The variability of female reproductive ageing

The delay in childbearing is an important societal change contributing to an increasing incidence of subfertility. The prevailing concept of female reproductive ageing assumes that the decline of both quantity and quality of the oocyte/follicle pool determines an age-dependent loss of female fertility. There is an apparent discrepancy between the ability to maintain a regular ovulatory cycle pattern and the several years earlier cessation of female fertility. This latter is largely explained by an age-related increase of meiotic non-disjunction leading to chromosomal aneuploidy and early pregnancy loss, such that most embryos from women > or =40 years old are chromosomally abnormal and rarely develop further. The final stage of reproductive ageing-the occurrence of menopause-shows a huge variation between women. Age at last birth in natural fertility populations, which marks the end of female fertility, shows an identically wide variation as age at menopause, but occurs on average 10 years earlier. Given the high heritability for age at menopause, the variation in both age of menopause and last birth are probably under genetic control by the same set of genes. Some of those genes must carry heritable variants which modulate the rate of ovarian ageing and give rise to the wide age variations for the various phases of reproductive ageing.     

Results of conservative management of epithelial malignant and borderline ovarian tumours

Conservative management of at least part of both the ovary and uterus can be proposed in patients with borderline ovarian tumour, in order to preserve fertility potential. This conservative management could be carried out even in patients with borderline ovarian tumour associated with non-invasive peritoneal implants (if complete resection of peritoneal disease has been performed). When facing persistent infertility after this conservative surgery, ovarian induction or an in-vitro procedure could be proposed in patients with an early-stage disease, though the number of attempts must be limited. Removal of the preserved ovary after completion of pregnancy(ies) is unnecessary if patients agree to careful follow-up. In patients with epithelial ovarian cancer, conservative management could safely be performed in young patients who wish to preserve fertility function and who fulfil the following criteria: unilateral tumour (stage IA), grade 1 (and 2?), adequate staging surgery and careful follow-up. Removal of the preserved ovary should be carried out after completion of pregnancy(ies) in order to reduce the risk of ovarian tumour recurrence.     

Preserving the reproductive potential of men and boys with cancer: current concepts and future prospects

The introduction of ICSI has totally changed the reproductive prospects for boys and men who are treated for cancer. With post-pubertal boys and adult men, semen cryopreservation should be offered to every patient undergoing a cancer treatment since preservation of fertility cannot be guaranteed for an individual patient and treatment may shift to a more sterilizing regimen. In the ICSI era, all semen samples, even those containing only a few motile sperm, should be accepted for cryopreservation. Patients who are azoospermic at the time cancer is diagnosed may be offered testicular sperm extraction and cryopreservation of testicular tissue. With pre-pubertal boys, no prevention of sterility by sperm banking is possible since no active spermatogenesis is present. However, in the next decade, prevention of sterility in childhood cancer survivors will become a major challenge for reproductive medicine. In theory, testicular stem cell banking is the only way of preserving the future fertility of boys undergoing a sterilizing chemotherapy. In animal models, testicular stem cell transplantation has proved to be effective; however, it remains to be shown that this technique is clinically efficient as well, especially when frozen-thawed cells are to be transplanted. Malignancy recurrence prevention is an important prerequisite for any clinical application of testicular stem cell transplantation. Although still at the experimental stage, cryobanking of testicular tissue from pre-pubertal boys may now be considered an acceptable strategy.     

Genetic and teratogenic effects of cancer treatments on gametes and embryos

Male and female germ cells vary in their sensitivity to the mutagenic effects of chemotherapy and radiotherapy, depending on their stage of maturation and the agent used. Although sperm DNA damage exists following treatment, no increase in genetic defects or congenital malformations was detected among children conceived to parents who have previously undergone chemotherapy or radiotherapy. The use of assisted reproductive technologies and micromanipulation techniques might increase this risk; hence caution should be exercised. In female cancer patients, miscarriage and congenital malformations are not increased following chemotherapy. However, when IVF and embryo cryopreservation is practised between or shortly after treatment, possible genetic risks to the growing oocytes exist, and hence the babies should be screened. During pregnancy, the potential teratogenic effects of chemotherapy influence the choice and timing of therapy. Termination is usually recommended in the first trimester. Second- and third-trimester exposure does not usually increase the teratogenic risk and cognitive development, but it may increase the risk of poor obstetric outcome and fetal myelosuppression. During the first two weeks after fertilization of the embryo, radiation is lethal but not teratogenic. High doses of radiation during pregnancy induce anomalies, impaired growth and mental retardation, and there may be an increased risk of childhood leukaemia and other tumours in the offspring.     

Fibroids, infertility and pregnancy wastage

Uterine fibroids are often found in women of reproductive age. Different types of fibroids may affect reproductive outcome to a different extent, with submucous, intramural and subserosal fibroids being (in decreasing order of importance) a cause of infertility and pregnancy wastage. Fibroids may also produce a number of complications during pregnancy. Women who are scheduled for assisted conception should be advised to have submucous and possibly intramural fibroids removed prior to IVF. Large fibroids (>5 cm), wherever their location, should be considered individually, with the reproductive history being an important consideration. Miscarriage rates are significantly reduced following myomectomy. Open myomectomy should be the route of choice when there are large subserosal or intramural fibroids, multiple fibroids or entry into the uterine cavity is to be expected. Proper assessment of the benefits and risks of surgery for individual patients should be carefully considered before offering a procedure.     

A meta-analysis of pregnancy outcomes in women with polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a common reproductive disorder associated with many characteristic features, including hyperandrogenaemia, insulin resistance and obesity which may have significant implications for pregnancy outcomes and long-term health of the woman. This meta-analysis was conducted to evaluate the risk of pregnancy and neonatal complications in women with PCOS. Electronic databases were searched for the following MeSH headings: PCOS, hyperandrogenism, pregnancy outcome, pregnancy complications, diabetes mellitus, type II. A handsearch of human reproduction and fertility and sterility was also conducted. Studies in which pregnancy outcomes in women with PCOS were compared with controls were considered for inclusion in this meta-analysis. Fifteen of 525 identified studies were included, involving 720 women presenting with PCOS and 4505 controls. Women with PCOS demonstrated a significantly higher risk of developing gestational diabetes [odds ratio (OR) 2.94; 95% confidence interval (CI): 1.70-5.08], pregnancy-induced hypertension (OR 3.67; 95% CI: 1.98-6.81), pre-eclampsia (OR 3.47; 95% CI: 1.95-6.17) and preterm birth (OR 1.75; 95% CI: 1.16-2.62). Their babies had a significantly higher risk of admission to a neonatal intensive care unit (OR 2.31; 95% CI: 1.25-4.26) and a higher perinatal mortality (OR 3.07; 95% CI: 1.03-9.21), unrelated to multiple births. In conclusion, women with PCOS are at increased risk of pregnancy and neonatal complications. Pre-pregnancy, antenatal and intrapartum care should be aimed at reducing these risks.     

Hormones and cardiovascular health in women

Cardiovascular diseases (CVDs) may have their origin beforebirth: the combination of being small at birth and having anoverly rich post-natal diet increases the likelihood of obesityand of acquiring a specific metabolic syndrome in adulthoodthat carries an increased risk of CVD. The incidence of CVDand mortality is very low in women of reproductive age but risesto a significant level in older women. In this article, we discussCVD in relation to hormonal contraception, pregnancy and polycysticovarian syndrome (PCOS) in younger women and menopause in olderwomen. Women with PCOS have a higher risk of diabetes and hypertension,but studies to date have not shown an effect on CVD events.Use of combined hormonal contraception has only small effectson CVD because of the low baseline incidence of myocardial infarction(MI), stroke and venous thromboembolism (VTE) among young women.Women with existing risk factors or existing CVD, however, shouldconsider alternative contraception. In pregnancy, CVD is rare,although, in the West, it now accounts for a significant proportionof maternal mortality as the frequency of obstetrical causesof mortality has substantially declined. The frequency of VTEis 15 per 10 000 during pregnancy and the post-partum period.In older women, menopause causes a slightly higher risk of MIafter allowing for age, although there is substantial heterogeneityin the results of studies on menopause and age at menopauseand MI. A larger effect might have been expected, because estrogenreduces the risk of developing atherosclerosis in premenopausalwomen, whereas in post-menopausal women who may have establishedatherosclerotic disease, estrogen increases the risk of myocardialdisease through the effects on plaque stability and clot formation.Recent trial results indicate that hormone treatment in menopausedoes not favourably affect the risk of MI, stroke or other vasculardisease. Thus, prevention of CVD should rely on diet and fitness,low-dose aspirin and treatment of hypertension, hyperglycaemiaand hyperlipidaemia.     

Intrauterine insemination: a systematic review on determinants of success

Intrauterine insemination (IUI) is a frequently indicated therapeutic modality in infertility. Here, a systematic review of the literature was performed to examine the current status of clinical and laboratory methodologies used in IUI and the impact of female and male factors on pregnancy success. Emphasis was centred in questioning the following: (i) the value of IUI against timed intercourse; (ii) IUI application with or without controlled ovarian hyperstimulation; (iii) timing and frequency of IUI; and (iv) impact of various parameters (male/female) on the prediction of pregnancy outcome. The odds of multiple pregnancy occurrence and its risk factors, as well as the cost-effectiveness of IUI treatment compared with more complex assisted reproductive technologies are discussed. A computerized literature search was performed including Medline and the Cochrane library, as well as a crossover search from retrieved papers. It is concluded that although IUI is a successful contemporary treatment for appropriately selected cases of female and/or male infertility, further research is needed through well-designed studies to improve the methodologies currently utilized. Importantly, the clinical management of the infertile couple should be performed in an expedited manner taking into consideration the age of the woman, the presence of multifactorial infertility and cost-effectiveness of the available treatment alternatives.     

Extra-uterine pregnancy following assisted conception treatment

Ectopic pregnancy may be the only life-threatening disease in which prevalence has increased as mortality has declined. The most prominent theory to explain this phenomenon involves increased sensitivity of serum beta-human chorionic gonadotrophin (HCG) immunoassay and improved quality of transvaginal ultrasound, combined with a heightened awareness and increased suspicion of the condition among clinicians which has allowed early detection of ectopic pregnancy. Laparotomy, once the standard treatment of ectopic pregnancy, has been replaced almost entirely by operative laparoscopy. This is associated with a shorter hospital stay, fewer post-operative analgesic requirements, reduced costs and lower risk of adhesion formation. Laparotomy, however, remains necessary in cases with haemodynamic instability and with exceptional locations, e.g. cervical, abdominal and interstitial implantation. In selected cases, non-surgical management has also obtained high success rates. Among medical therapies, the most common is systemic or local administration of methotrexate. The other option is expectant management involving follow-up using serial serum HCG measurements and ultrasound scans. Thus, life-threatening ectopic pregnancy is now evolving into a medical disease, with the possibility of lower-cost treatment, faster recovery and higher subsequent fertility. In this review we assess the risk of extra-uterine implantation after assisted conception treatment, the accuracy of various diagnostic tools and focus on the efficacy, safety and the fertility outcomes of surgical and nonsurgical management of ectopic pregnancy.     

Cochrane review: post-operative procedures for improving fertility following pelvic reproductive surgery

The objectives of the study was to determine the effectiveness of post-operative procedures following female pelvic reproductive surgery. A systematic review employing the principles of the Cochrane Menstrual Disorders and Subfertility Group was used. Five randomized controlled trials were included. Participants were women undergoing pelvic reproductive surgery; interventions were any post-operative procedure designed to improve fertility; outcomes were pregnancy, live birth, ectopic pregnancy and miscarriage rates and the rates of tubal patency and procedure-related complications. Summary statistics were expressed as odds ratios. The results showed that the odds of pregnancy, live birth, ectopic pregnancy and miscarriage were not significantly altered by post-operative hydrotubation nor second-look laparoscopy with adhesiolysis. Whether hydrotubation was early or late and whether hydrotubation fluid contained steroid or not had no significant impact on the odds of pregnancy, live birth, ectopic pregnancy or miscarriage. The odds of pregnancy and live birth were significantly increased and infective complications significantly decreased by hydrotubation with fluid containing antibiotic compared with hydrotubation with fluid containing no antibiotic, in late hydrotubation following tubal stent removal 6 weeks after tubal surgery. The odds of at least one patent Fallopian tube were significantly increased with late hydrotubation following tubal stent removal compared with early hydrotubation in women who had no tubal stenting, but this intervention had no significant impact on the odds of pregnancy, live birth, ectopic pregnancy or miscarriage. In conclusion, there is insufficient evidence to support the routine practice of hydrotubation or second-look laparoscopy following female pelvic reproductive surgery. The studies on which this conclusion is based were either poor quality or underpowered. Post-operative hydrotubation with fluid containing antibiotic following tubal surgery may offer benefit over hydrotubation fluid without antibiotic. A randomized controlled trial of post-operative hydrotubation with antibiotic-containing fluid versus no hydrotubation for improving fertility following tubal surgery is justified.     

Obesity and reproductive disorders in women

Obesity, particularly the abdominal phenotype, is associated with several reproductive disturbances. Whereas mechanisms by which obesity affect fertility are complex and still not completely understood, an important role appears to be played by the presence of a condition of functional hyperandrogenism and hyperinsulinaemia, which accompanies the insulin-resistant state. In women with the polycystic ovary syndrome, abdominal obesity may be co-responsible for the development of hyperandrogenism and associated chronic anovulation, through mechanisms primarily involving the insulin-mediated overstimulation of ovarian steroidogenesis and decreased sex hormone-binding globulin blood concentrations. By these mechanisms, obesity may also favour resistance to clomiphene and gonadotrophin-induced ovulation and reduce outcomes of IVF/ICSI procedures. Due to the beneficial effects of weight loss, lifestyle intervention programmes should represent the first-line approach in the treatment of infertile obese women. Insulin-sensitizing agents may add further benefits, particularly if administered in combination with hypocaloric dieting. Therefore, individualized pharmacological support aimed at favouring weight loss and improving insulin resistance should be widely extended in clinical practice in obese infertile patients. This may be beneficial even during pregnancy, thereby permitting favourable physiological delivery and healthy babies.     

Human reproductive failure I: immunological factors

Human reproductive failure may be a consequence of aberrant expression of immunological factors during pregnancy. Although the relative importance of immunological factors in human reproduction remains controversial, substantial evidence suggests that human leukocyte antigens (HLA), antisperm antibodies, integrins, the leukaemia inhibitory factor (LIF), cytokines, antiphospholipid antibodies, endometrial adhesion factors, mucins (MUC1) and uterine natural killer cells contribute to reproductive failure. In contrast, fewer data support the roles of anti-trophoblast antibodies, anti-endometrial antibodies, T-cells, peripheral natural killer cells, anti-HLA antibodies, blocking antibodies and suppressor cells in reproductive failure. Although immunological factors involved in reproductive failure have been studied traditionally using assays for antibodies and/or antigens, detailed research on these factors demonstrates conflicting results in humans. Maternal and fetal immunology is also difficult to investigate in humans. For these reasons, molecular assays may serve as a valuable alternative to investigate how the immune system affects reproductive outcome. In Part I of this review, immunological factors involved in human reproductive failure are summarized and critically evaluated. Immunogenetic and interacting factors in human reproductive failure will be summarized and evaluated in Part II.     

Recurrence of leiomyomata after myomectomy

Abdominal myomectomy (by laparotomy or by laparoscopy) enables all the myomata to be excised while maintaining reproductive function. The actual risk of recurrence after abdominal myomectomy is difficult to assess because of methodological problems. Studies using life-table analysis find a cumulative risk of clinically significant recurrence of approximately 10% at 5 years for myomectomy by laparotomy. This risk probably underestimates the true prevalence of myomata as assessed by systematic ultrasound investigation. After laparoscopic myomectomy there appears to be a greater risk of recurrence. In one third of cases, recurrence becomes the reason for a hysterectomy. The risk of recurrence increases when there is more than one myoma. The use of gonadotrophin-releasing hormone agonists preoperatively could increase the risk of recurrence. Persistence or recurrence of the myoma thus reduces the chances of conception or taking a pregnancy full term after the myomectomy. It is essential to obtain the most complete exeresis possible in order to reduce the risk of recurrence to a minimum. However, it is inevitable that small, undetectable nuclei will remain within the myometrium whatever approach is used (laparoscopy or laparotomy). It would be an advantage to know what the growth factors are and how to identify groups at high risk of recurrence so that the treatment strategies could be better adapted and appropriate prophylactic methods developed.     

Fertility in female cancer survivors: pathophysiology, preservation and the role of ovarian reserve testing

The improved long-term survival of adolescents and young women treated for cancer has resulted in an increased focus on the effects of chemotherapy on ovarian function and its preservation. These women may seek advice and treatment regarding their reproductive status, including ways of preserving their fertility and preventing a premature menopause--factors that can have a profound impact on their quality of life. This article comprehensively reviews ovarian reserve testing (ORT) in general. Special emphasis is placed on patients with cancer, including the pathophysiology of gonadal damage following chemotherapy, fertility preservation and the potential role of ORT. Baseline parameters of ovarian reserve [FSH LH, estradiol, inhibin B and anti-Mullerian hormone (AMH)] have not yet performed sufficiently well in predicting poor outcome in assisted reproduction, but biochemical markers of ovarian reserve appear to be better than chronological age. Inhibin B and AMH show potential for future use. Dynamic testing appears to show much promise, especially stimulated levels of inhibin B and estradiol. The most promising tests of ovarian reserve are the biophysical markers, where total antral follicle count was found to be most discriminatory followed by ovarian volume. Combination of biochemical, biophysical and clinical markers of ovarian reserve may also improve predictive capacity. However, there is a lack of data pertinent to ORT in cancer. As yet there is no single clinically useful test to predict ovarian reserve accurately. Patients with cancer represent a distinct cohort who have particular concerns about their future fertility and the possibility of a premature menopause, they can benefit greatly from knowledge of their functional ovarian reserve. Large, prospective, randomized, adequately controlled studies specific to different geographical areas are required in a control population of comparable reproductive age to determine the potential role of ORT in clinical practice.     

The position of diagnostic laparoscopy in current fertility practice

In everyday clinical practice, it is not always clear if and when exactly in the fertility work-up a diagnostic laparoscopy should be offered. The aim of this review is to analyse the available evidence with respect to alternative diagnostic methods for detecting tuboperitoneal infertility and with respect to the position of diagnostic laparoscopy in women with infertility. A literature search of the National Library of Medicine and the National Institutes of Health (PubMed) was performed using the key words 'diagnostic laparoscopy and infertility'. The study methodology was carefully considered in an effort to present conclusions preferably based on randomized controlled trials (RCTs). The routine use of diagnostic laparoscopy for the evaluation of all cases of female infertility is currently under debate. According to data published in retrospective non-controlled studies, diagnostic laparoscopy after several failed cycles of ovulation induction enables the detection of a significant proportion of pelvic pathology amenable to treatment. A Cochrane review has shown that laparoscopic ovarian diathermy in clomiphene-resistant polycystic ovarian syndrome is at least as effective as gonadotrophin treatment, and results in a lower multiple pregnancy rate. The role of laparoscopy before the start of treatment with intrauterine insemination is controversial, according to one RCT. In women with bilateral ultrasonically visible hydrosalpinges, two RCTs have demonstrated increased implantation and pregnancy rates in IVF cycles after salpingectomy. Although RCTs which have studied the benefit of laparoscopic surgery in moderate or severe endometriosis are still lacking, its value has generally been accepted. In conclusion, some specific clinical settings, solid evidence is available to recommend the use of diagnostic laparoscopy in current fertility practice. There is however a need for more RCTs to answer remaining questions regarding its value in the diagnosis and treatment of some patients with infertility.     

Mood disorders and fertility in women: a critical review of the literature and implications for future research

A medline literature review of fertility and mood disorder articles published since 1980 was performed in order to critically review the literature regarding a relationship between mood disorders, fertility and infertility treatment. Previous studies suggests that mood disorders, both in the bipolar and unipolar spectrum, may be associated with decreased fertility rates. Most studies report that women seeking treatment for infertility have an increased rate of depressive symptoms and possibly major depression (none showed evaluated mood elevations). Many, but not all, studies found that depressive symptoms may decrease the success rate of fertility treatment. Treatments for infertility may independently influence mood through their effects on estrogen and progesterone, which have been shown to influence mood through their actions on serotonin. Studies are limited in scope and confounding variables are many, limiting the strength of the results. In conclusion, a range of existing studies suggests that fertility and mood disorders are related in a complex way. Future studies should use clinical interviews and standardized and validated measures to confirm the diagnosis of mood disorders and control for the variables of medication treatment, desire for children, frequency of sexual intercourse, age, FSH levels, menstrual cycle regularity in assessing an interrelationship between mood disorders and fertility.     

Inhibins in female and male reproductive physiology: role in gametogenesis, conception, implantation and early pregnancy

A great deal of new information has arisen in the recent years concerning inhibin physiology and clinical relevance in reproductive medicine. It is now recognized that the two inhibin isoforms, named inhibin A and inhibin B, are produced by the gonads in the course of gamete maturation and in women have a different pattern of secretion throughout the menstrual cycle. Since inhibins are also produced by placenta and fetal membranes, it has been suggested that there is an involvement in physiological adaptation of pregnancy. Evidence from several sources has underlined the clinical usefulness of the measurement of inhibin-related proteins in the diagnosis and follow-up of different fertility disturbances and early pregnancy viability. In the male, inhibin B is produced in the testis, principally by the Sertoli cells. Inhibin B expression and secretion are positively correlated with Sertoli cell function, sperm number, and spermatogenic status and are negatively correlated with FSH. This review covers the most recent advances on the role of inhibins in human reproductive function. Considerable progress in the understanding of inhibin physiology has resulted from selective measurement of the two inhibin molecular forms, named inhibin A and B. Newly recognized alterations of inhibin levels in gynaecological diseases as well as in normal and pathological pregnancy are discussed, with particular emphasis on the potential clinical usefulness of assessing inhibin levels in serum and other biological fluids.     

The present and future state of hormonal treatment for male infertility

Although male factors contribute to over half of all cases of infertility, most infertile men are described as 'idiopathic oligo/asthenozoospermic' rather than diagnosed precisely; hence, specific medical treatment is not possible. One uncommon but treatable cause of male infertility is gonadotrophin deficiency in which gonadotrophin replacement therapy is highly effective at inducing spermatogenesis and fertility. Hormonal therapy is a logical approach for empirical drug therapy given the fundamental role of hormonal regulation in spermatogenesis. However, treatment with GnRH analogues, gonadotrophins, androgens, anti-estrogens, aromatase inhibitors, growth hormone- and prolactin-suppressing drugs is ineffective in unselected infertile men. Prolonged high-dose glucocorticoid therapy for sperm autoimmunity may improve pregnancy rates modestly, but the risks are generally unacceptable compared with IVF or ICSI. For these reasons, modern reproductive technologies, notably ICSI/IVF, have become the de-facto standard empirical treatment of male infertility, despite involving significant though infrequent risks to the fetus and mother. There remains a potential for hormonal methods to improve sperm quality or ultrastructure in subgroups of infertile men more responsive to hormonal manipulation or using novel protein or gene-targeted therapies or biochemical approaches based on post-hormonal receptor mechanisms that stimulate spermatogenesis. How such novel hormonal methods will develop in conjunction with improved ICSI/IVF or cloning technologies, and the potential role of adjunctive hormonal therapy remains to be clarified.     

Infertility in the third millennium: implications for the individual, family and society: condensed meeting report from the Bertarelli Foundation's second global conference

Primary infertility is a key issue in the developed world, while the developing world has high rates of secondary infertility. The impact of HIV/AIDS on fertility is insufficiently explored. One of the most important barriers to access to infertility treatment is cost; at the same time the role of social and cultural factors in restricting access should not be underestimated. IVF has become the standard therapy for female infertility, and ICSI for infertility of the male partner. However, the use of these therapies should not be initiated without a thorough investigation and, whenever possible, individual diagnosis of the underlying causes of infertility. Multiple gestation remains one of the most challenging and controversial issues in the treatment of infertility. Current IVF practices are often blamed for this; in this respect, attention should also be focused on the role of ovarian stimulation in ovulation induction. National guidelines and national registries for assisted reproductive technology (ART) are becoming more widespread and are expected to play an important role in promoting best practice in ART in the future.     

The risk of monozygotic twins after assisted reproductive technology: a systematic review and meta-analysis

BACKGROUND: It is estimated that there is at least a 2-fold rise in theincidence of monozygotic twinning after assisted reproductivetechnology compared with natural conception. This can resultin adverse pregnancy outcomes. METHODS: We searched MEDLINE, EMBASE and SCISEARCH for studies that estimatedthe risk of monozygotic twinning and its association with anyparticular assisted reproductive technique. Monozygotic twinningwas defined by ultrasound or Weinberg criteria. A meta-analysisof the proportion of monozygotic twins was performed using bothfixed and random effects models. RESULTS: The search revealed 37 publications reporting on the incidenceof monozygotic twins after assisted reproductive techniques.Twenty-seven studies met the inclusion criteria and were includedin the meta-analysis. The summary incidence of monozygotic twinsafter assisted conception was 0.9% (0.8–0.9%). The incidenceof monozygotic twins in natural conception is 0.4%. Blastocysttransfer and intracytoplasmic sperm injection are associatedwith 4.25 and 2.25 times higher risk of monozygotic twins. CONCLUSIONS: The risk of monozygotic twins in assisted conception is 2.25times higher than the natural conceptions. Larger studies reportingon monozygotic twinning following single-embryo transfer orafter post-natal confirmation of zygosity with DNA analysisare warranted before definitive conclusions can be drawn andguidelines produced. In order to provide adequate pre-conceptionalcounselling, it is important to monitor the incidence of monozygotictwins in both natural and assisted conceptions. We suggest buildinga national multiple pregnancy database based on accurate diagnosisof zygosity.