A changing pattern in the association of oral contraceptives and the different groups of congenital limb deficiencies.

A case-control study on different groups of isolated congenital limb deficiency was performed in a ten-year population-based and revised Hungarian data set. A higher rate of one contraceptive pill type with relatively high dose (ethynodiol diacetate 1.0 mg + ethinyloestradiol 0.05 mg) used in the periconceptional period was found in the mothers of cases with terminal transverse defect (adjusted relative odds 1.9 with 95% confidence interval of 1.1-3.4). This risk is minimised by the use of recent low-dose pills.

PIP: In Hungary, researchers analyzed 1975-1984 population-based and revised data on 537 children with isolated congenital limb deficiency (CLD) (i.e., cases with at least 1 affected limb) and data on 537 age-matched controls with no CLD. They wanted to determine the association between periconceptional use of oral contraceptives (OCs) and CLD. Personal examination and/or medical documents confirmed reported diagnoses. They separated the isolated CLD cases into terminal transverse CLD, amniogenic CLD, radial and tibial CLD, ulnar-fibular CLD, split hand and/or foot CLD, and intercalary CLD. Periconceptional use of Bisecurin (relatively high dose of 1 mg ethynodiol diacetate and 0.05 mg ethinyl estradiol) was significantly associated with terminal transverse CLD (adjusted odds ratio [AOR] = 1.9; p = 0.03). It was also significantly associated with monomelic CLD (AOR = 1.6; 9.6% vs. 2.9%; p = 0.0015). The monomelic cases comprised 19 terminal transverse cases, 6 amniogenic cases, 7 radial cases, 3 atypical split hand cases, and 2 ulnar cases. 19 of the 20 terminal transverse cases were monomelic. Periconceptional use of Continuin (0.5 mg ethynodiol diacetate alone) was associated, but not significantly so, with terminal transverse CLD (6 cases vs. 1 control; p = 0.06). These findings suggest that use of OCs with a high dose of ethynodiol diacetate increases the risk of terminal transverse defect. Use of low dose OCs likely minimizes this risk.

[An unusual case of intercalary type of limb abnormalities]. / A végtaghiányos rendellenesség-csoporton belüli intercalaris típus szokatlan esete.

Authors report about a case of total lack of middle phalanxes on the 3d and 4th fingers and a hypoplasia of the surrounding phalanges on the left hand. This is the first report on this type of intercalary type in congenital limb deficiency group. They call attention to one of the so far not sufficiently emphasized hazard of previous periconceptional oral contraceptive use. If there is not enough time left for the total regeneration after the discontinuation of contraceptives, such kind of malformation may develop in the fetus due to the insufficiency of fetal-placental circulation.

Efficacy and safety of ethynodiol diacetate, 1 mg, with ethinyl estradiol, 35 micrograms, with an emphasis on contraceptive efficacy. A phase IV trial.

A phase IV trial evaluated the efficacy and safety of a monophasic oral contraceptive formulation, ethynodiol diacetate, 1 mg, plus ethinyl estradiol, 35 micrograms (EDA 1 mg with EE 35 micrograms) (Demulen 1/35). Nine hundred eighty-three community-based obstetrician-gynecologists treated a total of 7,759 patients with EDA 1 mg with EE 35 micrograms for one to eight months. Clinical evaluation forms on 6,382 patients were amenable to analysis for safety (including breakthrough bleeding, ovarian cyst formation and complexion changes); 5,412 patients were evaluable for efficacy (prevention of pregnancy), with a total of 21,440 cycles recorded. The study results were interpreted in terms of the impact on clinical management of oral contraceptive users and the methods, strengths and weaknesses of phase IV trials, particularly as they relate to confirmation of the results reported here.

PIP: From August 1988-June 1989, 983 physicians participated in a phase IV trial by following 7759 women using the monophasic oral contraceptive (OC), Demulen 1/35 (1 mg ethynodiol diacetate and 35 ug ethinyl estradiol) to evaluate its efficacy and safety. The total number of cycles for the study stood at 21,440. In addition, the total woman-years stood at 1787. Only 6382 patients could be evaluated for safety. 4.4% of the patients had adverse reactions to the OC, but only 1.7% of all patients stopped taking it. The leading side effects included nausea (67 cases), headache (45), amenorrhea (42), emotional changes (30), breast pain (19), dysmenorrhea (12), and 11 cases of weight gain, abdominal/pelvic pain, and bloating. Of the 280 reported adverse reactions, only 87 (31%) were considered severe. The leading serious adverse reactions were depression (10) and hypertension (6). Only 5412 patients could be used to determine efficacy. The physicians initially reported 121 (2.2%) pregnancies during the study. The researchers learned that 33 of the 84 returned 2nd questionnaires (response rate, 70%) reported that the women conceived after enrollment but before taking the OC. 36 conceived while taking it, but 8 did not take it daily. Noncompliance may have contributed to pregnancy for the remaining 28 cases. Therefore the 36 confirmed pregnancies made for a failure rate of .7%. 85.7% of the pregnancies happened in the 1st 3 months of taking the OC. Either patient noncompliance or true medication failure accounted for treatment failure. Therefore it is important for physicians to instruct patients on how to take OCs correctly.

Incidence of breakthrough bleeding during oral contraceptive therapy.

A phase IV, open-label, multicenter survey of 983 obstetrician-gynecologists was conducted to evaluate the incidence of intermenstrual bleeding in 6,382 women receiving a low-dose monophasic oral contraceptive, ethynodiol diacetate, 1 mg, with ethinyl estradiol, 35 micrograms (EDA 1 mg with EE 35 micrograms) over a six-month period. Most patients (75%) did not experience intermenstrual bleeding during therapy. Follow-up questionnaires were sent to the physicians of the 1,526 women reporting breakthrough bleeding or spotting; 1,027 follow-up questionnaires (67%) were returned. The questionnaires revealed that approximately one-fifth of the patients were placed on EDA 1 mg with EE 35 micrograms to regulate preexisting bleeding; of them, 71% reported an improvement, 13% reported worsening, and 16% reported no change in their cycle regularity. Most breakthrough bleeding or spotting (91%) occurred in the first three months of therapy in women with preexisting irregular bleeding as well as in those using the oral contraceptive solely for birth control. Although a fair proportion of women experienced intermenstrual bleeding, very few (5.1%) discontinued therapy because of it. Thus, the study demonstrated that the incidence of breakthrough bleeding and spotting appears to be within or below the range reported for other monophasic and multiphasic oral contraceptives. Further, in agreement with previously published reports, the data suggest that cycle control will improve after three months of oral contraceptive use.

Complexion changes in oral contraceptive users. Results from a phase IV multicenter trial evaluating the safety and efficacy of ethynodiol diacetate, 1 mg, with ethinyl estradiol, 35 micrograms.

An open-label, phase IV, multicenter survey of obstetrician-gynecologists was conducted to evaluate the efficacy and safety of a low-dose monophasic oral contraceptive, ethynodiol diacetate, 1 mg, with ethinyl estradiol, 35 micrograms. Surveys from 983 community-based physicians reported on 6,382 women. Most patients did not experience "clinically noticeable complexion changes" (5,695/6,382, or 89.2%). Of the 687 patients with complexion changes, nearly three-fourths reported an improvement (501/687, or 72.9%). A follow-up questionnaire was sent to 127 respondents (18.6%) who reported worsening of the complexion; 70% of the questionnaires were returned. Most complexion worsening was of slight degree (63%), reported by the patient and not the physician (84% vs. 16%), and experienced during the first two to three months (84%). Although the literature includes many references to skin condition "improvement" on oral contraceptives, this report of a descriptive study gives clinicians as estimate of the incidence and severity of complexion changes in actual use.

PIP: An open-label, phase IV, multicenter survey of obstetrician-gynecologists was conducted to investigate the efficacy and safety of a low-dose monophasic oral contraceptive (OC), ethynodiol diacetate, 1 mg, with ethinyl estradiol (EE), 35 mcg. Surveys from 983 community-based physicians reported on 6382 women, most of whom did not experience "clinically noticeable complexion changes" (5695/6382 or 89.2%). Of the 687 who did, nearly 3/4 reported an improvement (501/587 or 72.9%). A followup questionnaire was sent to 127 respondents (18.6%) who reported worsening of their complexions; 70% of the questionnaires were returned. Most had a slight degree of complexion worsening (63%) as reported by the patient and not the physician (84% vs 16%), and these changes were experienced during the 1st 2-3 months (84%). Although the literature includes many references to skin condition improvement while taking OCs, this report of a descriptive study gives clinicians an estimate of the incidence and severity of complexion changes during actual use. (author's modified).

Incidence of ovarian cyst formation in women taking ethynodiol diacetate, 1 mg, with ethinyl estradiol, 35 micrograms.

A total of 7,759 women were treated with ethynodiol diacetate, 1 mg, with ethinyl estradiol, 35 micrograms (EDA 1 mg with EE 35 micrograms) in a field study involving 983 obstetrician-gynecologists evaluating the incidence of ovarian cyst formation. Six thousand three hundred eighty-two patients were evaluable; 1,377 could not be evaluated because of failure to meet inclusion criteria or inconsistent or incomplete data collection. Cysts were detected in 80 patients at the time of the final visit. Follow-up questionnaires were received on 61% of patients and confirmed the presence of 12 newly formed ovarian cysts in patients taking EDA 1 mg with EE 35 micrograms. Only three women required an operation for ovarian cysts; two women had functional ovarian cysts (one follicular and one luteal), and one had a neoplastic cyst (cystadenoma). Thus, the incidence of ovarian cyst formation requiring surgical intervention was 0.05% in women taking EDA 1 mg with EE 35 micrograms.

Oral contraception: a review.

PIP: This review of the development of oral contraceptives (OCs) begins with a summary of research between 1920 and 1950 that led to the first highly effective, orally active progestogen for human use. Enovid by Searle, the first marketed OC, began being distributed in 1960; it was combination of 9.85 mg of norethynodrel and .150 mg of mestranol. Research on combination norethynodrel-containing products revealed that the dosage was too high. Discussion focuses on preparations containing norethisterone, norethisterone acetate, medroxyprogesterone diacetate, norgestrel, other Norgestrel products available outside the US, progestogen, as well as the sequentials and the multiphasics. The active phase of clinical development was during 1950s and 1960s. The Food and Drug Administration (FDA) had an active role in regulating OCs; OCs with more than .05 mg of estrogen were removed from the market; FDA permitted ethinyl estradiol as a substitute for mestranol. Pregnancy rates appear lower in clinical trials than among the general population. 3% during the first year is considered more characteristics of the failure rate among the general population. It appears that intermenstrual bleeding (IMB) has decreased as doses have been decreased, but strict comparison between studies and over time is not possible. There is valid documentation of the rate of IMB with low-dose OCs, or of differences between new OC users and prior OC users, or of the impact of the strength of OC components.^ieng

Clinical experience with the progestogen-only pill.

Experience with the progestogen-only pill (POP) in a family planning clinic is presented. From the clinic records, 408 women were identified who had opted to use a POP. Of these, 50 women had used the POP during lactation and these were excluded from the analysis. The remaining 358 women used the POP for up to 150 months, giving a total of 18,125 women-months of use. Three pregnancies occurred, giving a Pearl Index of 0.2 per 100 women-years. Non-menstrual side effects were minor and were reported by 77 women. For the women who discontinued the POP, the main reason was menstrual irregularity (47.5%). However, despite the long-term use by most of the women, almost 40% maintained a mostly regular menstrual pattern. Our findings suggest that the POP provides a very acceptable method of oral contraception for many women and that it should be more actively promoted.

Exacerbation of adenomyosis symptomatology by estrogen-progestin therapy: a case report and histopathological observations.

The present case report illustrates the hormonal sensitivity of adenomyosis. Administration of an estrogen-progestin combination for what was felt to be symptomatic endometriosis resulted in exacerbation of symptoms and growth of adenomyomas. Histopathologic examination of the hysterectomy specimen revealed a pattern of decidualization previously unreported, but consistent with current theories of experimental in vivo and in vitro decidua formation.

PIP: A 32 year old woman underwent exploratory surgery because she had severe dysmenorrhea, the physicians found fibroids, and they excised pelvic endometriosis. 1 year later, she sought the assistance of the Center for Fertility and Reproductive Endocrinology at the Columbia Hospital for Women in Washington, D.C. because of continual dysmenorrhea and pain. A physician at the center treated her with Ovulen, a continuous estrogen/progestin therapy, yet her pain worsened. Upon a pelvic reexamination 16 months later, a physician noted a tender, enlarged, and irregularly shaped uterus (16 cm from fundus to cervix and 726g). Further, pelvic sonography detected multiple leiomyomas, 1 being 9x7 cm. The physician did a laparotomy to perform a myomectomy and therefore preserve fertility, but could not establish cleavage planes. Thus she needed to undergo a hysterectomy. Pseudodecidualized adenomyotic islands were found in the enlarged posterior myometrial wall. The results of this woman's use of Ovulen are similar to previous research on prostaglandins' role in which they act as intermediaries in decidual metaplasia. This case report affirms that progestins do not treat adenomyosis and cause significant exacerbation of its symptoms. Based on previous research and this case, the author believes that an undefined luminal component and progestin stimulation causes development of a decidual response in the uterus. Once the stimulus is defined, be it chemical, infectious, or mechanical, researchers could identify other approaches for the symptomatic relief of this debilitating and difficult to diagnose ailment.

Clinical experience with ethynodiol diacetate 0.5 mg daily as an oral contraceptive.

Femulen, a progestogen only oral contraceptive (ethynodiol diacetate 0.5mg), was evaluated for its contraceptive efficacy and safety in 425 women aged between 16 and 47 years. This was a multicentre open study carried out in General Practice and Family Planning clinics. Five pregnancies were reported, three of which were a result of patient failure. The net pregnancy rate at one year for method failure was 0.5%. No ectopic pregnancy was reported. The median length of the menstrual period was between four and five days and the average length of the non-bleeding interval remained between 24 and 25 days throughout the study. Blood pressure on the whole remained within normal limits. However, there was a small decrease in both systolic and diastolic blood pressure which did not reach significant levels. Body weight was unaltered and no abnormality was found in cervical smears. Femulen was shown to be an effective and acceptable contraceptive in women of varying ages.

PIP: Femulen, a progestogen only oral contraceptive (ethynodiol diacetate 0.5mg), was evaluated for its contraceptive efficacy and safety in 425 women aged between 16 and 47 years. This was a multicenter open study carried out in General Practice and Family Planning clinics. 5 pregnancies were reported, 3 of which were a result of patient failure. The net pregnancy rate at 1 year for method failure was 0.5%. No ectopic pregnancy was reported. The median length of the menstrual period was between 4 and 5 days and the average length of the non-bleeding interval remained between 24 and 25 days throughout the study. Blood pressure on the whole remained within normal limits. However, there was a small increase in both systolic and diastolic blood pressure which did not reach significant levels. Body weight was unaltered and no abnormality was found in cervical smears. Femulen was shown to be an effective and acceptable contraceptive in women of varying ages.

Progestins and oral contraceptive-induced lipoprotein changes: a prospective study.

In order to determine the effects on plasma lipoproteins of oral contraceptives containing progestins with varying androgenic potency, 136 healthy women were randomized into 3 groups and followed prospectively for one year while receiving either 50 mcg ethinyl estradiol and 1.0 mg ethynodiol diacetate (EED), 50 mcg ethinyl estradiol and 1.0 mg norethindrone acetate (ENA), or 50 mcg ethinyl estradiol and 0.5 mg d-1 norgestrel (ENG). Comparison was made to a self-selected group of 50 women using alternative means of contraception. Plasma cholesterol increased by 7-9% and triglycerides by 32-57% in all 3 groups (p less than 0.05). ENG use resulted in other significant lipoprotein changes including an 18% increase in low density lipoprotein cholesterol (LDL-C), a 13% fall in high density lipoprotein cholesterol (HDL-C) and a 27% decline in HDL2 cholesterol (HDL2-C) (p less than 0.05). Apoprotein A-I (Apo A-I) increased by 9% with ENA and by 11% with EED (p less than 0.05), but did not change significantly with ENG. This prospective study demonstrates that in oral contraceptive agents with identical estrogen, progestins with different androgenic potency produce major and different changes in plasma lipoproteins.

PIP: In order to determine the effects on plasma lipoproteins of oral contraceptives containing progestins with varying androgenic potency, 136 healthy women were randomized into 3 groups and followed prospectively for 1 year while receiving either 50 mcg ethinyl estradiol and 1.0 mg ethynodiol diacetate (EED), 50 mcg ethinyl estradiol and 1.0 mg norethindrone acetate (ENA), or 50 mcg ethinyl estradiol and 0.5 mg d-1 norgestrel (ENG). Comparison was made to a self-selected group of 50 women using alternative means of contraception. Plasma cholesterol increased by 7-9% and triglycerides by 32-57% in all 3 groups. ENG use resulted in other significant lipoprotein changes including an 18% increase in low density lipoprotein cholesterol, a 13% fall in high density lipoprotein cholesterol and a 27% decline in high density lipoprotein-2 cholesterol. Apoprotein A-1 increased by 9% with ENA and by 11% with EED, but did not change significantly with ENG. Khis prospective study demonstrates that in oral contraceptive agents with identical estrogen, progestins with different androgenic potency produce major and different changes in plasms lipoproteins.

Action of hormonal contraceptives on the coagulation system and some of its inhibitors.

Changes in the level of inhibitors of the coagulation system, primarily of thrombin neutralizing factors have been studied during the prolonged use of four products of contraceptive preparations containing various amounts of oestrogens and progestogens, two fixed dose pills (Bisecurin, Ovidon), a low dose combination pill (Rigevidon) and a biphasic preparation (Anteovin). Thrombelastographic values referred to hypercoagulability while the results of other examinations indicating activation of the coagulation system did not show definite changes in comparison with the control. The activity and quantity of antithrombin III decreased but never below 80%. Except Anteovin all contraceptives significantly enhanced alpha 1-antitrypsin while alpha 2-macroglobulin levels, remained nearly the same as the control values. Attention is called to that the increased alpha 1-antitrypsin level may be a biochemical risk factor. The results showed that the increased coagulability and disposition to thromboembolic disorders caused by hormonal contraceptives may be attributed not only to the decrease of thrombin inhibitors but also to increased alpha 1-antitrypsin levels which may cause increased inhibition of the fibrinolytic system.

PIP: Inhibitors of the coagulation system were measured in 71 women taking 4 oral contraceptives for 1-8 years, 2 combined pills, Bisecurin and Ovidon, a low-dose combined pill, Rigevidon, and a biphasic, Anteovin. The article begins with a review of the clinical significance and recent research on serine protease inhibitors. The pill formulations were: Bisecurin, 50 mcg, ethinyl estradiol and 1 mg ethinodiol diacetate; Ovidon, 50 mcg, ethinyl estradiol and 250 mcg, d-norgestrel; Rigevidon, 30 mcg ethinyl estradiol and 150 mcg, d-norgestrel; Antiovin 50 mcg, ethinyl estradiol and 50 mcg, d-norgestrel for 11 days and with 125 mcg d-norgestrel for 10 days. Thromboelastographic values r and I, indicating hypercoagulation, were significantly higher for pill users compared to 28 controls. No change was seen in prothrombin time (PT), and partial prothrombin time (PTT), fibrinogen values or ethanol gelation. Antithrombin III biological activity and quantity assayed immunologically decreased as much as 20%. The fixed dose pills significantly enhanced alpha 1-antitrypsin, a possible biochemical risk factor for thromboembolic disease. Alpha 2-macroglobulin levels did not change. The results showed that the increased coagulability and enhanced incidence of thromboembolic disorders associated with oral contraception may be caused by a decrease in thrombin inhibitors as well as increased alpha 1 antitrypsin, which inhibits the fibrinolytic system.

Ultrasound demonstration of increased frequency of functional ovarian cysts in women using progestogen-only oral contraception.

Asymptomatic volunteer women with a regular pattern of uterine bleeding and using the progestogen-only oral contraceptive pill were compared with control women who were not exposed to hormones. Pelvic ultrasound scanning at the end of the next bleeding episode after recruitment demonstrated functional cysts with maximum diameters ranging between 30 and 58 mm in eight of the 21 pill users, four of whom also had palpable ovaries, three cysts regressed during the next cycle. Of the 13 women with normal ovaries initially, four developed a new functional cyst of which two were associated with pain. Of the 12 women with cysts seven complained of pain at some time during the monitored cycle. Among 21 control women only one symptom-free (42 mm) cyst was shown on the initial postmenstrual ultrasound scan and this resolved painlessly during the scanned cycle with ovulation from the opposite ovary. Ovulation was also demonstrated in 16 of the remainder; but in none of the three control women who developed asymptomatic functional cysts (35-47 mm in size) while under observation. Since 11 of the 14 pill-users who failed to ovulate also had a functional cyst, the contraceptive efficacy may depend in part on this association. Pain symptoms may make the method less acceptable and give rise to diagnostic problems and inappropriate therapies.

Norethisterone concentration in breast milk and infant and maternal plasma during ethynodiol diacetate administration.

Twelve women with established lactation of 4-8 weeks duration were given a low-dose progestogen-only contraceptive, ethynodiol diacetate 0.5 mg (Femulen) daily. On the seventh and eight day of the study, prior to the mother's taking the pill, a blood sample was taken from her and from the infant. Further blood samples were collected from the mother 4 and 12 hours later. Breast milk samples were collected at every feed on day 7 and day 8. Ethynodiol diacetate is rapidly metabolised in humans, changing into the metabolite norethisterone which is found in both blood and milk. Hence, norethisterone concentrations were estimated. On day 7 and day 8, four hours after ingestion of the pill, the median norethisterone maternal plasma concentration was 1.60 ng/ml and it fell to a median level of 0.30 ng/ml prior to the next dose of the pill. At this time the median infant concentration was 0.10 ng/ml but the maximum observed level was 0.50 ng/ml. In the breast milk the norethisterone concentration appears to peak at around 4-8 hours following the ingestion of the pill. The maximum observed concentration in breast milk was 0.84 ng/ml. The amount of norethisterone ingested by the infant averaged 0.02% (6.65 micrograms) of the dose of ethynodiol diacetate ingested by the mother. The maximum observed on any one day was 0.07% (27.52 micrograms). The above results indicate that the amount of progestogen ingested by the infant from its mother's milk is small and is unlikely to pose a risk to the infant.

[Arterial occlusion in the ocular fundus induced by oral contraceptives]. / Oralis anticoncipiens szedése során kialakult szemfenéki arteriás occlusio.

PIP: To counter the paucity of documention on thromboembolic disorders caused by oral contraceptives (OC), a case study is presented describing the incidence of occlusion of arteria centralis retinae in a 24-year old woman after prolonged use of an OC, Bisecurin. She had taken Bisecurin for 4.5 years and had gained 20 kg during that time, but stopped usage 1 month before admission. She was hospitalized with severe deterioration of vision in the left eye. An eye examination indicated an edematous condition of the retina and reddening of the macula. Acuity of vision value for the left eye was .01 vs. 1.0 for the right, which was confirmed by fluorescein fundus angiography. Moderately decreased antithrombin III (AT III) activity was also ascertained. Treatment consisted of immediate retrobulbar injection with Tolazolin followed by Rheomacrodex, Cavinton infusions, B1 and B12 injections, Oradexon subconjunctival injection as well as vitamin B complex, Cavinton, and Colfarit tablets and a fat-free diet. Significant improvement of the left eye condition appeared 4 weeks later. Periodic follow-ups showed the healing of the condition around the macula; however, the patient suffered permanent damage to the retina due to the arterial occlusion above and below the macula. The disturbed lipid values of metabolism were also returned to normal, as borne out by normal dextrose loading results 8 months later (glucose tolerance was abnormal during examination at admission). The estrogen and progesterone components of OCs have been shown to reduce AT III levels, shorten heparin-thrombin coagulation time, increase fibrinogen levels, decrease HDL cholesterol levels, and produce excess TXA2 (thromboxan) resulting in vasoconstriction and thrombocyte aggregation. The risk of thrombosis is 6 times higher in OC users than in nonusers, although other susceptibility factors (obesity, diabetes, hypertension) also contribute to thrombosis.^ieng

The effect of oral contraceptive therapy and of pregnancy on serum folate levels of rural Sri Lankan women.

Serum folate level, packed cell volume and haemoglobin concentration of apparently healthy rural Sri Lankan women, between 20 and 45 years and earning up to Rs. 500 (Sri Lankan Rs. 35 congruent to 1 pound Sterling) per month, were estimated during pregnancy and when on oral contraceptive (OC) treatment with Ovulen 50 (ethinyl oestradiol 0.05 mg, ethinodiol diacetate 1 mg). Ovulen 50 administration led to a fall in serum folate levels which occurred very rapidly during the first 6 months and more slowly thereafter, stabilizing at 2.2 ng/ml in women of very low economic status and at 2.9 ng/ml in the more privileged. There was a steady fall in serum folate concentrations during pregnancy, the levels at the end of pregnancy being higher than those in women under OC treatment for 9 months. The need for folate supplementation during OC treatment is stressed.