but was not considered a requirement in the present study. Furthermore, patients with recently terminated pregnancies comprised only a small proportion of our group, whereas other studies have included large numbers of women whose oral contraception was initiated at the time of their postpartum visit. Only one woman in the present report was lactating during the course of treatment. This population may therefore be characterized as consisting of a closely supervised group of women having had considerable educational advantages, of low parity, or nulligravid, and in general, not recently pregnant. Transportation, communication, and follow-up presented no major obstacles in treating these patier.ts, all of whom were readily able to return periodically for examination and medication In the light of these considerations, of significant interest are: ( 1) the low incidence of patient dropouts in the first several cycles of administration and (2) the absence of any pregnancies during 2,594 cycles of use. Under the most favorable conditions, extrapolating from accepted contraceptive failure rate figures,” the numbers of pregnancies which might have been anticipated over a comparable period of time with the vaginal diaphragm and jelly or condom, for example, would have been in the range of 10 to 20 and upward of 28 pregnanctes with the standard calendar rhythm method.

1078

Wallach,

Watson,

and

Garcia

A multitude of factors may be responsible for differences in the frequency of associated reactions which vary from one group of patients to another. General conclusions rcgarding side effects cannot be drawn from experiences within a single group. For esample, weight loss was experienced more frequently than weight gain among American Indians using Enovid,” and nausea and breakthrough bleeding were also of minor consequence in this same group of patients. In comparison, in the present series weight gain was experienced more often than weight loss and nausea and breakthrough bleeding were noted to a somewhat greater extent. This higher incidence of associated cornplaints in the private patient may reflect numerous and diverse features including among others: conscientiousness in recording such details, a less impersonal physicianpatient relationship in which the patient is not hesitant to reveal discomforting side effects, a sophisticated awareness of potential effects, anticipation of associated reactions because of the pretreatment discussion, and a possibly lowered threshold for discomfort. The entire subject of side effects and their varying manifestations in different groups is highly speculative. The assessment is not only very complex but also would require considerable study through rigidly controlled investigations. The minor influence of associated effects on patient acceptance in the present study may be inferred from the low dropout rate, especially in the initial cycles when maximum incidence of breakthrough bleeding and nausea seem to occur. Moreover, a high level of motivation probably plays a considerable role in the degree of tolerance of these reactions exhibited by the private patient. The absence of significant alterations of liver function studies and lack of evidence of hepatic impairment corroborate the experiences in Haiti and Puerto Rico which included patients with over 50 cycles of use.‘” Reversible jaundice of a cholestatic type, however, has been reported in association with use of an estrogen-progestogen combination ( Lyndiol) .I” Furthermore, Eisalo,

Jarvinen, and Luukkainen” reported abnormalities in hepatic function studies ( BSP. transaminasr j in postmenopausal women receiving the same agent. Thcsc studies wen’ subsequently carried out ag-ain by Eisalo. Jarvincn, and Luukkainrn” in women of reproductive age, and although occasional abnormal results occurred, there was no e\,idencr to suggest impairment of liver function. These authors concluded that ;~CC itself may have exerted an influence in producing abnormal liver function results.” although Bakke’s figures’!’ failed to support the concept that menopausal women eshibit peculiar hepatic sensitivity to mcstrano1 or to norethynodrel. Recent studies confirm the opinion that oral contraceptives cause little or no impairment of hepatic function,‘“, “ll-L1:! Endocrine assays* performed during the sixty-ninth and seventieth cycles of Enovid administration did suggest some suppression of gonadotropin and estrogen excretion dut,ing the use of the oral contraceptives. ‘I’ht prompt resumption of ovulation even after, long-term suppression. clinically apparent from pregnancies which are frequently established shortly after termination of oral COIItraception, is endocrinologically documented in this sequence of studies. Considerations affecting the use of an oral contracepti1.e and its mode of administration among an indigent group of American ltrdians in an underdeveloped area were c’mphasized in our previous publication.” At that time it was indicated that in spite of language barriers and the lack of proximity and accessibility of the clinic, oral contraceptives wcrc readily acceptable and employed with favorable results. Similar obstacles were not encountered in the present group of private* patients. A strong motivation for effective fertility control. a willingness to participate in research endeav.ors. and enthusiastic acceptance of oral contracepti\.(3 were prominent featttres in these women.

Acceptance

of

oral

contraceptives

1079

REFERENCES

E. T., Olson, H. J,, Wolf, L., Finkel1. Tyler, stein, S., Thayer, J., Kaplan, N., Levin, M., and Weintraub, J.: Obst. & Gynec. 18: 363, 1961. Baird, D.: Brit. M. J. 2: 1141, 1965. Editorial: Obst. & Gynec. Surv. 15: 411, 1961. Editorial: Obst. & Gynec. Surv. 17: 164, 1962. Clinical Aspects of Oral Gestogens, World Health Organization Technical Report, Series No. 326, Geneva, 1966, World Health Organization. Wallach, E. E., Beer, A. E., and Garcia, C-R.: 24~. J. ‘&ST. & GYXEC. 97: 984, 1967. Donayre, J,, and Fincus, G.: Metabolism 14: 418, 1965. Tyler, E. T.: Brit. M. J. 2: 843. 1964. Goldzieher, J. W., Becerra, C., Gual, C., Livingston, N. B., Jr., Maqueo, M., Moses, L. E., and Tietze, C.: Ant. J. &ST. & GYS~C. 90: 404, 1964. 10. Rice-Wray, E., Schulz-Conteras, M., Guerrero, I.. and Aranda-Resell, A.: J. ,4. M. A. 180: 355. 1962.

11. 12. 13. 14. 15.

16. 17. 18. 19. 20. 21. 22.

Goldzieher, J. W., Moses, L. E., and Ellis. L. T.: J. A. M. A. 180: 359, 1962. Rovinsky, J. J.: Obst. & Gynec. 23: 840, 1964. Mears, E., and Grant, E. C. G.: Brit. M. J. 2: 75, 1962. Pullen, D.: Brit. M. J, 2: 1016, 1962. Garcia, C-R., Pincus, G., Rocamora, H.. and Wallach, E. E.: In Proceedings of the Sixth Pan-American Congress of -Endocrinology, Mexico Citv. 1965. Amsterdam. 1966. Excerpta Mediia FouAdation, p. 191. ’ Cullberg, G., Lundstrom, R., and Stenram. V.: Brit. M. J. 1: 695, 1965. Eisalo, A., J&inen. P. A., and Luukkainen, T.: Brit. M. 1. 2: 426. 1964. Eisalo, A., J&vinen,‘P. A., and Luukkainen, T.: Brit. M. J. 1: 1416, 1965. Bakke, J. L.: Brit. M. J. 1: 631, 1965. Swyer, G. I. M., and Little, V.: Brit. M. J. 1: 1412, 1965. Larsson-Cohn, U.: Brit. M. J. 1: 1414, 1965. Linthorst, G.: Brit. M. J. 2: 920, 1964.