Sperm banking and assisted reproduction treatment for couples following cancer treatment of the male partner

In recent years, the survival of young males suffering from cancer has been improved. Development of new techniques such as IVF and intracytoplasmic sperm injection enables even low quality spermatozoa to be used successfully. It is possible therefore to preserve fertility potential of cancer patients before embarking on adjuvant chemotherapy and radiotherapy. Recognizing the importance of protecting the fertility potential of these young males, we present our recommendations for sperm cryopreservation based on the 11 year experience of Bourn Hall and the British Joint Council for Clinical Oncology consultation report. This paper discusses the options available for patients who recover from cancer to become fathers. In many cases patients are concerned about possible abnormalities and teratogenic risks to their future children who have been conceived naturally or by fertility treatment. The data available in the literature may reassure the medical community that there is no such increased risk. However, due to the relatively small number of children born after such treatment, a long-term follow-up is required. There is an ongoing debate regarding the justification for the programme due to the small number of patients who make use of their banked spermatozoa. The authors believe in the importance of protecting the fertility potential of cancer patients, enabling them to father their genetic children in the future while fighting their illness.     

In-vitro fertilization with donor sperm after failure of artificial insemination

This retrospective study compares results of artificial inseminationby donor (AID) and in-vitro fertilization (IVF) trials, andespecially of IVF treatment with fresh donor spermatozoa inpatients who were unsuccessfully treated on 18 occasions byAID using frozen semen. AID gives cumulative pregnancy rateof 54.6% after six trials. But after 18 trials, 22.4% of thepatients were still not pregnant. Treating them with IVF gavea probability of pregnancy as good as in the other IVF patients,53.9% after six trials. However, pregnancy loss rates differedresulting in cumulative normal pregnancy rates of 16.2% in AIDcycles ranking from 19 to 24 compared with 41.8% when goingto IVF. In ‘ex-ATD’ women, significantly more follicleswere punctured, but the number of oocytes obtained and fertilized,embryos replaced, and the incidence of pregnancy did not differfrom the other patients. Considering separately the variousinfertility factors encountered in the patients, the pregnancyrates still did not differ between ex-AID women and the others.Changing from long-term failed AID to IVF is certainly acceptableand even more so with the newly introduced technique of trans-vaginalpuncture. The female infertility factors involved in AID failureare corrected in IVF.     

Perinatal outcome and developmental studies on children born after IVF

Since the first birth after IVF, many scientific papers have been published on the technical aspects of the IVF procedure, but few studies have addressed the issue of the perinatal outcome of IVF pregnancies and of the children's development and well-being. A high rate of adverse outcome has been demonstrated in a large group of IVF pregnancies. Prematurity, low birth weight and perinatal mortality are higher than in the general population. The majority of these complications are related to multiple births, but they are also found in singleton pregnancies. An analysis of the multiple risk factors involved in these complications is needed. The infertile status of IVF patients clearly plays a role in the risk of adverse outcome. Age and parity may be important factors. The role of IVF itself has not been demonstrated convincingly. The effect of ovarian stimulation deserves further study. Most of the studies published on the follow-up of IVF children are reassuring, but it is clear that these studies are not sufficient to eliminate without doubt any adverse effects on the well-being of IVF children. All IVF pregnancies should be followed with great care, not because they are more precious than spontaneous pregnancies, but because they are exposed to an increased risk of complications. The main problem of IVF remains the high rate of multiple pregnancies, including twins.     

Outcome and follow-up of children born after IVF-surrogacy

This study addresses various outcomes and follow-up of children born after IVF-surrogacy. Recent reports on perinatal outcome after IVF-surrogacy and on data generated by the Society of Assisted Reproductive Technology (SART) Registry between 1991 and 1995 were examined. A review of recently published perinatal outcomes of children born after IVF-surrogacy, including the developmental information of 110 children after the first 2 years of life, was undertaken. The birth weights for singleton pregnancies following IVF-surrogacy and IVF were similar, whereas the birth weights of twins and triplets born from the IVF-surrogates were significantly heavier than those delivered from conventional IVF patients. Preterm delivery was increased in twin and triplet gestations in all segments analysed. The incidence of low birth weight was significantly lower in children born after IVF surrogacy than in those born after IVF, for all births recorded. The incidence of congenital abnormalities following IVF and IVF-surrogacy was within the expected range for spontaneous conceptions. Speech delays were predominant in the multiple births, but neither speech nor motor delays persisted at 2 years of age in children born after IVF-surrogacy. These findings would imply that a gestational carrier would provide potential environmental benefits for the infant.     

Neuromotor, cognitive, language and behavioural outcome in children born following IVF or ICSI-a systematic review

BACKGROUND: The effect of in vitro fertilization (IVF) or intracytoplasmicsperm injection (ICSI) on the developing human brain is unclear.The objective of this study is to evaluate neurodevelopmental(ND) outcome of children born following these techniques. METHODS: This systematic review includes studies which compare a groupof children born following IVF/ICSI to children born after naturalconception by assessing outcome in terms of neuromotor development,cognition, speech/language and behaviour. Specific attentionis paid to the studies’ methodological quality based onstudy design, attrition, blinding of the assessor, validityof ND tests used, confounders included and group size or poweranalysis. RESULTS: Twenty-three out of 59 studies had a good methodological qualityincluding 9 register-based (RB) and 14 controlled studies. RBstudies suggested that IVF/ICSI per se does not increase therisk for severe cognitive impairment (i.e. mental retardation)or neuromotor handicaps such as cerebral palsy (CP), the associationof IVF/ICSI and CP being brought about by the association ofassisted conception with risk factors, like preterm birth. Ingeneral, controlled studies of good quality did not report anexcess of ND disorders in IVF/ICSI-children. However, the majorityof studies followed the children during infancy only, therebyprecluding pertinent conclusions on the risk of ND disordersthat come to the expression at older ages, such as fine manipulativedisability or dyslexia. CONCLUSIONS: A negative effect of assisted conception on the developing humanbrain is not identified; however, further research of high methodologicalquality in children beyond pre-school age is needed.     

The varicocele dilemma

There is probably no subject that is more controversial in the area of male infertility than varicocele. The overwhelming majority of non-urologist infertility specialists in the world are extremely sceptical of the role of varicocele or varicocelectomy in the treatment of male infertility. Directors of most assisted reproductive technologies (ART) programmes view the enthusiasm with which urologists approach varicocelectomy as a potential impediment to the couple that is getting older and do not have much time left to become pregnant using ART. There are many credible, well-controlled studies which show no effect of varicocelectomy on fertility. There are also a few 'controlled' studies that favour varicocelectomy, but all can be criticised on the basis of patient selection bias. Thus the great weight of evidence from controlled studies is against varicocelectomy and the reports supporting varicocelectomy are extremely weak. Finally, the reports that semen parameters are improved by varicocelectomy is flawed by uncontrolled observations and the failure to take into account the variability of semen analysis in infertile men and its regression toward the mean. Many control studies have demonstrated that, because of this variability, men with an initially low sperm count tend later to have higher sperm counts in the absence of any treatment whatsoever.     

Gamete intra-fallopian transfer with cryopreserved donor semen following AID failure

Results are presented of gamete intra-Fallopian transfer with cryopreserved donor semen in cases of male infertility with azoospermia or extreme oligozoospermia. The female partners had no detectable infertility problems and they had first received 10 cycles of intracervical AID without success. Forty-one GIFT cycles performed on 22 such patients gave an overall pregnancy rate of 26.8% (11/41). In 64% (9/14) of these cases, pregnancy occurred after the first GIFT attempt. From these results it is suggested that GIFT with donor semen may be a reasonable alternative after AID failure. The probable reasons for success of GIFT are discussed.     

Cohort follow-up of couples with primary infertility in an ART programme using frozen donor semen

BACKGROUND: This study was designed to determine the crude cumulative live-birth rates in a cohort initiating frozen donor semen treatment until completion. METHODS: This cohort study included 588 couples with primary infertility in one University Hospital centre. The treatment sequence involved first artificial insemination (AID) followed by IVF if necessary (IVF-D). Live birth, drop-out for personal or medical reasons and recourse to IVF-D were recorded for all patients. Live births and drop-out were expressed both as rates per cycle and crude cumulative rates. RESULTS: At the completion of AID and IVF-D cycles, 406 couples in the cohort (69%) achieved a live-birth and 182 couples (31%) discontinued treatment. In most cases, couples stopped treatment for personal reasons (74%) whereas fewer couples were denied further treatment for medical reasons (26%). CONCLUSIONS: This is the first report on the crude cumulative live-birth rate in a cohort after AID and IVF-D cycles. Although calculation based on crude cumulative live-birth rate shows lower results in comparison with life table analysis, this method allows patients to obtain an insight into their actual chances of achieving a successful pregnancy.     

Fertilization in vitro of human oocytes by spermatozoa collected in different stressful situations

It has been shown that semen quality is impaired in couplesundergoing in-vitro fertilization (IVF), probably due to stress.A possible effect of stress on the ability of spermatozoa tofertilize human oocytes in vitro was analysed in the presentstudy composed of 26 couples with normozoospermic men undergoingIVF. A semen sample was obtained during the infertility work-upand was cryopreserved (sample 1). A second sample (sample 2)was provided after oocyte retrieval during the IVF cycle. Sample1 was thawed and both samples were washed and preincubated foroocyte insemination. One-hundred-and-five oocytes were inseminatedusing thawed sample 1, and 120 with sample 2.Semen parameterssuch as density, progressive motility and percentage of abnormalforms were compared between sample 1, before and after freezing,and sample 2. Only motility was significantly (P<0.01) decreasedby cryopreservation in sample 1, but no parameter was significantlydifferent when fresh sample 1 was compared to sample 2. Thefertilization rate was 78.6% using sample 1 in comparison to87.5% when sample 2 was employed (not significant, NS). Cleavagerates were 77.7 and 89.7%, respectively (NS). A group of fivepatients undergoing IVF who needed donor semen served as a controlfor the effect of sperm cryopreservation on IVF. In these cases,the donor was asked to provide a fresh sample. Half of thissample was frozen and thawed. Subsequently, fresh and thawedsamples were prepared for insemination and oocytes inseminatedeither with the fresh preparation (n=24) or the frozen and thawedspermatozoa (n=22). There was a significant (P<0.05) decreasein motility in the thawed sample, but fertilization and cleavagerates were not different. These data suggest that the stressfulsituation induced by IVF treatment in normozoospermic men doesnot affect the ability of spermatozoa to fertilize human oocytesin vitro. Cryopreservation of human spermatozoa before IVF maybe a good policy in couples especially suspected of being understress during this procedure.     

The relationship between fertility potential measurements on cryobanked semen and fecundity of sperm donors

Sperm penetration assay (SPA) scores obtained from cryobanked semen were correlated with therapeutic insemination (TI) fecundity in a group of established sperm donors, thereby evaluating the efficacy of the SPA in screening donors for sperm banking. While the SPA has been used to separate fertile from infertile males, we altered assay conditions to use frozen semen and to distinguish performance among fertile donors. Three frozen ejaculates from 11 pregnancy-proven donors were analysed. Of 905 TI cycles, 275 recipients achieved 95 pregnancies. There were no significant relationships between fecundity and donor semen, washed sperm parameters, sperm recoveries or recipient age. A significant relationship was revealed between mean SPA scores (range 8.7-66.6 penetrations/ovum) and donor fecundity (range 0.04-0.16, P < 0.03). Sperm concentration was varied in an effort to establish the most sensitive test condition. Using 0.25x10(6) motile spermatozoa/ml, a highly significant relationship was observed (P < 0.002). The four donors with the lowest SPA scores achieved the four lowest fecundities. It is concluded that a modified SPA can be used on frozen donor semen to estimate donor fertility potential. If applied routinely in donor semen banking, poor quality applicants could be excluded, thereby increasing pregnancy rates while decreasing donor screening costs.     

Andrology: Strategies in frozen donor semen procreation

Data were analysed from 710 couples who had been assessed todetermine the effectiveness and the drawbacks of three differentmethods of insemination using frozen donor semen. Intracervicalinsemination (ICI) was the first method used when the womenhad no tubal disorder: 255 pregnancies were achieved in a totalof 2558 cycles (10%). Intrauterine insemination (IUI) associatedwith ovarian stimulation resulted in 152 pregnancies over 966cycles (16%). In-vitro fertilization (IVF) was proposed after12 insemination failures using either of the other methods orwhen the initial gynaecological examination had revealed abnormalitiessuch as tubal occlusions; 48 pregnancies were obtained in 262cycles (18.3%). The pregnancy rate using ICI was significantlyhigher when two inseminations were performed per cycle, comparedwith one insemination per cycle (12.3 versus 7%, P < 0.001).The number of motile spermatozoa per straw was correlated withthe pregnancy rate when using ICI, rising from 9% with <4X10⁶motile spermatozoa to 13.8% with 4–8X10⁶ and 17.2% with>8X10⁶. No relationship was found between the number of motilespermatozoa and the pregnancy rate using IUI and IVF. The incidenceof primary ovulatory disorder was higher among women whose husbandswere oligozoospermic than among those whose husbands were azoospermic(19 versus 9%, P < 0.01), but ovarian stimulation improvedthe fecundity of subfertile women. The outcome of pregnancieswas also analysed for the three methods. From these data, strategicplans have been proposed to maximize the pregnancy rate forwomen undergoing therapeutic donor insemination with frozensemen.     

Effect of overweight and obesity on assisted reproductive technology--a systematic review

Obesity is known to be associated with sub-optimal reproductive performance but its direct effect on the outcome of assisted reproduction techniques (ART) is less clear. This present study aimed to perform a systematic review of the available evidence to assess the effects of obesity on the outcome of ART. A number of observational studies were identified. Interpretation of the results was compromised by variations in the methods used to define overweight and obese populations and inconsistencies in the choice and definition of outcome measures. Compared with women with a BMI of 25 kg/m(2) or less, women with a BMI > or = 25 kg/m(2) have a lower chance of pregnancy following IVF [odds ratio (OR) 0.71, 95% CI: 0.62, 0.81], require higher dose of gonadotrophins (weighed mean differences 210.08, 95% CI: 149.12, 271.05) and have an increased miscarriage rate (OR 1.33, 95% CI: 1.06, 1.68). There is insufficient evidence on the effect of BMI on live birth, cycle cancellation, oocyte recovery and ovarian hyperstimulation syndrome. Further studies with clear entry criteria and uniform reporting of outcomes are needed to investigate the true impact of weight on the outcome of ART.     

Achievement of second parenthood in an ART programme using frozen donor semen: cohort follow-up

BACKGROUND: This study was designed to determine the efficacy of a programme using frozen donor semen in a cohort of patients returning for treatment after previously conceiving through donor insemination (DI). METHODS: The cohort included 222 couples with secondary infertility (previous live birth) in one University Hospital Centre. The treatment sequence involved DI cycles until completion. Live births, drop-out for personal or medical reasons and recourse to IVF with donor semen (IVF-D) were recorded for all patients. Live births were expressed as both rate per cycle and crude cumulative rate. RESULTS: At the end of the DI cycles, 65% of couples in the cohort achieved second parenthood. Most of them (77%) succeeded after only four DI cycles. The majority of couples who stopped treatment did so for personal reasons. CONCLUSIONS: Patients involved in a second parenthood project belong to a 'selected' population. Management and counselling of such patients need to reconcile the early efficacy of DI cycles, the invasiveness of the IVF-D procedure and the availability of donor semen.     

Follow-up of children born after ICSI

The comparison of outcome of assisted reproductive technology (ART) children and naturally conceived children may be hampered by the difference in characteristics of the infertile patients such as age and genetic risks. Follow-up studies are further hampered by the type of neonatal surveillance protocol, the number of individuals lost to follow-up, the size of the cohort study, and the lack of standardization, for example to define major anomalies. The limited available data on ICSI fetal karyotypes reveal that, in comparison with a general neonatal population, there is: (i) a slight but significant increase in de-novo sex chromosomal aneuploidy (0.6% instead of 0.2%) and structural autosomal abnormalities (0.4% instead of 0.07%); and (ii) an increased number of inherited (mostly from the infertile father) structural aberrations. Available data indicate that in 8319 liveborn ICSI children, the mean percentage who do not originate from singleton pregnancies was 40% (range 32.6-60.8% according to centre). Most multiples are twins, but there are also 4.4% triplets (in one survey 13.2%). This substantial increase in multiple pregnancies must be considered the most important complication of ART. The different percentages of major and minor congenital malformations cannot be compared, but overall the data in large and reliable surveys does not indicate a higher rate of malformations in ICSI children than in naturally conceived children. To date, only three studies have examined the medical and developmental outcome of ICSI children at 1 and 2 years. These do not reveal obvious problems, but in future further comparison of matched cohorts of children and case-control studies are needed before final conclusions can be drawn.     

Female and male lifestyle habits and IVF: what is known and unknown

There is no greater tribute to the importance and efficacy of IVF than the fact that >1 x 10(6) babies have been born to infertile couples since its clinical introduction in 1978. Despite enormous advances regarding the technical aspects of the IVF procedure, the parents' contribution has virtually been ignored when considering aspects that influence success rates. This systematic review focuses on the effects of female and male lifestyle habits (specifically: smoking, alcohol and caffeine use, and psychological stress) on the reproductive endpoints of IVF (i.e. oocyte aspiration, fertilization, embryo transfer, achievement of a pregnancy, live birth delivery, and perinatal outcomes, e.g. low birthweight, multiple gestations). What is currently known in the field of lifestyle habits and IVF? There is compelling evidence that smoking has a negative influence on IVF outcomes, whereas for stress, the evidence is suggestive but insufficient due to the heterogeneity of studies. The evidence for the effects of alcohol and caffeine on IVF is inadequate, and therefore unknown, due to the scarcity of studies.     

Environmental and occupational factors affecting fertility and IVF success

Reproductive function has been shown to be sensitive to changes in the physical, psychosocial and chemical environments. Although reproductive effects of occupational exposure to hazardous chemicals have been well documented in the literature, the potential effects of chemical contaminants at levels representative of contemporary exposures in the general population are much less certain. Evidence for adverse effects of exposure to environmental contaminants is more conclusive among the lower animals than for humans where considerable controversy remains. In addition to potential reproductive hazards of exposure to environmental contaminants, there is also evidence for adverse reproductive effects of the physical and psychosocial environments. In this review we focus on the difficulties involved in linking exposure to putative hazardous substances in environmental and occupational settings to adverse reproductive outcomes, especially success of IVF procedures. We highlight the plausibility of adverse events through animal and cell studies and the application of these results to the interpretation of human data. We consider both the male and female partners since it is essentially their combined contributions of gametes which may be affected by chemicals, which lead to successful outcomes.     

Assisted reproductive technologies and the risk of birth defects--a systematic review

BACKGROUND: The risk of birth defects in infants born following assisted reproductive technology (ART) treatment is a controversial question. Most publications examining the prevalence of birth defects in ICSI and IVF infants compared to spontaneously conceived infants have serious methodological limitations; despite this, most researchers have concluded that there is no increased risk. METHODS: We carried out a systematic review to identify all papers published by March 2003 with data relating to the prevalence of birth defects in infants conceived following IVF and/or ICSI compared with spontaneously conceived infants. Independent expert reviewers used criteria defined a priori to determine whether studies were suitable for inclusion in a meta-analysis. Fixed effects meta-analysis was performed for all studies and reviewer-selected studies. RESULTS: Twenty-five studies were identified for review. Two-thirds of these showed a 25% or greater increased risk of birth defects in ART infants. The results of meta-analyses of the seven reviewer-selected studies and of all 25 studies suggest a statistically significant 30-40% increased risk of birth defects associated with ART. CONCLUSIONS: Pooled results from all suitable published studies suggest that children born following ART are at increased risk of birth defects compared with spontaneous conceptions. This information should be made available to couples seeking ART treatment.     

Antisperm immunity in natural and assisted reproduction

Research conducted in the last 40 years has provided evidence that antisperm antibodies (ASA) can impair the fertilizing capacity of human spermatozoa. It is established that ASA can be present at different sites, can act against different antigens and can impair fertility in various ways. In fact, in the past it was amply demonstrated that ASA can act negatively on sperm motility and on cervical mucus penetration. In recent years, owing to the improvement and spreading of IVF techniques, it has been possible to demonstrate the effect of antibody-bound spermatozoa at the level of in-vitro gamete interaction. The literature demonstrates that the various previously used treatments for immunological infertility, i.e. medical therapy, intrauterine insemination with husband's spermatozoa (AIH) and IVF, usually had poor success. The primary choice of treatment in immunological infertility, especially in the most severe cases and when the sperm head is involved, is ICSI. ASA evaluation in all couples who undergo the various techniques of insemination or IVF is imperative.     

The accuracy of multivariate models predicting ovarian reserve and pregnancy after in vitro fertilization: a meta-analysis

BACKGROUND: To review the accuracy of multivariate models for the predictionof ovarian reserve and pregnancy in women undergoing IVF comparedwith the antral follicle count (AFC) as single test. METHODS: We performed a computerized MEDLINE and EMBASE search to identifyarticles published on multivariate models for ovarian reservetesting in patients undergoing IVF. In order to be selected,articles had to contain data on the outcome of IVF in termsof either pregnancy and/or poor response and on the predictionof these events based on a multivariate model. For the selectedstudies, sensitivity and specificity of the test in the predictionof poor ovarian response and non-pregnancy were calculated.Overall performance was assessed by estimating a summary receiveroperating characteristic (ROC) curve, which was compared withthe ROC curve for the AFC as the current best single test. RESULTS: We identified 11 studies reporting on the predictive capacityof multivariate models in ovarian reserve testing. All studiesreported on the prediction of poor ovarian response, whereasnone reported on the occurrence of pregnancy. The sensitivityfor prediction of poor ovarian response varied between 39% and97% and the specificity between 50% and 96%. Logistic regressionanalysis indicated that cohort studies provided a significantlybetter discriminative performance than case–control studies.As cohort studies are superior to case–control studies,further analysis was limited to the cohort studies. For thecohort studies, a summary ROC curve could be estimated, whichhad a shape similar to that previously made for the AFC. CONCLUSIONS: The accuracy of multivariate models for the prediction of ovarianresponse in women undergoing IVF is similar to the accuracyof AFC. No data are available on the capacity of these modelsto predict pregnancy, let alone live birth. On the basis ofthese findings, the use of more than one single test for theassessment of ovarian reserve cannot currently be supported.     

Human semen analysis

Rapid developments have occurred in the management of coupleinfertility due to a male factor. These have stimulated renewedinterest in semen analysis, which has become more correct, morereliable and more informative. The so-called basic semen analysis,which includes subjective estimation of sperm concentration,motility and morphology, has largely become obsolete. It hasbeen replaced by several alternative techniques such as thehome testing of semen by the man himself, the elaboration ofmethods and equipments for the exact assessment of conventionalsperm characteristics, and the measurement of new parametersevaluating the functional state and capacity of spermatozoa,accessory sex glands and seminiferous epithelium. The presentpaper covers the following items: (i) conventional methods ofsemen analysis, (ii) the resazurin test and home fertility scoring,(iii) advanced methods for the objective assessment of conventionalsperm characteristics and motility parameters.