Infertility, ovulation induction treatments and the incidence of breast cancer--a historical prospective cohort of Israeli women.

CONTEXT: Ovulation induction drugs may be associated with increased breast cancer risk. Results so far have been inconclusive. OBJECTIVE: To evaluate the association between infertility, exposure to ovulation induction drugs and the incidence of breast cancer. DESIGN: Historical prospective cohort and nested case-control study. SETTING: Institutional practice PATIENTS: About 5,788 women attending five infertility centers in Israel between 1964 and 1984. INTENTION: Abstracting of medical records and telephone interviews. MAIN OUTCOME MEASURE: Breast cancer incidence was determined through linkage with the National Cancer Registry database. Standardized incidence ratios (SIRs) and 95% confidence intervals were computed by comparing the observed to the expected cancer rates in the general population. In addition, a nested case-control study within the cohort was performed with interviews of breast cancer cases and two matched controls. RESULTS: The study cohort included 120,895 women years of follow-up. Compared to 115.2 expected breast cancer cases, 131 cases were observed (SIR = 1.1; 95% CI 0.9-1.4). Risk for breast cancer was significantly higher for women treated with clomiphene citrate (SIR = 1.4; 95% CI 1.0-1.8). Similar results were noted when comparisons were carried out between treated and untreated women, and when multivariate models were applied. In the nested case-control study, higher cycle index (OR = 2.2; 95% CI 1.0-4.8) and treatment with clomiphene citrate (OR=2.7; 95% CI 1.3-5.7) were associated with higher risk for breast cancer. CONCLUSION: Infertility and usage of infertility drugs in general are not associated with increased risk for breast cancer. However, for infertile women treated with clomiphene citrate, breast cancer risk is elevated.

Monoamniotic twins: an update on antenatal diagnosis and treatment.

OBJECTIVE: Monoamniotic twins are very uncommon and are characterized by a high perinatal mortality rate. Cord entanglement, prematurity, congenital anomalies and twin to twin transfusion are reportedly the main causes of death, which usually occurs before 24 weeks' gestation. The aim of this study was to review the newly developed methods for diagnosis and treatment and suggest a reasonable approach to the management of these rare cases. METHOD: We reviewed the English-language literature in the past 15 years through Medline search and subsequent examination of individual publications. RESULTS: In the past two decades, newer technologies such as advanced ultrasonography and color flow Doppler studies have enabled early diagnosis of this condition and its complications. Furthermore, new treatment modalities such as fetoscopy with laser coagulation of vascular anastomoses and treatment with non-steroidal anti-inflammatory drugs such as sulindac, to reduce amniotic fluid volume, may have contributed to a better outcome. Also, occlusion of one umbilical cord (fetal reduction) at an early stage has been suggested to prevent late complications. CONCLUSION: Cumulative experience suggests that the majority of cases can be diagnosed reliably at an early gestational age. Treatment with medical amnioreduction, surgical amnioreduction or fetal reduction in selected cases may be offered before 24 weeks' gestation. Later, intensive antepartum fetal surveillance should probably be offered until 32 weeks, at which point elective preterm delivery may be considered to prevent possible fetal death.

Ovulation induction and risk of endometrial cancer: a pilot study.

OBJECTIVE: To determine whether women with endometrial carcinoma are more likely to have been exposed to fertility drugs, in particular clomiphene, than healthy population controls. STUDY DESIGN: A nationwide case-control, pilot study. About 128 living women 35-64 years old, with a histologically confirmed diagnosis of endometrial carcinoma that was first diagnosed and reported to The Israel Cancer Registry between 1 January 1989 and 31 December 1992 were enrolled. The controls were 255 women from the same dialing areas selected by random digit dialing. A variety of demographic and clinical parameters were compared between cases and controls. A multivariate logistic model, controlling for age, was used to assess the independent effects of factors found to be significantly associated with endometrial cancer on univariate analysis. RESULTS: About 7 women with endometrial carcinoma (5.5%) and 10 healthy controls (3.9%) reported that they had used any fertility drug (crude odds ratio (OR) 1.4; 95% confidence interval (CI) 0.47-4.2). Use of fertility drugs did not meet the criteria for entry into the logistic model. The following parameters were found to be independently associated with endometrial cancer controlling for age, European-American background OR=2.2, (95% CI 1.3-3.7, P=0.004); nulliparity OR=2.7 (95% CI 1.1-6.5, P=0.03); history of infertility OR=1.8 (95% CI 1.0-3.3, P=0.05); BMI> or =27 OR=2.3 (95% CI 1.4-3.9, P=0.001). The use of oral contraceptives and IUD were found to be protective, OR=0.29 and 0.37, respectively, (95% CI 0.14-0.61, P=0.001 and 0.19-0.70, P=0.003, respectively). CONCLUSIONS: We found no evidence that the use of ovulation induction agents, including clomiphene citrate, are associated with a higher risk of endometrial carcinoma. The association between infertility drugs and endometrial carcinoma should be examined in other, larger studies.

Soluble ICAM-1 and E-selectin levels correlate with clinical and biological aspects of severe ovarian hyperstimulation syndrome.

OBJECTIVE: To assess the potential involvement of the soluble endothelial cell-leukocyte adhesion molecules E-selectin and intercellular adhesion molecule-1 (ICAM-1) in the pathophysiology of capillary hyperpermeability in the ovarian hyperstimulation syndrome (OHSS). DESIGN: Controlled clinical study. SETTING: Women hospitalized for severe OHSS after ovulation induction for IVF at two tertiary medical centers. PATIENT(S): Eleven patients with severe OHSS undergoing IVF and 20 controls who had received a similar ovulation induction regimen and did not develop OHSS. INTERVENTION(S): Serial serum samples were obtained from all patients with OHSS from admission until discharge. Ascitic fluid was obtained from all patients by therapeutic paracentesis. Serum was obtained from all controls 4-8 days after ET. MAIN OUTCOME MEASURE(S): Samples were assayed for soluble E-selectin and soluble ICAM-1 by using enzyme-linked immunosorbent assay and results were correlated with clinical and biological aspects of OHSS. RESULT(S): Compared with controls, patients with severe OHSS had higher levels of soluble ICAM-1 and lower levels of soluble E-selectin detected in serum and ascites. Serum levels of soluble ICAM-1 decreased, while soluble E-selectin levels increased along with clinical and biological improvement. Serum soluble ICAM-1 showed significant positive correlation and serum soluble E-selectin showed significant negative correlation with clinical and biological aspects of severe OHSS. CONCLUSION(S): Soluble ICAM-1 and soluble E-selectin seem to be involved in the pathophysiology of capillary hyperpermeability in severe OHSS.

Hydroxyethylstarch versus human albumin for the treatment of severe ovarian hyperstimulation syndrome: a preliminary report.

OBJECTIVE: To compare the efficacy and safety of 6% hydroxyethylstarch and human albumin as colloid solutions for treatment of severe ovarian hyperstimulation syndrome (OHSS). DESIGN: Controlled cohort study. SETTING: Tertiary medical center. PATIENT(S): Sixteen patients with severe OHSS. INTERVENTION(S): Six percent hydroxyethylstarch (6 patients) and human albumin (10 patients). MAIN OUTCOME MEASURE(S): Urine output, number of abdominal and pleural drainage procedures, complications, duration of hospitalization, and perinatal outcome. RESULT(S): Patients who received 6% hydroxyethylstarch had higher urine output, needed fewer abdominal and pleural paracenteses, and had a shorter hospital stay than those who received human albumin. In each group, no adverse effects or congenital malformations were observed and the rates of miscarriage were similar. CONCLUSION(S): These results suggest that 6% hydroxyethylstarch may be superior to albumin as a colloid solution for the treatment of severe OHSS.

Is laparoscopic appendectomy safe in pregnant women?

BACKGROUND: Because of limited laboratory and clinical data, no accepted guidelines concerning the safety of laparoscopic appendectomy (LA) in pregnancy have been established yet. In this prospective study, we evaluated the safety and outcome of LA in pregnant women as compared with the same control group of pregnant women who underwent open appendectomy (OA) during the same period. METHODS: During the years 1996 to 1999, 11 consecutive pregnant women (mean age, 27 years; range 21-39 years; gestation age range, 7-34 weeks) who underwent LA were prospectively evaluated and compared with a matched group of 11 women (mean age, 30 years; range 18-42 years; gestation age range, 11-37 weeks) who underwent OA. The following parameters were analyzed: obstetric and gynecologic risk factors, length of procedure, perioperative complications, length of stay, and outcome of pregnancy. Both groups were well matched in age and risk factors for pregnancy loss. RESULTS: There was no significant difference in the length of procedure (60 vs. 46 min) and the complications rate (one in each group) between the LA and OA groups, respectively. There was no conversion in the LA group. The length of postoperative stay was shorter in the LA group (3.6 vs 5.2 days; p = 0.05). There was no fetal loss or other adverse outcome of pregnancy in either group, and all the women in both groups had normal full-term delivery. The infants' development was normal in both groups for a mean follow-up period of 30 months. CONCLUSIONS: According to this relatively small-scale study laparoscopic appendectomy in pregnant women may be as safe as open appendectomy. This procedure is technically feasible in all trimesters of pregnancy and associated with the same known benefits of laparoscopic surgery that nonpregnant patients experience.

The outcome of grand-multiparous pregnancies of Arabic and Jewish populations in peripheral and central areas of Israel.

OBJECTIVE: To compare the antepartum and intrapartum course of Jewish and Arab great-grandmultiparas from central and peripheral areas in Israel to age-matched control multiparous women. METHODS: Medical records of four groups of parturients were compared: great-grandmultiparas (para > or = 9) and multiparae (para 2-5) delivering at Nazareth E.M.M.S. hospital (mostly Arabs) and Hadassah-Ein-Kerem hospital in Jerusalem (mostly Jews). The control groups consisted of demographically and geographically matched multiparas. Data was collected on prenatal care received, antepartum complications, as well as the intrapartum complications traditionally associated with high parity (e.g. malpresentation, placental abnormalities, peripartum hemorrhage, shoulder dystocia). Neonatal records were also examined to determine any neonatal morbidity or mortality. RESULTS: There were 139 and 141 great-grandmultiparas in the Nazareth and the Jerusalem study groups, respectively (mean parity was 10.1 and 10.9, respectively), and 142 and 139 multiparas in the Nazareth and the Jerusalem control groups, respectively (mean parity was 2.9 and 2.5, respectively). The rate of physician visits during the prenatal period in the Nazareth and the Jerusalem study groups was 2.3 +/- 2.4 and 3.2 +/- 2.7, respectively (p=0.0041). This rate was significantly higher in the controls of both areas (4.0 +/- 3.0 and 4.9 +/- 2.9, respectively). There was no difference in the rate of nurse visits in all groups in all areas. Maternal and neonatal outcomes were similar in both study groups, and were also similar in the control groups, but perinatal mortality was higher in both great-grandmultiparous groups compared to the controls (11/280 and 2/281, respectively; p<0.05). CONCLUSIONS: The differences in the intensity of prenatal care between these rural and urban areas did not affect the maternal outcomes of great-grandmultiparous pregnancies. In addition, there were no significant differences in maternal outcomes between great-grandmultiparas and multiparas in rural and urban areas although prenatal care was less intense in the former. However, increased incidence of perinatal mortality in the great-grandmultiparas may be due to factors unrelated to prenatal care intensity or quality.

Women's reproductive health: monotheistic religious perspectives.

It is important to those who practice reproduction techniques to learn about the different religious attitudes related to reproductive health problems. Religion exerts an influence on civil authorities in the field of reproduction such as prevention or procreation and in issues such as abortion and infertility therapy. The Jewish attitude towards reproduction can be learned from the fact that the first commandment of God to Adam was be fruitful and multiply. Judaism allows the practice of all techniques of assisted reproduction when the oocyte and sperm originate from the wife and husband, respectively. All Rabbinical rulings permit the use of contraception for medical indications. Economic difficulties and inconveniences of raising children are not indications for birth control practice. According to Judaism abortion on demand is forbidden but it may be performed if the mother's life is in danger. The attitude toward reproductive practice is different among the different divisions of Christianity. The practice of assisted reproduction is not accepted by the Vatican, however, it may be practiced by Protestant, Anglican and other Denomination's. According to the Roman Catholic doctrine the primary purpose of marriage is procreation. The contraceptive act destroys the potential of producing new life by sexual intercourse and violates the purpose of marriage and, therefore, is a sin against nature. The Christian tradition views the embryo as a human being since conception and, therefore, abortion is strictly forbidden. According to Islam, the procedure of IVF and ET is acceptable, however, it can be preformed only if it involves the husband and the wife. It allows contraception practice only under some circumstances and only in some special cases abortion can be preformed. Religion, being concerned with affairs that are regarded as extraordinary and as having unique importance in life, is an intrinsic aspect of the culture of all societies, religious groups, however, still exert influence on the civil authorities in issues of reproduction such as contraception, procreation, abortion, and infertility therapy. They have been active in pressing their bioethical positions on the public arena in pluralistic societies. Developments in science and technology in reproduction raise new religious questions that do not always have clear answers. The role of theology in bioethics is foremost to clarify for the different religious communities the perceived attitudes toward these developments. Therefore, it is important to those who practice reproduction techniques to learn about the different religious attitudes related to reproductive health problems.

BRCA1 and BRCA2 gene mutations: decision-making dilemmas concerning testing and management.

The identification of the BRCA genes, and their possible etiologic relationship with various forms of inherited cancer, has been recognized universally as a cornerstone in the search of cancer's genetic susceptibility. Female BRCA gene mutation carriers are found to carry an increased risk of developing breast or ovarian cancer and to a lesser degree, colon cancer, and male BRCA mutation carriers are also related to an increased risk of breast, colon, or prostate cancer. Although genetic testing promises a possible future presymptomatic determination and treatment of women who are genetically susceptible to cancer, current data reveal certain dilemmas and uncertainties regarding our ability to interpret the results from testing and offer effective management options. In addition, several complex ethical, legal, and social issues have been revealed with the advent of this new information, which also confirm the need for additional research regarding the most effective use of this genetic information and for the establishment of appropriate clinical management strategies.

Ethics and assisted reproduction.

In vitro fertilization and assisted reproductive technology have made great progress during the last 20 years. Genetic material donation, human embryo cryopreservation, selective embryo reduction, preimplantation genetic diagnosis and surrogacy are currently practiced in many countries. On the other hand, embryo research is practiced only in a small number of nations, whereas human cloning has thus far been universally condemned. The rapid evolution and progress of all these techniques of assisted reproduction has revealed certain ethical issues that have to be addressed.

Ethical aspects of reproduction in the next century.

Doubtless, the technological advancements achieved in the current century in the area of young women's reproductive health care have also led to the evolution of very important ethical issues that will have to be dealt with in the coming century. Abortion, perhaps the most controversial issue of all, continues to raise a number of ethical issues related to the rights of the women versus the rights of the fetus, which, in addition to the risk of sexually transmitted diseases including the human immunodeficiency virus, emphasize the need for adequate family planning and sexual education. Genetic testing for late-onset diseases, disease susceptibilities, and carrier status may offer medical or psychological benefits; however, several complex ethical, legal, and social issues have been revealed with the advent of this new information. New family structures deviating from the traditional heterosexual couple, consisting of either single or lesbian mothers, have appeared, raising serious disputes regarding the welfare of the child. Important demographic changes are expected in the world population in the 21st century, characterized mainly by a significant increase of the older age groups.

Human umbilical cord blood banking and transplantation: a state of the art.

Human umbilical cord blood has proven to be a feasible alternative source of hematopoietic stem cells for pediatric and some adult patients with major hematologic disorders. This has promoted the establishment of cord blood banks for use in unrelated transplants worldwide. The banking of umbilical cord blood offers many advantages: absence of donor risk, absence of donor attrition, immediate availability, and the ability to expand available donor pools in targeted ethnic and racial minorities currently underrepresented in all bone marrow registries. Preliminary clinical experience suggests that, due to the immunological immaturity of cord blood cells, graft versus host disease might be lower than when using bone marrow from adult donors and HLA restrictions might be less stringent. Techniques to improve the efficacy of blood banks are currently under investigation. Closed cord blood collection methods have proven to be superior to open in reducing the risk of microbial contamination. Efficient banking requires volume reduction of cord blood units without significant loss of progenitor cells, in order to decrease storage space and cost, and this may be achieved by using the separation techniques. Cryopreservation and thawing techniques have been established and do not seem to affect the viability and progenitor cell recovery or the feasibility of CD34(+) selection and ex vivo expansion. Nevertheless, many scientific, ethical, and social questions have arisen in connection with cord blood banking that need to be addressed.

Maternal-fetal conflict.

Advances in prenatal care have brought about a greater understanding as to the special status of the fetus to the point that it is considered a patient in its own regard. Pregnant women generally follow the medical recommendations of their physicians that are intended for the benefit of their baby. Any situation where maternal well-being or wishes contradict fetal benefit constitutes a maternal-fetal conflict. Such situations include a broad range of possible interventions, non-interventions, and coercive influences. In such cases, the attending physician is expected to attain an attitude that involves either the respect of the woman's autonomy and right to privacy, which precludes any approach other than to accept her decision, or to modify this absolute for the beneficence of the fetus. Current ethical viewpoints range from absolute respect for maternal autonomy with no persuasion allowed, to gentle persuasion and to others which permit intervention and overriding of the woman's autonomy. Court-ordered decisions enforcing the pregnant woman to undergo a procedure in order to improve fetal outcome have been criticized as an invasion of a woman's privacy, limitation of her autonomy, and taking away of her right to informed consent.

Postpartum umbilical cord blood collection for transplantation: a comparison of three methods.

OBJECTIVE: This study was undertaken to compare 3 methods of collection of human umbilical cord blood. STUDY DESIGN: Seventy-five women with uncomplicated vaginal deliveries were divided equally into 3 groups. One of 3 cord blood collection methods was applied to each woman. Method 1 was collection of cord blood into a standard donation blood bag. Methods 2 and 3 used a syringe to perform a sodium chloride solution flush and drain, which included withdrawal of cord blood by a syringe until the delivery of the placenta, followed by flushing through a catheter one of the umbilical arteries with sodium chloride solution and collection of the cord blood either into an open sterile container (method 2) or into a standard donation blood bag (method 3). Analyses included comparisons among the 3 groups of volume collected, total number of white blood cells, and bacterial contamination rates (positive culture results). In addition a correlation was made between the different variables and the collected cord blood nucleated cells. RESULTS: Cord blood collection by the blood bag method (method 1), which is presently the standard clinical practice, resulted in a mean blood volume of 76.4 +/- 32.1 mL and a mean total white blood cell count of 835 +/- 507 x 10(6) cells. With collection methods 2 and 3, in which as much blood as possible was withdrawn by syringe while the placenta was still in utero followed by a second collection after infusion of the umbilical artery with sodium chloride solution, the mean volume collected was significantly higher (P <.05) at 174.4 +/- 42.8 mL and 173.7 +/- 41.3 mL, respectively, with significantly higher (P <.001) mean total white blood cell counts of 1624 +/- 887 x 10(6) cells and 1693 +/- 972 x 10(6) cells, respectively. A direct correlation was observed between the cord blood volume collected and placental weight, whereas no correlations were observed with maternal age, pregnancy duration, or the neonate's weight. Bacterial contamination was significantly higher (P =.04) in cord blood collections obtained by method 2 (48%) than by methods 1 (16%) and 3 (19%). CONCLUSIONS: The syringe-assisted sodium chloride solution flush collection method with a blood bag (method 3) was found to be the most effective method for human umbilical cord blood collection. This method doubles the total white blood cells collected with respect to current yields, which may make cord blood transplantation applicable for adults.

Voluntary and involuntary sterilization: medical, ethical, legal and religious aspects.

Surgical voluntary sterilization has become one of the most widely used methods of contraception, with vasectomy and tubal sterilization being the most commonly employed techniques, associated with a low failure, morbidity, mortality, and long-term sequelae rate. As sterilization is related with the elimination of the possibility for procreation, a number of ethical, legal and religious issues have arisen, leading often to personal misjudgements, legal disputes, and failures in applying family planning. Involuntary sterilization is currently not practiced, except in cases of severely mentally retarded people, who are unable to appreciate the consequences of their acts or care for their children and who may have a high likelihood of propagating hereditary disease.

Clinical aspects of ovarian hyperstimulation syndrome.

Ovarian hyperstimulation syndrome (OHSS) is characterized by massive transudation of protein-rich fluid (mainly albumin) from the vascular space into the peritoneal pleural and to a lesser extent to the pericardial cavities. The intensity of the syndrome is related to the degree of the follicular response in the ovaries to the ovulation inducing agents. OHSS is still a threat to every patient undergoing ovulation induction. The pathophysiology of OHSS is of extreme importance in the face of the increased use of ovulation induction agents as well as the development of sophisticated assisted reproductive techniques. The correlation found between plasma cytokine activities and the severity of OHSS suggests that plasma cytokines may be involved in the pathogenesis of OHSS and may serve as a means of monitoring the syndrome during the acute phase and throughout convalescence. The interactions between cytokine and non-cytokine mediators of the syndrome, such as the renin-angiotensin system and vascular endothelial growth factor were recently clarified. Awareness of possible mechanisms and factors in the pathophysiology of OHSS will hopefully provide opportunities to design specific treatment regimens effective for both prevention and treatment of this potentially fatal iatrogenic condition. Among IVF patients with severe and critical OHSS, pregnancy rates, multiple gestations, miscarriage, preterm premature rupture of the membranes, prematurity, and low birth weight rates are significantly higher than those reported previously for pregnancies after assisted conception. The incidence of other obstetrical complications, as well as congenital malformations and Cesarean section rates are not significantly different.

Induction of ovulation and borderline ovarian cancer--the hormonal connection?

While the data regarding the possible association between fertility drugs and invasive ovarian cancer are inconclusive, there is evidence to suggest an association between induction of ovulation and borderline ovarian tumors. The plausibility of these results is heightened by the finding that estrogen receptor expression is a common feature of ovarian borderline tumors. On the other hand, recent data indicate that in contrast to the crucial role of germline mutations in the pathogenesis of invasive ovarian cancer, these mutations play a minor role, if any, in the pathogenesis of borderline ovarian tumors. This evidence suggests that the differences between invasive and borderline ovarian tumors are not based on minor morphological criteria, but that, most probably these represent two different entities, with different clinical behavior, and that borderline tumors might be associated with hormonal factors rather than genetic mutations.