Fortunately, you have help: The Assisted Reproductive Technology Success Rates, a compendium of results from 300 or so clinics that are members of the Society for Assisted Reproductive Technology (SART). You can order copies by phone (888- 299-1585) or click on to the World Wide Web (Actually, it will take lots of clicks: The directory prints Out in three parts, 150 pages each.) And note: As of this printing, the directory currently available is based on 1995 records; the 1996 edition is expected to be available by year’s end. Also, starting with the 1996 directory, centers will be audited (on a random basis) as part of a government crackdown on misleading claims and practices at fertility clinics.
How do you interpret the numbers each center presents? Unscrupulous practitioners would probably like you to focus on one figure only: The number of live births achieved after embryos have been transferred to the mother’s womb. Why not? By definition, that has to be the highest figure, since it would eliminate from consideration all those cycles that had to be canceled at earlier points in the process because things hadn’t gone well—the woman had failed to produce enough good eggs, for example, or the eggs had failed to fertilize.
So the figure that’s generally most meaningful is the one that’s most comprehensive: Number of live births per cycles initiated, a figure that’s popularly called the “take-home baby rate.” But even that number isn’t as revealing as it sounds. Smaller, local centers, for example, may treat couples from the area. If the woman becomes pregnant, fine. If she doesn’t, though, she may move on to a larger clinic, which handles more difficult cases, explains Zev Rosenwaks, M.D., director of the Center for Reproductive Medicine and Infertility at New York Hospital-Cornell Medical Center in New York. The smaller center ends up with a high success rate—but all that reflects is the fact that the clinic’s largely treating couples who get pregnant more easily.
Other more insidious practices can be at work too. Centers have a great stake in publishing high success rates: They could, therefore, be bumping up couples with “easier” cases to the top of a waiting list, in hopes their higher odds will raise the center’s overall success rates. Or centers could be rejecting couples with severe problems or assigning such couples to a “research group,” so their numbers will be kept out of the overall rates. Conversely, centers whose figures seem on the low side may be more accepting of such difficult cases.
“Centers where thousands of IVF cycles have been performed and many hundreds or thousands of women have become pregnant almost surely have mastered IVF,” says Joseph D. Schulman, M.D., director of the Genetics & IVF Institute in Fairfax, Virginia. And look for experience in your particular problem, advises Dr. Kearney.
Knowing certain specifics can signal whether a center is top-notch. Find out what percent of cycles a center cancels, advises Dr. Silber. “If the cancellation rate’s higher than 15 to 20 percent in women under 39, that’s a red flag,” he warns. Similarly, if a center is doing ICSI, embryos should be placed back in the womb successfully nearly all the time. “Failure should occur less than 2 percent of the time,” says Dr. Silber, “and only in patients with few or poor eggs.
High numbers of complications signal that a center may not be paying close enough attention. You could ask specifically about ovarian hyperstimulation risk, suggests Dr. Rosenwaks. “With careful monitoring, a center’s rate should be exceedingly low, less than 1 percent.”
Generally, IVF babies are no more likely to suffer birth defects or other abnormalities, studies show. But male babies conceived through ICSI do have a higher risk of certain genetic defects. The reason: Men who have extreme infertility problems (very low sperm counts or no sperm at all) may have an inherited defect on their Y-chromosome, which they in turn may pass to their sons.
In 1995, 28 percent of all assisted-reproductive technology births were twins, triplets, or higher- order births, according to the SART figures. You can avoid the risk of multiple births by limiting the number of embryos that are transferred back to the mother. But then you also cut the chances of success. Is there a happy medium, so to speak? Going beyond mere numbers, some specialists believe that checking the quality of embryos might be the ticket. Last spring, for example, the Northwest Center for Infertility and Reproductive Endocrinology in Margate, Florida, reported that they’d found the best “formula” for maximizing pregnancy rates while limiting higher-order (triplets or more) multiple conceptions:
One way around the problem of multiple births is to transfer a larger number of embryos, then “reduce” the number early in pregnancy (by injecting one or more fetuses with a solution that causes them to die). Aside from the painful emotional issues reduction raises, it is not a panacea: While it does cut your risks, in a study comparing “reduced” twins (from quadruplets) with twins that started out that way, the reduced twins averaged lower weights at birth and were more likely to be delivered early, possibly because of complications from the reduction procedure itself or possibly because of problems related to the implantation of a larger number of fetuses to begin with.
IVF is not like rolling dice, Dr. Kearney explains, where the more rolls, the greater your odds of success. Rather, couples with the fewest problems are more likely to get pregnant ”on an earlier throw”; those who are older or who have more medical problems are less likely. Nor, obviously, do such couples’ chances improve with time.
Finances aside (though with IVF averaging $8,000 to $10,000 per cycle, few couples can put finances aside), the latest numbers suggest that it’s worth trying at least three cycles. A just-released SART study found that success rates remain almost equal for the first two cycles of IVF, and then decline only modestly. After more than four cycles, however, pregnancy rates drop significantly. At that point, couples may want to explore other technologies (such as using donor eggs) or turn their energies to other ways of creating a family or having children in their lives.
There are nearly 300 clinics affiliated with the Society for Assisted Reproductive Technology. How do you choose the best one for you? Start by collecting recommendations from doctors and others you trust, then ask probing questions before signing on with a facility. Also, Assisted Reproductive Technology Success Rates, a directory of data from centers across the country, can point you to clinics achieving higher-than-average pregnancy rates or treating a larger number of couples with particular problems. Based on the most recent directory figures, these ten centers stand out:
Fertility is the natural capacity of a living being to establish the clinical pregnancy through an intricate biological process “reproduction” with the assistance of reproductive system to produce offspring, the real existence of a species. The system has unifying characteristics in males and females of a species including Homo sapiens (humans)—the highest ranked animal species. It controls the development of structural and functional differences between males and females, and influences their behavior.1 Like the other physiological systems in our body, reproductive system also needs efficacious way to care for and to maintain fecundity, which is generally obtained using fertility regulators. Usage of such regulators have risen at least threefold in recent years, where most of the commercially available regulators are synthetic chemicals, often have adverse effects and toxicity. This emphasizes the need for developing biologically active substances as potential fertility regulators from various natural sources. In this regard, the therapeutic potentials of the secondary metabolites or natural products, produced by living organisms in their natural environment, has been considered as one of the best choices. Over the last five decades, research on development of natural fertility regulation have come to the forefront of new therapeutics development in fertility regulation. It has been found that worldwide varied communities are chiefly practicing the plant-based traditional medicines for fertility regulation.2 The purpose of this current chapter is to provide information about natural products involved in fertility regulation. While there are several reports, including many review articles, describing fertility regulatory properties of plants and plant extracts available in the literature, this chapter will only cover isolated natural products with fertility regulatory properties as evident from animal based in vivo studies, and wherever available from human clinical trials.
To understand potential involvement of natural products in the regulation of reproductive physiology and fertility, it is essential to have an idea about the human reproductive system. The following section will briefly discuss the reproductive system and its regulation, current fertility regulators, and inter-relationship between herbs and fecundity.
Fertility has been defined in many ways—from the demographers practice of simply recording the number of children born, to the precise (but difficult to measure) monthly probability of conception. Infertility is likewise variably defined, making comparison of data across studies difficult. Furthermore, there is debate about which measures/indicators/contributors are the most useful to try to track when trying to understand fertility/infertility, fecundity/subfecundity trends.
Fertility is defined as the ability to have a clinical pregnancy, whereas fecundity is clinically defined as the capacity to have a live birth, including gamete production, fertilization and carrying a pregnancy to term. In literature, fertility is often considered as the ability to get pregnant, which is best reflected by time to pregnancy (TTP). Fertility rate is defined as the average number of children per woman in a lifetime. The fertility rate is determined by time to pregnancy, pregnancy outcome (e.g. miscarriages) and personal choice. In women with rheumatoid arthritis (RA) a decreased fertility rate has been described long ago [38]; such decreased fertility may be ascribed, among other factors, to a prolonged TTP [39,40]. For women with IA other than RA, conflicting results have been reported [41,42].
In clinical practice, the decreased fertility observed in women with RA is a concern. In the past, when treatment options during pregnancy and during the preconception period were limited, TTP exceeded more than one year in roughly 40% of women with RA. This was associated with active disease, the use of prednisone in a daily dose exceeding 7.5 mg and the use of non-steroidal anti-inflammatory drugs (NSAIDs) [39]. How active disease may contribute to an increased TTP remains an unanswered question. A reduced ovarian reserve was described in patients with RA and spondyloarthritis (SpA) [43], whereas an inverse correlation between disease activity markers and anti-Müllerian hormone (AMH) levels, suggesting that disease activity can play a role [44]. Circulating interleukin (IL)-6 levels have been shown to correlate with TTP, even after correction for disease activity, suggesting that systemic inflammation may play a role [45]. Interestingly, in a small study, treatment with tumour necrosis factor-inhibitors (TNFi) was associated with a shorter TTP. However, this study was too small to correct for relevant confounders [46]. A decreased intercourse frequency in women with (active) RA has been suggested as an explanation for the lower fertility rate. Although sexual dysfunction is highly prevalent in women with RA, this has mainly been studied in postmenopausal women in long term relationships [47] while data in young RA patients with a wish to conceive are lacking. Lastly, it has been shown that women with RA may enter menopause at an earlier age compared to healthy controls, thereby reducing their reproductive lifespan [38]. This observation was made in times when strict control of disease activity was not common in RA patients; thus it could be envisaged that it provided an extra-articular feature of RA related to chronic elevated disease activity. It is not known whether such observation can be translated to women that have always been treated according to a treat-to-target approach aimed at remission.
In women with systemic lupus erythematosus (SLE), the prevalence of primary infertility does not seem to be different from the general population, while there are several factors that may contribute to secondary infertility: menstrual irregularity or amenorrhea due to severe flares, renal insufficiency-related hypofertility, menstrual disorders (e.g. due to endometriosis) and premature ovarian failure (POF). POF is due to accelerated reduction of the ovarian reserve due to either direct autoimmune oophoritis or to the use of cytotoxic drugs [48]. CYC exposure is one of the causes of premature ovarian failure described in SLE women; it is associated with lower levels of AMH which are directly related to cumulative doses and women’s age at the beginning of treatment [49,50]. It is recommended to offer fertility preservation methods, especially GnRH analogues, to all menstruating women with SLE who are going to receive alkylating agents [51].
Eliran MorDespite all these factors, TTP in women with SLE was found to be normal (except for those women that have been treated with CYC) [52]. Instead, women with SLE have decreased fecundity as a result of a higher rate of miscarriage, a lower rate of live birth and due to personal choices [53].
According to the latest international glossary on infertility and fertility care, infertility is defined as a disease characterized by the failure to establish a clinical pregnancy after 12 months of regular and unprotected sexual intercourse or due to an impairment of a person’s capacity to reproduce, either as an individual or with his or her partner. Female infertility, which is mainly caused by female factors comprising: ovulatory disturbances; decreased ovarian reserve; anatomical, endocrine, genetic, functional or immunological abnormalities of the reproductive system; chronic disease; and sexual conditions incompatible with coitus [80].
Whether the fertility of SS female decreases is inconclusive. Among the SS patients, 5.9 % had chosen not to have children due to the disease, but there was no indication of infertility as judged by the number of pregnancies [12]. More recent study also pointed out the number of pregnancies in SS patients was no less than that in controls, and 24 % of them with more than 3 pregnancies (high parity) [32]. Currently, there is limited evidence that directly indicating the fertility of SS patients is diminished. Karakus et al. [81] reported a significantly shorter duration of menstrual cycle in 24 SS patients compared to controls (26 vs.28 days, P = 0.043), lower serum anti miller hormone level (P = 0.001) and antral follicle count (P = 0.01) and higher luteinizing hormone level (P = 0.019). The volume of right ovary and left ovary was also lower, but did not reach statistical significance.
There are many factors that may influence the fertility of SS women. First, chronic inflammation may impair the proper functioning of the hypothalamic-pituitary-ovarian axis, leading to abnormal release of the gonadotropin releasing hormones and gonadotrophic hormones [82]. Second, systemic autoimmune diseases may affect female fertility through drug-related mechanisms. The immunosuppressive drugs routinely used to treat patients might indirectly or directly induce ovarian failure. Among these drugs, cyclophosphamide has the highest gonadotoxic potential.
Sandhya et al. [83] found vitamin D (VD) deficiency was seen in 141 (60 %) SS patients, whereas 60 (25.5 %) and 34 (14.5 %) had VD insufficiency and sufficiency, respectively. Serum VD level was found to be lower in SS than controls [84]. VD deficiency is relatively frequent in patients with SS, suggesting a possible role in the pathogenesis of the disease [85]. In the past two decades, a growing number of evidence has shown optimal physiological levels of VD in serum, follicular fluid, and oocyte are of high relevance for female reproduction. VD appears to not only have stimulatory effects on folliculogenesis, but also a negative impact on oocyte maturation, with appropriate concentration and supplementation [86]. The lack of VD has been associated with the decrease of live birth rates of women undergoing in vitro fertilization [87].
In a recent systematic review and meta-analysis, scholars demonstrated the risk of hypothyroidism was found to be higher in patients with SS than in controls (OR = 3.81; 95 % CI = 1.86–7.83, I2 = 59.0 %) [88]. Thyroid hormone level seem to play a positive role for ovulation and folliculogenesis [89]. Although the available evidence is limited, it seems to support a role of thyroid hormone in fertility and early pregnancy [89]. Further and future studies should focus on thyroid hormone disturbances and their clinical and pathophysiological effects. The presence of thyroid peroxidase autoantibodies (TPO-Ab) negatively influences folliculogenesis, embryo quality and pregnancy rates, but no data are available on the potential mechanisms [89]. TPO-Ab was detected in patients with SS combined with normal thyroid function [90].
Female SS patients seemed to have experienced more stressful life events, particularly negative stressful events, prior to the disease onset [91,92]. Gaskin et al. [93] demonstrated, in a nurse population, that working longer hours (more than 40 h per week) was associated with increased time to conceive, revealing a relation of tiredness or stress with reduced fecundity.
Finally, it was reported the incidence of endometriosis was higher in SS patients (8.5 % vs.2.1 %; P = 0.03). 6.3 % of patients have had surgical intervention due to endometriosis, while the control group is 0.7 % (P = 0.009) [12]. Recent studies have found patients with a history of endometriosis have an increased risk of SS (HR = 1.45, 95 % CI = 1.27–1.65), especially in the 20–39 age group (HR = 1.53, 95 % CI = 1.25–1.88) and within the first five years after the diagnosis of endometriosis (HR = 1.57, 95 % CI = 1.32–1.87) [94]. 10 %-15 % of women of reproductive age suffer from endometriosis [95], of which 20 %-30 % suffer from infertility [96]. The risk of infertility caused by endometriosis is significantly increased (OR = 3.3, 95 % CI = 3.1–3.5) [97]. There may be some relationship between SS and endometriosis, which may affect fertility in a way.
“Natural fertility” broadly refers to the level of fertility reached in the absence of birth control. The Hutterites and the Amish traditionally do not practice birth control, and they usually have very large families (10). In contrast, in much of the modern world fertility is lower than natural fertility levels because of a lengthening of the intervals between menarche and first birth and between successive births, or because of stopping childbearing once the desired family size is attained.
The idea behind the concept, developed by historical demographer Louis Henry (10, 11), was to create a physiologic benchmark against which researchers could judge the fertility patterns when contraception is used (12). At first, “fertility control” was operationalized to assess the stopping behavior, but later the concept was extended by demographers Coale and Trussell to include spacing (13). In alternative formulations, fertility control also includes traditional means of pregnancy avoidance such as coitus interruptus, sexual abstinence, celibacy, or delayed age at marriage. Fertility control has additionally been demonstrated as a response to economic stress in pre-transitional Europe (14).
Although many researchers have called into question the validity of a dichotomy opposing natural to controlled fertility (12), the analysis of populations in which childbearing is in principle unaffected by conscious choice has proved to be useful in the study of the influence of fertility on longevity. To be sure, fertility is never fully natural nor is it ever fully controlled, but deliberate control, when generalized, has the potential to introduce almost insurmountable problems of statistical modeling. For example, perceived health status may influence fertility decisions—a process that is usually not observable—and this may in turn lead to biased estimates of the effect of fertility on mortality if the less healthy individuals choose to limit their family size precisely because they assess their health to be poor (15). In contrast, in a natural fertility context, perceived health should not influence the decision to have another child, although poor health may itself be decisive if it affects fecundity (i.e., the biological capacity to reproduce).
Given natural fertility, life tables show that most married women bear children until age 35–39 years, with a drastic fall of fertility after these ages. Only a tiny minority conceive naturally and are able to bring a pregnancy to term successfully after the age of 45 years. Because there are no parity-specific checks to reproduction, late-fertile women usually also have the largest family sizes. These highly select women, who have been extensively written about, are shown to have long lives in many of the studies reviewed below. They represent an important puzzle for evolutionary theories of aging (16–18).
The definition of fertility is different from that of fecundity, so as infertility and infecundity. Fertility is defined as ability to conceive after 1 year of unprotected intercourse. In contrast, fecundity refers to reproductive behavior which allows for pregnancy to occur. The reported prevalence of infertility in the general population ranged from 2% to 8%, whereas the reported infertility rate in patients with inactive UC were similar [38,39]. Fertility can be affected by RPC and IPAA as well as proctocolectomy with Brooke end ileostomy [40,41]. The reported infertility rate in patients with RPC and IPAA ranged from 20% to 90%. [13,41] A majority of earlier studies, however, involved in open surgery while the impact of laparoscopic IPAA surgery on fertility has been shown to carry advantages, including female fertility.
The impact of RPC and IPAA on female fertility has been extensively studied. A Swedish retrospective study with interview, gynecological examination, and hysterosalpingography reported an infertility rate of 0% in UC patients without colectomy vs. 93% for UC women with RPC and IPAA [13]. A Lahey Clinic study of 110 patients reported an infertility rate of 5% in UC patients before IPAA and 16% after IPAA [16]. An additional study of 300 women reported an infertility rate of 38% in patients before IPAA and 56% in patients after IPAA [41]. Infertility in IPAA may improve over time. For example, a study reported that fertility reduced to 53% of patients with IPAA in a short term but the number increased to 76% after 6 years [42].
Fecundability may be a better marker than fertility for the measurement of ability to become pregnant. For example, a Scandinavian study of fertility in 237 patients with IPAA showed a reduction in births to 35% from the expected [43]. A second report from the same group, however, assessed fecundity and found an 80% reduction in fertility rate after IPAA [44].
The obstetrical literature defines infertility as the inability to conceive after 1 year of unprotected intercourse in the fertile phase of the menstrual cycle [5]. Fecundability is the chance of being pregnant in a single menstrual cycle and fecundity is the probability of achieving a live birth within a single reproductive cycle [6].
