Fertility Treatment: Do not be Distracted

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1 Fertility Treatment: Do not be Distracted Fertility Treatment: do not be distracted by worthless recommendation Fertility Treatment: Do not be Distracted When contemplating options for fertility treatment with your own eggs, it always boils down to continue frequent intercourse, ovarian stimulation / ovulation induction + IUI or some form of IVF. During consultation or when weighing your options do not lose perspective of the big picture. Many suggestions may present themselves and serve to distract you.

2 Men and Women load up on these distractions from the web, friends, primary care physicians or the couple themselves. Some of these recommendations are harmful because they shift the focus to non-proven interventions and most notably cause delay consultations with a reproductive endocrinologist and completing the infertility workup or starting treatment if needed. Do not be distracted by these arguments I am Healthy Many women in America consider being healthy as being fertile. The media also bombard us with photos of beautiful women in their forties with babies. Truly many women, are in great shape with ideal body weight, exercise regularly, have no medical problems and feel great about themselves. Fertility though speaks to a specific set of factors related to the ovaries, fallopian tubes and quality of sperm. Healthy women can have low egg reserve or blocked fallopian tubes or their partners have low sperm counts. Hence their fertility could be impaired. On the other hand, women not leading a healthy lifestyle or having a medical disorder can be very fertile if all fertility factors (tube, ovary, sperm) are functional. I did not try enough If you do not use birth control pills or condoms and you have having regular intercourse, then you are trying, irrespective of your conscious intentions. If you are you had regular intercourse for one year and are younger than 35 years or six months and 35 or older, then you have tried. Regular intercourse means two to three times a week. If you had intercourse with reasonable frequency for 6months to a year and you are not pregnant consult with a fertility specialist. There is a strong relationship between the length of trying

3 and pregnancy rate. The longer that you have been trying, the lower the chance for spontaneous conception. I did not time my ovulation Timing your ovulation is not required at all if you are trying to conceive. Actually timing your ovulation maybe harmful to your chance to conceive. Because the methods you would use to time ovulation (cervical mucus, ovulation prediction kits, basal body temperature or intelligent thermometers and apps) are not accurate, you may miss valuable time and have intercourse at the wrong time if ovulation takes place unexpectedly early. Moreover, you cannot get higher odds for getting pregnant above and beyond having intercourse three times a week because sperm will be available all the time when you ovulate. Several studies failed to show any increase in pregnancy rates using many of these timing methods. On Fertility Apps and other monitors Many (>4 million) websites discuss times intercourse utilizing other methods (fertility monitor, cervical mucus, calendar methods, urine LH kits..). More recently technology entrepreneurs are delved into the trying to conceive area and volunteered advice. There is no evidence to support that any calculation method improves the odds of getting pregnant over frequent intercourse. These non-scientific advice is a major distraction. Even if these apps collected data on how many women got pregnant, without a comparison group, is not a prove that they actually work. One study indicated that timed intercourse is associated with higher incidence of erectile dysfunction (43%) and extramarital sex (11%). My progesterone level is not optimal For almost all women, low progesterone level is not a cause for infertility. In natural cycles, progesterone starts to rise after ovulation. Levels of 3 nanogram/ml or more

4 indicates ovulation, Optimal levels to maintain the lining of the uterus are 8 to 10ng/mL. Levels less than 8 (luteal phase defect) may lead to miscarriage because progesterone is not adequate to maintain the lining of the uterus but it is not a cause for not getting pregnant (infertility). Progesterone is monitored, and supplemented if low, during fertility treatment but in itself low progesterone is not a cause for infertility. On Clomid & Letrozole Clomiphene is widely used as initial fertility treatment. This use is commonly not appropriate because a. clomid is used without infertility workup (checking ovarian reserve, sperm analysis and fallopian tubes) b. clomid is used without performing basic tests related to the safety of getting pregnant (infectious disease and genetic screening) c. clomid is used by women that are not likely to benefit from it e.g regularly ovulating women with low ovarian reserve and unexplained infertility. Women that are most likely to benefit from clomid are women with chronic anovulation e.g women with polycystic ovary syndrome (PCOS). d. clomid is commonly used with no monitoring using ultrasound. If you do not get pregnant, one would not know if you did ovulate or not % of women do not respond to clomid. If you are destined to get pregnant, there is a possibility that you have many eggs developing in the ovary because you are unduly sensitive to the medicine. Strong response to clomid makes you at risk for multiple pregnancy e. clomid is commonly use for extended periods of time while the majority of pregnancies take place in the first 3 months. f. IUI is preferred to intercourse only, in clomid cycles because it can cause the cervical mucus to be thick. IUI

5 bypasses the cervical mucus and deposit the sperm into the cavity of the uterus g. Letrozole is similar to clomid regarding the use and indication but there is evidence that pregnancy is higher after letrozole compared to clomid. Use clomid or better ltrozole for the right indication, with monitoring and for 3 (max 6) months only. On Setting Time Limits For each fertility treatment step: intercourse, ovarian stimulation + IUI or IVF define the number of cycles you will try before proceeding to the next step. Statistically, these treatments are more likely to succeed in the first three treatment attempts. Subsequently, the chance for getting pregnant diminishes and you and your physician should consider moving to another treatment. Do not loose track of your age and ovarian reserve You have normal fallopian tubes and partner sperm and you ovulate every month. Younger women are encouraged to try (have regular intercourse). The duration of trying on your own should be guided by ovarian reserve tests and age. Younger women with good reserve can try a bit longer than older women or women with low reserve. This recommendation should be based on scientific information not general perception. Do not accept the advice keep trying from any one without considering you age and without performing the tests for ovarian reserve (vaginal ultrasound, AMH and FSH on day 3). Female age is the most important factor in occurrence of a healthy pregnancy and should be the prime consideration even if ovarian reserve tests and other factors are normal. There is a plethora of low quality information, recommendation

6 and advice out there. Women accumulate them from multiple sources or just using there simple logic. They can lead to delay in fertility testing and fertility treatment that could be detrimental to future fertility. Fertility Treatments You Should Avoid Which Fertility Treatments You Should Avoid? Infertility is defined as inability to conceive after one year (6 months in women >35 years) of regular unprotected intercourse (no contraception) and in the absence of any known cause for infertility. Earlier referral is recommended in older women 35 years or more, unable to have intercourse (e.g erectile dysfunction..), genetic (e.g cystic fibrosis carrier), medical or pregnancy related risk factor (e.g systemic lupus, hepatitis C, HIV, hepatitis B ), if a fertility factor is suspected (no ovulation,pcos, hypothalamic amenorrhea, male factor, endometriosis, tubal disease..) or if fertility preservation is desired following cancer diagnosis. Evidence is accumulating of the most effective fertility treatments after fertility assessment. Many fertility treatments are offered indiscriminately, they have little chance of succeeding or are risky (ovarian hyperstimulation

7 syndrome, multiple pregnancy). In general simple logic does not determine if a treatment is effective or not. It is only through well conducted studies we can prove the efficacy of such a treatment. Moreover, considering the final outcome- a live healthy newborn- should be the one to look for in such a study. The following is not a medical advice, but a review of recent evidence related to fertility treatment options. You should discuss treatment with your fertility specialist. It is possible that sometimes these treatments are indicated for fertility treatment in special circumstances. Fertility treatments you should avoid may include: You should not time your ovulation If you have access to intercourse with a male partner every other day, timing ovulation using any method, does not increase your chance for natural conception. If you have intercourse twice or more a week you have excellent chance of conceiving within one year. Studies evaluating timed intercourse using basal body temperature charts, urine LH kits, cervical mucus, failed to show improvement in pregnancy rate beyond intercourse every other day. No evidence that fertility apps improve the chance for conception. Age category (years) Pregnant after 1 year (12 cycles) (%) Pregnant after 2 years (24 cycles) (%)

8 Use letrozole instead of clomid for ovulation induction in PCOS There is high quality evidence that letrozole (aromatase inhibitor) is superior to clomid for induction of ovulation in women with PCOS and yeilds higher pregnancy rates. 750 infertile women with a diagnosis of PCOS, aged of years, were enrolled: 376 patients were assigned to receive clomiphene 50 mg/day and 374 were assigned to receive letrozole 2.5 mg/day in doses escalating to 7.5 mg/day for a total of 5 days per cycle for up to five cycles. The drugs were provided in identical capsules over the same schedule. Ovulation rates with letrozole were significantly superior to clomiphene. Monthly chance for pregnancy and for a live birth was 30% higher in the letrozole group. Avoid undergoing clomid or letrozole cycles without ultrasound monitoring Although twins and higher order multiple pregnancies are not as common as in gonadotropin (injection medications) use [8% versus 30%] clomid is probably responsible for more twins than any other treatment because of its widespread use. Do not undergo ovulation induction without ultrasound monitoring to evaluate response and the number of follicles developing. Consider cycle cancellation if many follicles appear in the ovary. Metformin alone is inferior to clomid in induction of ovulation and improving fertility There is strong evidence that clomid is superior to metformin in ovulation induction in women diagnosed with PCOS. Letrozole or clomid are the medications of choice for induction of ovulation, not metformin. There is also no strong evidence

9 that metformin reduces the chance for miscarriage. Do not use oral medications for unexplained infertility Unexplained (idiopathic) infertility is diagnosed in women who failed to conceive with regular ovulation, patent fallopian tubes and near normal patent sperm analysis. Women with unexplained infertility, mild male factor or minimal endometriosis do not conceive mostly because of chromosomal abnormalities of the egg. Ovarian stimulation using oral medications usually yields one or two eggs (close to natural cycles) while using injection medications can produce more eggs thus increasing the chance that one of them is healthy. There is no evidence that oral medications increase the odds of pregnancy in women with UEI. Avoid gonadotropins-iui and proceed directly to IVF In women receiving oral medications (clomid)-iui proceeding directly to IVF or proceeding immediately to IVF as first line treatment and avoiding injection medication-iui is more successful in achieving pregnancy, is faster and minimizes the risk of multiple pregnancy. The FASTT trial randomized 247 couples to receive three cycles of clomiphene citrate (CC)/IUI then three cycles of FSH/IUI and then up to six cycles of IVF versus 256 couples to an accelerated treatment, that omitted the three cycles of FSH/IUI. An increased rate of pregnancy was observed in the accelerated arm and pregnancy was achieved 3 months faster. Per cycle pregnancy rates for CC/IUI, FSH/IUI, and IVF were 7.6%, 9.8%, and 30.7%, respectively. The observed incremental difference was a savings of $2,624 per couple for accelerated treatment. The study demonstrated that FSH/IUI treatment was of no added value.

10 The FORT-T trial randomized couples with 6 months of unexplained infertility with female partner aged years to treatment with two cycles of clomiphene citrate (CC) and intrauterine insemination (IUI), follicle stimulating hormone (FSH)/IUI, or immediate IVF, followed by IVF if not pregnant. The cumulative clinical pregnancy rates per couple after the first two cycles of CC-IUI, FSH-IUI, or immediate IVF were 21.6%, 17.3%, and 49.0%, respectively. The majority (84%) of live-born infants resulting from treatment were achieved via IVF. Immediate IVF demonstrated superior pregnancy rates with fewer treatment cycles in the immediate IVF group. Avoid using DHEA, GH or aspirin as adjuvants to IVF There is no conclusive evidence that pretreatment, prior to IVF, with dehydroepiandrosterone (DHEA), growth hormone (GH) or other medications improves the pregnancy rate r live birth rates. Avoid transferring two or more embryos when feasible Multiple pregnancy carries an higher risk to the mother and to the health and neurological functions of the newborn. Outcomes in twins are definitely inferior to singleton babies. Women <38 years with a good quality embryo in there first or second IVF cycles should consider single embryo transfer. In the third cycle consider double embryo transfer. Avoid routine use of pre-implantation genetic screening to improve the pregnancy rate after IVF Chromosome analysis of embryos is available. There is no conclusive evidence that PGD will increase the chance for a

11 live newborn. PGD will definitely not make the embryos healthy. If accurate, it will just enable finding the healthy embryo faster but the total number of healthy embryos, if any, will remain the same per completed IVF cycle. The accuracy of the test is no 100%, it is costly and require taking one or few cells from each embryo. Young women with good ovarian reserve have excellent pregnancy rate even with single embryo transfer. Moreover embryo freeze-thaw cycles yield comparable outcomes to fresh IVF cycles. Older women and women with low egg reserve produce a small number of embryos, which means that testing is not an efficient approach. PGD may have some role in older women e.g.>40 years producing a large number of embryos e.g >6 embryos. These women are the outliers. Avoid using a physician with no experience in managing fertility problems This will likely cause delay, reduce success and may increase complications. If you seek a specialist care, avoid any treatment that you do not understand its rationale. The choices are usually expectant treatment (regular intercourse), ovarian stimulation-iui or IVF. Know the expected success rate and multiple pregnancy rate for each option offered to you by a reproductive endocrinologist. Fertility Treatment Men Should Avoid Avoid treating abnormal sperm parameters with oral or injection medications or supplements. No such treatment was demonstrated to improve the chance for a live born in female partner. Avoid surgery for varicocele even if sperm parameters are abnormal. Surgery for varicocele is a treatment that was not proven to increase the odds of live born in female partner.

12 To lean more about fertility treatments please visit nycivf.org Letrozole vs Clomid for Ovulation Induction in PCOS Letrozole vs Clomid for Ovulation Induction in PCOS Polycystic Ovary Syndrome (PCOS) is associated with two of the following criteria: a. No ovulation (anovulation) or less frequent ovulation b. Hign male hormone (androgen) c. Polycystic appearance of the ovaries: large number of small follicles Clomid is an oral medication that modulate or mask the estrogen receptor leading to release of internal FSH from the brain

13 Polycystic Ovary Letrozole is an oral medicine that reduces estrogen production from the ovary through antagonizing the function of the aromatase enzyme, responsible for making estrogen. The brain respond by releasing FSH. Which one is better? In a recent good quality study, 750 infertile women, aged of years, with a diagnosis of PCOS were studied. The women were randomly allocated to CC vs. letrozole for 5 treatment cycles. CC 50mg every day for 5 days (days 3-7 of cycle), or B) letrozole 2.5mg every day for 5 days (days 3-7 of cycle), for a total of 5 cycles or 25 weeks. The dose will be increased in subsequent cycles in both treatment groups for non-response or poor ovulatory response up to a maximum of 150 mg of CC a day ( 5 days) or 7.5mg of letrozole a day ( 5 days). 27.5% of women who received letrozole (Femara) had a live birth, compared with 19.5% of women treated with clomiphene. One quarter were clomid resistant and never ovulated. Letrozole was associated with lower multiple pregnancy rates.

14 Letrozole appears to improve live birth and pregnancy rates in subfertile women with anovulatory PCOS, compared to clomiphene citrate. Letrozole should be considered as a first line agent for induction of ovulation in women diagnosed with PCOS. In general it is adviced that oral medication are tried first in PCOS before proceeding to injection medications (gonadotropins). Gonadotropins induce multiple ovulation and increase the risk for multiple pregnancy. If oral medications fail to induce ovulation or no pregnancy ensues, it is preferable to proceed to IVF with single embryo transfer and not injectable medications IUI to avoid twins and higher order multiple pegnancy. Avoiding Twins Following Fertility Treatment Avoiding Twins Following Fertility Treatment requires careful consideration of fertility treatment options Many couples try to avoid twins for many reasons: Baby related: preterm delivery, before 37 weeks, that may result in prematurity, need for a long intensive treatment and possible neurological impairment and other diseases. Mother related: twin pregnancy is more risky than singleton.

15 3. Social reasons: financial, emotional and personal burdens on the family Counseling from reproductive endocrinologists about the risk of multiple pregnancy is very important before initiating fertility treatment. Twins can be avoided with fertility treatment (Selective Reduction) by avoiding injection medications during IUI cycles, single embryo transfer during IVF cycles and fetal reduction if twin pregnancy takes place. The chance for twin pregnancy following fertility treatment can be minimized or avoided if one Avoid treatments that cause multiple embryos to reach the uterus and / or Fetal reduction of twins to singleton Avoiding Twins Following Fertility

16 Treatment : do not allow multiple embryos to reach the uterus Fertility treatments include IUI and IVF IUI. The ovaries are stimulated for 10 days or so then sperm is concentrated and injected inside the uterus. Risk for twins increase with the use of injection medication (30%) versus oral medicine (clomid 8%). The risk is also higher in the first cycle versus later cycles, in younger women, wemen with PCOS, when many large follicles (> 14mm) on ultrasound and with high estrogen levels. Even when with meticulous monitoring of stimulation, the risk of twins is not zero. IVF. The ovaries are stimulated and retrieved, fertilized in the lab then one or more embryos are transferred in the uterus. The number of embryos transferred is selected based on the implantation potential per embryo. Embryo implantation is related to female age and morphology or shape of the embryo. When one embryo is transferred (elective single embryo transfer) the risk for twins is (1%) due to embryo splitting versus about 30% when two embryos are transferred. The American Society for Reproductive Medicine recommend single embryo transfer for younger women with good quality embryos. Single embryo transfer should be considered for all women who want to avoid twins. Avoiding Twins Following Fertility Treatments : Fetal Reduction Fetal reduction means one pregnancy sac is removed from the uterus while the other sac is left. First there is the option is of CVS. The sacs are sampled and tested for their chromosomes to select the normal ones. The procedure of

17 reduction is performed using a needle not surgery. Studies showed that reduction prolongs pregnancy and improve survival and quality of the remaining babies even when 5% chance of loosing both babies due to the procedure is considered. This is not abortion. This is an attempt to give the remaining babies better chance at survival and healthy life. Conclusion: Know your personal risk for multiple pregnancy, Avoid using injection medication for IUI, consider single embryo transfer after IVF and if pregnant with twins consider fetal reduction.