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The Pregnancy Miracle by Lisa Olson

The Pregnancy Miracle, Infertility cure book by Lisa Olson is an extensive 279 pages pregnancy book that consists of a simple and effective 5 step holistic & ancient Chinese system. This easy to follow, step-by-step pregnancy book has illustrations and diagrams to ensure everything is easy to follow and understand. Pregnancy Miracle System focuses largely on Eastern medicine remedies for infertility. This isn't to say that all you need is a Chinese traditional doctor, and youre all set. The book also combines western tools and ideals that not only promote the ease of conception, but also increase overall well being. Pregnancy Miracle is not a magic bullet or even something like this and if you are looking for a quick fix solution to Infertility for any Get Pregnant Quickly and Naturally in 3 days hyped up program this product is not for you. This book has incorporated certain scientific techniques to control the problem of infertility and tells how to practice these techniques correctly. Read more here...

Pregnancy Miracle Summary


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Author: Lisa Olson
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Highly Recommended

All of the information that the author discovered has been compiled into a downloadable ebook so that purchasers of Pregnancy Miracle can begin putting the methods it teaches to use as soon as possible.

When compared to other e-books and paper publications I have read, I consider this to be the bible for this topic. Get this and you will never regret the decision.

Female Infertility Treatment

Table 5.1 summarizes the main causes of female infertility successfully treated by IVF divided into three main categories. In the majority of IVF patients, mature oocytes can be retrieved approximately 25 of patients referred for IVF treatment continue to present with tubal blockage as the primary disorder. Approximately 20 may present with combined aetiologies, including tubal blockage as well as ovulatory or immunological disorders, cervical factors, coital problems and endometriosis. Seventeen per cent present with 'unexplained' infertility where no specific aetiology has been identified. Donation of oocytes depends upon the availability of willing oocyte donors, which is restricted in most countries. IVF surrogacy can be used for patients who can produce mature oocytes for fertilization, but are unable to carry a pregnancy to term the patient's own oocytes are fertilized with her partner's sperm, and resulting embryos transferred to a host surrogate after appropriate counselling...

Male Infertility Treatment

ICSI was initially developed as the treatment of choice in cases where only extremely low numbers of sperm could be found in an ejaculate its use has since been extended to cover a variety of infertility disorders of both male and female origin. Couples who have suffered recurrent failure of fertilization after in vitro fertilization-embryo transfer (IVF-ET) may have one or more disorders of gamete dysfunction, in which there is barrier to fertilization at the level of the acrosome reaction, zona pellucida binding or interaction, zona penetration, or fusion with the oolemma. ICSI is always indicated for patients who have unexplained failure of fertilization in two or more IVF-ET cycles. Until the mid-1990s, virtually all testicular pathologies resulted in untreatable male sterility this situation was completely reversed by combining ICSI with surgical techniques to recover samples from the epididymis and directly from the testis (Hirsh, 1999 DeVos & Van Steirteghem, 1999).

In vitro Fertilisation

Whereas animal and lower plant IVF-systems can easily make use of naturally free-living gametes, sperm, egg and central cells of angiosperms presuppose their isolation, because the embryo sac is generally deeply embedded in the ovule, and the sperm cells are enclosed in pollen grains or tubes. Micromanipulation techniques and skills are prerequisites for the isolation, fusion and culture of single cells. These methods were developed originally for experiments with somatic cells 19-22 . They were adapted and improved for investigations with gametic cells 23-25 . By use of these methods, experimental access to single gametes, fertilisation and postfertilisation events under continuous microscopic observation with defined conditions are possible, for example, isolation, selection and fusion of pairs of gametic protoplasts. Also, this allows to design detailed experiments to follow precisely timed early events of zygote, embryo and endosperm formation after gamete fusion. Fig. 1. Isolated...

Preliminary Tests For Ivf And

Preliminary tests for couples undertaking PGD are as for IVF (see Chapter 5). A gynaecological and medical history should be taken. Rubella immunity should be checked and immunization offered if necessary. Haematological screening (sickle cell and thalassaemia) and screening for Tay-Sachs disease is offered if appropriate. The male partner should be asked to produce a semen sample for analysis. As for all patients undergoing IVF, PGD patients are tested for HIV and hepatitis B and C before they undergo treatment. It is our policy also to visualize the endometrial cavity and uterus by hystero-salpingography or hysterosalpingo-contrast sonography using a contrast medium prior to IVF. This is particularly required for women who have had repeated evacuations of the uterus for recurrent miscarriage or following termination of pregnancy, as these women are at risk of Asherman's syndrome and intrauterine adhesions (Figures 8.2 and 8.3).

Assisted reproduction

Or using intrauterine insemination with their partner's sperm (Salha et al., 1999). Furthermore, if surgically obtained sperm is used for intra-cytoplasmic sperm injection (ICSI) the risk of pre-eclampsia in an ensuing pregnancy is increased (11 ) compared to pregnancies resulting from in vitro fertilization or ICSI using ejaculated sperm (4 ), suggesting a protective effect of semen exposure (Wang et al., 2002). Readers interested in a more in-depth discussion of this subject are referred to the chapter on immune maladaptation in pre-eclampsia by Dekker and Robillard in this book. Because of the effect of certain medical conditions (for example, renal disease) or their treatments (for example, cyclophosphamide for systemic lupus erythematosus) on fertility, these issues related to assisted reproduction are extremely pertinent. Regrettably, however, the desire of women to have children tempers the assimilation of possible risks associated with assisted reproduction. It is the...

Germ Cell Development In Humans And Infertility

Infertility is common among both men and women. Although human reproduction and fertility have been studied for many years, few genes have been identified that contribute to human germ cell production. However, several studies have demonstrated that the age at onset of menopause has a significant genetic component this property is likely to reflect the quantity and quality of female germ cells that are formed and differentiated. Family history is a significant predictor of early menopause (menopause at age

Prevalence of infertility in women

I The percentage of women of reproductive age (15-49 years) at risk of becoming pregnant (not pregnant, sexually active, not using contraception and not lactating) who report trying for a pregnancy for two years or more Numerator. Number of women of reproductive age (15-49 years) at risk of becoming pregnant (as defined above) who report trying unsuccessfully for a pregnancy for two years or more x100 j Denominator Total number of women of reproductive age at risk of becoming pregnant (as

Screening For Agerelated Aneuploidy In Couples Undergoing Routine

Women of 36 years or older are usually offered prenatal diagnosis for chromosome abnormality in an established pregnancy that reaches 16 weeks. This is based on the risk of aneuploidy of about 1 in 250, which exceeds the risk of the procedure to the pregnancy. At conception, however, the risk of aneuploidy is clearly much higher, since about 50 of pregnancies that miscarry before 13 weeks are chromosomally abnormal (Hassold & Jacobs, 1984). The only monosomy which is represented in the miscarriage data is X monosomy, which is estimated to occur in 1 of conceptions, but only 1 in 5000 births. It seems evident that autosomal monosomy in humans is lethal at around the time of implantation. It can be estimated that the overall risk of aneuploidy and triploidy at conception is about 12 for all maternal ages, but for women over 40 this is generally increased, to greater than 50 (Hassold & Jacobs, 1984). This is the logic behind attempting to screen for age-related aneuploidy in older IVF...

Surgical Treatment of Female Infertility

Posterior Cul Sac

Due to widespread availability of assisted reproductive technologies, the need for reproductive surgery in infertile women has declined in recent decades. However, surgery still has a place in the management of infertile women. For example, young women with pelvic adhesions or blocked fallopian tubes that impair their fertility may benefit from early surgical intervention. On the other hand, women over the age of 35 with a long history of infertility or those who require a laparo-tomy for correction of their disorders are better treated with in vitro fertilization. Laparoscopy should only be performed after complete investigation of infertility such as semen analysis, hysterosalpingogram and assessment of ovulation. In the era of assisted reproductive technology, laparoscopy is not a routine test. However, it is indicated in young women with an abnormal hysterosalpingogram or a history of salpingitis, sexually transmitted disease, previous pelvic surgery, or endometriosis. The...

An Overview of Female Infertility

Medical Algorithm

According to the 1995 National Survey of Family Growth, the percentage of women reporting some form of fecundity impairment rose from 8 in 1988 to 10 in 1995 which some believe is related in part to a trend toward delayed child-bearing. Numerous observational studies have demonstrated that 80-90 of couples that have unprotected intercourse for 12 months will conceive. Thus, the accepted definition of an infertile couple is the failure to conceive after 12 months of intercourse without any form of birth control. Evaluation for infertility is indicated for couples who fit this definition as well as those who have significant risk factors for infertility who may have less than 12 months of exposure to the possibility of pregnancy (e.g., history of oligomenorrhea or sexually transmissible infections). The general causes of infertility and the frequencies are listed in Table 13.1. In this chapter we will focus on the female factors affecting infertility (Table 13.2). When evaluating a...

Coverage Of The Cost Of Ivf And

In eight countries (Australia, Belgium, France, Germany, Italy, the Netherlands, Spain and Sweden), the IVF component of the cost of PGD, usually up to four to six IVF cycles, is covered by the social security system. The couple, however, pay the diagnostic component. In the United Kingdom, the availability of coverage is dependent on the regional funding scheme providing coverage to individual couples. Therefore the National Health Service does not always cover PGD (J. Harper, personal communication). In Greece, Lebanon and Thailand, the entire cost of PGD is the responsibility of the patient. In the USA the situation varies from state to state and is often dependent on individual states' insurance regulations and the power afforded by state legislatures to political lobbying groups concerned with women's health care, infertility, or religious opposition to prenatal diagnosis and pregnancy termination. Some states have been influenced by support groups for infertility patients and...

Your Environment Your Fertility Is There a Link

Fertility, the ability of people to produce offspring, was a concept formerly applied only to the female. Demographers traditionally defined the fertility rate as the average number of live-born children per woman of reproductive age. However, fertility is one of the few measures that reflect the joint health of two individuals, and we have only recently begun to appreciate the extent to which fertility depends on the health and environment of both the male and female partner, as well as the interaction between partners. Males appear to be solely responsible for infertility in about 20 of infertile couples and contribute to infertility in another 30-40 . Using the demographic definition above, fertility declined 50 worldwide between 1950 and 2000. Between 1976 and 1998, the percent of women in the United States aged 35-39 who were childless increased from 10.5 to 19.8 . Moreover, the number of annual office visits for infertility increased from 600,000 to 2 million between 1968 and...

Alternative Medicine and Female Infertility

The role of acupuncture in reproductive endocrinology is based upon a more modern and scientific approach that has begun to emerge in the past two decades. A review on acupuncture and female infertility suggested possible etiologies why acupuncture may improve female fertility. Acupuncture has been shown to induce a rise in p-endorphin levels that persists for up to 24 hours after treatment. Beta-endorphin is derived from its precursor protein, pro-opiomelanocortin (POMC), which is present in abundant amounts in neuronal cells of the arcuate nucleus of the hypothalamus, pituitary, medulla, and in peripheral tissues including intestines and ovaries. POMC cleaves to form adrenocorticotropic hormone and p-lipoprotein. Cleavage of p-lipoprotein results in the formation of neuropeptides including p-endorphin. Endometrial thickness, morphology, and uterine artery blood flow have been implicated as crucial parameters for implantation success of human embryos. Despite conflicting results in...

Infertility Treatments And Preterm Birth

Infertility treatments have allowed thousands of couples who have difficulty conceiving to fulfill their desire to have children. In the United States in 2002, 7.3 million women, or 12 percent of women ages 15 to 44, had physical difficulty becoming pregnant or carrying a baby to term. Approximately 2.1 million of these women, or 7 percent of all women between the ages of 15 and 44, were infertile, defined as not becoming pregnant after 12 months when the couple is not using contraception (CDC, 2002b). Two percent of women had had an infertility-related medical appointment within the previous year, and an additional 10 percent reported that they had received services for infertility at some point in their lives. The use of infertility treatments has risen dramatically in the past 20 years and has been associated with the trend to delay childbearing (see Chapter 1). In 2002, 33,000 American women delivered babies as a result of the use of infertility procedures this is more than twice...

Disparities in Infertility Treatment

As discussed in Chapter 4, socioeconomic differences in multiple gestations have not been well studied (Kramer et al., 2000). The literature on infertility, utilization of treatment, and outcomes of treatment has been focused on white and socieconomically advantaged populations. While the extent to which various racial-ethnic minority populations and subpopulations experience fertility problems is not precisely known , a series of recent reports developed from a workshop, Health Disparities in Infertility, began to shed light on infertility problems among racial-ethnic minority populations (Berkowitz and Davis, 2006). This workshop was sponsored by the National Institute of Child Health and Human Development, Office of Behavioral and Social Sciences Research, and Office of Research on Women's Health of the National Institutes of Health, and Agency for Healthcare Research and Quality. In an effort to assess whether racial-ethnic or socioeconomic disparities exist in infertility,...

Effects on Female Fertility

Radiation produces dose-related gonadal damage to both the germ cell and the endocrine component of ovarian tissue. Experience with external beam radiotherapy suggests that the probability of infertility for a given dose of radiation increases with age treatment with 4Gy will produce infertility in only 30 of young women but in 100 of those over the age of 40. In addition, resumption of menstruation has been seen in adolescents irradiated to doses as high as 20 Gy 4 . The same age effect is recognized following exposure to chemotherapy drugs. Despite the documented ovarian dysfunction following radioiodine therapy, there is no indication that this is correlated with lasting infertility. Several large studies have reported that exposure to radioiodine does not affect the outcome of subsequent pregnancy or offspring 6,9-12 . An early study in children and adolescents treated with a mean total dose of 196mCi of radioiodine reported a 12 incidence of infertility, 1.4 incidence of...


As well as to eliminate sperm contamination, ICSI will be required for male cystic fibrosis carriers that have congenital absence of the vas deferens and sperm aspiration is required to obtain the sperm and ICSI for efficient fertilization (see Chapter 5). In some cases of chromosomal translocations, a low sperm count may be present and the use of ICSI required to obtain fertilization. Males with Y chromosome deletions will also require ICSI (Figure 8.9). There have been reports that ICSI is associated with an increase in birth defects. Kurinczuk and Bower (1997) reported a two-fold increase (odds ratio 2.03, 95 confidence interval 1.4 to 2.93) in birth defects in 420 infants liveborn after ICSI and nearly 50 higher incidence of a minor defect (odds ratio 1.49, 95 confidence interval 0.48 to 4.66). Their results differed from the Belgian group (Bonduelle et al., 1996) who used a narrow definition of what constituted a birth defect and who concluded that there was no increase in the...

Female Fertility

During the primary characterization of the first SSAT transgenic mouse line, we soon found that the female members of the line were infertile. The apparent reason for the infertility was uterine hypoplasia and the absence of corpora lutea in the ovary (7). The female reproductive organs (uterus and ovary) of transgenic mice likewise displayed slightly different gene expression pattern in comparison with the wild-type animals, namely the expression of lipoprotein lipase and glyceraldehyde-3-phosphate dehydrogenase was elevated in the transgenic females (22). It is, however, entirely unknown whether these changes contribute to uterine hypoplasia and ovarian hypo-function.

Male Infertility

Male infertility is the sole cause of 20 of couple infertility and contributes an additional 30 as a cause for combined couple infertility. Most men seeking infertility counseling and evaluation are referred through gynecologists or primary care physicians caring for the female partner. Thus, specialized knowledge or training about infertility is very important as is the ability to work closely with reproductive endocrinologists and gynecologic physicians. With the advancement of assisted reproductive technologies (ART) and microsurgical techniques, many men previously labeled as sterile are now capable of fathering children. Because of the anxiety and stress that is often associated with couple infertility, male patients often describe difficulty with erections. Obviously, if sexual intercourse is not occurring then conception is impossible This information must be addressed specifically with the patient as he may not volunteer it. Erectile dysfunction secondary to various disease...

Lifestyle Modification

Weight reduction, of as little as 3-5 , has been associated with improvements in ovulation rates in PCOS women who are overweight or obese. Although studies are consistent in this regard, no large scale controlled trials are available to assess improvements in pregnancy rates. There are no specific dietary regimens that target PCOS and effective weight reduction has been demonstrated with a wide variety of approaches.

Hormonal Contraception

There are 6.3 million pregnancies annually in the United States, and almost half of them are unplanned. Approximately 50 of the women who become pregnant unintentionally are using some form of contraception at the time of conception. In the United States, unintended pregnancy, especially among women under age 25, is more of a problem than in other Western nations, with teen pregnancy rates in five northern European countries and Canada ranging from 5-53 of the U.S. rate. This is thought to be due, at least in part, to the fact that adolescent women in the U.S. are less likely than their European counterparts to use contraception of any kind most specifically, hormonal contraceptives. Each contraceptive method has characteristics that are more or less beneficial for an individual woman, such as efficacy, cost, frequency of intervention, protection against sexually transmitted infections (STIs), and other health benefits (Tables 7.1 and 7.2). In general, efficacy of a method increases...

Gonadotropin Releasing Hormone Analogs

Gonadotropin releasing hormone analogs (GnRH) cause a temporaty medical menopause resulting in hypogonadism and hypoestrogenism by acting on the pituitary to reduce gonadotropin synthesis and secretion. Most of the side effects experienced occur because of the hypoestrogenic state including hot flashes, vaginal dryness, mood lability and decreased libido. The GnRH agonists have been shown to work well in reducing pain symptoms associated with endometriosis such as dys-menorrhea, dyspareunia, and noncyclic pelvic pain. GnRH agonists are often initiated with the onset of menses, but a more rapid response is observed with mid-luteal administration. A limit of 6 months per treatment course is required due to loss of bone mineral density during therapy, but this can be extended via the addition of 'add-back' therapy with estrogens. Retreatment with these drugs is supported by limited data. Several investigators have studied the use of GnRH agonists as surgical adjuncts. Their use...

Reproductive Endocrinology Diagnostic Imaging

Hsg Patient Images

Many mullerian anomalies present later in life, not with primary amenorrhea, but in the workup of primary infertility or recurrent pregnancy loss. MRI may also be useful in the evaluation of these women, for its ability to identify and distinguish the fibrous tissue of a septate uterus from the myometrium of bicornuate uterus. The former patients can benefit from hysteroscopic resection of their septum the latter patients cannot. It is important to distinguish an arcuate or didelphic uterus from a septate uterus before recommending treatment. A uterine septum can be safely resected, decreasing the risk of recurrent miscarriage. An arcuate uterus is a normal variant, without negative impact on reproductive outcome and does not require additional abdominal imaging. Conversely, patients with a didelphic uterus Infertility The workup of female infertility usually begins with an assessment of sexual and menstrual history, followed by a diagnostic workup to identify and treat a particular...

Assisted Reproductive Technology

Assisted reproductive technology (ART) is by definition any treatment or procedure that includes the handling of oocytes and sperm or embryos outside the body for the purpose of establishing a pregnancy. In vitro fertilization (IVF) is the most common ART procedure. The first IVF baby was conceived in 1978 (Louise Brown) in Lancashire, England. IVF has been used in the United States since 1981. In vitro fertilization (IVF) A process including controlled ovarian hyperstimulation, surgical removal (retrieval) of oocytes, fertilization in the laboratory, and transcervical transfer of embryos into the uterus. Donor oocytes Eggs that are removed from one woman's ovaries to be used by another for IVF. Indications often include premature ovarian failure, gonadal dys-genesis, recurrent IVF failure, natural menopause, and inheritable disorders. Intracytoplasmic sperm injection (ICSI) A micromanipulation technique that involves injecting a sperm directly into an egg in order to facilitate...


Women of reproductive age who have undergone bariatric surgery require counseling and management of subsequent pregnancies. Patients with adjustable gastric banding should be advised that they are at risk of becoming pregnant unexpectedly after weight loss following surgery. All patients are advised to delay pregnancy for 12-18 months after surgery to avoid pregnancy during the rapid weight loss phase in order to avoid malnutrition and small-for-dates features in the neonate. After restrictive procedures (where iron containing foods such as red meat may be poorly tolerated) increased iron is needed. After gastric bypass procedures (in which the duodenum where most iron is absorbed is bypassed) increased iron must be taken during pregnancy to allow adequate absorption in the proximal jejunum. Furthermore, adequate calcium intake or supplementation should be verified. Women with a gastric band should be monitored by their general surgeons during pregnancy because adjustment of the band...


Reported in the literature however, prolactinomas can be locally destructive, especially the macroadenomas. In addition to affecting pituitary function by a local mass effect, they can invade the optic chiasm as well as the adjacent cavernous sinus causing cranial nerve neuropathies (CN III, IV, V1, V2, VI). In women, the slightest elevation in prolactin can cause menstrual disturbances. Men, on the other hand, tend to present with symptoms of local mass effect. Physiologic effects of hyperprolactinemia in men (low libido, impotence, and infertility) are less sensitive to the hyperprolactinemia than symptoms in females (oligomenor-rhea or amenorrhea).

Ovulation Induction

Ovulation Stimulation

Approximately 25 of infertility can be attributed to ovulatory disorders. The goal of ovulation induction is to restore fecundity by restoring regular, ovulatory cycles. Ovulation induction may also be used for controlled ovarian hyperstimulation (COH) for treatment of other causes of infertility such as mild moderate en-dometriosis, unexplained infertility, and for assisted reproductive techniques such as in vitro fertilization (IVF). When used in ovulatory patients, the goal of ovulation induction is not to restore ovulatory cycles but to increase fecundity through ovarian stimulation (Table 15.1). The World Health Organization (WHO) has provided a simplified classification system for disorders of ovulation. This grouping system describes the etiology of anovulation, and the most appropriate treatment for patients with ovulatory dysfunction is determined by their classification. WHO Group I patients have low follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels and...

The Menstrual Cycle

Reproductive cycles begin at puberty as the hypothalamic pulse generator is activated and GnRH is secreted. Menstrual cycles are the most irregular during the 2 years after menarche and during the 3 years before menopause. Once a cyclic pattern is established, the menstrual cycle serves as a highly sensitive indicator of an intact hypothalamic pituitary ovarian (H-P-O) axis. To the clinician, the monthly cycle of endometrial degeneration and regeneration provides confirmation that the infertile patient has ovulatory cycles. After ovulation the GnRH pulse generator is slowed for the luteal phase. LH, FSH and estradiol levels fall but some LH is essential to maintain CL function. The accumulation of LH receptors during the follicular phase sets the stage for the extent of luteinization and the functional capacity of the corpus luteum. Normal luteal function requires optimal preovulatory follicular development and continued tonic LH stimulation. A defective luteal phase can contribute to...


Infertile Discharge

Amenorrheic patients with evidence of estrogen production and an intact uterus require further evaluation to determine the etiology of their amenorrhea (Fig. 3.2). Pregnancy, even in a patient with primary infertility, always needs to be considered and eliminated as an etiology of amenorrhea. Thyroid disorders and hyperprolactinemia are common disorders associated with amenorrhea, therefore thyroid stimulating hormone and prolactin levels should be assessed. It is useful to perform a progestin challenge test in these individuals to assess the amount of estrogen production and the competency of the uterine outflow tract. A progestin challenge test takes advantage of endogenous estradiol and usually causes withdrawal bleeding within 2 to 7 days after cessation of progestins. Multiple formulations of progestins can be used (Table 3.1), and any amount of bleeding is considered a positive test. Lack of withdrawal bleeding should be further evaluated with another progestin challenge test...


A careful history is of course essential to the management of any patient presenting with abnormal bleeding. The date of onset of the presenting episode and her prior menstrual history need to be determined along with the presence of concomitant symptoms of any kind. Also important are the patient's general obstetrical and gynecologic history, including her pregnancy and infertility history, prior pelvic surgeries, abnormalities noted on prior exams, Pap smear results, and contraceptive method. A history of any significant medical problems should be noted, and inquiries made about symptoms suggestive of endocrine and bleeding disorders and about family members having similar problems. Sensitivity for detecting intracavitary lesions similar to that of hysteroscopy. Less sensitive for detection of intracavitary lesions than SSH or hysteroscopy, but may be warranted when a less common Mullerian anomaly is suspected or in infertilty patients when tubal status is also a concern. Pelvic MRI...


Diagnosis of endometriosis is often problematic. Although patients classically present with pelvic pain, dysmenorrhea, dyspareunia, pelvic mass and infertility, there are also many patients who are asymptomatic. It has been found that 25 of all women who experience pelvic pain and 40-50 of infertile women have endometriosis. Most symptoms that women experience are a result of local infiltration of endometriosis into the pelvis pelvic pain, dyschezia (painful defecation), abdominal bloating, dyspareunia, back pain, dysuria and suprapubic pain. Menstruation can greatly accentuate these symptoms.

Vivian Lewis MD

VADEMECUM Reproductive Endocrinology and Infertility LANDES BIOSCIENCE Austin, Texas U.S.A. Reproductive endocrinology and infertility edited by Vivian Lewis. p. cm. -- (Vademecum) Includes bibliographical references and index. ISBN-13 978-1-57059-702-2 (alk. paper) 1. Endocrine gynecology . 2. Infertility, Female--Endocrine aspects. I. Lewis, Vivian, M.D. II. Series. DNLM 1. Genital Diseases, Female. 2. Endocrine System Diseases. 3. Infertility, Female. WP 140 R4247 2007 RG159.R452 2007 618.1--dc22

The National Academies

To begin, the committee would like to thank the sponsors of this report. Funds for the committee's work were provided by the National Institute for Child Health and Human Development, the Centers for Disease Control and Prevention, the Health Resources and Services Administration, March of Dimes, Burroughs Wellcome Fund, American College of Obstetricians and Gynecologists Environmental Protection Agency, National Institutes of Health Office of Research on Women's Health, American Society for Reproductive Medicine, and the Society for Maternal-Fetal Medicine. The committee thanks Capt. Donald Mattison, Scott Grosse, and Samuel Posner, who served as project officers and who were instrumental in the initiation of this activity. The committee thanks Ann Koontz, Marina Weiss, Nancy Green, Lisa Potetz, Enriqueta Bond, Nancy Sung, Ralph Hale, Nicole Owens, Lanelle Bembenek Wiggins, Vivian Pinn, Loretta Finnegan, Robert Rebar, and Richard Depp for their support and guidance on the committee's...

Vascular defects in different disorders of pregnancy

In summary, the results of all these studies indicate that the former black-and-white picture has been replaced by the more subtle concept of a spectrum of histopathological changes that may occur throughout different disorders of pregnancy. Such a concept is also more in line with present ideas on the complexity of pregnancy-associated diseases (Brown et al., 2000), which may represent different patterns of maternal pathophysiological response to early implantation or placentation defects (Roberts and Lain, 2002). In an extreme situation, when the mother cannot cope with defective early placentation, spontaneous early miscarriage would occur. Indeed, specimens of spontaneous miscarriage often show defective trophoblast invasion and physiological change in spiral arteries (Hustin et al., 1990 Khong etal., 1987), and this has also been shown to be the case for early pregnancy losses in women with antiphospholipid syndrome (Sebire etal., 2002).

Trophoblast invasion the extracellular matrix and cell adhesion molecules

The adhesion of cells to each other, to other cell types and to the ECM relies on the expression of CAMs and their ligands. At implantation, the trophoectoderm attaches to the uterine epithelial surface and CAMs play a major role. Interstitial and intravascular invasion of maternal tissue by trophoblast requires a new repertoire of CAM expression. Understanding the part played by adhesion molecules in pregnancy is paramount because pre-eclampsia as well as several pregnancy-associated disorders including fetal growth restriction, miscarriage and infertility problems have been linked to abnormalities in expression of particular CAMs and or their ligands (Lyall, 1998). The majority of CAMs fall into one of four families the immunoglobulin superfamily, the integrins, the selectins and the cadherins.

Primary Prevention of Genetic Disorders and Place of Preimplantation Genetic Diagnosis

Environmental programs, (2) discouragement of pregnancy at advanced ages through community education and family planning, (3) periconcep-tion folic acid supplementation or multivitamin fortification of basic foodstuffs, (4) rubella vaccination, (5) avoidance of alcohol consumption and smoking during pregnancy, and (6) prenatal and (7) prepregnancy (preimplantation) diagnosis. The decision to adopt any of the available preventive programmes depends on the differences in health services development, ethnic distribution of congenital disease, and the local attitudes to genetic screening and termination of pregnancy. For example, induced abortions are still not permissible in many countries on eugenic grounds. On the other hand, an increasing number of countries are gradually permitting prenatal diagnosis and termination of pregnancies for medical indications even in some strict religious settings.

Clinical Aspects Of

During consultations to discuss PGD a large amount of information is discussed with the couple and so it is advisable to give the patients information leaflets on IVF and PGD and a written summary of the consultation. Communication with the patient's GP and clinical geneticist is essential. After the consultation the patients should be given time to discuss the option of PGD, but if they decide to embark on treatment, all the necessary preliminary tests required for IVF should be undertaken (see above and Chapter 5). It is important to explain to the patients exactly what will occur during the PGD cycle which diseases are being tested for, the limitations of the procedure, the possibility that all of the embryos may be affected, and the pregnancy rates must be discussed with the patients before treatment. For PGD to be successful, a good number of embryos are required so that at least two unaffected embryos of good morphology are available for transfer. Therefore, patients require...

Example from the literature

Slevin et al. (1990) asked 106 consecutive patients with solid tumours to complete questionnaires about their willingness to receive chemotherapy. They were told that the more-intensive regimen was likely to have considerable side-effects and drawbacks, such as severe nausea and vomiting, hair loss, frequent tiredness and weakness, frequent use of drips and needles, admission to hospital, decreased sexual interest, and possible infertility. They were given different scenarios, such as (a) small (1 ) chance of cure, (b) no cure, but chance of prolonging life by three months, and (c) 1 chance of symptom relief only. All patients knew they were about to commence chemotherapy, and thus considered the questions seriously. Cancer nurses, general practitioners, radiotherapists, oncologists and sociodemographicallv matched controls were asked the same questions.

Approaches to Preimplantation Genetic Diagnosis

Introduced in 1990 as an experimental procedure, preimplantation genetic diagnosis (PGD) is now becoming an established clinical option in reproductive medicine. The number of apparently healthy children born after PGD is already close to 2000, validating that there is no ostensible evidence of any incurred adverse effect. Approximately 7000 PGD cases have been performed in more than 50 centres around the world, allowing hundreds of at-risk couples not only to avoid producing offspring with genetic disorders, but more importantly, to have unaffected healthy babies of their own without facing the risk of pregnancy termination after traditional prenatal diagnosis. Without PGD it is likely that few of these children would have been born. The natural extension of PGD's ability to allow transfer of euploid embryos is its positive impact on the liveborn pregnancy outcome. This is especially applicable to poor prognosis IVF patients (prior IVF failures, maternal age over 37). Introduction of...

Practical Preimplantation Genetic Diagnosis

Proximately 7000 PGD attempts worldwide have resulted in the birth of close to 2000 apparently unaffected children, with overall congenital malformation rate not different from population prevalence 27,28 . With the highly improved accuracy of genetic analysis and indications expanding well beyond those for prenatal diagnosis, more than 1000 PGD cycles are now performed annually. As seen in Figure 2.1, the experience during the years 2001-2002 shown has resulted in the birth of nearly the same number of children as during the entire preceding decade since the introduction of PGD. PGD offers special attractions not possible with traditional prenatal diagnosis. One is to avoid clinical pregnancy termination. This is especially attractive for couples carrying translocations, couples at risk for producing offspring with common diseases of autosomal dominant or recessive etiology, and, finally, for couples wishing to have not only an unaffected child, but an HLA-compatible cord blood donor...

Economic empowerment interventions for women

In response to these situations, interest has been growing in implementing income-generation interventions, such as microfinance projects - another form of social or structural intervention - as a means of empowering women in their relationships and reducing their material dependence on men. Several studies of micro-credit interventions targeting women and their fertility outcomes (pregnancy rates and contraceptive use) indicated that economic empowerment translated into increased self-esteem, improved social networks, increased control over household decision-making, increased bargaining power and increased contraceptive use (137). Micro-financing has only recently been applied to HIV prevention, so few empirical examples of interventions exist. One large-scale community-level randomized controlled trial in South Africa of an integrated, comprehensive intervention that

Single Cell Genetic Analysis

Single-cell genetic analysis includes single-cell DNA and FISH analysis, which have become important tools for application of PGD in assisted reproduction and genetic services, providing a practical option for couples at genetic risk to avoid the birth of an affected offspring and have a healthy child of their own.

Analysis and interpretation

The TFR is probably the most commonly used demographic indicator. It is closely associated with contraceptive prevalence and other indicators of reproductive health such as the maternal mortality ratio. It is a useful indicator of population momentum and a good proxy measure for the success (or failure) of family planning services. The TFR may also be used as a measure of poor physical reproductive health, since high parity ( 5 births) represents a high risk of maternal morbidity and mortality. As mentioned above, disaggregation of the ASFRs is useful in reflecting the age pattern of fertility, especially in high-risk groups such as adolescents and older women. TFRs are not useful in gauging the direct impact or success of family planning programmes. Family planning programmes can reduce total fertility only by reducing unintended as opposed to intended fertility. Nevertheless, there is strong empirical evidence that high contraceptive prevalence is associated with a low TFR and that...

Data sources and collection methods

Records kept by organized family planning programmes are another main source of information about contraceptive practice. Such records are crucial to effective monitoring and management of programmes, and they have the potential to provide timely updates and detailed trend information about numbers and characteristics of programme clients. Programme statistics have the serious drawback, however, of excluding the use of contraception obtained outside the programme, including modern methods supplied through non-programme sources (the private sector) as well as methods that do not require supplies or medical services. Other problems relate to incomplete data, double counting of users who enter the service delivery system at more than one point, deliberate inflation of service statistics, and poor data quality owing to other activities competing for the attention of those recording the information.

Preimplantation Genetic Diagnosis for Single Gene Disorders

As mentioned, preimplantation genetic diagnosis (PGD) was introduced 14 years ago with the purpose of performing genetic testing before pregnancy, in order to establish only unaffected pregnancies and avoid the need for pregnancy termination, which is the major limitation of traditional prenatal diagnosis 1, 2 . Despite the requirement for ovarian hyperstimulation and in vitro fertilization (IVF), needed to perform genetic testing of oocyte or embryo prior to transfer, PGD has been accepted in most parts of the world, with an overall number of approximately 7000 PGD cases performed by the present time, which have resulted in the birth of close to 2000 healthy children 3, 4 . At least 2000 of these PGD cycles were performed for single-gene disorders, and as will be shown below, is presently offered for some indications that have never been practiced in prenatal diagnosis, such as late-onset diseases with genetic predisposition and preimplantation HLA typing, making PGD not only an...

Autosomal Dominant Disorders

Combined PGD for SMAand aneuploidy. (4) Pedigree of the family undergoing PGD for SMA. Both parents are carriers of the deletion in SMN1 gene. Paternal haplotype was predicted by multiplex heminested single sperm PCR analysis. Maternal haplotype was established by sequential PB1 and PB2 analysis. As a result of IVF-PGD cycle, healthy twins were born. Positions of polymorphic markers linked to SMN1 gene and applied for improving accuracy of the mutation analysis are shown next to the paternal haplotypes. (B) Oocytes 3,8, and 11 were predicted to be normal by polar bodies analysis. The embryos resulting from these oocytes were subjected to aneuploidy testing using five chromosome-specific probes. Trisomy for chromosome 13 was detected in embryo 8 and monosomy 18 in embryo 10. Blastomeres from the remaining 13 embryos were subjected to multiplex heminested PCR to perform simultaneous mutation, linked polymorphic marker, and aneuploidy analysis for chromosomes 13,16,18,21 and...

Intendedness of Pregnancy and Preterm Delivery

Thus, although the research available on the association of the intendedness of pregnancy and preterm delivery is limited, that which is available suggests that women with unintended pregnancies are more likely to deliver preterm, and as a consequence, their infants are at higher risk of being of low birth weight. Understanding the pathways from unintended conception to preterm labor and delivery by the use of multilevel approaches would be useful in elucidating the etiology of preterm birth for at least some subgroups of women. Unmeasured socioeconomic factors that may be confounded with unintended pregnancies must be carefully controlled in future studies. In addition, it is critical to refine measures of intendedness to be sure they are valid and reliable if this arena of research is to be pursued. Reducing unintended pregnancies through family planning and other mechanisms could indirectly reduce the rates of preterm delivery and related adversities (IOM, 1995). Disparities in...

Homozygous or Double Heterozygous Recessive Conditions

As mentioned, the first case of PGD for PKU was performed in a couple with compound heterozygous affected partner presented for PGD in connection with their first offspring with PKU, and their 50 risk of producing another affected child. The 31-year-old mother was a carrier of R408W mutation in exon 12 of phenylalanine hydroxylase (PAH) gene, while the affected father was compound heterozygous for R408W and Y414C mutations in the same exon. Following maturation of oocytes in a standard IVF protocol, PB1s were removed following maturation of oocytes. Then, following fertilization of oocytes by ICSI, PB2 were removed using the micromanipulation techniques described in Chapter 2. PB1 and PB2 were amplified by heminested multiplexPCR,

Threshold of evidence needed for widespread implementation

Studies sometimes reported results for multiple measures of each behaviour, for different time periods, for different subgroups or for combinations of these. Thus, some studies reported only one or a small number of significant positive effects on behaviour as well as a large majority of results that were not significant. To avoid presenting only the positive results and to provide a more balanced overview, the following rules for summarizing results were adopted. First, for different measures of the same outcome behaviour all measures across all the studies were rank-ordered according to their probable impact on prevalence. For example, the use of condoms over a long period of time was ranked higher than condom use at first sexual intercourse. Only the results from the highest ranked measure reported in each study were included in the tables. Second, because short-term effects on behaviour would have little impact on HIV prevalence, only those results reported for periods of 3 months...

Bone marrow transplantation

Is a good HLA match for the donor), the success rate appears to be close to 90 . It is lower if there is already iron loading of the liver or if the transplant is carried out in older patients. The main complications are severe infection during the period of transplantation and either acute or chronic graft-versus-host disease. So far, after over 15 years of surveillance, there have been no reports of secondary bone marrow malignancies in children treated in this way. A number of approaches are being tried to overcome the problem of lack of matched donors. In a few cases, HLA typing has been carried out after in vitro fertilization to attempt to obtain an HLA-matching sibling, although there is still considerable ethical concern about this approach. It is still too early to determine the role of haemopoietic stem cell therapy for the treatment of this disease.

Scoring Zygotes On

Inseminated oocytes must be dissected the day following insemination in order to assess fertilization. Oocytes at this time are normally covered with a layer of coronal and cumulus cells. These are carefully dissected away in order to clearly visualize the cell cytoplasm and examine for the presence of two pronuclei indicating normal fertilization. Oocytes that have had ICSI treatment have all cells removed prior to injection, and these can be directly scored for fertilization without further treatment. Scoring for pronuclei should be done between 17 and 20 hours after insemination, before pronuclei merge during syngamy (Figure 5.5) (see Chapter 6 p. 91). Single pronucleate zygotes obtained after conventional IVF have recently been analysed by fluorescence in situ hybridization (FISH) to determine their ploidy of 16 zygotes, 10 were haploid and 6 were diploid (4 XY and 2 XX). It seems that during the course of their interaction, it is possible for human gamete nuclei to associate...

Risk For Multiple Gestations

Multiple gestations are more common as a result of assisted reproduction than as a result of natural conception because of the transfer of multiple embryos and a higher incidence of spontaneous twinning with any single embryo. The risk of monozygotic twinning after implantation of a single embryo appears to be increased in pregnancies conceived by IVF compared with the rate during spontaneous conceptions however, this risk is relatively low, with only a 1 to 2 percent chance of having twins with implantation of a single embryo (Adashi et al., 2004). Therefore, the major cause underlying the increased risk of multiple births as a result of the use of ARTs is the number of embryos transferred. Results from a recent study suggest that IVF with a single blastocyst-stage embryo (at 5 days) versus the typical transfer with an embryo at the cleavage stage (3 days) in women under age 36 results in a higher rate of pregnancy and delivery. Of the two cases of multiple pregnancies, both occurred...

Maternal and Child Risks

The use of ARTs and ovulation promotion has raised concern about potential risks to the women who undergo these procedures and the children who are conceived as a result. Some investigators have speculated about the effects of fertility drugs on the risk of breast cancer and cancers of the reproductive system. A study by Klip and colleagues (2000), in which a cohort of women in The Netherlands was monitored for 5 to 8 years, found no increase in the risk of breast cancer or ovarian cancer in women who underwent IVF compared with that in subfertile women who had not undergone IVF. The study also found that both women who had undergone IVF and subfertile women did not have an increased risk for endometrial cancer. The authors suggest a potential link between endometrial cancer and subfertility. Of central interest in the discussion of the unintended consequences of the use of ARTs is the well-being of the children conceived through the use of these procedures. Although large-scale and...

Reducing Rates of Multiple Gestation

The oversight of ART practices currently occurs at both the governmental (federal and state) and nongovernmental levels, and both governmental and nongovernmental entities also provide the public with guidance on such practices. For a more detailed overview of the goals, scope, requirements, mechanisms, and efficacy of ART-related policies, the reader is referred to Reproduction and Responsibility The Regulation of New Biotechnologies (The President's Council on Bioethics, 2004). The Fertility Clinic Success Rate and Certification Act of 1992 was designed to provide consumers with reliable information about the services provided by and the success rates of fertility clinics throughout the United States. Data are reported by the Society for Assisted Reproductive Technology (SART) and are published by the CDC. This act also provides states with a standard process for the accreditation of embryo laboratories. In most states, the states oversee access to services and determine whether and...

Genetic Research and Genetic Counseling in Psychiatric Patients

The human genome is the heritage of all humanity and is not patentable as such. A fundamental purpose of assisted reproduction techniques is to medically treat the effects of human infertility and to facilitate procreation if other treatments have proven unsuitable or inefficient. Assisted reproduction techniques may also be used for diagnosing and treating hereditary diseases as well as for authorized research. The production of identical human individuals by cloning should be banned. The use of stem cells for therapeutic purposes should be allowed provided that it does not involve the destruction of embryos. 16

Clinical risk factors

Several large-scale prospective prophylactic studies of pre-eclampsia have now been completed and despite being disappointing in regard to successful prophylaxis, have yielded useful data in relation to the clinical epidemiology of pre-eclampsia. The low-dose aspirin study of 1995 (Sibai et al., 1995) revealed that systolic blood pressure at entry, prepregnancy obesity, the number of previous abortions or miscarriage and smoking history were risk factors for development of pre-eclampsia. Cigarette smoking during pregnancy was associated with a reduced incidence of pre-eclampsia. However, race was not a risk factor for pre-eclampsia in this study. A multivariate logistic regression equation based on these four factors could define a tenth of the population at very high risk and another tenth of the population at very low risk. In the subsequent CPEP study (Sibai et al., 1997) risk factors for pre-eclampsia were found to be body mass index, systolic blood pressure and diastolic blood...

Gametogenesis And Preimplantation Embryo Development 87 Fertilization

In nature, fertilization is a highly specialized example of cell-to-cell interaction. The introduction of ICSI in assisted conception treatment bypasses the majority of events that were previously thought to be essential for the fertilization process, opening a whole new area of questions and molecular events which are yet to be elucidated (Hewitson et al., 1999). The discussion here is limited to 'natural' fertilization without reference to ICSI.

Improving Sample Resolution And Information Content

Steroid concentrations (especially estrogen) have been used to examine pregnancy rates among free-ranging mammals (Kirkpatrick et al. 1990). This technique could be modified to distinguish male- and female-derived fecal samples. Even greater sample resolution is possible by using emerging molecular techniques. As indicated earlier, fecal samples contain epithelial cells shed from the intestine walls of the animal depositing the sample. DNA extracted from these cells has been used to identify the species that deposited the sample. Recently, several investigators have used this approach to identify sex and individual genetic markers (Kohn and Wayne 1997 Reed et al. 1997). Therefore, it is possible to substantially increase the resolution of fecal samples so that researchers can track the diet of identified free-ranging individuals. The information obtained from fecal samples could be enhanced even more by using digestibility correction factors that...

Pgd For Agerelated Aneuploidy

The technique of FISH has led to considering that all women undergoing IVF, particularly women of advanced maternal age (35 years and older), should be screened for numerical aberrations for the most clinically significant chromosome syndromes, trisomies 13, 16, 18, 21 and 22, as well as sex chromosome anomalies involving the X and Y chromosomes (see Chapter 12 p. 217). It has been suggested that screening oocytes and preimplantation embryos may increase the implantation rate, decrease the miscarriage rate, and eventually lead to reducing the current need for prenatal diagnosis. The latter aspect may be especially important to patients who may not wish to undertake the risk of miscarriage associated with the invasive procedures of prenatal diagnosis, chorionic villus sampling and amniocentesis (Reubinoff & Shushan, 1996). Multicentre, randomized trials are required to demonstrate whether such screening does in fact enhance implantation, reduce miscarriages and increases the actual...

Gene Expression In Human Preimplantation Embryos

The most common outcome of fertilization is embryonic death around the time of implantation, with estimates of loss ranging from 50 to 80 . The major cause of embryonic failure is an unbalanced chromosome constitution due to aneuploidy, polyploidy or, less frequently, chromosome deletion or duplication. There now exists the technological means to define the underlying molecular processes by which chromosome aberrations lead to loss of embryonic viability. The ability to analyse the chromosome complements of spermatozoa, oocytes and preimplanta-tion embryos combined with recombinant DNA technology applicable to single cells provides the means for such studies. It should be possible, therefore, to compare chromosomally normal and abnormal preimplantation embryos with regard to expression of specific genes and whether their expression is directly associated with embryonic death or simply a secondary consequence of a generalized genomic imbalance. Such studies may eventually contribute to...

Results of allogeneic transplant

Figure 13.3 shows the survival of patients who received allogeneic BMT for severe aplastic anaemia. Patients who have successful transplants without chronic GvHD have a good quality of life. Children grow normally and have normal endocrine function. Males and females remain fertile and there seems to be no increased risk of congenital abnormalities or miscarriages compared with the normal population. Fertility returns rapidly after the transplant and patients may become pregnant within

PGD for Fanconi Anemia with Preimplantation HLA Matching

PGD was performed using a standard IVF protocol combined with micromanipulation procedure to biopsy single blastomeres from the day 3 cleaving embryos, as described in Chapter 2. Blas-tomeres were tested for IVS 4+4 A-T mutation in FANCC gene using polyacrylamide gel analysis of PCR product digested with Sca I restriction enzyme, according to the method of single-cell PCR analysis, also described in Chapter 2.

Where is the critical paternal antigen and how is the female organism exposed to the paternal HLA message

However, based on his study of pregnancies after intra-uterine insemination, Smith et al. (1997) suggested that the protective factor is on the spermatozoa themselves and not in the seminal fluid. This was strongly supported by a subsequent study by Wang et al. (2002). They used a very elegant model to confirm the protective effect of previous sperm exposure and to analyse whether or not this protection is conveyed by sperm cells or seminal plasma. These authors looked at outcomes in pregnancies following Intra-Cytoplasmatic Sperm Injection (ICSI), where fertilization is achieved by injecting the sperm into the oocyte plasma. ICSI is used initially in cases where there are severe semen defects, including azoospermia. In some patients it is necessary to obtain sperm surgically. Couples in which the male partner has azoospermia and where sperm cells are obtained surgically provide an ideal ''model'' to test the protective partner-specific immune-tolerance conveyed by sperm cells. The...

Referrals For Preimplantation Diagnosis

Patients referred for PGD differ from IVF patients in that most are fertile. They show a number of different histories, but basically are referred because they are carrying an inherited disorder which they could pass on to their child. The genetic basis of disease is described in Chapter 2. Many couples have already had an affected child and are bringing up a handicapped child, or have suffered the tragedy of losing a child, especially if from a progressive disabling disease (e.g. Duchenne muscular dystrophy, thalassaemia major, cystic fibrosis). Others have experienced recurrent miscarriage of genetic origin or are seeking pre-pregnancy advice because of an affected family member (e.g. cystic fibrosis). PGD offers the selection of female unaffected embryos in families with serious X-linked disorders, for which the only option is termination of all male pregnancies (of which half would be unaffected). Couples may have experienced repeated terminations of pregnancy One of the commonest...

Mutations In A Gene Resulting In Different Diseases

Occasionally, different mutations in a single gene can give rise to different phenotypes. An example of this is provided by different mutations in the cystic fibrosis gene, CFTR. Mutations in CFTR have been found in otherwise healthy males with infertility caused by congenital bilateral absence of the vas deferens (CBAVD). These patients do not have other features of cystic fibrosis such as pulmonary or pancreatic disease. However, the vast majority of males with typical cystic fibrosis have CBAVD, so isolated CBAVD arising from CFTR mutations represents a very restricted expression of the cystic fibrosis phenotype.

Clinical Aspects Of Preimplantation Diagnosis Cancelled Cycles

As with all IVF cycles, problems may occur during IVF cycles for PGD. Treatment cycles may be cancelled before the egg collection if the follicular response is poor and rarely, there are no oocytes at follicular puncture. It is possible that failed fertilization results in no embryos for diagnosis, or the embryos are not suitable for embryo biopsy. After PGD, it may be discovered that all the embryos are affected with the disease, in which case there will be no embryos suitable for transfer. For some diseases such as cystic fibrosis, 3-thalassaemia or sickle cell disease some of the embryos may be diagnosed as carriers of the disease and it may be advisable to replace some of these embryos if they are of good quality.

Preimplantation Hlatyping

This relatively low number of unaffected HLA-matched embryos detected in the present series may be influenced by advanced reproductive age of the women involved (approximately 35 years), known to affect significantly the number of available embryos for testing and also the success rate of assisted reproduction. The mean number of embryos available per cycle was under 10 from these women, which clearly limits the chances for finding a sufficient number ofunaffected embryos that are also HLA matched to a sibling. Assuming that one in four embryos is expected to be HLA matched and three of four unaffected, the overall probability of HLA-matched embryos to be also unaffected could not be expected to be higher than 1 in 5.3 embryos. So with the availability of only 8.5 embryos on the average with conclusive results in our material, only 1.6 HLA-matched unaffected embryos may have been detected. Assuming also that not all embryos develop to the status acceptable for transfer, approximately...

Issues of interpretation

Conclusions on syphilis prevalence in the general population based on sample surveys of pregnant women attending antenatal clinics should be made with caution. First, the numerator is not representative of all pregnant and non-pregnant women. Second, the sample is not necessarily representative of all pregnant women, only of women who choose to attend for antenatal care. Third, syphilis serology may not correlate directly with STI prevalence. STIs are a major cause of infertility in developing countries, and infertile women are not effectively accessible through antenatal care. This may lead to an underestimation of the STI prevalence in all women. Conversely, since non-pregnant women include those who are not sexually active and therefore are not at risk of STI, the prevalence among pregnant women may be an overestimation of the prevalence in all women. Moreover, it is representative of this group of women only where all pregnant women are screened and not just those judged by...

Preimplantation HLA Matching Without PGD

The first experience for preimplantation HLA matching without testing for the causative gene included 13 IVF cycles initiated for nine couples wishing to have another child who may also be a potential cord blood donor for the affected siblings with leukemia, or Diamond-Blackfan anaemia (DBA) 20 . These conditions require bone marrow transplantation and have also been successfully treated by cord blood transplantation 24 . Although mutation testing may also be required in combination with HLA typing in DBA, which can be caused by mutations in the gene encoding ribosomal protein S19 on chromosome 19 (19q13.2) or another gene mapped to chromosome 8 (8p23.3-p22), the majority of DBA are sporadic with no mutation detected, such as in both cases performed in this study 14 . A standard IVF protocol was combined with micromanipulation procedure to remove single blastomeres from the day 3 cleaving embryos, as described above. HLA genes were tested simultaneously with the short tandem repeats...

Diagnostic And Strategic Considerations

If sampled sequentially, two independent manipulations are required with the possibility of intracytoplasmic sperm injection (1CSI) in between (for PCR-based cases), making a total of three manipulations on the same oocyte embryo. Conversely, the simultaneous sampling of both the first and second polar bodies following fertilization could lead to degeneration of the first polar body (and subsequent diagnostic failure) between the time of oocyte retrieval and biopsy following fertilization (Munne et al., 1995).

Catherine S Stika And Marilynn C Frederiksen

Relates to the changing age of reproduction. Pregnancy once was mainly undertaken by healthy, younger women, but the age of reproduction now includes women ranging in age from 10 to approximately 50 years, and with in vitro fertilization and egg donation, even older women undertake pregnancy. Moreover, the age of a woman's first pregnancy has been steadily rising in the United States, with an increasing number of first pregnancies occurring after age 30 (2). The expansion of the reproductive age range, coupled with the occurrence of pregnancy later in life, increases the number of women who may require drug therapy for diseases present prior to pregnancy and who may need to continue therapy during pregnancy. Knowledge of drug therapy during pregnancy is needed if these women with underlying diseases are to be optimally treated.

The Potential for Pregnancy While on a Trial Drug

What is the risk of pregnancy occurring in a study participant while a new drug is being developed The author is not aware of any published figures, but from the author's experience in industry and from questions to colleagues, pregnancy does occur during drug development, even in those patients apparently taking adequate contraceptive precautions. A typical NDA database for most drugs will involve between 2000-4000 patients, of which perhaps one-third are female and exposed to study medication. It is not surprising, therefore, that given an average failure rate of the contraceptive pill of 2 , or even with the most stringent compliance, a failure fate of 0.5 100 women years will result in occasional pregnancy (Trussell et al, 1990). Other methods, such as the diaphragm, condoms and IUDs, can carry even higher failure rates, depending on whether 'usual' or 'perfect compliance' calculation of 18-6 , 12-2 and 30.5 , respectively, are used (Trussell et al, 1990). If we assume an average...

Preimplantation Genetic Diagnosis for Chromosomal Disorders

With the advent of PGD for aneuploidies it has become possible to directly test the outcome of the first and second meiotic divisions, using PB1 and PB2, as described in Chapter 2. PB1 is extruded following maturation of oocytes, representing a by-product of meiosis I, while PB2 is a by-product of meiosis II and is extruded following the exposure of oocytes to sperm or ICSI. As will be described below, the frequency and types of chromosomal errors detected by this approach are different from what was described in the traditional studies ofmeiotic chromosomes in metaphase II (MII) oocytes, according to which chromosomal anomalies in oocytes originate mainly from the errors of whole bivalents as a result of chromosomal nondisjunctions 5 . In contrast, direct testing of meiotic outcome using PB1 and PB2 analysis showed not only a higher prevalence of meiotic errors, but also significant contribution of chromatid, rather Based on the above data, PB1 testing was applied clinically for the...

Conserved Genes In Organisms That Specify Germ Cells Via Germ Plasm And Inductive Mechanisms

Pumilio and Nanos homologs have also been identified in mammals, including humans (Rongo et al., 1997 Castrillon et al., 2000 Tanaka et al., 2000 Mochizuki et al., 2001 Jaruzelska et al., 2003 Moore et al., 2003 Tsuda et al., 2003). Indeed, a number of factors that interact in invertebrate germ cells have also been shown to interact in vertebrates, including the Pumi-lio and Nanos proteins (Jaruzelska et al., 2003 Moore et al., 2003 Tsuda et al., 2003). Moreover, the loss of function of some homologs results in infertility in particular, the loss of function of Nanos2 results in the defective development of male germ cells, and the loss of Nanos3 function results in the impaired maintenance of PGCs during migration in both sexes (Tsuda et al., 2003). Other known vertebrate Nanos homologs include Xcat-2 in Xenopus and Nosl and Nos2 in zebrafish the products of these genes have been shown to localize to germ plasm in these species, and zebrafish Nosl has been shown to be required for...

Sexually Transmitted Diseases

The importance of safe sex practices and a discussion of the risks associated with the range of sexually transmitted diseases pertinent to the destination should be included as part of the pretravel visit (Hawkes and Hart, 1998). Women should be reminded that they are at a higher risk of acquiring a sexually transmitted disease from an infected partner owing to the fluid dynamics of sex. In general, women suffer disproportionately to men from the long-term complications of sexually transmitted diseases. Complications include pelvic inflammatory disease, chronic pelvic pain and infertility.

Sperm Separation Methods

Establishment of a pregnancy of a female fetus could also be achieved if sperm could be separated into X- and Y-bearing populations. There have been publications reporting on the use of various methods to separate X or Y chromosome-bearing sperm (Ericsson, 1994 Vidal et al., 1993). The initial aim of these methods was to select the sex of the fetus for social reasons (see below) for couples that already had several children of one sex (Chapter 14 p. 258). However, if an efficient method could be found for separating X-bearing sperm, this could be used for inseminating women at risk of transmitting X-linked disease. Techniques using albumin gradients were reported to separate either X- or Y-bearing sperm, depending on the exact method used (Ericsson, 1994) and methods using Percoll and Sephadex gradients were tried (Vidal et al., 1993). Unfortunately, using FISH to confirm the ratio of male and female sperm in samples prepared by these methods, it has been shown that there is no...

What is the Best Time to Travel

Women can travel during all stages of their pregnancy, but the safest time is during the second trimester (between 18 and 24 weeks) according to the American College of Obstetricians and Gynecologists. During the first trimester there is a risk of spontaneous miscarriage and the theoretical risk from immunizations, needed medications and or exposure to infectious disease might have a greater effect on the developing fetus. During the third trimester, preterm labor and or other complications, such

Options for Emergency Care

All pregnant women traveling to a less developed country should purchase a travel health insurance policy that provides a worldwide 24 h medical assistance hotline number. This service would provide telephone contact with medical personnel who can help arrange emergency medical consultation and treatment, monitor care and provide emergency evacuation to a more advanced medical facility if necessary. Each policy must be reviewed carefully to make sure that it covers the expenses associated with a normal pregnancy (such as delivery) together with the possible complications of pregnancy, such as a miscarriage early in pregnancy or pre-eclampsia in the third trimester. The policy should also cover expenses associated with care of the neonate. Worldwide Assistance and AEA SOS insurance policies cover complications of pregnancy through the third trimester (Table 24.8).

Prevention of haemolytic disease of the newborn

The decrease in cases due to anti-D, so that other antibodies now account for a higher proportion of occurrences. This reduction has been achieved by the routine administration of 500 IU (100 g) anti-RhD immunoglobulin to all RhD-negative mothers within 72 h of delivery of a RhD-positive infant. Extra doses of 50-75 IU (20-25 g) per additional millilitre of red cells may be required for the small number of women ( 1 ) who have a transplacental bleed greater than that covered by the standard dose (which covers 4 mL of packed cells). Anti-RhD immunoglobulin is also indicated after spontaneous or therapeutic abortion or threatened miscarriage and all procedures that might lead to a feto-maternal bleed (amniocentesis, external version, abdominal injury, chorionic villus sampling) the dose is 250 IU (50 g) up to 20 weeks' gestation and 500 IU thereafter. It is critical that a Kleihauer acid elution test for detection and quantification of fetal red cells is performed on a maternal blood...

Pgd For Couples Carrying Balanced Chromosome Rearrangements

This high-risk group includes couples where one partner is a carrier of a chromosomal rearrangement that predisposes to the production of chromosomally unbalanced gametes, as described in Chapter 2. The most common types are Robertsonian and reciprocal translocations. Robertsonian translocations between chromosomes 13 and 14 and 13 or 14 and 21 occur repeatedly and are common in the population (1 in 1000-2000), whereas with the exception of the t(llq 22q), each reciprocal translocation is unique to the family. Usually couples where one individual is a translocation carrier can achieve normal pregnancies, with the help of prenatal diagnosis if necessary. Those that present for preimplantation diagnosis are a select group at the extreme end of the normal range, who have suffered repeated spontaneous or induced abortions as a result of a series of abnormal conceptions. Table 12.1 illustrates this by showing the reproductive histories of four couples referred to the UCL Centre for PGD. In...

Malaria and Pregnancy

Malaria acquired during pregnancy has severe consequences. If a woman is pregnant or plans to become pregnant and cannot defer travel to a high-risk area, appropriate chemoprophylaxis is essential. Pregnancy is associated with an increased susceptibility to malaria both during pregnancy and during the postpartum period (Diagne et al., 2000). Pregnancy increases susceptibility and clinical severity of falciparum malaria in women both with and without existing immunity, i.e. women living in and traveling to endemic areas. A pregnant traveler visiting an endemic area is at significant risk for malaria infection and its devastating consequences for her and her fetus.

Plasmodium vivax Infection

Of pregnancy until delivery, and pregnancy outcome was recorded. The effect of P. vivax infection on anemia and pregnancy outcome were compared with the effect of either P. falciparum or the effect of no evidence of malaria infection during the pregnancy. P. vivax malaria was not associated with miscarriage, stillbirth or with a shortened duration of pregnancy but it was associated with maternal anemia and low birthweight. The effects of P. vivax infection are less striking than those of P. falciparum infection but antimalarial prophylaxis against P. vivax in pregnancy is still justified (Nathwani et al., 1992 Nosten et al, 1999).

Multidrugresistant Falciparum Malaria

For women of reproductive age it is recommended that they do not become pregnant while taking the drug and for 3 months afterwards. While there are no adequate and well-controlled studies of atovaquone and or proguanil hydrochloride in pregnant women, Malarone may be used if the potential benefit justifies the potential risk to the fetus. The proguanil component of malarone acts by inhibiting the parasitic dihydrofolate reductase. To date there are no clinical data indicating that folate supplementation diminishes drug efficacy. Women of childbearing age receiving folate supplements to prevent neural tube birth defects may continue to take these supplements while taking Malarone. In clinical trials, there was only one subject who became pregnant while taking Malarone. She delivered a healthy term infant.

Clinical Outcomes Following Preimplantation Genetic Diagnosis

Be further improved by the above-mentioned new developments in DNA analysis of single cells (see Chapter 2). As presented in Chapter 3, a relatively high pregnancy rate (approximately 39 ) was observed in PGD for single-gene disorders, despite transfer of only 2.2 embryos per cycle on the average. This maybe explained by the fact that these are fertile couples of younger reproductive age (under 35 years) compared with the poor-prognosis IVF patients referred for aneuploidy testing.

Exercise and Activity Guidelines

For a woman with a normal pregnancy there are no known contraindications to exercise during the pregnancy. Recent reviews have documented the benefits of exercise during pregnancy (Agnostini, 1994 Artal, 1996 Clapp, 2000). The incidence of infertility, spontaneous abortion, congenital malformation and placental abnormalities is not increased in women who continue a strenuous weight-bearing type of exercise (running, aerobics, crosscountry skiing, stair stepping, and so forth) throughout early pregnancy. The concern that continuing a strenuous exercise program or beginning to exercise in mid to late pregnancy might lead to preterm labor or premature rupture of the membranes is not supported by current data. Previous concern about exercise during pregnancy has been related to the hypothetical risks of strenuous maternal exercise, including resulting in fetal stress, competing for blood flow and depriving the fetus of oxygen, fetal hypoxia and thermal stress resulting in neural tube...

Scuba Diving during Pregnancy

More women of reproductive age are scuba diving. Diving vacations to exotic locales are becoming popular. This raises the question of the safety of diving for women who are pregnant or who are planning to become pregnant. Most international federations and the Undersea and Hyperbaric Medical Society advise against scuba diving for pregnant women or those planning a pregnancy, but no randomized trials provide a solid scientific basis. The fetal circulation is characterized by the exclusion of the pulmonary circulation by two right-to-left shunts. As the lung appears to act as a filter against the progression of microbubbles to the main circulation, the fetus may be particularly exposed to gas emboli (Morales et al., 1999). The effects of scuba diving on pregnancy have been reviewed in detail (Camporesi, 1996). The review summarizes physiological changes induced by immersion diving and decompression effects on male and female divers. The study concluded that there is no contraindication...

Iiicurrent Challenges

Technical as well as economic hurdles must be overcome before therapies based on tissue engineering will be able to reach the millions of patients who might benefit from them. One long-recognized challenge is the development of methods to enable engineering of tissues with complex three-dimensional architecture. A particular aspect of this problem is to overcome the mass transport limit by enabling provision of sufficient oxygen and nutrients to engineered tissue prior to vascularization and enhancing the formation of new blood vessels after implantation. The use of angiogenic factors, improved scaffold materials, printing technologies, and accelerated in vitro maturation of engineered tissues in bioreactors may help to address this problem. Of particular interest is the invention of novel scaffold materials designed to serve an instructive role in the development of engineered tissues. Methods to prepare improved cell-scaffold constructs by growth in bioreactors before implantation...

The Work Of The Eshre Pgd Consortium

In 1997, the European Society of Human Reproduction (ESHRE) PGD Consortium decided to conduct a survey on the subject to determine the current status and future direction of governmental regulation of PGD. A questionnaire was sent to every centre practising PGD. The questionnaire sought information on the legal status of in vitro fertilization (IVF and PGD activities) throughout the world. This information was supplemented by a review of legal documents from the European Council and various state governments in the USA. Based on this review and the results of the questionnaire a summary was developed of the current status of PGD (Viville & Pergament, 1998).

Who Is Selecting Obstetrics and Gynecology as a Career Path

The American College of Obstetricians and Gynecologists (ACOG) has slightly more than 49,000 members, of whom more than 31,000 are practicing in the United States (personal communication, R. Hale, 2005). Of that number, 44 percent are women. An additional 1,500 osteopathic obstetricians and gynecologists practice obstetrics. Urban and suburban areas tend to have the highest concentrations of obstetricians and gynecologists it is rare for areas with populations of less than 10,000 to have an obstetrician-gynecologist. In those areas family physicians tend to be the obstetricians, although their numbers are dropping rapidly because of the cost of liability Insurance. Approximately 1,100 residents in obstetrics and gynecology complete their training each year. Of this number slightly more than 10 percent go into subspecialty training. Of those who pursue subspecialty training, approximately 30 percent choose maternal-fetal medicine, 25 percent select oncology, 30 percent enter...

Countries With Legislation That Specifically Addresses

France has adopted two laws covering human embryo research and the practice of PGD (Viville & Nisand, 1997). French law permits human embryo research in exceptional cases and only if the study represents a direct benefit to the embryo under study, especially in terms of improving its chance of implantation, or if knowledge concerning the physiology and pathology of human reproduction is enhanced. Embryo research cannot be performed to modify the embryo's genome or alter embryonic development. A second law specifically concerns the practice of PGD. This act differs from other nations' laws by linking the practice of PGD to prenatal diagnosis and not to research on human embryos. The conditions under which PGD may be practised are strict (1) centres must be licensed for PGD and ART-IVF and their activity is subject to an annual evaluation (2) the couple seeking PGD must have a high probability of giving birth to a genetically affected child (3) the genetic defect must be of a particular...

Countries Without Legislation

In its attempt to develop guidelines on human embryo research and PGD, the Belgium Committee of Medical Ethics of the National Scientific Research Fund (FGWO-FNRS) has been influenced by the British Warnock commission. Belgium is currently in the process of drafting a law addressing these issues. In the Netherlands, following intense debate, the IVF Committee of the Health Council announced findings that should permit the creation of a law addressing PGD. According to these conclusions, human embryo research should be allowed for major health issues, such as improving IVF or establishing PGD protocols, only if animal models are not suitable. In addition, research should be performed on surplus embryos and eventually on created embryos, if surplus embryos are unavailable. These activities will be under the supervision of a central committee.

Returning To Ethical Concerns

The ESHRE survey revealed a general agreement on the prohibition of creating embryos for research purposes, the exception being the Netherlands and the United Kingdom. It appears that the scientific community has agreed that embryo research should only be performed for major health issues and that research should be mindful of specific ethical considerations. The major health issues that are justifying embryo research include improving ART-IVF technology, increasing knowledge concerning the physiology and pathology of human reproduction, or efforts to benefit the embryo itself, by diagnosing genetic disorders. Moreover, research on human embryos should be performed only if animal models are not suitable. In addition, it appears that the rule introduced in the United Kingdom of allowing embryo manipulation up to '14 days after fertilization' has been widely adopted, with the exception of France. Concerns about the eugenic potential of PGD represented the major argument against its...

Ethical Social and Legal Issues

Couples to reproduce and face prenatal diagnosis and termination of pregnancy 1, 2 . So any legal restrictions of these patients' choices may only force them to achieve their goal by traveling to the other countries where the regulations regarding PGD are more liberal. The most recent review on the status of PGD in different countries 38 showed that international legal practices range from explicit legalization (e.g., the Netherlands, United Kingdom, France, Spain) to more or less lawless control as in Belgium and the United States, to legal prohibition through restrictive laws as in Italy, Germany, Austria, and Switzerland. However, even in these countries, there is a tendency to ease such legal restrictions. For example, there is no interdiction of PGD in Austria, neither through the law on reproductive medicine, nor through the law on genetic engineering, unless the polar body or blastomere biopsy would be misinterpreted as interference in the germ cell lineage, which wouldbe...

Ethical Social And Legalissues

Finally, PGD raises many ethical issues, which are not unique to its clinical practice and instead are the same as in assisted conception 11 . One of the major criticisms concerns the selection of the embryos according to certain genetic parameters and destruction of others. In fact, the selection of a few embryos for transfer from approximately a dozen available after hyperstimulation is a routine practice of IVF, the remaining embryos being either frozen or discarded. Such embryo selection is usually done routinely based on morphological criteria, which has the goal of identifying the embryos with highest developmental potential. PGD, on the other hand, allows improvement of the embryo selection, by applying genetic tests, which has shown that perfectly morphologically normal embryos maybe chromoso-mally abnormal, and so destined to be lost during preimplantation and postimplantation development. As described in Chapter 5, approximately half of oocytes and embryos obtained from...

Introduction to prenatal diagnosis PND in clinical genetics

Preimplantation genetic diagnosis (PGD) represents a 'state-of-the-art' procedure which potentially avoids the need to terminate affected pregnancies through identification and transfer of only unaffected embryos established from in-vitro fertilization (IVF) (Handyside et al, 1990).

Ethical Considerations

Ethical considerations also need to be taken into account when discussing PGD (Chapter 13). Ethical practices in assisted reproductive techniques and PGD continue to provoke considerable media interest. The use of oocyte donation and surrogacy for gay couples, gamete donation of a different race than the parents (Berkowitz, 1999) and the use of sperm after a man's death have had a huge amount of publicity in recent years. The problem is that a third party, the IVF clinic, is involved in these abnormal cases of reproduction and so must be responsible for the treatment they offer.

Additional considerations in design of singlecell genotyping for PGD using realtime PCR

Thus the overall strategy we designed (Vrettou et al., 2004) involved a first-round multiplex PCR (approximate time 1.5 h), containing P-globin gene first-round PCR primers (Setl or Set2) for the amplification of a region of the P-globin gene surrounding the case-specific mutations along with fluorescently-labeled primers for amplification of two polymorphic microsatellite markers GABRB3 (at the GABAA receptor b3 locus in the Angelman Prader-Willi region on chromosome 15) and D13S314 (Table 17.2). The first-round multiplex PCR was followed by 1) real-time nested PCR with hybridization probes for analysis of P-globin gene alleles (approximate time 40 min), and in parallel, 2) size analysis of the two microsatellite markers on an automatic sequencer (approximate time 35 min) for monitoring and precluding contamination. Genomic DNA from the parents in each cycle was amplified in parallel along with blank samples from the IVF unit and PCR premix blanks.

Protocol 175 Realtime PCR protocols for singlecell genotyping and PGD

PGD is a multi-step procedure combining expertise both in reproductive medicine and genetic diagnosis. PGD includes embryo biopsy, cell lysis and genotype analysis. For all PGD cycles, precautions against contamination have to be most stringent at all stages. Manipulation of cells and PCR set-up are carried out in separate UV-treated laminar flow hoods. PCR set-up employs dedicated PCR pipettes and pipette tips with filter. In the first round PCR, negative (blank) controls include 2 tubes containing IVF medium and 2 tubes with cell lysis mixture (prepared alongside cell biopsies in the IVF unit), and 1 tube containing PCR mixture alone (prepared in genetics laboratory during PCR set-up). To exclude contamination within the system all negative controls from the first round PCR should be analyzed for the presence of amplified hypervariable microsatellite loci (see below), and additionally subjected to nested PCR analysis in the LightCycler . It is recommended that one-use disposable...

Majella Doyle Md Mba Liver And Transplant Surgery Mail

Pak Chung, MD, FACOG, Cornell Institute for Reproductive Medicine, Weill Cornell Medical College, New York Presbyterian Hospital, New York, NY Marc Goldstein, MD, Professor of Urology and Reproductive Medicine, Surgeon-in-Chief, Male Reproductive Medicine and Surgery, Cornell Institute for Reproductive Medicine, and Department of Urology, The New York Weill Cornell Medical Center Senior Scientist, The Population Council, Center for Biomedical Research, New York, NY Carin V. Hopps, MD, Fellow in Male Reproductive Medicine and Microsurgery, Department of Urology and Cornell Institute for Reproductive Medicine, The New York Weill Cornell Medical Center The Population Council, Center for Biomedical Research, New York, NY Sonya Kashyap, MD, FRCS (C), Cornell Institute for Reproductive Medicine, Weill Cornell Medical College, New York Presbyterian Hospital, New York, NY

Pathogenesis And Immunology

The presence of Giardia in the gut leads to antigen processing and a host immune response. This response can result in clearance of the parasite with the development of partial immunity, as well as to production of disease in some cases. Much of the understanding of the host response comes from rodent models (mouse and gerbil). Early studies of experimental infection in mice demonstrated clearance of infection over a 3-4 week period (Roberts-Thomson et al., 1976b). Parasites reached peak levels in 7-14 days and then gradually declined over the next 1-2 weeks. When mice were rechallenged, they did not become infected and appeared immune (Roberts-Thomson et al., 1976a). Some parasites persisted below the level of detection when female mice became pregnant, they excreted parasites again (Stevens and Frank, 1978). Additional important findings from these studies were the changes noted on histology of the small bowel. There was a mononuclear inflammatory infiltrate in the intestinal...

Get Pregnant - Cure Infertility Naturally

Get Pregnant - Cure Infertility Naturally

Far too many people struggle to fall pregnant and conceive a child naturally. This book looks at the reasons for infertility and how using a natural, holistic approach can greatly improve your chances of conceiving a child of your own without surgery and without drugs!

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