medications

Courtesy of IVF PHOENIX

Lupron

Lupron is an injectable medication used to down-regulate the pituitary gland and prevent the release of certain hormones such as luteinizing hormone (LH) and follicle stimulating hormone (FSH). Without LH or FSH, the ovary will not produce follicles that, in turn, will decrease the production of estrogen and progesterone. When Lupron is discontinued, the pituitary gland will resume normal production of FSH and LH.

In fertility treatment, Lupron is primarily used during superovulation cycles to control the release of the hormones described above. Daily exposure to Lupron reduces the chance of the release of LH causing premature rupture of the ovarian follicle. Without Lupron up to 30% of superovulation cycles can experience spontaneous premature release of LH that leads to cancellation of the cycle. With Lupron control, this figure is reduced to less than 10%.

Lupron can also be used to cause medical menopause for the treatment of endometriosis, breast cancer, prostate cancer, and uterine fibroids. Lowered estrogen levels tend to curb the progression of the disease and its associated pain. In the case of endometriosis, the pain free interval may be extended without the need for additional surgery.

Prolonged usage of Lupron to induce medical menopause will accelerate bone loss (osteoporosis) and increase the risk of coronary artery disease. In addition, after discontinuing Lupron, you may have an increased number of ovarian follicles that increases your chance of multiple gestation.

Pergonal/Clomiphene Citrate

Pergonal, Metrodin, and Clomiphene Citrate are medications indicated for women who are infertile. The purpose of these drugs is to induce or enhance ovulation, or, to super-stimulate the ovaries of women undergoing assisted reproductive technologies such as IVF/GIFT/ZIFT. Pergonal consists of 75 IU of FSH (follicle stimulating hormone) and 75 IU of LH (luteinizing hormone) per ampule and is given by injection. Metrodin consists of 75 IU of purified FSH per ampule and is also given by injection. There are other injectable medicines that are recombinent forms of FSH. Altogether, these injectable meds are called Gonadotropins. Clomiphene is an anti-estrogen pill that causes the pituitary gland to secrete greater amounts of FSH.

The potential risks of these drugs include:

• Ovarian hyperstimulation syndrome. Some women may develop significant enlargement of the ovaries that may, in severe cases, require hospitalization, intravenous fluid replacement, plasma expanders, and removal of the abdominal fluid.
• Multiple births

a) 15% of all pregnancies are twins.
b) 5% are triplets or greater.

• The potential for selective reduction of multiple gestations to enhance fetal viability and maturity.
• Higher miscarriage rate.
• Higher risk of pre-term/premature delivery.

Vascular thrombosis

a) An arterial thrombosis (blood clot) can occur with severe ovarian hyperstimulation syndrome.

b) A venous thrombosis (blood clot) can occur unpredictably, but is associated most commonly with persons who have a personal or family history of venous thrombosis or clotting disorder.

• Hemoperitoneum (blood in the abdominal space) can occur from ruptured ovarian cysts.
• Febrile reaction/cellulitis may occur at the injection site.
• Ovarian cancer. One study suggests that the use of Clomiphene increases the lifetime risk of developing ovarian cancer by 4.5%. Reliable data is not available for injectable gonadotropins (Pergonal), but the risk may be slightly higher.
• Adnexal Torsion (Twisting of the ovary) occurs less than 1% of the time. This occurs when the stimulated ovary twists on itself and cuts off its own blood supply. Surgery is required to untwist or remove the affected ovary.
• Ectopic/Tubal Pregnancy. The incidence is increased slightly from 1-2% to 1-3%.

The usual dosage of Pergonal or Metrodin varies from 1-8 ampules per day for 7-14days. The usual dosage of clomiphene citrate is 50-250mg per day for 5 days. The response of the ovary is carefully monitored by the use of ultrasound to measure the number and size of the follicles.

Human Chorionic Gonadotropin (hCG)

Human Chorionic Gonadotropin (hCG) is the hormone produced by the human placenta. It is also used to trigger ovulation in women treated with Pergonal, Metrodin, or clomiphene citrate. The action of hCG is similar to that of LH in that it stimulates the eggs/oocytes to mature and be released from the ovary.

HCG can cause headaches, irritability, or depression; swelling and pain at site of injection. When used with Pergonal or Metrodin, it may cause or increase ovarian hyperstimulation syndrome.

The usual dosage of hCG is 5,000-10,000 units given by injection at the exact time the physician advises.

Progesterone

Progesterone is the hormone produced by the corpus luteum following ovulation. Progesterone plays an important role in embryo implantation and the maintenance of early pregnancy. Progesterone supplementation is commonly used when ovarian progesterone production is felt to be inadequate to initiate or maintain a pregnancy or to counterbalance the estrogen effect produced from multiple follicles encountered during superovulation therapy. Although the FDA has never approved the administration of progesterone in pregnancy, many studies have demonstrated the efficacy and relative safety of progesterone supplementation in these circumstances. Current information suggests that progesterone supplementation does not increase the risk of birth defects over the baseline rate of approximately 3%.

Progesterone supplementation may be administered orally, intramuscularly, or vaginally and can cause lethargy, mood swings, depression, and breast tenderness; local pain or irritation at the site of the injection; or, irritation of the vagina or perineum with vaginal medication.

The usual dosage for Progesterone given by injection is 50-100mg once a day. The usual dosage for Progesterone given by vaginal tablets is 50-200mg three to four times per day.

Estrogen

The use of supplemental estrogen in pregnancy is a controversial subject. Diethylstilbestrol (DES), a semi-synthetic estrogen, was given during the 1940’s through the 1960’s prevent miscarriages in high-risk women. It was later discovered that this drug caused certain abnormalities of the cervix and led to a higher incidence of vaginal cancer in the female offspring and testicular cancer in the male offspring exposed to the drug. A current review of the literature supports the safety of supplemental estrogen during pregnancy.

The estrogen we recommend today closely resembles the estrogen made by the ovary. The most active form is that estrogen is estradiol, typically in the form of 17-beta estradiol. Currently this medication is available in an oral (Estrace), injectable (Estradiol valerate), vaginal (Estrace Cream) and transdermal (Estraderm) preparations. These hormones differ from DES in that they are biologically identical to estrogen made from the ovary.

During the 1970’s and 1980’s, Russia and Slavic countries used these estrogen preparations as therapy for patients suffering from recurrent miscarriage and achieved moderate success with no reported increase in fetal anomalies. In the western countries, the explosion of assisted reproductive technologies, e.g., IVF, has created a need to re-implant frozen embryos into hormone manipulated uterus. Since corpus luteum is not functioning in the uterus of the woman undergoing this procedure, they require supplemental hormones until they are through the first 8 weeks of the pregnancy. There have been no reported increases in the rate of fetal anomalies in infants born from this method, however, recent reports of increased incidence of congenital anomalies have been associated with fresh ART/IVF cycles. In a woman who was born without ovaries and who received donated embryos, there was no increase in fetal anomalies using the hormonal supplementation needed to support the pregnancy.

The largest group of women achieving pregnancy with the use of supplemental estrogen is the group who utilized super-ovulation in association with IVF, GIFT, or ZIFT. During a cycle that is stimulated to produce multiple follicles, natural estrogen (estradiol) levels are 3-10 times higher than a normal cycle. Exposure to such high levels of estrogen has not been associated with an increase in the rate of fetal anomalies. French researchers have also published higher implantation and pregnancy rates with the use of supplemental estrogen before ovulation and in the luteal phase that occurs after ovulation.

At IVF Phoenix we recommend the use of estrogen in the follicular phase (before ovulation) of development with additional estrogen that starts 4-5 days after the LH surge or “trigger shot” of hCG. In a normal spontaneous cycle, estrogen drops following the LH surge and slowly increase during the luteal phase. With ART cycles, we attempt to imitate this process and improve the development of the lining of the uterus through the use of vaginal, transdermal, or injectable estrogen. (The bioavailability--amount the body can use--is greater when the medication is given by one of these routes rather than when taken orally.)

Experience has shown that there is a significant difference in estrogen levels in women who experience recurrent spontaneous miscarriages. It is not clear if factors leading to miscarriage also caused a reduction on the production of estrogen, or if low estrogen somehow played a role in causing the miscarriage. What is clearer is the fact that newer estrogen products are structurally and biologically similar to estrogen produced by the ovary and placenta and exposure to elevated levels of estrogen does not create an increase in fetal malformations.

Aspirin/Heparin/Prednisone

The use of heparin, baby aspirin, and prednisone may be suggested to help you achieve or maintain a pregnancy. Although there is little published evidence on the benefit of these medications (except in cases of recurrent spontaneous miscarriage and pregnancy complicated by preeclampsia), the premise is that the unexplained infertile woman may actually be able to achieve fertilization and embryo development but the embryo fails to implant. In that sense, they are having very early miscarriages. There are many theories on why this occurs: lack of blocking antibodies, the presence of autoimmune disorders that activate the immune system to over-respond and injure the pregnancy, the prevalence of silent hyperclotting states. We believe that patients with endometriosis, salpingitis isthmica nodosa, Hashimoto's thyroiditis, Raynaud's disease, lupus, rheumatoid arthritis, and other autoimmune disorders may initiate a response that makes a woman's blood more likely to over-clot.

In infertile patients, blood flow in the ovary and uterine lining/endometrium is predictive of outcome. In other words, the ability of the endometrial to develop adequately to support a pregnancy determines whether or not the pregnancy will be successful. The use of low dose aspirin pre-conceptually (cycle day three and on) has improved pregnancy outcomes. Dr. Alan Beer, Chicago, has published improved pregnancy rates among women who suffer recurrent miscarriages using heparin, also starting on cycle day three.

Infertility is associated with higher perinatal morbidity and mortality: three fold risk of stillbirth, five fold risk of preeclampsia, four fold risk of miscarriage, two fold risk of pre-term labor, and increased risk of intrauterine growth retardation. Current literature is beginning to pose associations of these complications with increased clotting and fibrin formation. Since 1993 we have suggested that the invariance among all these things may be fibrin deposition with vessel spasm and abnormalities in implantation and development of the placenta. This means there may be a hidden clotting disorder (s) that is unmasked during pregnancy and interferes with the maternal-fetal interchange. Excessive fibrin deposition is the most common finding of the placenta in these situations. If soluble fibrin monomer (SFM) in a non-pregnant state is greater than 40, the risk of stillbirth is 5%. In our experience of 8 patients who had SFM greater than 100, 6 achieved pregnancy and 4 of the 6 delivered babies between 30 and 34 weeks.

Recent literature shows a direct connection with polycystic ovarian syndrome, insulin resistance, and increased net clotting. The defect, a deficient anti-clotting mechanism, makes normal clotting a problem. The end result is an elevated fibrin deposition. (A scab is made of fibrin.) It is our belief that elevated fibrin is also associated with many abnormal reproductive states.

Over the past few years, there has been much interest focused on the role of nitric oxide (NO) as an enhancer of uterine blood flow as well as a mediator of blood vessel smooth muscle dilation in other areas of the body. Heparin increases nitric oxide that in turn leads to improved blood flow throughout the body: Hands are warmer and less blotchy and most of the thin endometrial linings we see improve. Because we have seen a significant number of women with defined clotting problems, heparin appears to address the clotting issues as well as the vessel spasm issues and improve pregnancy outcomes. Other medications that may produce increased nitric oxide formation include Viagra and calcium channel blockers (used to treat high blood pressure).

Heparin, a naturally occurring substance produced from our blood vessels, helps maintain the blood flowing as a liquid. Given by injection (subcutaneous or intravenous), it is a large molecule that does not pass through the placenta. Excessive amounts of heparin, however, will prevent blood from clotting that can lead to bleeding. For this reason, heparin doses are monitored through blood tests (prothrombin time, or, PTT) drawn four to six hours after the morning dose and carefully titrated to keep your PTT slightly above normal. Short-term use of heparin is considered safe. Long-term heparin use, however, is associated with increased bone loss. Pregnancy is a bone-losing situation and heparin adds to that loss. As a result, the risk of a bone fracture is thought to be as high as 15%. The fracture could be as slight as a stress fracture in the hand or foot or as significant as a vertebral crush fracture as seen in elderly postmenopausal women. Unfortunately, taking calcium does not appear to reverse that effect. Another risk associated with long-term heparin use is a drop in circulating platelets. Platelets help initiate the blood clotting mechanism that blocks small holes in the vessel walls. If platelet counts drop, heparin will have to be discontinued and another medication considered. A drop in platelets, called thrombocytopenia, occurs in 1-3% of the patients on long-term heparin therapy and most often resolves spontaneously once the heparin has been discontinued. Heparin can also cause bruises and wheals to form at the site of the injection and an infection can develop if the injections are not done using aseptic technique.

A daily baby aspirin has been shown to be effective in several disease states during pregnancy including preeclampsia and recurrent miscarriage associated with antiphospholipid antibodies. Aspirin, in conjunction with heparin, is used to treat women who have “sticky” activated platelets due to spasms of the small blood vessels that cause a shearing effect on the platelets. The aspirin is thought to decrease the stickiness of the platelets, thereby permitting it to flow through the small vessels easier. A combination therapy of aspirin and heparin or aspirin and prednisone has shown equivalent success in women who experience recurrent miscarriage. While aspirin can pass through the placenta and affect the baby's platelets, one baby aspirin daily is considered safe for both the baby and the mother. The use of more aspirin would begin to disable platelets until there weren't enough active platelet to do assist in the clotting process. Aside from disabling platelets, aspirin can affect the ductus arteriosus in the fetus and cause it to narrow leading to potential closure that can alter fetal blood flow and create decreased oxygen levels in the fetus. Low blood oxygen or hypoxia can injure the fetal brain or other organs and can cause fetal death. This narrowing effect is not noted until after 20 weeks gestation, so your doctor may consider monitoring the patency of the ductus arteriosus vessel at that time. If vessel narrowing occurs and is considered dangerous, you can be expected to discontinue the aspirin. In most cases, the narrowing should stop and may reverse.

Chronic use of aspirin may irritate the stomach, cause bleeding in the intestines, or ringing in the ears (tinnitus). If any of these symptoms occur, your doctor will either monitor the symptoms or have you stop the aspirin completely. When to discontinue aspirin and heparin is controversial and will vary from doctor to doctor but use of these medications up to two days before delivery have been shown to be safe.

Prednisone is given when there is evidence of autoantibodies. These may be antinuclear antibodies (ANA), antiphospholipid antibodies (APA), antithyroid antibodies, etc. The literature has many articles supporting the association of ANA with a poor pregnancy outcome, but ANA is an ill-defined marker. For this reason, we add steroids, like prednisone, to cover for an immune reaction that may injure the early pregnancy. The side effects of prednisone may dissuade your doctor from recommending this medication as a first choice, long-term treatment as it also induces bone loss, causes weight gain, hypertension, sleep and mood disturbances, glucose intolerance, and aseptic necrosis of the femoral head.

Since the early implanting embryo does not require the larger blood flow of a 6week gestation, why would hypercoagulation due to any cause be a problem in early implantation? This question is an excellent one and one that we continue to struggle to answer. Obviously, hypercoagulation is not the only issue in the early implantation (Biological Response Modifiers), but the autoantibodies may be associated with another immune problem. An older study of in-vitro fertilization patients who were diagnosed with the presence of APA had a successful pregnancy outcome reduced by half. In a small prospective trial, the women were treated with a steroid during follicle development and in the luteal phase during IVF and GIFT cycles. Those patients who did not have a positive APA received no benefit or reduction in pregnancy rates whether they took steroids or not. In those patients who were APA positive and took steroids, 8 out of 10 got pregnant; in the group that declined steroids, none of the 25 was able to get pregnant. Our observation has been that embryos from certain women will display fragmentation and blebbing that we believe is due to an immunologic reaction. The worse the embryo looks, the less likely it is that it will result in a pregnancy.