Long-term effects on offspring of intrauterine exposure to deficits in nutrition

The number of cell divisions during embryonic and fetal life makes the embryo/fetus particularly vulnerable to effects resulting from exposure to an adverse intrauterine environment. Exposure to drugs and irradiation at this stage of development are able to cause congenital malformations and various cancers in later life. In-utero exposure to hyperglycaemia is able to lead to future diabetes that is heritable, but not genetic in origin. Fetal malnutrition causing growth restriction is able to lead to an increased risk of developing type 2 diabetes, hypertension and ischaemic heart disease in later life, especially if the growth restriction is followed by catch-up growth postnatally. This review discusses the various mechanisms by which these effects may occur, and presents the difficulties that will have to be faced if their world-wide health burdens are to be reduced.     

Clinical implications of uterine malformations and hysteroscopic treatment results

Uterine malformations consist of a group of miscellaneous congenital anomalies of the female genital system. Their mean prevalence in the general population and in the population of fertile women is approximately 4.3%, in infertile patients approximately 3.5% and in patients with recurrent pregnancy losses approximately 13%. Septate uterus is the commonest uterine anomaly with a mean incidence of approximately 35% followed by bicornuate uterus (approximately 25%) and arcuate uterus (approximately 20%). It seems that malformed uterus and especially septate uterus is not an infertility factor in itself. However, it may have a part in the delayed natural conception of women with mainly secondary infertility. On the other hand, patients with uterine malformations seem to have an impaired pregnancy outcome even as early as their first pregnancy. Overall term delivery rates in patients with untreated uterine malformations are only approximately 50% and obstetric complications are more frequent. Unicornuate and didelphys uterus have term delivery rates of approximately 45%, and the pregnancy outcome of patients with untreated bicornuate and septate uterus is also poor with term delivery rates of only approximately 40%. Arcuate uterus is associated with a slightly better but still impaired pregnancy outcome with term delivery rates of approximately 65%. Women who have undergone hysteroscopic septum resection and have been reported in the different series comprise a highly selected group of symptomatic patients with term delivery and live birth rates of only approximately 5%. Hysteroscopic treatment seems to restore an almost normal prognosis for the outcome of their pregnancies with term delivery rates of approximately 75% and live birth rates of approximately 85%. It seems, therefore, that hysteroscopic septum resection can be applied as a therapeutic procedure in cases of symptomatic patients but also as a prophylactic procedure in asymptomatic patients in order to improve their chances for a successful delivery.     

Consequences on offspring of abnormal function in ageing gametes

The present review aims to analyse (i) the molecular, biochemical and cellular changes that accompany oocyte and sperm ageing in any of the internal or external environments where they can reside, and (ii) the consequences of the abnormal function in ageing gametes on pre- and post-implantation development and later life of offspring. This review also aims to propose and discuss cellular/molecular mechanisms framed within the 'free radical theory of ageing'. It appears that the ageing of gametes prior to fertilization may affect many molecular, biochemical and cellular pathways that may jeopardize not only pre- and post-implantation embryo/fetal development but also later life of offspring. Consequences of gamete ageing range from decreased vigour (with the concomitant decrease in intelligence, reproductive fitness and longevity) of apparently normal-looking offspring to severe congenital, epigenetic and/or genetic anomalies. All these effects may be easily prevented by efficient diffusion of both the potential risks of gamete ageing and the steps that should be taken by couples wishing to achieve pregnancy to guarantee a correct maturational synchronization of gametes at fertilization. Although in-vitro antioxidant therapy appears to protect from or retard the ageing process of gametes, it may not assure the total absence of negative effects on the resulting offspring.     

The effects of radiotherapy and chemotherapy on female reproduction.

High dose chemotherapy and radiotherapy have radically increased long-term survival of young cancer patients, but major side effects of these treatments are ovarian failure and infertility. Knowledge of the risks and probabilities of ovarian failure caused by treatment is crucial for patients and physicians in order to make informed choices that will best serve patients' interests. This review presents data on ovarian damage and failure following exposure to radiotherapy, chemotherapy and ablative therapy. The risk is evaluated from the published literature according to patient's age, treatment protocol and also according to the diagnosis of some common malignancies. Many of these patients will not be sterilized immediately following treatment, but will suffer from premature menopause. In order to prevent sterilization, ovarian transposition before pelvic irradiation is mandatory. Besides cryopreservation of ovarian tissue and embryos before administration of chemotherapy, the possible protective effect of pituitary-ovarian down-regulation is discussed. The mechanism of primordial follicles damage induced by radio/chemotherapy is presented as well as the role of apoptosis signalling pathways underlying destruction. Increased knowledge of these mechanisms could help to identify potential effective inhibitors that can block the path of primordial follicles destruction and reduce ovarian failure rate.     

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.     

Biparental hydatidiform moles: a maternal effect mutation affecting imprinting in the offspring

Highly recurrent hydatidiform moles (HMs) studied to date are not androgenetic but have biparental genomic contribution (BiHM). Affected women have an autosomal recessive mutation that causes their pregnancies to develop into HM. Although there is genetic heterogeneity, a major locus maps to chromosome 19q13.42, but a mutated gene has not yet been identified. Molecular studies have shown that maternal imprinting marks are deregulated in the BiHM trophoblast. The mutations that cause this condition are, therefore, hypothesized to occur in genes that encode transacting factors required for the establishment of imprinting marks in the maternal germline or for their maintenance in the embryo. Although only DNA methylation marks at imprinted loci have been studied in the BiHM, the mutation may affect genes that are essential for other forms of chromatin remodelling at imprinted loci and necessary for correct maternal allele-specific DNA methylation and imprinted gene expression. Normal pregnancies interspersed with BiHM have been reported in some of the pedigrees, but affected women repeatedly attempting pregnancy should be counselled about the risk for invasive trophoblastic disease with each subsequent BiHM.     

Low-dose aspirin for in vitro fertilization: a systematic review and meta-analysis

Despite recent advances in ovarian stimulation regimens and laboratory techniques, the pregnancy rate of assisted reproduction remains relatively low. New methods that would potentially improve implantation rates are needed. One proposed strategy involves enhancement of blood flow at the implantation site with the use of low-dose aspirin. We conducted a systematic review and meta-analysis to investigate the effect of low-dose aspirin on likelihood of pregnancy in women undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI). An electronic search of the literature was conducted targeting reports published over the last 26 years. Only randomized controlled trials (RCTs) comparing aspirin with placebo or no treatment in IVF/ICSI women were included in the meta-analysis. A number of relevant outcomes including pregnancy and live birth (LB) rates were investigated. Pooled relative risk (RR) and 95% confidence interval (CI) were calculated using a random-effects model. Inter-study heterogeneity among the trials was assessed using the Cochran's Q test. Ten RCTs were identified from the literature search, six of which met the criteria for inclusion in the meta-analysis. Clinical pregnancy (CP) rate per embryo transfer (ET) was not found to be significantly different between patients who received low-dose aspirin and those who received placebo or no treatment (RR 1.09, 95% CI 0.92-1.29). None of the other outcomes, including CP per cycle, spontaneous abortion or ectopic pregnancy per CP and LB rate per cycle or ET was found to differ significantly between the compared groups. On the basis of up-to-date evidence, low-dose aspirin has no substantial positive effect on likelihood of pregnancy and, therefore, it should not be routinely recommended for women undergoing IVF/ICSI.     

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.     

Turner's syndrome and fertility: current status and possible putative prospects.

Women with Turner's syndrome should be carefully followed throughout life. Growth hormone therapy should be started at age 2-5 years. Hormone replacement therapy for the development of normal female sexual characteristics should be started at age 12-15 years and continued for the long term to prevent coronary artery disease and osteoporosis. Most women with Turner's syndrome have ovarian dysgenesis; therefore, they are usually infertile, and in very rare cases have spontaneous menses followed by early menopause. Only 2% of the women have natural pregnancies, with high rates of miscarriages, stillbirths and malformed babies. Their pregnancy rate in oocyte donation programmes is 24-47%, but even these pregnancies have a high rate of miscarriage, probably due to uterine factors. A possible future prospect is cryopreservation of ovarian tissue containing immature follicles before the onset of early menopause, but methods of replantation and in-vitro maturation still need to be developed. Should these autologous oocytes indeed be used in the future, affected women would need to undergo genetic counselling before conception, followed by prenatal assessment.     

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.     

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.     

Development of contraceptive vaccines for humans using antigens derived from gametes (spermatozoa and zona pellucida) and hormones (human chorionic gonadotrophin): current status

Contraceptive research has entered a new phase of developmentwith the advent of hybridoma and DNA recombinant technologies.During the past 5 years, significant advances have been madein this area and now it seems that realistic prospects existfor the development of contraceptive vaccines for use in humansand animals (veterinary, wild and domestic), applicable to boththe female and male sexes. Contraceptive vaccines will be valuablesupplements to the presently available methods of family planning,and, due to high specificity, the occurrence of limited side-effectsif any, low cost and infrequent administration, contraceptivevaccines may have greater acceptability than the currently availablemethods. Mammalian reproduction starts with the unison of gametescontributed by the male and female partners. Both spermatozoonand oocyte have antigens on the cell surface that are unique,tissue-specific, immunogenic and accessible to antibodies, andbinding of the antibodies to these antigens can cause inhibitionof gamete function, resulting in a failure of fertilization.Fertilization is followed by embryogenesis, with the early embryoproducing several proteins, some of which, eg. human chorionicgonadotrophin (HCG), have a vital role in the establishmentand maintenance of early pregnancy. Again, these proteins areaccessible to antibodies, and their immunoneutralization cancause anti-fertility effects with loss of early embryo. Thus,the antigens derived from proteins on spermatozoa, oocyte andearly embryo, especially HCG, constitute interesting moleculesfor the development of contraceptive vaccines. The aim of thepresent article is to review the current status of developmentof contraceptive vaccines based on antigens derived from spermcell, oocyte zona pelluci-da and HCG, and to discuss their relativemerits and future development.     

Thyroid autoimmunity and hypothyroidism before and during pregnancy

In the present review, an attempt was made to describe current knowledge and concepts concerning the complex relationships that link thyroid autoimmunity (TAI) and hypothyroidism with female and male infertility, as well as abnormalities occurring during pregnancy, such as pregnancy loss and maternal and fetal repercussions associated with hypothyroidism. In the case of infertility, although the clinical relevance of TAI is somewhat controversial, when all available information is considered the results strongly suggest that when infertility is due to well-defined female causes, autoimmunity is involved and TAI constitutes a useful marker of the underlying immune abnormality, independently of thyroid function disorders. In the case of pregnancy loss, the vast majority of available studies clearly establish that TAI (even with no overt thyroid dysfunction) is associated with a significant increase in miscarriage risk. To find an association, however, does not imply a causal relationship, and the aetiology of increased pregnancy loss associated with TAI remains presently not completely understood. With regard to maternal repercussions during gestation, the main risk associated with TAI is the occurrence of hypothyroidism and obstetric complications (premature birth, pre-eclampsia, etc.). Thus, systematic screening of TAI and hypothyroidism during early pregnancy, monitoring of thyroid function with/without L-thyroxine treatment and follow-up during post-partum have proved helpful and important in order to manage these patients adequately. Finally, with regard to potential repercussions affecting the offspring, recent evidence suggests that thyroid maternal underfunction, even when considered mild (or subclinical), may be associated with an impairment of fetal brain development. When present only during the first half of gestation, maternal hypothyroxinaemia is a risk factor for impaired fetal brain development, due to insufficient transfer of maternal thyroid hormones to the feto-placental unit. When hypothyroidism is not restricted to the first trimester and worsens as gestation progresses (as in untreated hypothyroidism), the fetus may also be deprived of adequate amounts of thyroid hormones during later neurological maturation and development, leading to poorer school performance and lower IQ.     

Long-term effects in progeny of paternal environment and of gamete/embryo cryopreservation

In addition to gross malformations, many problems relating to the formation of gametes and embryos can generate, within a continuum of abnormalities, a number of problems that are less evident. On the basis of genetic and/or biochemical or cytological changes, these effects generally appear long after birth as functional difficulties that range from growth changes and altered endocrine functions and cancer to very late behavioural disorders. Such problems may have effects on males and females before conception, on the embryo during gestation, and may also impact on the success of assisted reproduction techniques. For this reason, we have examined the experimental and clinical data that indicate the long-term consequences, for progeny, of iatrogenic and toxic environmental factors on the male reproductive system, and in particular the effect that one specific condition-cryopreservation-may have on gametes and the conceptus. We then focus on the interpretation given to these data which, in general, emphasize the need not only for further experiments to help understand the mechanism of anomalies and increase the level of vigilance in humans, but also to extend follow-up investigations in children.     

Reproductive functions of the ageing male

Delayed childbearing is a common phenomenon in industrialized countries. This review focuses on age-associated alterations of male fertility and genetic risks. Semen volume, sperm motility and sperm morphology decrease with age, whereas the data concerning sperm concentration are conflicting. The age-related changes of semen parameters reflect the histological modifications which are found to varying degrees in individual testes. Men aged >40 years contribute to reduced fertility and fecundity of a couple, especially when the female partner is also of advanced age. Because relatively few children are born to older fathers and genetic diseases are rare, there is little statistical power supporting an association of genetic diseases in the offspring with advancing paternal age. Nevertheless, autosomal dominant diseases and some diseases of complex aetiology, such as schizophrenia, are associated with advancing paternal age. The single point mutations in sperm which are responsible for achondroplasia and Apert's syndrome, two autosomal dominant diseases, increase with the man's age. In case of Apert's syndrome this increase is believed to be due to a pre-meiotic selection of mutant spermatogonia. Although structural chromosome anomalies and disomies of certain chromosomes increase in sperm with the man's age, paternal age is, with the exception of trisomy 21, not associated with numerical or de novo structural chromosomal aberrations in newborns. However, even if the genetic risk for progeny from older fathers is slightly increased, the risk to the individual is low.     

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.     

Ovarian tissue cryopreservation and transplantation: a review

The review covers current options for ovarian tissue cryopreservation and transplantation and provides a systematic review of the existing literature from the last 10 years, taking into account all previously published reviews on the subject. The different cryopreservation options available for fertility preservation in cancer patients are embryo cryopreservation, oocyte cryopreservation and ovarian tissue cryopreservation. The choice depends on various parameters: the type and timing of chemotherapy, the type of cancer, the patient's age and the partner status. The different options and their results are discussed, as well as their putative indications and efficacy. The review concludes that advances in reproductive technology have made fertility preservation techniques a real possibility for patients whose gonadal function is threatened by premature menopause, or by treatments such as radiotherapy, chemotherapy or surgical castration.     

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.     

Treatment with immunosuppressive and disease modifying drugs during pregnancy and lactation.

Active rheumatic disease may necessitate the treatment of pregnant and lactating patients with disease modifying (DMARD) or immunosuppressive drugs. This review summarizes data from the literature, and attempts to give some recommendations. Possible teratogenic effects of gold, penicillamine, and chloroquine are still disputed. As long as the issue is not settled, it seems prudent to stop using these agents as soon as pregnancy is diagnosed. Hydroxychloroquine has been used by some rheumatologists for treating pregnant patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) without malformations detected in the neonates. Sulphasalazine does not increase the rate of congenital abnormalities. Selected case reports have not shown any teratogenicity of cyclosporine A so far. However, the drug may cause fetal retardation. The use of standard doses of azathioprine does not increase the risk of congenital anomalies. By contrast, the antitumor agents cyclophosphamide, chlorambucil, and methotrexate are possibly teratogenic when given during early pregnancy, but may be less harmful in late pregnancy. Data on the excretion of DMARD and the cytostatic drugs are sparse. Because of insufficient data, breast feeding is not recommended in patients on antimalarials, penicillamine, cyclosporine A, and cytostatic drugs. Intramuscular gold and sulphasalazine seem to impose no major risk on the nursing infant.     

Risk and benefit of drug use during pregnancy

Environmental teratogenic factors (e.g. alcohol) are preventable. We focus our analysis on human teratogenic drugs which are not used frequently during pregnancy. The previous human teratogenic studies had serious methodological problems, e.g. the first trimester concept is outdated because environmental teratogens cannot induce congenital abnormalities in the first month of gestation. In addition, teratogens usually cause specific congenital abnormalities or syndromes. Finally, the importance of chemical structures, administrative routes and reasons for treatment at the evaluation of medicinal products was not considered. On the other hand, in the so-called case-control epidemiological studies in general recall bias was not limited. These biases explain that the teratogenic risk of drugs is exaggerated, while the benefit of medicine use during pregnancy is underestimated. Thus, a better balance is needed between the risk and benefit of drug treatments during pregnancy. Of course, we have to do our best to reduce the risk of teratogenic drugs as much as possible, however, it is worth stressing the preventive effect of drugs for maternal diseases (e.g. diabetes mellitus and hyperthermia) related congenital abnormalities.