Recurrent Pregnancy Loss: The Basics
Miscarriage is far more common than most people think. One in every four clinically-recognized pregnancies is lost in the first trimester. Overall, the rate of miscarriages rises with increasing maternal age. A spontaneous abortion or miscarriage is defined as loss of a pregnancy before 20 gestational weeks. The American Society for Reproductive Medicine (ASRM) recommends that couples who have two or more spontaneous miscarriages warrant an evaluation.
Nutrition affects women and men’s health in many ways and has now been demonstrated to affect our chances at pregnancy. Particularly, the types of carbohydrates, fats, and proteins that we eat or drink can each have an impact on how regularly women ovulate (the release of mature eggs from the ovary). In addition, lifestyle choices that we make each day, such as exercising, drinking caffeine or alcohol, or smoking cigarettes also impact the likelihood of getting pregnant and also the developing fetus (the growing baby inside).
The last several decades have propelled assisted reproduction technologies (ART) into one of the most controversial and revolutionary medical therapies in the United States and around the world. The impact is so profound that today nearly 1% of babies born in the United States are conceived by in-vitro fertilization (IVF). The last few years have added focus and research on improving pregnancy outcome, and furthermore in establishing and defining health consequences from the utilization of these techniques. It has also allowed evaluation of the impact of health related issues upon the success of assisted reproduction. The focus of this summary is to update the reader on leiomyomata (fibroids of the uterus), hydrosalpinges (blocked fallopian tubes), smoking and decreased ovarian reserve on ART outcomes. Moreover, it will serve to examine the recent data and controversies on perinatal outcomes and birth defects as related to ART.
Leiomyomata and ART...
The ABC’s A fundamental step in understanding how fertility medications work, is to review some basic physiology (see figure). At the beginning of a menstrual cycle, Follicle Stimulating Hormone (FSH) is produced by a part of the brain called the pituitary gland. As the name implies, the primary function of FSH is to stimulate the growth of an ovarian follicle. In addition to containing an egg, the follicle has cells on its periphery which respond to FSH by producing estradiol (E2), a form of estrogen. E2 is a signal to the brain to reduce the amount of FSH it is producing; in this way it limits the amount of FSH that is secreted in any one menstrual cycle. Of the many follicles that can be stimulated to grow in a cycle, typically the one that has the most receptors for FSH flourishes and survives. Once this dominant follicle reaches maturity, Luteinizing Hormone (LH) is then released by the pituitary gland. LH not only provokes the chromosomal maturation of the egg, but also begins the process of ovulation in which the egg is released from the follicle, which will then be captured by the fallopian tube and await sperm for fertilization. Both FSH and LH are also called gonadotropins.
Reproductive medicine has provided many wonderful options for women seeking to preserve their reproductive potential. From the advent of medications to stimulate egg production, to the development of in-vitro fertilization (IVF), many individuals have benefited from this technology. IVF is now commonplace and is no longer considered experimental or unusual. Fertility preservation (egg freezing) uses some of the same technologies perfected with IVF to allow women to delay childbearing. Egg freezing prevents the eggs from aging and therefore can be used to minimize the loss of fertility that occurs with advancing age. This loss of fertility starts in the late twenties and rapidly accelerates in the mid-thirties so that most women in their early forties have permanently lost their ability to conceive. The best option currently available to preserve fertility is to freeze eggs. By freezing one’s eggs, a woman is essentially preserving her egg’s potential for the future – eggs frozen from a 30-year-old women will
always function as if they came from a 30 year old, even if they are not used for another 10 to 15 years.
Egg freezing is the best option for the right patient. When an egg is frozen, its fertility potential is preserved indefinitely. Due to the natural loss of fertility that occurs with advancing age, we strongly recommend women freeze their eggs before their mid-thirties and most certainly before age forty. It is important that you have confidence in the center providing this service.
The Science Behind Egg Freezing...
Human oocyte cryopreservation, or “egg freezing,” has long been an elusive goal of cryobiologists. Although sperm and embryos (fertilized eggs) have been successfully frozen and subsequently thawed to create healthy children for decades, egg freezing has only recently become a successful reality. The cryopreservation of human oocytes is highly beneficial for several reasons, most importantly to preserve a woman’s fertility. Oocyte storage allows: (i) women at risk of becoming sterile due to cancer to preserve their oocytes prior to radio- or chemotherapy or ovariectomy; (ii) the salvage of an in-vitro fertilization (IVF) cycle when no sperm is available; (iii) the alleviation of religious and ethical concerns of embryo storage; (iv) the elimination of donor-recipient synchronization problems; (v) a “quarantine period” on donated oocytes similar to that of donated semen; and (vi) women to delay reproduction until later in life, providing them with more reproductive choices.
In the late 1980’s, Dr. Sherman Silber in St. Louis, proved that sperm obtained directly from the scrotum could be used to successfully fertilize eggs and achieve viable pregnancies. While this procedure was originally intended for men who are born with an obstruction in the genital tract (congenital absence of the vas deferens), it has become clear over the past decade that men with previous vasectomies can benefit from similar procedures as well.
The development and maturation of sperm occurs in the testes. The testes also produce most of the testosterone in men. The sperm begins its trip in the male through an enlarged portion of the ducts called the epididymis. This duct eventually becomes the vas deferens (vas). Along the route of the vas, the prostate and seminal vesicles add the fluid portion
of the ejaculated semen. When a vasectomy has been performed, the vas deferens is blocked before the area where the seminal vesicles add the fluid. That is why these men still produce semen, but no sperm. Dr. Silber microsurgically removed sperm from the epididymis and achieved viable pregnancies through assisted reproductive procedures, thus proving that sperm do not have to make the trip through the ducts to achieve fertilizing potential....
The decrease in female fecundity beginning after the age of 30 and exaggerated after 40 is a well documented finding. This age-related decline in fertility is the result of several factors that contribute to overall reproductive failure. Women over 35 require a longer period to achieve conception than younger women, and a higher percentage of older women will never achieve pregnancy. In addition, the rate of early pregnancy wastage increases substantially during the 30's, and is over 50% after age 40.
With the aging of the baby boom generation and social trends to delay childbearing, the treatment of women =40 years of age who desire fertility has become a major challenge of today’s fertility specialists. For many women, the option to exercise other choices while deferring their reproduction has resulted in the need to use new reproductive technologies while treating their infertility. These technologies include controlled ovarian hyperstimulation (COH), intrauterine insemination (IUI), and assisted reproductive techniques (ART).
Preimplantation genetic diagnosis (PGD) and screening (PGS) refer to the procedures involved in obtaining genetic makeup of the embryo(s) prior to their transfer into the uterus.
Genetic errors arise from deletions or insertions of genetic material, abnormal numbers of whole chromosomes or genes, and even from misplacement of a single base in the DNA sequence. Genetic abnormalities can range from relatively harmless to severe: from vitamin deficiencies and food allergies to cancer, birth defects and infant mortality. In recent years, significant advances in technology have enabled researchers to trace many disorders and diseases to their roots in the genetic code. Chromosome stretches, or even isolated genes, can now be used as markers to identify individuals at risk for certain illnesses. Additionally, the Human Genome Project, which aims to identify the chromosome location and DNA sequence of every human gene, is providing an ever-expanding catalogue of potential genetic markers along with the OMIM data base (Online Medelian Inheritance in Man). The ability to recognize these genetic warning signs is rapidly becoming the most effective tool for prevention, diagnosis and treatment of genetically based disorders....
Over the last several decades we have witnessed a significant increase in survival rates for oncology patients. Due to the use of combination chemotherapy and radiotherapy many young patients are now living long, healthy, productive lives. While combination regimens have been designed to avoid acute toxic effects, many have resulted in unanticipated gonadal toxicity (harm to sperm or eggs). As such, an increasing number of cancer survivors are now facing difficulties in having families as well as hormonal deficiencies.
Preservation of Reproductive Options in Men...
Infertility is a complex medical, emotional and social condition that afflicts more than four million reproductive-age couples in the United States. Successful fertility treatment includes not only achieving pregnancy, but also achieving it in the most efficient and cost effective manner possible. The frequently ignored psychological toll of repeated treatment failures must also be considered. To achieve success, it is imperative that a timely and complete evaluation of both partners be performed. As our knowledge of reproductive physiology has expanded, the fertility workup has evolved as well. In this article, the contemporary fertility workup will be discussed. Attention will also be given to organizing the evaluation to prevent unnecessary testing.
Evaluation of the Male...
Since the very first IVF procedure, the theoretical ability to perform egg donation or gestational surrogacy has existed. It took doctors and society a few years to realize this fact and embrace the concept. Considering the wide variation in the legal status of egg donation and surrogacy throughout the world, it is also clear that not all societies have fully accepted these alternatives. In the U.S., especially in California, these procedures are helping many couples have children when they may not have been able to in the past. In addition, their high success rates demonstrate the true potential of assisted reproduction when all factors have been optimized.
This article will review the medical indications for both egg donation and surrogacy. We will briefly consider how egg donors and surrogate mothers are chosen and screened.
Since the process for egg donation and gestational surrogacy are actually similar, we will discuss them together. Finally, a few thoughts about the legal and ethical aspects of third party parenting will be considered....
Reproductive medicine has expanded treatment options to many who would otherwise not be able to have children. Despite these advances, many still experience challenges and the emotional distress of unsuccessful treatment. While some continue treatment, others succumb to these stresses and give up pursuing treatment or seek unproven therapies.
First and foremost, it is important to stress that the lack of success is not the patient’s fault. Nor does it mean that a carefully thought-out treatment plan will always be successful. Often it is in a couple’s best interest to take a step back and take a break from treatment. Taking time to “reconnect” with your partner is vital to a healthy relationship. It is also vital that your physician take a second look at your case, reviewing your records and course of treatment to date. It may be necessary to pursue further testing or to update some tests. It may be necessary to change course in your treatment or it may be determined that you are on the right track. Much of fertility is about the numbers...in other words, with continued treatment, many will find success. Even under the very best of circumstances, there is no guarantee that a treatment will result in a successful pregnancy.
For the male, an in-depth evaluation of the sperm can yield useful information. Beyond the routine semen analysis, it may be necessary to evaluate the chromosomes for evidence of environmental stresses. Excessive exposure of the testis to heat or to environmental toxins can result in fragmentation of the chromosomes, thus compromising the opportunity for a successful conception. The Sperm Chromatin Structure Assay (SCSA) evaluates the chromosomal structures for any evidence of excess stress. When abnormal results are uncovered, it is important for the male to undergo a complete evaluation, looking for any abnormal blood flow patterns to the testis or environmental exposure to toxins. Exposure to smoking and excessive heat should be avoided. Dilated blood vessels to the testis may need to be removed. When these measures are unsuccessful, there is evidence that reveals the direct extraction of the sperm from the testis may improve treatment success. The extraction of sperm, Testicular Sperm Aspiration, is a painless office procedure that is performed under anesthesia, which allows for removal of newly produced sperm before it is adversely affected by negative factors....
Couples going through infertility have many decisions to make. For couples who have gone through in-vitro fertilization (IVF) and have extra frozen embryos which they no longer need, the decision of what to do with their frozen embryos is difficult. They can choose to have the IVF clinic thaw and discard the embryos, donate them to research, or donate them to another infertile couple (embryo donation). Not all infertility practices have active embryo donation programs. Currently, HRC Fertility is not participating in embryo donation, but referrals to National Embryo Adoption or Snowflakes Agency are available upon request.
Recently, a 2002 SART-RAND survey was generated by the IVF clinics in the United States documenting the number of embryos stored and their current disposition. Nearly 400,000 embryos are stored, the majority of which (88.2%) are targeted for patient use. Patients are holding these embryos in storage for future use in helping them get pregnant. Less than 3% of couples are willing to donate to research, and just over 2% are in storage for embryo donation.
In addition, there is a lot of debate about human embryos in the media today. Embryos have stem cells, almost magical cells that can become any tissue in the human body. Researchers say stem cells might one day be used to save adult lives, and many academic centers are boosting their efforts to become a major center in this hot branch of biomedical science. In 2004, California voters agreed to pay for stem cell research when they approved Proposition 71....
There are a multitude of factors contributing to a couple’s inability to conceive, including male factor, uterine factor, tubal factor, pelvic factor, and ovulatory dysfunction. The majority of these factors can be circumvented through the application of advanced reproductive treatments like in-vitro fertilization (IVF). The success of IVF depends on three primary components: good quality embryos, a technically uncomplicated embryo transfer, and a receptive intrauterine environment for embryo implantation. When we talk about “good quality embryos” the two most common criteria discussed are rate of embryo growth, and embryo grade. The rate of embryo growth is determined by the number of cells, or blastomeres, contained within the embryo on a specific day of development. For example, on the third day following egg collection and insemination, an appropriately developing embryo should consist of six to eight cells. It is believed that embryos growing at a slower rate have
a less favorable chance of implantation. The grade of the embryo is determined by the appearance of the individual blastomeres. A high-grade embryo contains blastomeres that are symmetrical in size and shape, without evidence of intracellular fragmentation. Conversely, embryos made up of asymmetrical cells with a significant degree of fragmentation, are less likely to successfully initiate a pregnancy.
There is another critically important component of the embryo that does not get as much attention. This important structural component is the elastic outer shell, which surrounds the embryo, known as the zona pellucida (ZP). The ZP is formed from a matrix of various proteins that are secreted by the egg, and in photographs appears as a translucent halo enveloping the embryo. The ZP has several important functions. During the process of fertilization, it serves to prevent the access of more than one sperm to the egg. Following fertilization, the ZP keeps the cells of the embryo together during early development, until the embryo reaches the blastocyst stage. At the blastocyst stage, the embryo has enough structural integrity that it no longer needs the protection of the ZP. In fact, it is mandatory that the blastocyst break free of the ZP, once it is in the uterine cavity, in order to successfully implant within the uterine wall.This eventual escape from the ZP by the expanding blastocyst is called
Standard IVF protocols include culturing of embryos within the laboratory for three days, followed by transfer of cleavage stage embryos (6 to 8 cells), on Day 3, to the uterine cavity. Following transfer, the embryos must continue to progress to the blastocyst stage, shed the ZP, and embed into the uterine wall. In 1989 Cohen and his co-investigators observed a higher implantation rate in patients undergoing IVF, who had the ZP of their embryos mechanically opened. They therefore hypothesized that artificially creating a gap in the ZP might serve to facilitate embryo hatching and implantation. Microscopic manipulation of the ZP, in order to augment hatching and implantation, subsequently became known as “assisted hatching”. Prospective randomized clinical studies have been performed in order to evaluate the effectiveness of assisted hatching. Several studies report a significant increase in embryo implantation and clinical pregnancy rates, in select groups of patients whose embryos have undergone this procedure. These select patient groups include women greater than 38 years of age, those with elevated Day 3 FSH levels, couples with previous IVF failures, embryos with an abnormal appearing zona pellucida, and when using previously cryopreserved embryos. Some IVF programs will globally perform assisted hatching on all embryos prior to transfer, but the data on this are less clear....
Ovulatory dysfunction is one of the most common causes for reproductive difficulty in otherwise fertile couples. Once successful ovulation is achieved, fertility is often restored. For many years, the first line of pharmacologic ovulation induction has involved the use of selective estrogen receptor modulators (SERMs), of which clomiphene citrate (CC) has been most extensively studied. The first trial of CC resulted in successful ovulation induction in approximately 80% of women, and ultimately half were able to achieve pregnancy. (1) The use of CC for superovulation in patients with unexplained infertility (2) has also been the mainstay when coupled with intrauterine insemination. Yet despite advances in ultrasonographic technology, hormone assays, and urinary leutinizing hormone kits, success with CC has not changed dramatically. Therefore, it is important that we evaluate our options for ovulation induction and superovulation.