Human reproduction is extraordinarily wasteful. The reasons for this have taxed all of the contributors to this book. As we move into the 21st century it is sobering to reflect on the fact that we have failed to harness the power of the evolving revolution in molecular medical biology to answer the fundamental question: why is the fate of a fertilized egg so hazardous and so unsuccessful? The following account summarizes our limited knowledge of the epidemiology of miscarriage and then moves on to consider some of the medical causes of miscarriage. The contribution of genetic abnormalities to the problem of pregnancy wastage is discussed elsewhere in this volume.

Epidemiology and the medical causes of miscarriage.

Embryonic karyotype of abortuses in relation to the number of previous miscarriages

Recurrent miscarriage (RM) is a heterogeneous condition. A large number of studies has recently been published, yet many of them have conflicting conclusions. The various aetiological factors, management, prognostic features and outcomes of a subsequent pregnancy in women with RM are reviewed.

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Recurrent miscarriage: aetiology, management and prognosis

Pregnancy rate following one cycle of IVF and ET can be as high as 60%. But even in the very successful units, some couples fail repeatedly. The causes for repeated implantation failure (RIF) may be because of reduced endometrial receptivity, embryonic defects or multifactorial causes. Various uterine pathologies, such as thin endometrium, altered expression of adhesive molecules and immunological factors, may decrease endometrial receptivity, whereas genetic abnormalities of the male or female, sperm defects, embryonic aneuploidy or zona hardening are among the embryonic reasons for failure of implantation. Endometriosis and hydrosalpinges may adversely influence both. In this mini review, we discuss the suggested methods for evaluation and treatment of RIF: repeated hysteroscopy, myomectomy, endometrial stimulation, immunotherapy, preimplantation genetic screening (PGS), assisted hatching, zygote intra-Fallopian transfer (ZIFT), co-culture, blastocyst transfer, cytoplasmic transfer, tailoring stimulation protocols and salpingectomy for hydrosalpinges.

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Investigation and treatment of repeated implantation failure following IVF-ET

We present the first evidence that genetically damaged human spermatozoa are able to form normal pronuclei in oocytes after intracytoplasmic sperm injection (ICSI). The role of reactive oxygen species (ROS) as a cause of chromatin and DNA damage is well recognized. The same class of molecule can be found in the semen of males with severe infertility, who remained infertile until the advent of ICSI. In this study we have investigated the role of ROS in the induction of chromatin damage, DNA strand breakage and the subsequent ability of spermatozoa to decondense and form pronuclei after ICSI. Spermatozoa from normozoospermic men participating in our research programme were exposed to oxidizing environments created by co-incubation with hydrogen peroxide, reduced nicotinamide adenine dinucleotide phosphate (NADPH) or activated white cells. The subsequent ability of the spermatozoa to decondense in vitro was examined using sequential incubations in EDTA, dithiothreitol and sodium dodecyl sulphate, and the amounts of DNA strand breakage were assessed using an in-situ nick translation protocol. Finally, cells exposed to hydrogen peroxide, NADPH and activated leukocytes were microinjected into hamster oocytes, and their ability to decondense and form normal pronuclei was determined. The results indicate that human sperm chromatin becomes cross-linked under conditions of oxidative stress and exhibits increased DNA strand breakage, yet the rate of pronucleus formation is no different from that of untreated control cells. The ability of genetically damaged spermatozoa to achieve normal fertilization following ICSI has implications for the practice of this form of assisted conception therapy.

Oxidative damage to DNA in human spermatozoa does not preclude pronucleus formation at intracytoplasmic sperm injection.

PROBLEM: Efficacy of immunotherapy for treatment of recurrent spontaneous abortion (SA) has been controversial. The low treatment effect of white blood cell immunization lead to investigations of alternative treatments including intravenous (IV) immunoglobulin (Ig). To evaluate the efficacy of IVIg for treatment of recurrent SA, a prospective, randomized, double blinded, placebo-controlled trial was performed.



METHODS: Ninety-five women experiencing two or more consecutive spontaneous abortions with no known cause were randomized and received either IVIg 500 mg/kg/month or placebo (albumin).



RESULTS: Of 95 women participating in the study, 47 received IVIg and 48 received placebo. Medication was discontinued in 34 women who failed to conceive within four cycles. The remaining 61 women achieved pregnancy. Pregnancy outcomes included 29 deliveries and 32 recurrent SA. Among women delivering live births 18 (62%) received IVIg and 11 (38%) received placebo. By contrast, 21 (66%) women experiencing recurrent SAs received placebo and 11 (34%) received IVIg. Among 61 women who conceived, 29 received IVIg and 32 received placebo. Of the 29 women who conceived and received IVIg, 18 (62%) delivered live births and 11 (38%) experienced recurrent SA. Of 32 women who conceived and received placebo 11 (34%) delivered live births and 21 (66%) had recurrent SA. The difference in live birth rates between women receiving IVIg and placebo was significant (P = 0.04, odds ratio 3.1).



CONCLUSION: IVIg is effective in enhancing the percentage of live births among women experiencing unexplained recurrent SA.

Intravenous immunoglobulin for treatment of recurrent pregnancy loss

Intracytoplasmic sperm injection facilitates fertilization even in the most severe forms of male infertility: pregnancy outcome correlates with maternal age and number of eggs available *

The aim of this study was to determine the effectiveness of intravenous (i.v.) immunoglobulin (Ig) for treatment of individuals experiencing failure after in-vitro fertilization (IVF) and embryo transfer. A total of 29 women with unexplained infertility who failed to become pregnant after IVF/embryo transfer were divided into two groups based on performance in previous IVF cycles: 16 women had fertilization of > or = 50% of oocytes retrieved and/or produced > or = 3 embryos each cycle and 13 had fertilization of or = 50% and generate at least three embryos per cycle.

Intravenous immunoglobulin for in-vitro fertilization failure

Oocyte donation is a useful model for the assessment of potential factors affecting implantation since embryos generated are from younger oocytes than in in-vitro fertilization programmes and are therefore expected to have higher and more consistent implantation rates. Transvaginal sonographic measurement of endometrial thickness, echogenic pattern and uterine artery impedance, measured as pulsatility index (PI) and resistance index (RI), were retrospectively compared in 99 recipient women following 117 fresh embryo transfers that resulted in 51 conception cycles and 66 non-conception cycles. The prevalence of a multilayered echogenic pattern was significantly greater (91.2%) in conception than in non-conception (44.4%) cycles. No differences in endometrial thickness, PI or RI were observed between conception and non-conception cycles. However, no pregnancy occurred when the PI was > or = 3.4 (sensitivity 100%). The number of days or cumulative dose of oestrogen intake and the serum oestradiol concentration prior to progesterone administration were not different in the multilayered pattern versus other echogenic pattern groups. The data show that it may be beneficial to await achievement of a PI < 3.4 and a multilayered pattern endometrium prior to embryo transfer in an oocyte donation programme.

Lois Krysa

Papers

Intravenous immunoglobulin for treatment of recurrent pregnancy loss

Intracytoplasmic sperm injection facilitates fertilization even in the most severe forms of male infertility: pregnancy outcome correlates with maternal age and number of eggs available *

Intravenous immunoglobulin for in-vitro fertilization failure

Uterine receptivity in an oocyte donation programme.

Comparisons of pregnancy loss patterns after intracytoplasmic sperm injection and other assisted reproductive technologies