The use of nomegestrol acetate subdermal contraceptive implant, uniplant, during lactation.

Uniplant is a single contraceptive implant intended for one year use. It contains the progestogen nomegestrol acetate. The clinical performance and the effect of its use during the first postpartum year on breastfeeding performance and growth and health of the infants were studied and compared to the findings in a parallel group who used an intrauterine contraceptive device (IUD) in a prospective, non-randomized study. This was carried out in Assiut, Egypt. Two-hundred-forty fully breastfeeding mothers asking for initiation of contraception early postpartum were assigned according to their choices into either nomegestrol subdermal contraceptive implant (Uniplant) (120 women) or intrauterine contraceptive device (CuT 380A) (120 women). The mother and infant pairs were followed up at monthly intervals during the first three months and at two-month intervals thereafter up until the first birthday of the baby. No pregnancy occurred in the two groups. Amenorrhea was significantly more prolonged in the Uniplant group than in the IUD group. There were no significant differences in net continuation rates between the two groups (88.3 versus 92.4 per 100 women, respectively). There were no significant differences between the two groups in the number of breastfeeding episodes, time of weaning, and the cumulative rates of full and partial breastfeeding. There were no significant differences between the two groups in infant weight, weight gain per day, or in infant linear growth. There were no significant differences in the incidence of important health problems affecting the infants of the two groups. However, there were seven infant deaths, six of them were in the Uniplant group. Uniplant subdermal contraceptive implants can be offered as a new contraceptive option suitable for nursing mothers.

PIP: During November 1992-November 1994 at Assiut University Hospital in Egypt, 120 of 240 fully lactating women requesting contraception during the second postpartum month chose the nomegestrol acetate contraceptive subdermal implant Uniplant, while the other 120 chose the copper-releasing IUD CuT 380A. This prospective, non-randomized study evaluated the use of Uniplant during lactation. The mothers and their infants were followed-up once a month for 3 months and then every 2 months up to the infants' first birthday. Neither group experienced a pregnancy. Women in the Uniplant group were less likely to have resumed menstruation at 12 months postpartum than those in the IUD group (38% vs. 63%; p 0.001). The 12-month net continuation rates were statistically similar (88.3% for Uniplant users and 92.4% for IUD users). Reasons for IUD discontinuation were infant death (6), lost to follow up (5), irregular bleeding (2), and depression (1). Reasons for Uniplant discontinuation were lost to follow up (4), irregular bleeding (2), moving to a distant residence (2), and infant death (1). The 2 groups were similar in terms of breast feeding episodes, time of weaning, and the cumulative rates of full and partial breast feeding. Health problems (diarrhea, fever, and cough) affected the infants of both groups at similar incidence rates. The infants in both groups had similar weight, weight gain per day, and linear growth. Six of the 7 infant deaths occurred in the Uniplant group. The difference in the infant death rate was not significantly different, however. Gastroenteritis was responsible for 5 infant deaths. Bronchopneumonia and unexplained convulsion claimed the life of 1 infant each. These findings suggest that Uniplant is an acceptable and effective contraceptive method during lactation and has no adverse effect on infant growth and health.

Mechanism of action of the intrauterine contraceptive device: evidence for a specific biochemical deficiency in the endometrium.

The precise mechanism of action of the intrauterine contraceptive device (IUCD) is uncertain. In this study we compared the circulating concentrations of a specific endometrial protein, placental protein 14 (PP14), in 62 women with an IUCD and 16 controls. The concentrations of PP14 were substantially lower in IUCD users. There was no difference in the concentrations of another and less specific endometrial protein, insulin-like growth factor binding protein-1 (IGFBP-1). There was no difference in PP14 concentrations between those women with and without intermenstrual bleeding. We conclude that the reduced concentrations of PP14 in IUCD users reflect defective endometrial function in these women, probably related to the contraceptive effect. We propose that the measurement of PP14 might be a means of comparing the efficiency of different devices.

Relationship between the changes in maternal serum placental leucine aminopeptidase (P-LAP) activity and umbilical artery waveforms in normal pregnancy.

The relation between placental leucine aminopeptidase (P-LAP) activity in maternal sera and umbilical artery waveforms (systolic/diastolic ratio, S/D) obtained by pulsed Doppler has been examined by cross-sectional study in 26 normal pregnancies during weeks 26-38. A negative correlation was seen to exist suggesting that P-LAP may have a role in the regulation of uteroplacental blood flow.

Multicenter clinical trial on the efficacy and acceptability of a single contraceptive implant of nomegestrol acetate, Uniplant.

Uniplant, a single Silastic implant containing nomegestrol acetate, provides contraceptive efficacy for one year. Uniplant use for one year was studied in 1,803 healthy women of reproductive age, enrolled from 10 centers in 9 countries, after informed consent. Implants were placed subdermally either in the upper arm or in the gluteal region. Two-hundred-seventy-six subjects discontinued prior to completing one year of study. Cumulative discontinuation rate at 12 months was 15.72%. Medical reasons for discontinuation were principally menstrual-related. Fifteen pregnancies occurred during the one year study period, resulting in a 12-month net cumulative pregnancy rate of 0.94%. Approximately 56% of subjects using Uniplant had bleeding patterns similar to normal menstruation. Results from this study confirm that Uniplant is an efficient, well tolerated, 12-month contraceptive implant, with the advantage of easier insertion and removal of the single implant compared to other multiple implant methods.

Heterogeneity of human prolactin levels in serum during the early postpartum period.

The distribution of molecular forms of prolactin in serum of women during the 1st postpartum week was studied using column chromatography. Serum was analyzed 1, 4 and 7 days postpartum. Using this technique, three molecular forms of prolactin were detected with approximate molecular weights of < or = 100, 48 and 22 kDa; these were termed 'big-big', 'big' and 'little' prolactin, respectively. The relative amount of each form was measured in relation to the total amount of immunoreactive prolactin eluted from the column. Throughout the first postpartum week big-big prolactin represented a minor fraction of the total immunoreactive prolactin in the serum of lactating women: 4.9%, 5.2% and 4.6% on days 1, 4 and 7, respectively. There was a gradual decrease in the higher molecular weight forms of prolactin (big-big plus big prolactin) from the 1st to the 7th postpartum day. This was associated with a significant increase of the little prolactin from 62.8 +/- 7.2% at the 1st postpartum day to 72.6 +/- 6.5% at the 7th day (p < 0.05).

Sonographic assessment of ovarian and endometrial changes during long-term Norplant use and their correlation with hormonal levels.

OBJECTIVE: To study the probability of ovulation and subclinical abortion during long-term use of Norplant and to assess the concomitant endometrial development. DESIGN: This was a prospective nonrandomized comparative study. The ovaries and endometrium were assessed daily by ultrasonography during 59 menstrual cycles in 50 women who were using Norplant for > 1 year. Serum concentrations of E2, P, FSH, LH, pregnancy specific beta 1 glycoprotein (Sp1), and hCG were also daily measured. The findings were compared with those in 35 ovulatory cycles in normal fertile women not using contraception. SETTING: Clients of the Family Planning Clinic of Assiut University Hospital (Norplant users) and the hospital women staff (controls). RESULTS: Sonographic and hormonal evidence of ovulation were observed in one third of Norplant users; two of them resulted in conception. However, the majority of these ovulatory cycles showed low midcycle peaks of E2, FSH, and LH and evidence of luteal phase defect (LPD). Excessive follicular enlargement was observed in 46% of the cycles. Norplant users had significantly thinner endometrium that did not exhibit the normal phasic changes in sonographic texture. Apart from conceptive cycles, no rise in Sp1 or hCG was observed. CONCLUSIONS: Norplant acts mainly by inhibiting ovulation, but when this occurs, it is associated with LPD and subnormal endometrial development. Subclinical abortion does not contribute to the contraceptive effect.

PIP: 59 cycles in 50 women with Norplant inserted 18-48 months previously were observed daily with ultrasonic scanning and analysis of serum estradiol, progesterone, FSH, LH, pregnancy-specific beta1 one-glycoprotein (Spl) and hCG, compared to 38 menstrual cycles in matched controls not using contraception. Subjects were all parous, married clients at the Family Planning Clinic of Assiut University Hospital, Assiut, Egypt, or hospital staff controls. 35 of the 38 control cycles were ovulatory, and 3 conceptions were noted by ultrasonic and hormonal criteria. In Norplant users there were waves of folliculogenesis, some even occurring during vaginal bleeding. Estradiol levels were highest when the largest follicles were seen in anovulatory cycles, and lowest in quiescent cycles with no follicle development. This correlation was highly significant (p0.01).

Superiority of amniotic fluid index over amniotic fluid pocket measurement for predicting bad fetal outcome.

Semiquantitative amniotic fluid volume (AFV) determination is a component of the fetal biophysical profile (BPP). To assess decreased AVF we did BPPs of 174 fetuses within 1 week of delivery. Two methods were used: measurement of the single largest vertical pocket (oligohydramnios = depth < 1 cm) and the four-quadrant amniotic fluid index (AFI) (oligohydramnios = AFI < or = 5 cm). AFV, as determined by each method, was related to measures of fetal outcome (perinatal mortality, fetal distress, Apgar score, meconium-stained amniotic fluid, and intrauterine growth retardation [IUGR]). The AFI was more sensitive in predicting mortality (87.5%) and the following measures of perinatal morbidity: low 5-minute Apgar score (88.8%), fetal distress during labor (86.6%), meconium-stained amniotic fluid (63.6%), and the presence of IUGR (79.4%). The sensitivity of amniotic fluid pocket measurement of < 1 cm was 75%, 72.2%, 66.6%, 47.7%, and 55.8%, respectively, for the same measures. Using the AFI instead of a single pocket measurement in BPP assessment increased the sensitivity and positive predictive value of the BPP from 64.7% to 76.4% and from 45.8% to 68.4%, respectively. Our data suggest that qualitative AFV measurement using the AFI is superior to that of the single largest pocket in multiple component fetal biophysical testing.

Oral versus local treatment of vaginal candidosis.

A comparative study was conducted to compare the results of the use of oral and local vaginal therapy in the treatment of vaginal candidosis. Forty-five patients with clinical and mycological evidence of vaginal candidosis were recruited and were randomly allocated to one of the treatment groups. Twenty-four patients received ketoconazole orally (400 mg/day for 5 days) and 21 patients received nystatin vaginal pessaries (100,000 units twice/day for 7 days). Seven out of 20 rectal swabs (35%) were positive for Candida albicans. Both drugs were significantly effective in relieving patients symptoms and physical signs. The mycological cure rates were 87.5% and 81%, and the relapsing rates were 0% and 5.9% for the ketoconazole and nystatin groups, respectively. Ketoconazole oral therapy had generally slightly higher results than local nystatin therapy in the treatment of vaginal candidosis, yet the difference was statistically insignificant.

Acceptability of injectable contraceptives in Assiut, Egypt.

The present work was a randomized comparative study of two injectable progestogen-only contraceptives. The first group (200 subjects) received 150 mg of depotmedroxyprogesterone acetate (Depoprovera) every 84 +/- 7 days and the second (200 subjects) received 200 mg of norethisterone enanthate (Noristerat) every 56 +/- 7 days. Acceptors of injectable contraceptives in Assiut, Egypt, were mainly women looking for fertility termination. Menstrual disruption was the main side effect among both treatment groups. Amenorrhoea was the commonest menstrual complaint and was the main reason for discontinuation in both groups. Only one pregnancy occurred during NET-EN use; two more pregnancies occurred, one in each of the two groups but there were indications that conception preceded the first injection. Menstrual irregularities were generally more frequent with DMPA users. However, DMPA had better one-year continuation rates than NET-EN (68.8 +/- 3.5 and 57.1 +/- 3.6 per 100 women, respectively).

Levonorgestrel concentrations in maternal and infant serum during use of subdermal levonorgestrel contraceptive implants, Norplant, by nursing mothers.

The transfer of levonorgestrel to infants was studied in 42 lactating women in whom the contraceptive subdermal implants, Norplant, were inserted 30 to 40 days postpartum. The women breastfed their infants for one year. Simultaneous mother and infant blood samples were taken once during the year. The levonorgestrel serum concentrations were measured by radioimmunoassay. During the first postinsertion month, the levonorgestrel concentration in the infants serum amounted, on the average, to 5% of the maternal concentration. Thereafter, the ratio ranged from 8 to 13%. The implications of this finding are discussed.

Influence of levonorgestrel contraceptive implants, NORPLANT, initiated early postpartum upon lactation and infant growth.

This study was undertaken to investigate the effect of use of levonorgestrel contraceptive implants, NORPLANT, by breastfeeding mothers on lactational performance and infant growth. NORPLANT implants were inserted between days 30 and 42 postpartum in 50 lactating women. Two control groups of breastfeeding mothers, 50 each, were studied in parallel: the first used an intrauterine device (Cu T380-Ag) and the second used either barrier or no contraception. There was no difference in lactational performance among the three groups. The increments in infant weight and height in the three groups were within the normal range for Egyptian infants. However, the rates of weight and height gain in the early postpartum months were slightly, but significantly, lower in the NORPLANT group than in the two control groups. However, by the sixth postpartum month, there were no significant group differences in these growth parameters. The possible confusing effect of supplementary feeding is discussed.

PIP: This study investigates the effect of using the levonorgestrel contraceptive implant, NORPLANT, by breastfeeding mothers on lactation and infant growth. NORPLANT implants were inserted between days 30 and 42 postpartum in 50 lactating women. 2 control groups of breastfeeding mothers, 50 each, were studied in parallel: the 1st used an intrauterine device (Cu T380-Ag) and the 2nd used either barriers or no contraception. There was no difference in lactational performance among the 3 groups. The increments in infant weight and height in the 3 groups were within the normal range for Egyptian infants. However, the rates of weight and height gain in the early postpartum months were slightly, but significantly, lower in the NORPLANT group than in the 2 control groups. However, by the 6th postpartum month, there were no significant group differences in these growth parameters. The possible confusing effect of supplementary feeding is discussed.

A study of interaction between levonorgestrel and ethanol.

Female Wistar rats were pair-fed a diet containing either ethanol (5%) or isocaloric carbohydrate substituent. After 6 weeks, a single dose (5 micrograms/kg) of levonorgestrel was given to the animals in each group either orally, subcutaneously or intravenously. Plasma levels of levonorgestrel at different time intervals were measured by RIA. Chronic alcohol administration did not affect plasma levels of levonorgestrel after oral administration. When the drug was given subcutaneously, plasma levels and AUC were significantly decreased in the alcoholic compared to control group. Following intravenous administration, the elimination half-life of levonorgestrel was shorter while the metabolic clearance was higher in the alcohol-treated group rather than the control group.

Prognostic value of biochemical tests in the assessment of fetal outcome in threatened abortion.

Maternal concentrations of serum progesterone, oestradiol, chorionic gonadotrophin, Schwangerschaftsprotein 1 and placental protein 5 were measured in 67 patients with threatened abortion. The levels of all biochemical variables were significantly reduced in those patients who had an unfavourable outcome. The clinical efficiency of each of these tests was very similar.

Circulating levels of placental proteins, placental protein 5 (PP5), placental lactogen and Schwangerschafts-protein 1 (SP1), in antepartum eclampsia.

Placental protein 5 (PP5), Schwangerschaftsprotein 1 (SP1) and human placental lactogen (hPL) were measured in 36 serum samples from seven women with antepartum eclampsia. PP5 levels were generally elevated, hPL levels were reduced and SP1 levels were within the usual ranges.

Placental protein 5 is related to blood coagulation and fibrinolytic systems.

Previous studies have shown that placental protein 5 (PP5) forms complexes with heparin. In order to further elucidate the biological role of PP5 we studied the effect of plasmin and thrombin on the immunoreactivity of PP5, and the possible functional antiplasmin and antithrombin effects of purified PP5. Varying concentrations of plasmin and thrombin were added to pregnancy plasma, and the PP5 levels, measured by radioimmunoassay, were found to be elevated by 558% (plasmin and 48-87% (thrombin). Incubation of radiolabeled PP5 with plasmin resulted in the formation of radioactive fragments with smaller molecular weights. Functional studies using a chromogenic substrate confirmed that purified PP5 has an antiplasmin activity. An average increase of 15% was observed in the antiplasmin activity when 200 ng purified PP5 was added to 150 microliters of pregnancy serum. Thus, there are certain similarities between PP5 and antihrombin III. Both form complexes with heparin and have antiplasmin properties, and both were found to be heat labile. But, functional studies utilizing a chromogenic substrate failed to demonstrate any antithrombin III-like activity in the purified PP5 preparation that had antiplasmin activity. Our results show that the function of PP5 is related to the blood coagulation and fibrinolytic systems, at least through its inhibitory action on plasmin.

Maternal serum levels of placental protein 5 in complications of late pregnancy.

Maternal serum levels of placental protein 5 (PP5) were measured during the third trimester in women with normal and abnormal pregnancies. PP5 levels were significantly elevated in patients with preeclampsia, diabetes, intrauterine growth retardation associated with preeclampsia, and twin pregnancy.

Placental protein 5: disappearance from the circulation after delivery.

Blood was collected from 8 women following delivery at term. The decline in serum concentrations of placental protein 5 following the delivery of the infant's head was studied for 12 h. Placental protein 5 levels fell very rapidly with a half-life of 5-39 min. In the majority of women placental protein 5 was undetectable after 12 h (i.e. less than 2 microgram/l).

Immunohistochemical demonstration of placental protein 5 in trophoblastic tumours.

An immunoperoxidase technique was used for the detection of placental protein 5 (PP5) in tissue specimens from trophoblastic tumours. PP5 was detected in all of 15 cases of hydatidiform mole, in two out of six destructive moles and in one of seven choriocarcinomas. Though the biological importance of PP5 is not clear, its association with inactivation of plasmin suggests a role in the control of placental invasiveness.