ESC expert statement on the effects on mood of the natural cycle and progestin-only contraceptives.

Hormonal fluctuations during the natural cycle, as well as progestins used for hormonal contraception, can exert effects on mood especially in vulnerable women. Negative effects of levonorgestrel-releasing intrauterine contraception on mood are rare.

Contraception for the perimenopausal woman.

Perimenopause, or the menopause transition, is a time in a woman's life that bridges her reproductive years through to the non-surgical cessation of ovulation, or menopause. For many women this time is one of changes: changes in gynecological issues, onset of symptoms not experienced in her youth and increasing risks for adverse medical conditions. Despite the clear changes that occur for many women during this time, one critical issue is frequently ignored, namely, that, until the onset of menopause, she is exposed to pregnancy if sexually active, and pregnancy for older reproductive women is fraught with considerable increases in morbidity and mortality compared to younger women. This paper will present a review of the reproductive issues of the perimenopause and interventions geared to preventing pregnancy and relieving menopause-related symptoms. As counseling remains a critical aspect in empowering women to make informed choices about their health care, this paper will present current evidence that will help clinicians provide accurate reproductive counseling to women in the menopause transition.

Androgens and menopause.

The cessation of ovarian sex steroidigenesis, either as result as surgical extirpation, certain medical therapies or the gradual cessation of ovarian function, leads to menopause with all its associated physiological, physical and lifestyle changes. The changing hormonal milieu of menopause is most commonly associated with declining levels of estrogens. However, ovarian senescence also results in declining levels of androgens. Indeed, it is the loss of physiological levels of estrogens and androgens that result in the varied signs and symptoms of menopause including vasomotor symptoms, bone mineral density loss, reduced interest in sex, alterations in mood and energy and hair loss, among others. This paper will provide a review of the role of androgens in the menopause and assess the potential of androgen therapies in the management of the menopause.

Alternatives to oral regimens of contraception.

Alternatives to oral contraceptives are an integral part of contraception used worldwide. In order to empower women to correctly use contraception for as long as they choose not to become pregnant, healthcare practitioners and their patients must be educated about these methods as well as the full spectrum of available birth control options. Effective counseling is a key factor in helping a woman effectively chose a method that is appropriate for her. In order for contraceptive counseling to be effective, information should be accurate and provided in an unbiased manner. This review will help provide healthcare practitioners with current information regarding the use of nonoral contraceptives so as to facilitate the counseling of women and allow them to make informed and appropriate contraceptive decisions.

Chemical and biological characterization and clinical evaluation of botanical dietary supplements: a phase I red clover extract as a model.

Botanical dietary supplements, as compared with nutritional supplements or single-component pharmaceutical drugs, are typically less-refined preparations derived from bulk plant material and, as such, require a modified approach to their development, production, and evaluation. An integrated, multidisciplinary team of scientific and clinical investigators is required in order to develop high quality phytomedicines and rigorously evaluate their safety and efficacy. Research on botanicals involves unique challenges as plant source materials frequently vary in chemical content and may contain unwanted pesticides, heavy metals, contaminant plant species, or other adulterants. Ideally, a botanical formulation should be standardized, both chemically and biologically, by a combination of analytical techniques and bioassays. This combination approach provides multiple measures by which reproducible quality and efficacy of botanical supplements may be achieved, and is particularly useful for botanical products for which the active compound(s) have not yet been identified. Safety and toxicity should be evaluated during the supplement development process in both in vitro and in vivo systems. A number of liquid chromatography-mass spectrometry methods can aid in the assessment of purity, bioavailability, toxicity, metabolism, and molecular target profiling of botanical extracts. Clinical investigators must appreciate the complexity of multi-component phytomedicines and adjust trial protocols accordingly. This review highlights practical considerations of value to basic science and clinical investigators engaged in the study of botanical supplements. Lessons and examples are drawn from the authors' experience in designing and developing a red clover (Trifolium pratense L.) standardized extract for evaluation in Phase I and Phase II clinical trials.

Characterization of an unbalanced de novo rearrangement by microsatellite polymorphism typing and by fluorescent in situ hybridization.

Unbalanced de novo rearrangements, difficult to characterize by conventional cytogenetic techniques, may be elucidated by molecular approaches. By dinucleotide repeat polymorphism typing and fluorescence in situ hybridization (FISH), we have defined the composition of an unbalanced de novo translocation (46,XX,15p+) in a child with multiple congenital anomalies. Use of a microsatellite repeat D5S208 (localized to 5p15) and polymerase chain reaction (PCR) analysis confirmed that the extra segment originated from the short arm of chromosome 5. Amplification of the patient's DNA with primers for dinucleotide repeats D5S350 and D5S118 showed that the entire 5p (from 5pter to 5q11) was present in 3 copies. FISH confirmed the trisomic status of 5p, and further revealed the presence of centromeres of both chromosomes 5 and 15 on the rearranged chromosome thus delineating its dicentric nature. This information allowed us to redefine the de novo rearrangement in this patient as 46,XX,dic der(15)t(5;15)(q11;p11).

Amniocentesis performed at 14 weeks' gestation or earlier: comparison with first-trimester transabdominal chorionic villus sampling.

OBJECTIVE: To compare our initial experiences with early amniocentesis and transabdominal chorionic villus sampling (CVS). METHODS: We compared the diagnostic and pregnancy outcomes of our initial 250 patients undergoing early amniocentesis (at or before the 14th completed week of gestation) or transabdominal CVS (performed between 9.5-12.9 weeks' gestation). In both groups, the indication for prenatal diagnosis was advanced maternal age (35 years or older at estimated date of delivery). RESULTS: No diagnostic errors were made using either technique, and the culture failure rate for both methods was 0.8% (two of 250). Seven cytogenetic abnormalities in the early amniocentesis group and seven in the transabdominal CVS group were detected. Nine of the 250 women undergoing early amniocentesis reported spontaneous miscarriages following the procedure, compared to five in the transabdominal CVS group. The loss rates were 3.8% in the early amniocentesis group and 2.1% in the transabdominal CVS group among continuing pregnancies. Frequencies of premature delivery, small for gestational age infants, and associated structural defects in both groups were comparable. CONCLUSIONS: At this time, early amniocentesis cannot be assumed to be equal to conventional transabdominal CVS or amniocentesis with regard to safety or accuracy; only a large cohort randomized study will adequately determine the safety and efficacy of early amniocentesis.

Ultrasound-guided fetal skin sampling for prenatal diagnosis of genodermatoses.

OBJECTIVE: To evaluate the safety and diagnostic efficacy of ultrasound-guided fetal skin sampling for the prenatal diagnosis of genodermatoses. METHODS: Seventeen pregnancies seen over 6.5 years were analyzed retrospectively. Fifteen were at risk for junctional epidermolysis bullosa and two for recessive dystrophic epidermolysis bullosa. Under ultrasound guidance, a biopsy forceps was inserted through a 14-gauge catheter and directed toward the fetus (thorax, back, or buttocks) to obtain skin samples. The procedures were performed at a mean of 18.3 weeks' gestation (range 16.5-19.5). RESULTS: Fetal skin sampling was successful in all cases; the mean number of biopsies taken was 3.6 (range two to five). Five of the 17 fetuses were determined to be affected, each with junctional epidermolysis bullosa; these pregnancies were terminated electively and the prenatal diagnoses confirmed. The remaining 12 pregnancies resulted in the delivery of healthy infants at or after 37 weeks' gestation. There were no pregnancy-related complications, specifically preterm rupture of the membranes or preterm labor. Three of the 12 infants had minor skin blemishes believed to be due to the skin sampling. CONCLUSION: Ultrasound-guided fetal skin sampling is the procedure of choice when fetal skin is required for prenatal diagnosis of genodermatoses.

Transplacental needle passage in early amniocentesis and pregnancy loss.

OBJECTIVE: To determine whether transplacental needle passage affects the frequency of pregnancy loss in early amniocentesis. METHODS: We reviewed 380 consecutive cases of amniocentesis performed before 14.9 weeks' gestation because of advanced maternal age (at least 35 years old). Procedure and pregnancy outcome data were obtained from reviews of patients' charts and telephone contact with patients or referring physicians. RESULTS: Transplacental needle passage occurred in 147 cases (38.7%). Pregnancy loss rates were similar in the transplacental and nontransplacental groups. Only the frequency of bloody taps was significantly increased among women undergoing early transplacental amniocentesis. CONCLUSION: Transplacental needle passage in cases of amniocentesis performed before 14.9 weeks' gestation does not appear to increase the risk of pregnancy loss. Therefore, deferring early amniocentesis to a later time at which nontransplacental amniocentesis may be performed should be reserved only for cases complicated by placental vessels, placental vascular lacuna ("placental lakes"), or subchorionic hematomas that should not be traversed by a needle.

Maternal serum screening for fetal Down syndrome in women less than 35 years of age using alpha-fetoprotein, hCG, and unconjugated estriol: a prospective 2-year study.

OBJECTIVE: To evaluate prospectively maternal serum screening with alpha-fetoprotein (AFP), hCG, and unconjugated estriol (uE3) as a screen for fetal Down syndrome. METHODS: Women less than 35 years of age were offered screening between 15-20 weeks' gestation. Screening results calculated by an algorithm to be equal to or greater than 1:274 (the risk of a 35-year-old for fetal Down syndrome at the second trimester) were considered positive. If gestational age was confirmed by ultrasonography, genetic counseling and amniocentesis were offered. RESULTS: In the first 2 years of our program, 9530 women were screened, of which 686 (7.2%) were found to be screen-positive. Ultrasonographic examination explained the abnormal values in 379 (4.0%). The remaining 307 (3.2%) received genetic counseling and 214 (2.2%) elected amniocentesis or CVS. Four cases of fetal Down syndrome and one de novo chromosomal marker were detected. In three additional cases of fetal Down syndrome, triple-analyte screening failed to identify the pregnancies to be at increased risk. None of the seven cases of fetal Down syndrome would have been detected through screening with maternal serum alpha-fetoprotein (MSAFP) and age alone. CONCLUSIONS: Measurement of MSAFP, hCG, and uE3 in women less than 35 years old is an effective screening test for fetal Down syndrome, with a sensitivity of 57% in our study and an amniocentesis rate (false-positive rate) of 3.2%.

High frequency of cytogenetic abnormalities in fetuses with cystic hygroma diagnosed in the first trimester.

OBJECTIVE: The purpose of this study was to evaluate the association between fetal cystic hygroma detected in the first trimester and fetal cytogenetic abnormalities. METHODS: Visualization of a prominent (2.5 mm or larger) anechoic or hypoechoic separation of the fetal skin line from the posterior body wall led to the diagnosis of fetal cystic hygroma; presence or absence of septations within the cystic hygroma was documented in each patient. Fetuses with additional structural defects were excluded from this study. All eligible women were offered prenatal cytogenetic studies (ie, chorionic villus sampling, amniocentesis). RESULTS: Cytogenetic studies were performed on all 32 affected fetuses. Fifteen of 32 fetuses (46.9%) had abnormal complements. Septations within the cystic hygroma were demonstrated in 18 fetuses; nine of these had abnormal karyotypes. Of the 12 women carrying fetuses with normal chromosome complements who elected to continue their pregnancies, 11 delivered infants with no evidence of cystic hygroma. CONCLUSIONS: Prenatal cytogenetic analysis should be offered to women with fetal cystic hygroma diagnosed in the first trimester. Normal outcome is likely in those showing no chromosome abnormalities.

Dilation and evacuation for second-trimester genetic pregnancy termination.

Dilation and evacuation (D&E) is the most common procedure for second-trimester pregnancy termination currently used by United States obstetrician-gynecologists. Although this method carries morbidity and mortality rates significantly lower than methods requiring labor induction, the procedure most commonly used for second-trimester genetic terminations seems to be labor induction (eg, vaginal prostaglandin suppositories). Many geneticists appear reluctant to recommend D&E over induction methods of pregnancy termination because they perceive that fetal abnormalities cannot be consistently confirmed by evaluation of the products of conception obtained by D&E. We report here 60 consecutive patients who underwent D&E (14-22 weeks' gestation) after detection of fetal abnormalities. The prenatal diagnoses were confirmed in all cases. Our experience thus indicates that D&E is reliable in confirming most prenatal diagnoses and should be the procedure of choice when second-trimester pregnancy termination is chosen because of fetal abnormalities.

Late first-trimester invasive prenatal diagnosis: results of an international randomized trial.

OBJECTIVE: To assess, in a randomized trial, the safety and accuracy of amniocentesis and transabdominal chorionic villus sampling (CVS) performed at 11-14 weeks of gestation, given that this time frame is increasingly relevant to early trisomy screening. METHODS: We compared amniocentesis with CVS from 77 to 104 days of gestation in a randomized trial in a predominantly advanced maternal age population. Before randomization, the feasibility of both procedures was confirmed by ultrasonography, and experienced operators performed sampling under ultrasound guidance; conventional cytogenetic analysis was employed. The primary outcome measure was a composite of fetal loss plus preterm delivery before 28 weeks of gestation in cytogenetically normal pregnancies. RESULTS: We randomized 3,775 women into 2 groups (1,914 to CVS; 1,861 to amniocentesis), which were comparable at baseline. More than 99.6% had the assigned procedure, and 99.9% were followed through delivery. In contrast to previous thinking, in the cytogenetically normal cohort (n = 3,698), no difference in primary study outcome was observed: 2.1% (95% confidence interval 1.5, 2.8) for CVS and 2.3% (95% confidence interval, 1.7, 3.1) for amniocentesis. However, spontaneous losses before 20 weeks and procedure-related, indicated terminations combined were increased in the amniocentesis group (P =.07, relative risk 1.74). We found a 4-fold increase in the rate of talipes equinovarus after amniocentesis (P =.02) overall and in week 13 (P =.03, relative risk = 4.65), but data were insufficient to determine this risk in week 14. CONCLUSION: Amniocentesis at 13 weeks carries a significantly increased risk of talipes equinovarus compared with CVS and also suggests an increase in early, unintended pregnancy loss. LEVEL OF EVIDENCE: I

Segregation analysis and genetic counseling when both parents carry balanced chromosomal translocations.

OBJECTIVE: To assess the risk of chromosomally abnormal offspring and discuss counseling approach when both parents carry balanced translocations. DESIGN: Theoretical segregation analysis is performed and use of empiric data is used in genetic counseling. SETTING: Patients are referred to Division of Reproductive Genetics at the University of Tennessee, Memphis. PATIENTS, PARTICIPANTS: The mother, heterozygous for reciprocal translocation 46,XX, rcp(7;13)(p21;q22) and father, heterozygous for Robertsonian translocation 45,XY,rob(13q;14q) were referred for genetic counseling concerning risks of chromosomally abnormal offspring. INTERVENTIONS: Segregation analysis, genetic counseling, and chorionic villus sampling. MAIN OUTCOME MEASURE(S): A cumulative risk was derived to use for counseling purposes. Cytogenetics using GTG-banding was performed on cultured chorionic villus cells. RESULTS: Theoretical risk of this couple having chromosomally abnormal offspring was 40.5%. On the basis of empirical data and risk factors inherent in the specific translocations, the maternal contribution at midtrimester was 3.5%; the paternal contribution was 1% to 2%. The sum of these risks was used in counseling. CONCLUSIONS: The fetus was found to be 46,XY,rcp(7;13)(p21;q22).

Molecular analysis to assign parental origin and distinguish de novo i(21q) from t(21q21q) in two Down syndrome fetuses.

OBJECTIVE: We sought to determine the origin of two prenatal cases of chromosome 21 rearrangements not amenable to clarification by conventional cytogenetic methodology. METHODS: Hypervariable repeat polymorphisms (chromosome 21) were used to determine the type of structural rearrangement and the parental origin of the rearranged chromosome. The repeats used were highly polymorphic and located very close to the centromere; thus, the likelihood of differences among the parental alleles and overall informativeness were increased. RESULTS: The rea(21q21q) chromosomes were identified as a Robertsonian translocation in one fetus and an isochromosome in the other. The extra chromosome material was found to be maternal in origin in both cases. CONCLUSION: The ability to clarify the origin of abnormal chromosomal rearrangements provides valuable information concerning possible mechanisms of aneuploidy, as well as clinical data that may have an impact in assessing a patient's risk for abnormal offspring.

Identification of p53 mutations in endometrial adenocarcinoma by polymerase chain reaction-single-strand conformation polymorphism.

OBJECTIVE: We determined whether mutations in p53 exons 5-6-7-8, as detected in the polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) test, might be correlated with stage or grade in endometrial adenocarcinoma. METHODS: We amplified sequences containing exons 5, 6, 7, or 8 in DNA from tumors and controls. Mutation within the amplified sequences was indicated by changes in electrophoretic mobility (band shifts) in the SSCP test. The results were analyzed statistically and compared with the results of other, similar studies. RESULTS: We identified 15 band shifts among 47 endometrial tumors studied (band shifts in two different exons in two cases) and none among 42 controls. Band shifts in exons 5 and 8 were associated uniformly with grade 2 or grade 3 histology. In other studies p53 mutations were correlated with advanced-stage malignancy. CONCLUSION: Further evaluation of particular p53 mutations and their relation to disease course in endometrial adenocarcinoma seems warranted. The PCR-SSCP test seems well-suited to this purpose.

Positive serum screening for fetal Down syndrome does not predict adverse pregnancy outcome in absence of fetal aneuploidy.

OBJECTIVE: The purpose of this study was to determine whether false-positive maternal serum screening for fetal Down syndrome is predictive of poor pregnancy outcome. METHODS: The pregnancy outcomes of 99 women having positive serum screening for fetal Down syndrome (study group)--based upon maternal serum alpha-fetoprotein (MSAFP), unconjugated estriol (uE3), hCG, and maternal age--were compared to the outcomes of matched control patients having negative serum screening results (control group). The outcome indices analyzed were fetal death, intrauterine growth retardation (IUGR), preeclampsia, and fetal anomalies. RESULTS: Between the study group and the control group, there were no statistically significant differences in pregnancy outcome with respect to fetal death, IUGR, preeclampsia, or fetal anomalies. CONCLUSIONS: Our findings demonstrate no apparent increase in the adverse perinatal outcomes analyzed in women having unexplained positive serum screening for fetal Down syndrome. Although further investigation is needed, these results provide no evidence to support increased antepartum surveillance in such patients.

Patient acceptability and satisfaction with Lunelle monthly contraceptive injection (medroxyprogesterone acetate and estradiol cypionate injectable suspension).

The results from a User Satisfaction Questionnaire, Treatment Assessment Questionnaire, and Global Well-Being Schedule questionnaire administered to women participating in an open-labeled, nonrandomized, parallel, controlled study comparing a new monthly injectable contraceptive containing 25 mg of medroxyprogesterone acetate (MPA) and 5 mg of estradiol cypionate (E2C) (MPA/E2C) (Lunelle Monthly Contraceptive Injection) and a triphasic norethindrone (0.5, 0.75, 1.0 mg)/0.035 mg ethinyl estradiol (NET/EE) oral contraceptive (Ortho-Novum 7/7/7) are reviewed. Approximately 85% of all 1103 women enrolled in the comparative trial completed their initial and final questionnaires. To better assess the comparison of a new and extant method of contraception, outcome data were divided among MPA/E2C users and new and previous oral contraceptive (OC) users. Despite the inherent inequalities in comparing an injectable to an oral method of contraception, few treatment assessment and satisfaction outcomes were significantly different when comparing MPA/E2C users to new OC (NET/EE) users. More women in the MPA/E2C study group reported discomfort with their method than women in either NET/EE study group; however, only 19.4% of MPA/E2C users rated the administration of their contraceptive to be moderately uncomfortable or worse, compared to 11.7% of new NET/EE users and 13.4% of previous OC users. Among MPA/E2C users, 86.3% reported no interference with social activities compared with 90.4% of new NET/EE users. MPA/E2C and new NET/EE users were also similar in their responses recommending their respective contraceptive method to friends, with > 90% of both groups stating that they had a very favorable experience and would definitely recommend their method to a friend. In general, MPA/E2C was well accepted by women in the study group. Their attitudes and perceptions are similar to those of women who were starting OCs for the first time. These data support the premise that MPA/E2C may become a well accepted, first-line contraceptive option for women in the US.

PIP: The results of a user satisfaction questionnaire, treatment assessment questionnaire, and global well being schedule questionnaire administered to women participating in an open-labeled, nonrandomized, parallel, controlled study is reported in this paper. The study compared a new monthly injectable contraceptive containing 25 mg medroxyprogesterone acetate (MPA) and 5 mg estradiol cypionate (E2C) with a triphasic norethindrone (0.5, 0.75, 1.0 mg)/0.035 mg ethinyl estradiol (NET/EE) oral contraceptive. Approximately 85% of 1103 women enrolled in the comparative trial completed their initial and final questionnaires. Despite the inherent inequalities in comparing an injectable to oral contraception, few treatment assessment and satisfaction outcomes were significantly different when comparing MPA/E2C users to new NET/EE users. More women in the MPA/E2C group reported discomfort with their method compared to the women in either the new or previous NET/EE user group. However, only 19.4% of MPA/E2C users rated the administration of their contraceptive to be moderately uncomfortable or worse, compared to 11.7% of new NET/EE users and 13.4% of previous NET/EE users. Among MPA/E2C users, 86.3% reported no interference with social activities compared with 90.4% of new NET/EE users. MPA/E2C and new NET/EE users were also similar in their responses recommending their respective contraceptive method to friends. These data support the premise that MPA/E2C may become the well-accepted, first-line contraceptive option for women in the US.

Oral contraceptives. Risks.

The modern combination oral contraceptive (OC) has become a mainstay in the effort to provide safe, reliable, and effective contraception. Safety concerns with OC use have largely been laid to rest as a result of multiple and extensive studies. Even so, misperceptions about the risks of OC use and a relative lack of recognition concerning the numerous and important noncontraceptive benefits limit their use, thus putting women in needless danger for unintended pregnancy. Indeed, even fears concerning breast cancer risk and OC use have been unsubstantiated by an abundance of data. Clinicians should be aware of the safety of low-dose OCs so that they can provide accurate and individualized counseling concerning the applicability of OCs and other contraceptive methods.

Cystic fibrosis.

Although mutation detection rates have not universally reached the 95% detection level recommended by the American Society of Human Genetics and are not likely to exceed 90% for many populations in the foreseeable future, CF carrier screening will probably be offered routinely in the near future. Although CF carrier information will be of benefit to some individuals and couples, the inability of conventional prenatal diagnosis to provide definitive diagnostic outcomes to some couples, specifically those couples in which only one partner has a detectable mutation, will make for considerable anguish and concern for some. Because genetic screening and counseling is meant to provide information and alleviate concerns and fears, the potential for CF screening to result in such a contradictory effect is of a continuing concern to those who provide obstetric and genetic services. In a National Institute of Health-sponsored workshop, Menutti and colleagues recommended that those populations to which carrier screening should be offered might include individuals and couples in high-risk groups (e.g., Ashkenazi Jews, central or northern Europeans, one partner with CF, and individuals with a family history of CF) who seek preconception counseling, infertility care, or prenatal care. The workshop participants concluded, however, that before screening can be offered systematically to these individuals or couples, practice guidelines, educational materials for providers and patients, informed-consent protocols, and laboratory standards for testing must be developed. Further advances in DNA and protein analytic capabilities, such as microchip analytic systems and protein truncation assays, may make CF screening and diagnosis more accurate and less likely to result in equivocal outcomes. In addition, it is hoped that continuing improvements in CF therapies will increase the life expectancy and improve the quality of life for individuals affected with CF. Expanding our current knowledge of genotype-phenotype correlations will not only allow us better to predict clinical outcomes but also may improve our treatments for individuals with CF because more targeted therapies may be developed for CF caused by specific mutations. Nonetheless, educational and counseling issues will, for the foreseeable future, remain of critical importance to ensure appropriate clinical care to low- and high-risk individuals.