Impact on hepatic estrogen-sensitive proteins by a 1-year contraceptive vaginal ring delivering Nestorone® and ethinyl estradiol.

OBJECTIVES: Estrogen-sensitive hepatic proteins were assessed in women using a contraceptive vaginal ring (CVR) delivering 150mcg Nestorone® (NES) and 15mcg ethinyl estradiol (EE). STUDY DESIGN: A substudy of the Contraceptive Clinical Trials Network of the National Institute of Child Health and Human Development enrolled 129 participants, with assessments of factor VIII, fibrinogen, protein S (PS) and sex hormone binding globulin (SHBG). Thirty-six participants had used combined hormonal contraceptives (CHCs) in the cycle preceding first CVR use (recent users) and 70 had no history of recent use (nonusers). RESULTS: Mean values at baseline were within the normal range for all four proteins but were higher for factor VIII, fibrinogen and SHBG and significantly lower for PS in recent compared to nonusers. During NES/EE CVR use, factor VIII, fibrinogen and PS were within the normal range; however, SHBG levels were increased by nearly 100% at Cycle 13. The change from baseline to final evaluation was statistically significant for all proteins in nonusers. The change in recent users was significant for factor VIII at Cycle 6 and for SHBG at Cycles 6 and 13, but not for PS or fibrinogen. CONCLUSION: NES/EE CVR for up to 13cycles was associated with changes from baseline in plasma levels of factor VIII, fibrinogen and PS that were within the normal range, with SHBG levels above the normal range by Cycle 6. Nonusers of CHC before CVR showed wider changes in values versus recent users whose baseline values were increased by previous EE exposure. IMPLICATIONS: Recent use of CHCs demonstrated significant changes in all four measured hepatic proteins at baseline compared to nonusers. Use of the NES/EE CVR further changed these hepatic protein markers, but values remained within the normal range. Prebaseline exposure to estrogen can obscure interpretation of hepatic proteins changes associated with a second CHC.

Inclusion of women in clinical trials: a historical overview of scientific, ethical, and legal issues.

During the past 20 years, there has been a dramatic shift in scientific, ethical, and legal perspectives regarding the inclusion of women in clinical trials conducted in the United States. A historical overview of why women previously were excluded from clinical trials is presented, and the reasons for current policy changes are discussed. The clinical necessity for testing drugs in specific populations (e.g., women) to ensure appropriate dose regimens and to minimize the likelihood of adverse effects is discussed. The difficult issue of prescribing drugs for pregnant women is highlighted.

Historical background of changes in FDA policy on the study and evaluation of drugs in women.

The Food and Drug Administration (FDA) has recently made two important changes in its policy for the study and evaluation of drugs in women: (1) sex-specific analyses of the safety and efficacy of drugs will be required as part of all new drug applications, and (2) it will no longer be recommended that women of childbearing potential be restricted from participating in the earliest phases of drug trials. These changes have come about as a result of continuous efforts to individualize therapy, to improve upon the safety and efficacy of drugs, and to respond to important questions about whether the drug development process produces adequate information about the effects of drugs in women. In turn, these efforts are the outgrowth of a long history in the United States of changes in the clinical care for women, changes in the use of women as research subjects, changing attitudes about the balance between protection and risks for women in clinical trials, and national movements by women to focus on issues of their health care and to transform the male-oriented model of clinical research. The new FDA guidelines, published in July 1993, will provide guidance to researchers on accumulating valuable information on how drugs work in women and will help make it possible for physicians and other caregivers to consider the effects of gender on health and treatment.

The effect of fetal movement counting on maternal attachment to fetus.

The effect of fetal movement counting on maternal attachment to fetus was investigated in 213 women with uncomplicated singleton pregnancies at 28 to 32 weeks' gestation. Women were randomized into those who counted fetal movements using the Sadovsky (n = 63) or Cardiff (n = 62) charts and controls (n = 88). After 1 month of fetal movement counting, the Cranley 24-item scale with five subscales was used as a measure of maternal-fetal attachment. Univariate analysis revealed a statistically significant increase in total attachment scores and in each of the five attachment subscales among women who counted fetal movements (p less than 0.0001). Turkey's studentized range test confirmed significant differences between each of the Sadovsky and Cardiff groups compared with controls (p less than 0.05). Our study suggests that fetal movement counting may enhance the maternal-fetal attachment process.

The contributions of the nurse and the machine in home uterine activity monitoring systems.

The relative contributions of home tokodynamometry and daily nursing telephone contact to the success of preterm birth prevention programs remains a subject of debate. Because investigators have obtained conflicting data, a reinterpretation of published results was undertaken by proposing a dynamic interface between the nurse and the machine. Experience gained from the technology and the development of nursing expertise with assessment of patient symptoms are presented as interdependent factors, both of which are critical to a therapeutic nurse-patient relationship. It is proposed that this combined interactive expertise increases sensitivity to the early recognition of preterm labor. The nurse's role in providing social support to high-risk pregnant women is then identified as a potential additional independent contributing factor to reported observed reductions in preterm births. Discussion focuses on future research, public policy issues, and the need for expanding nurse-patient interactions into the home.

Length of gestation and nutritional composition of human milk.

A comparative analysis of the composition of milk produced during the first 14 days of lactation by mothers who deliver prematurely and those who deliver at term is described and these values are contrasted with the composition of donor milk specimens. Twenty-four-hour milk collections (days 3, 7, and 14 postpartum) were obtained from nine mothers delivered between 37 to 42 wk gestation (term) and from 14 mothers who delivered between 28 to 36 wk gestation (preterm). A single spot milk collection was obtained from nine mothers who were 6 to 10 months postpartum (donor). Term and preterm milk was compared on specific postpartum days using an analysis of covariance controlling for 24-h milk volume. The protein, carbohydrate, fat, and energy content varied in a similar fashion in term and preterm milk over the 14 postpartum days studied. Furthermore, there was no significant difference between the two milk groups on any single postpartum day evaluated in terms of protein, carbohydrate, fat, or energy concentration. The milk volumes were significantly greater from the mothers delivered at term on days 7 and 14 (p less than 0.01) and the protein content of both term and preterm milk was negatively correlated with milk volume (r = -0.6 or more on each day studied). The nutrient and energy composition of spot donor milk was highly variable and frequently quite different from either term or preterm 24-h milk collections. These data indicate that milk from mothers who deliver prematurely does not contain significantly different concentrations of nutrients or energy than milk from mothers delivered at term and suggest that the differences previously noted between the two groups may be related to 24-h milk volume.

PIP: A comparative analysis of the composition of milk produced during the first 14 days of lactation by mothers who deliver prematurely and those who deliver at term is described and these values are contrasted with the compostiion of donor milk specimens. 24 hour milk collections (days 3, 7, and 14 postpartum) were obtained from 9 mothers delivered between 37 to 42 weeks gestation (term) and from 14 mothers who delivered between 28 to 36 weeks gestation (preterm). A single spot milk collection was obtained from 9 mothers who were 6 to 10 months postpartum (donor). The milk was compared using an analysis of covarience controlling for 24 hour milk volume. The protein, carbohydrate, fat, and energy content varied in a similar fashion in term and preterm milk over the 14 postpartum days studied. There was insignificant difference between the 2 groups, though the milk volumes were significantly greater from the mothers delivered at term on days 7 and 14. The nutrient and energy composition of spot donor milk was highly variable and frequently quite different from either term or preterm milk collections. These data indicate that milk from mothers who deliver prematurely contains insignificantly different concentrations of nutrients or energy than milk from mothers delivered at term and suggest that the differences previously noted may be related to 24 hour milk volume.

Frequency of breast-feeding and serum bilirubin concentration.

Recent studies suggest that the three- to four-hour feeding regimens followed in many maternity units for breast-feeding mothers may not be physiological and that human infants should be fed more frequently. To determine the effects of frequency and length of brest-feeding in the first days after birth, we studied 55 mothers and their infants. Infants who nursed on average more than eight times per 24 hours in the first three days of life had significantly lower serum bilirubin levels (65. v 9.3 mg/fL, P less than .01) than those who fed less than eight times per 24 hours. The results of this investigation suggest that present breast-feeding policies that reduce or limit the number of feedings may interfere with the normal processes that eliminate bilirubin from the newborn infant.