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Subfertility in the era of assisted reproduction: changes and consequences.

OBJECTIVE: To review the major changes that have occurred during the last decade of assisted reproduction technology (ART) practice, looking at the various conditions that cause subfertility. DESIGN: A short review describing the progress that has been made during the last decade of ART practice, analyzing the various conditions that cause subfertility, is presented. The efficacy of ART as a treatment of these conditions is discussed. CONCLUSIONS: Assisted reproductive technology currently is used for a wide range of indications and has become an acceptable tool in the treatment of subfertile couples. Yet, there is an ongoing debate regarding the effectiveness of ART versus conventional treatment for the various conditions that cause subfertility. The effectiveness of IVF in terms of pregnancy rate (PR) was demonstrated only for patients with severe bilateral tubal disease and male subfertility. For couples with other causes of infertility the differences in PRs do not reach statistical significance, and the efficacy of IVF has not been demonstrated clearly to date. Moreover, much of the discussion about management of subfertility has centered on costs of ART and the cost-benefit of ART versus conventional therapy for subfertility. It has been shown that, in women with unexplained infertility, menotropin treatment is as successful, less expensive, and carries a smaller risk than the surgical approach used in ART. However, the exact role of ART in the management of polycystic ovarian syndrome, immunological infertility, and endometriosis still is to be determined. Yet, as embryo implantation after ART still is considerably lower than that of fertile couples who conceive naturally, we expect that the next major thrust improving the effectiveness of ART will occur after future elucidation of factors influencing embryonic implantation.

Anovulation↗

Progress we can be proud of: U.S. trends in assisted reproduction over the first 20 years.

OBJECTIVE: Documentation of the significant progress of assisted reproductive technology (ART) therapy in the United States. DESIGN: Tabulation of data from the annual published reports of ART activity in the United States for the years 1985 through 1999. SETTING: ART centers in the United States that report their results to the Centers for Disease Control and Prevention (CDC) via the Society for Assisted Reproductive Technology (SART). PATIENT(S): The annual reports included 647,208 cycles of treatment. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The number of clinics and cycles, and the rates of pregnancy, delivery, miscarriage, and multiple pregnancy were examined. Practice trends were also examined. RESULT(S): The number of clinics and cycles has grown steadily. The 155,661 clinical pregnancies led to 128,608 births and 177,745 babies born. The advent of intracytoplasmic sperm injection (ICSI) and the fall of GIFT and zygote intrafallopian transfer (ZIFT) are noted. Pregnancy rates have risen steadily in all therapies, and the number of deliveries of triplets or more has declined dramatically in the most recent reporting years. CONCLUSION(S): Over the years, ART therapies have steadily become more effective, with notable reductions in multiple pregnancies, the ability to avoid laparoscopy (for egg retrieval and in some cases tubal transfers), and effective therapy for serious sperm, egg, and uterine problems, none of which was true in the early years. This has occurred owing to the dedication and ingenuity of practitioners, and, notably, without federal regulation of clinical practice.

Female↗

Laparoscopic microsurgical anastomosis of the blocked, solitary post-ectopic Fallopian tube: case report.

The surgical options for the management of ectopic pregnancy include linear salpingotomy or salpingectomy. If salpingotomy is performed, subsequent tubal blockage may result and if this occurs in a solitary Fallopian tube then assisted reproductive technology is recommended as the treatment of choice. We describe a case report detailing the application of laparoscopic microsurgical tubal reanastomosis in two patients with post-ectopic blockage in a solitary Fallopian tube. Both patients conceived post-operatively and subsequently delivered term pregnancies. Laparoscopic microsurgery offers an alternative to assisted reproductive technology in patients with post-ectopic tubal obstruction in a single Fallopian tube.

Adult↗

Heterotopic pregnancy: report of three cases.

OBJECTIVE: Heterotopic pregnancy, defined as concomitant intrauterine and ectopic pregnancy, is a rare event. Assisted reproductive technologies have led to an increase in the number of heterotopic pregnancies. MATERIALS AND METHOD: From 1997 to 1999 three cases of heterotopic pregnancies were referred to the gynecological unit of the hospital of St. Pölten. The condition was diagnosed at 7, 8 and 12 weeks of gestation, respectively. Two patients had undergone assisted reproductive technologies and former pelvic surgery for tubal pregnancy. Two patients had intrauterine singleton pregnancies and one patient had an intrauterine twin pregnancy. In all cases the ectopic site presented as a ruptured tubal pregnancy and the treatment consisted of laparoscopic salpingectomy. RESULTS: In all patients the postoperative course was uneventful and the intrauterine pregnancy progressed. In one case recurrent preterm labor led to vaginal delivery at 33 weeks of pregnancy. In the case of twin pregnancy, a planned cesarean section was performed at 37 weeks of gestation. One patient delivered at term. All newborns were healthy. CONCLUSION: Knowledge of heterotopic pregnancy and understanding the epidemiological risk factors underlying this condition are important for early diagnosis with the aim of improving therapy and clinical outcome.

Adult↗

Fertility preservation and pregnancy outcome after malignancy.

PURPOSE OF REVIEW: The overall survival and cure rates of patients with childhood and adult malignancies have improved dramatically, but cancer treatment can be associated with diminished reproductive potential. However, research on the preservation of fertility in these patients has given patients new options. This article discusses the mechanisms of reproductive failure after cancer therapy and the currently available fertility preservation strategies. RECENT FINDINGS: Ovarian transposition is still a viable option if radiotherapy is to be used alone. Modifications in assisted reproductive technology that decrease peak estradiol levels are ideal for breast cancer survivors. Embryo freezing technology offers excellent pregnancy rates. Oocyte freezing is available for women without a partner, but there is more limited experience with this technique. Understanding the concepts of graft function after the autotransplantation of frozen-thawed ovarian tissue has resulted in great strides in the technical requirements for success. SUMMARY: Gonadotropin-releasing hormone analogues are the only available medical protection means for gonadotoxic chemotherapy. Assisted reproductive technology offers excellent results, but the protocols require a delay in implementing chemotherapy. Despite recent reports of embryo development after the transplantation of cryopreserved-thawed ovarian tissue, clinical experience is limited and the technique remains experimental.

Antineoplastic Agents↗

Follicle stimulating hormone as a predictor of fertility.

Tests for diminished ovarian reserve provide valuable prognostic information for women considering assisted reproductive technology. The best characterized screening tool for a general infertility patient is the clomiphene citrate challenge test. These screening tests do not have absolute sensitivity or specificity. Additionally, the predictive value of these tests can be low if used in a population at low risk. Patients with abnormal testing should be counselled that their chances of conception with assisted reproductive technology are poor. This may impact on the choice of aggressive treatment; however, the results of these tests should never be used to exclude patients from care.

Female↗

Fertility options for patients with stages IA2 and IB cervical cancer: presentation of two cases and discussion of technical and ethical issues.

BACKGROUND: Ten percent to 15% of women diagnosed with cervical cancer are in their childbearing years. Traditional therapy for stage IA2 and IB lesions, radical hysterectomy, negates future fertility potential. Assisted reproductive technology might offer these women fertility options. CASES: Two cases of young nulliparous women with stage IA2 cervical cancer, who underwent ovarian stimulation and oocyte retrieval followed by radical hysterectomy, were presented to illustrate the technical difficulties of oocyte stimulation and retrieval in the setting of cervical carcinoma. CONCLUSION: Many issues should be considered when counseling a woman with early-stage cervical cancer about future fertility. These include ethical issues of embryo freezing and gestational surrogacy and practical issues of ovarian preservation and transposition. No current guidelines exist to identify appropriate candidates for assisted reproductive technology in this setting.

Adult↗

Human embryo cloning prohibited in Hong Kong.

Since the birth of Dolly (the cloned sheep) in 1997, debates have arisen on the ethical and legal questions of cloning-for-biomedical-research (more commonly termed "therapeutic cloning") and of reproductive cloning using human gametes. Hong Kong enacted the Human Reproductive Technology Ordinance (Cap 561) in 2000. Section 15(1)(e) of this Ordinance prohibits the "replacing of the nucleus of a cell of an embryo with a nucleus taken from any other cell," i.e., nucleus substitution. Section 15(1)(f) prohibits the cloning of any embryo. The scope of the latter, therefore, is arguably the widest, prohibiting all cloning techniques such as cell nucleus replacement, embryo splitting, parthenogenesis, and cloning using stem cell lines. Although the Human Reproductive Technology Ordinance is not yet fully operative, this article examines how these prohibitions may adversely impact on basic research and the vision of the Hong Kong scientific community. It concludes that in light of recent scientific developments, it is time to review if the law offers a coherent set of policies in this area.

Cloning, Organism↗

The ovarian hyperstimulation syndrome.

OBJECTIVE: To review the up-to-date literature concerning the pathogenesis of, risk factors for, prevention of, and therapy for the ovarian hyperstimulation syndrome, and to provide suggestions for management of this syndrome. DESIGN: Literature review combined with on-site clinical experiences at the authors' institution of practice. PATIENT(S): Women who have risk factors for or manifest the ovarian hyperstimulation syndrome. INTERVENTION(S): Intravenous fluid management, thrombosis prevention techniques, paracentesis techniques, and critical care management protocols. MAIN OUTCOME MEASURE(S): Staging system of the ovarian hyperstimulation syndrome, criteria for outpatient versus hospitalization management, and indications for varying levels of interventional management. RESULT(S): The ovarian hyperstimulation syndrome, unique to the field of assisted reproductive technology, remains a largely elusive and unpredictable iatrogenic physiologic complication in the course of pharmacologic ovarian stimulation. Reliable information on risk factors, possible physiologic mechanisms, prevention techniques, and management is fortunately progressing, and overall advances are being made in this field. The present review is an attempt to summarize the modern literature regarding this syndrome and to use this current knowledge to provide a basis for acceptable management regimens. CONCLUSION(S): Ovarian hyperstimulation syndrome is a serious complication of assisted reproductive technology, with potential for critical morbidity and death. Physicians who prescribe medications known to be associated with this syndrome should be familiar with identifiable risk factors, means of prevention, and a system for staging and treating the disease and have a current knowledge base for putative models of pathogenesis.

Ambulatory Care↗

Serum free beta-HCG and alpha-fetoprotein levels in IVF, ICSI and frozen embryo transfer pregnancies in maternal mid-trimester serum screening for Down's syndrome.

BACKGROUND: The aim of this study was to compare the maternal mid-trimester free beta-HCG and alpha-fetoprotein (AFP) levels in pregnancies conceived by assisted reproduction technology and spontaneous pregnancies in Down's syndrome screening. The influence of the number of embryos transferred and the amount of gonadotrophins used on the marker levels was also evaluated. METHODS: The study population consisted of 58 IVF, 32 ICSI and 26 frozen embryo transfer (FET) singleton pregnancies. The levels of beta-HCG and AFP were compared with the control group of 6548 singleton spontaneous pregnancies. RESULTS: The false positive rate (FPR) in the Down's syndrome screening was 19% overall in assisted reproductive technology pregnancies, being highest (30.8%) in the FET group. The free beta-HCG multiples of the median (MoM) values were statistically significantly elevated only in the FET group (1.33 MoM; P = 0.012). A positive correlation between the number of embryos transferred and the marker levels was observed in the IVF group. No correlation was found between the amount of gonadotrophin medication used and the marker levels. CONCLUSIONS: The present data confirm that the overall FPR in the serum screening for Down's syndrome in assisted reproduction pregnancies is high, resulting in unnecessary invasive procedures.

Adult↗

Manipulation of domestic animal embryos and implications for development.

Assisted reproductive technologies, as applied to domestic animals, can exert both novel and wide-ranging influences on the development, viability and welfare of offspring. Some of the changes are evident immediately or soon after the time at which a manipulative procedure is carried out, while other changes may not be evident until later in development or, perhaps, may remain undetected throughout an animal's lifetime. The present review explores some of the consequences - in terms of foetal, placental, neonatal and post-natal effects - of exposing embryos of cattle, sheep and other species to in vitro culture per se or, during culture, to physically invasive technologies including gene injection and nuclear transfer. The innate sensitivity of oocytes and recently fertilized eggs to their in vitro environment is illustrated by an examination of the later developmental repercussions resulting from apparently innocuous choices related to in vitro culture medium formulations. In contrast, an inherent resilience and paradoxical readiness to resume development following the traumas of nuclear transfer procedures is also in evidence. The extent to which assisted reproductive technologies will succeed, where relevant, in the domestic animal sector will be influenced by our appreciation of embryo requirements, for both short- and long-term developmental fitness, during their earliest developmental stages. Evidence of species-specific needs is testimony to the challenges ahead. Ultimately, our ability and inclination to resolve the limitations associated with current procedures will probably be greatly enhanced if predictive indicators (genetic, epigenetic or functional markers) of later developmental fitness can be identified.

Animals↗

The detection of diminished ovarian reserve in infertile women.

Women in their mid to late 30s and early 40s with infertility constitute the largest portion of the total infertility population. These women frequently undergo multiple testing, and most will require expensive and invasive therapies, including assisted reproductive technologies, with markedly reduced pregnancy rates in those older than 40. These women also have a higher incidence of pregnancy loss even after documentation of fetal cardiac activity by ultrasonography. Identifying those women who have a very low chance of pregnancy (and a high chance of pregnancy loss) with their own gametes presents a daily challenge to the practicing clinician, especially before embarking on expensive treatments. This article reviews the contemporary investigation of reproductive aging with basal and provocative tests. Women with markedly diminished ovarian reserve should be counseled on their low chances of conception with their own gametes, even with assisted reproductive technologies.

Aging↗

Prenatal genetic counseling.

Continued advances in reproductive technology and prenatal diagnosis challenge genetic counselors in their provision of appropriate prenatal genetic counseling. Complex information must be communicated to the couple in a nondirective but supportive manner for the couple to make an informed decision. Often pertinent information must be gathered and disseminated in a short period of time as a pregnancy continues toward the point of viability, and options become limited. Prenatal genetic counseling strives to keep up with the changes in reproductive technology and prenatal diagnosis in an effort to meet the needs of the patient.

Abortion, Eugenic↗

Diverse phenotypes and fertility outcomes of patients with androgen insensitivity syndrome in a Chinese family harboring identical AR gene variant.

BACKGROUND: Androgen insensitivity syndrome (AIS) is a rare genetic disorder characterized by resistance to androgens, mainly due to mutations in the androgen receptor (AR) gene. It can manifest as complete AIS, partial AIS and mild AIS. While there have been studies linking specific AR gene mutations to AIS phenotypes, different clinical AIS phenotypes are also reported in patients with the same AR gene mutation. So far, the precise correlations between phenotypes and genotypes remain incompletely understood. METHODS: We conducted a thorough investigation involving four patients diagnosed with different types of AIS from a single Chinese family. Clinical manifestations, laboratory examinations, and fertility outcomes were well-documented. Furthermore, we performed genetic sequencing to detect possible pathogenetic variants. RESULTS: Whole exome sequencing identified a hemizygous missense variant (c.2263T > C; p.Phe755Leu) of AR gene in all four affected patients with different degrees of undermasculinisation and heterogeneous spermatogenesis. The proband, diagnosed with partial AIS, opted for treatment with donated sperm due to non-obstructive azoospermia, while their older sibling, diagnosed with complete AIS, was raised as a girl. His two maternal uncles were both diagnosed with mild AIS, the older uncle fathered two girls naturally, whereas the younger uncle utilized assisted reproductive technology to conceive a boy because of severe oligoasthenozoospermia. CONCLUSION: Our study first identified the same AR variant (c.2263T > C;p.Phe755Leu) in four affected patients displaying highly diverse phenotypes of AIS and fertility outcomes, thereby significantly expanding the phenotypic spectrum of AIS. Notably, we presented a clear insight into different fertility outcomes of AIS patients with identical AR (c.2263T > C;p.Phe755Leu) variant, which provided reliable evidence that males harboring this variant may obtain biological offspring naturally or in combination with assisted reproductive technology. Furthermore, our study underscored the potential role of androgen concentration in shaping the phenotypic diversity of AIS, warranting further investigation.

Adult↗

Dynamism to promote reproductive medicine and its development, Rihachi Iizuka.

Rihachi Iizuka has contributed strong leadership for the remarkable development of reproductive medicine which has undergone a complete transformation in the previous half century. The Keio University Hospital introduced artificial insemination as the first assisted reproductive technology in Japan. As it follows, lizuka and his colleagues first reported the live birth of a female infant in August 1949 after heterologous insemination: AID. Iizuka and his colleagues were also among the first to successfully inseminate a woman with sperm that had been frozen. He developed the new cryopreservation medium for human semen called "KS Cryo-medium". He also developed semen preparation methods of washing and concentrating sperm counts by centrifugation with Percoll (colloidal silica derivative) solution for oligozoospermic patients. These methods are broadly used in the clinical field. Furthermore, he developed the X-, Y-bearing sperm preseparation method using Percoll which is the so-called "gender selection" procedure for preventing X-linked genetic disorders. The most striking assisted reproductive technology was in vitro fertilization first carried out in Britain. Prior to the clinical application in Japan, the Japan Society of Fertilization and Implantation was established as the main organ for the exchange of official scientific information by lizuka in 1982. As rapid development and spreading of in vitro fertilization and its implicated technologies, lizuka and his colleague of the department had the first success of offspring following embryo freezing and thawing in Japan which was performed at the Tokyo Dental College Ichikawa General Hospital. Already the numbers of offspring following in vitro fertilization treatment has risen to approximately 1% of births in Japan. Rihachi lizuka still undertakes the responsibility for reproductive medicine as he has done so far.

Female↗

Infertility: etiologies, evaluation and treatments.

Approximately 12-15% of couples are considered infertile and seek medical care. This review will delineate the current etiologies of infertility and outline a detailed evaluation. Treatment of the infertile couple should be targeted towards specific causes with empiric therapies reserved for those with unexplained infertility. Currently, great advances in the area of assisted reproductive technology allow physicians to treat couples with severe male factor infertility and tubal disease who previously had little hope of conceiving. The most common etiologies of infertility include tubal and peritoneal disorders, ovulatory dysfunction and male factor. Other conditions causing infertility are mentioned in this review for completeness sake. Surgery often corrects infertility due to tubal and peritoneal disease while a variety of medications exist to successfully manage ovulatory dysfunction. Couples who fail to conceive with those conservative measures are candidates for assisted reproductive technology such as in vitro fertilization (IVF). Recent advances in IVF lab techniques allow for correction of severe male factor infertility through use of intracytoplasmic sperm injection.

Journal Article↗

Medical study: aspiring parents, genotypes and phenotypes: the unexamined myth of the perfect baby.

Although many have argued that assisted reproductive technologies ("ARTs") attract those with a desire to genetically engineer their offspring, this claim has yet to be verified. To address this question, we surveyed three groups: the general public, people enrolling in an in vitro fertilization ("IVF") program, and pregnant couples. We asked subject which traits they would select in their children if it were possible to use a magic wand to do so and to value genetic relatedness. In our sample, the potential parents who were using ARTs were less likely to express a desire to select traits in their offspring than were the general public, and just as likely as the pregnant couples, Those using ARTs , however, place greater importance on having genetically related children than the others. Thus, the widely held view that reproductive technology is utilized by those most likely to favor genetic engineering is falsified by out findings.

Analysis of Variance↗

Heterotopic abdominal pregnancy following in-vitro fertilization/embryo transfer presenting as massive lower gastrointestinal bleeding.

We present a case that, as far as we know, is the first report of lower gastrointestinal haemorrhage as a complication of heterotopic pregnancy induced by artificial reproductive technology. The heterotopic abdominal pregnancy caused erosion of the intestinal wall and massive rectal bleeding, 8 weeks after in-vitro fertilization/embryo transfer. The source of the bleeding could not be identified despite comprehensive investigation including gastroscopy, ultrasonography, sigmoidoscopy, 99Tc (technetium) scanning and angiography. Tagged-erythrocyte isotope scanning revealed an abnormal concentration in the left lower quadrant, compatible with active bleeding in the area of the terminal ileum. Laparotomy disclosed a heterotopic abdominal pregnancy, causing erosion of the intestinal wall at this site. As assisted reproductive technologies become more and more common this rare complication of intestinal erosion should be kept in mind in case of lower gastrointestinal bleeding.

Abdomen↗