- What are the side effects of IVF medications on babies? Most of the medication used for IVF are commenced and completed prior to the embryos being transferred. The main medications that are continued after the embryos are transferred to the uterus include natural estrogen and progesterone which should not carry any increased fetal risk having been used now for many years and also because we try to keep these hormones within the physiological range. Patients with additional medical problems especially those patients with abnormal immunology may also require to be on heparin which does not cross the placenta and therefore does not affect the baby. They may also need to be taking a very low dose of one baby aspirin a day and possibly monthly intravenous gamma globulin until the end of the first trimester. None of these medications are known to cause fetal abnormalities remembering that between 3% to 4% of pregnancies may be complicated by an abnormality discovered at birth even when no additional medications or technologies are required for conception.
- What are the side effects of medications used in IVF on patients? This is a very large topic mainly because of the large number of medications that are used in generating an IVF cycle and supporting the pregnancy thereafter. In general, the IVF medications used to prepare the uterus and to stimulate the ovaries are not known to carry any long-term risks of cancer of the ovary unless there is a family history of ovarian cancer. The commonest side effect would be some abdominal discomfort and bloating as the follicles increase in size especially if there are a large number of follicles. The commonest serious side effect would be ovarian hyperstimulation syndrome (OHSS) which should be entirely preventable with prolonged coasting (See OHSS question above).
List of Fertility Medications
Aspirin: Acetylsalicylic Acid (ASA) 80 mg is otherwise known as a baby aspirin and is taken once daily by mouth. The aspirin makes platelets in the blood less sticky and this helps blood to flow better through microscopic vessels like those in the developing placenta. Aspirin may be used alone during the IVF cycle or else in conjunction with Heparin therapy. The baby aspirin is one quarter of the strength of an adult aspirin and while it may cross the placenta, the dose is so low that there should be no adverse effects on the developing embryo and baby.
Combination
Progesterone/Estradiol
Suppositories: This suppository is inserted vaginally and is usually started one day after the embryo transfer. The progesterone and the estradiol are natural and extracted from the Mexican yam or the soybean and these steroid hormones maintain and promote synchronization of the lining of the uterus, thereby helping to establish and maintain good implantation.
Desogen (Reclipsen): Birth control pills are used to regulate the menstrual cycle. It is taken daily until instructed to stop by a Zouves Fertility Center nurse or doctor.
Dexamethasone: The embryo may be vulnerable to attack by the immune system. This pill may selectively suppress a woman’s immune system to avoid rejection, while the embryo is implanting into the uterus. This medication will begin on the same day as stimulation begins. Dosage is 0.5mg (half of 1mg tab) taken once daily with breakfast or lunch to avoid insomnia.
Doxycycline: This antibiotic is taken twice a day for 5 days. Administration of Doxycycline will commence on the day of egg retrieval or 3 days prior to embryo transfer. Doxycycline will prevent infections from occurring after the retrieval and also limit the risk of bacteria being introduced at embryo transfer. Doxycycline may also need to be taken at the beginning of the stimulation if directed by the doctor or nurse. Erythromycin may be taken at the beginning of the stimulation if directed by the doctor or nurse. Erythromycin may be substituted when appropriate.
Enbrel (Etanercept)
Humira: Enbrel/Humira is a Cox 2 anti-inflammatory medication developed for patients who have severe rheumatoid arthritis. They were approved by the Federal Drug Administration (FDA) for use in these patients in November of 1998. The Cox 2 inhibitors function is to bind with tumor necrosis factor (TNF) which is secreted by active natural killer cells. Patients with rheumatoid arthritis have been found to have elevated levels of TNF in their joints. They bind to the TNF, rendering it biologically inactive, resulting in significant reduction of inflammatory activity. These drugs are used with reproductive immunology patients where there is elevated natural killer activity, both peripherally and in the endometrial tissue. TNF produced by the natural killer cells in the uterus damages the DNA of blood vessels in the endometrium creating stromal hemorrhages which may decrease blood supply to the implanting embryo. The TNF also damages the DNA of the embryo and it may fail to grow, divide, and implant. Enbrel is administered by subcutaneous injection in the thigh, stomach, or back of the upper arm. It is given every 3 1/2 to 4 days and is packaged four doses in a box which provides a two-week supply. Each dose includes a syringe, one vial of Enbrel, one plunger and two alcohol swabs. The drug should be refrigerated and the manufacturer, Immunex Corporation, provides a toll free information service at 1-888-4Enbrel (1-888-436-2735) to answer any questions consumers may have. Humira is administered subcutaneously once every two weeks and comes in boxes of two syringes and is preloaded. The drug should also be refrigerated and the manufacturer, Abbott Laboratory, provides a toll free information service at 1-800-255-5162 to answer any questions consumers may have. The Cox 2 inhibitors are administered for at least 30 days and in some cases may be continued up until a heartbeat is seen on ultrasound at six weeks. Occasionally difficult cases may require more. The FDA classifies drugs into five categories in respect to pregnancy with Category A being deemed the safest. Enbrel/Humira have been classified as Category B and there have been studies in animals at doses 60-100 times higher than human doses that have revealed no evidence of harm to the fetus. At this time there are no formal studies with pregnant women. Current data suggest that the use of Enbrel/Humira does not reduce the body’s ability to fight cancer and also Enbrel should not increase a woman’s susceptibility to catch colds or viruses, but these medications should not be initiated in patients with an active infection or an active upper respiratory tract infection and also in patients who test positive for exposure to tuberculosis.
Estrace (estradiol acetate): Estrace is an estrogen medication used to relieve several conditions related to menopause, such as treating hot flashes and vaginal dryness, and preventing osteoporosis in postmenopausal women. Within IVF, Estrace is used to supply estrogen in a number of situations. It may be used to make the resting follicles more sensitive to the upcoming fertility medication. It may also be used to stimulate growth of the endometrial lining in patients who require a boost. Estrace comes in tablet form and can be used orally or vaginally.
Estradiol Suppositories: The active estradiol is extracted from either the Mexican yam or the soybean and is the same estrogen produced by the ovary and the placenta. In some cases, estradiol suppositories may be given at the start of stimulation to enhance the uterine lining or to make the ovaries more responsive to the fertility medication.
Estradiol Valerate: The same estradiol, extracted from the Mexican yam or the soybean, is prepared for intramuscular injection and is usually given twice a week to patients who are recipients of embryos. This would include patients doing IVF with egg donation, patients doing frozen embryo transfer and gestational surrogates.
Estrogen: Estrogen is one of the sex hormones, the other being testosterone. These hormones are secreted in short bursts and in women estrogen is produced by the ovaries, the peripheral fatty tissue and also by the placenta. Within assisted reproduction, estrogen is used to prepare the lining of the uterus in cycles where an egg donor is being used and also to prepare the lining of the uterus to receive frozen embryos. A small amount of estrogen may also be added in the luteal phase of an assisted reproductive cycle in order to help maintain the implantation and to balance progesterone levels which may be increased when multiple follicles are stimulated.
The estrogen used in assisted reproduction is estradiol and it is extracted from either the Mexican yam or from the soybean and is similar to the estrogen produced by the ovary and the placenta. This estradiol can be prepared in the form of a suppository which can be inserted vaginally and it can also be prepared for intramuscular injection where it is given twice a week in cycles incorporating egg donation, a controlled frozen embryo transfer or gestational surrogacy. Estrogen is also used in some stimulation protocols to try and make follicles more sensitive to the injectable fertility medications.
Folgard
(Folplex, Fabb): This medication is high dose folic acid consisting of 2.2 mg per tablet to which has been added Vitamin B6 and B12. This vitamin supplement is used in two specific situations, the first is for patients who carry one or two of the abnormal genes within Methyltetra-Hydrofolate Reductase (MTHFR) and also in patients with a history of neural tube defect in their family or their own obstetrical history.
Ganirelix:
(formerly called Antagon): Ganirelix is a gonadotropin-releasing hormone (GnRH) Antagonist. It acts by competitively blocking the GnRH receptors on the pituitary gonadotroph cells. The suppression of pituitary LH secretion by Ganirelix is more pronounced than the suppression of FSH. There is no detectable initial release of endogenous gonadotropins (LH or FSH) and this is consistent with an antagonist effect or a direct switch off. Upon discontinuing Ganirelix, the pituitary LH and FSH levels are fully recovered within 48 hours. Ganirelix is rapidly absorbed after subcutaneous injection with maximum serum concentrations reached approximately one hour after dosing. The half-life is 13 to 16 hours and steady state serum concentrations are reached after three days of treatment. Ganirelix is indicated for the inhibition of premature LH surges during ovarian hyperstimulation. Apart from known hypersensitivity to Ganirelix or GnRH analogs, and known or suspected pregnancy, there are no known contraindications.
Gonal F/Bravelle/Follistim
Repronex/Menopur
(FSH/hMG): This category of medication consists either of pure FSH or a mixture of FSH and LH and this family of medications is responsible for stimulating the ovary(ies) to make multiple follicles. Products like Gonal F and Bravelle contain almost pure FSH while products like Repronex and Menopur are collectively known as hMG and they contain equal parts of FSH and LH. The medications are given either by intramuscular or subcutaneous injection and they usually commence about 1 1/2 weeks after Lupron has been started. At Zouves Fertility Center we usually use a combination of a pure FSH product and an hMG product in proportions of approximately 80% and 20% respectively. The reason that we add a product containing LH is because some patients on Lupron may have very low levels of LH, where LH may be required for optimal follicular growth and development.
Humira/Enbrel: See Enbrel/Humira
Human Chorionic
Gonadotropin (hCG): This drug is an intramuscular injection, that can also be given subcutaneously, taken one time after determining follicles are mature. This will facilitate the maturation of eggs and is given thirty-six hours prior to egg retrieval. Dr. Zouves will determine when this injection will be given based on follicular development.
Intralipid (IL): Evidence from both animal and human studies suggests that Intralipid, administered intravenously, may enhance implantation and maintenance of pregnancy when the patient has had an abnormal NK cell level or Function Intralipid is a 20% intravenous fat emulsion which is usually used as a source of fat and calories for patients requiring parenteral nutrition. Intralipid consists of soybean oil as well as egg yolk phospholipids, glycerine and water.
In vitro investigations have revealed the ability of Intralipid to suppress the natural killer (NK) cytotoxicity. Fifty patients with abnormal natural killer levels received Intralipid infusions and 78% showed suppression of the natural killer activity to the normal range one week after infusion, 22% showed suppression but not yet into the normal range in these patients received a second infusion 2 to 3 weeks after the first and all but one of these 11 patients have normal natural killer levels the following week. Four patients required a third infusion and after the first, all showed normal natural killer activity. Forty seven of these 50 patients continued to have normalization of their NK levels for between six and nine weeks, two patients remained normal lives five weeks and in one patient the effect lasted for four weeks.
Conclusion of the study was that Intralipid was effective in suppressing in vivo abnormal NK cell function, suggesting that Intralipid can be used successfully as a therapeutic option to modulate abnormal NK activity in women with reproductive failure.
Intralipid has also been shown to be effective in enhancing live birth rates among women with elevated NK cell cytotoxicity and a history of recurrent implantation failure and pregnancy loss. Of 60 for women under age 40 who were experiencing recurrent implantation failure with elevated NK cell activity, the pregnancy rate for IVF cycle was 42%. Ten of 11 women were experiencing recurrent pregnancy loss and a successful pregnancy.
The advantages of Intralipid include the fact that it has been used for intravenous feeding for more than 30 years with very few side effects, and infusion costs between $450 – $700 and it is not a blood product.
Based on this in vitro as well as in vivo confirmation of the effective normalization of natural killer activity by Intralipid and also based on the significant cost saving, we will be recommending offering Intralipid as an alternative to IVIG, at a dose of 100 mL of 20% product diluted in 250 or 500 mL of normal saline infused over 1 to 2 hours.
Lovenox:
(Generic Enoxaparin): In high doses Lovenox is a blood thinner and is used to help prevent and remove blood clots. However, in low doses, as it is used in IVF, this medication promotes implantation and acts more like an anti-inflammatory medication and also decreases the viscosity of blood, thereby facilitating blood flow in the early- developing placenta.(Leuprolide Acetate)
Lupron Down Regulation
Lupron Micro Dose: Lupron (Leuprolide Acetate) is an angonist meaning that it causes release of FSH and LH from the pituitary gland. It is given daily or twice daily as a subcutaneous injection and is used in IVF in two different strengths. The first is the regular dose Lupron at 0.5 mg to 1 mg per day and this is usually started two weeks after the commencement of birth control pills and this dose of Lupron is used to down regulate and to suppress the pituitary gland to prevent a premature release of LH and therefore premature ovulation. The second dosage schedule of Lupron is called the micro dose Lupron and this microscopic dose of Lupron is given twice a day and is used to stimulate the release of a small amount of FSH and LH from the pituitary gland therefore being used as a stimulant rather than a suppressant. Because the micro dose is given twice a day it also works effectively to prevent the premature release of a surge of LH.
Lupron Down Regulation: See Lupron/Lupron Down Regulation/Lupron Micro Dose
Lupron Micro Dose: See Lupron/Lupron Down Regulation/Lupron Micro Dose
Metformin
(Glucophage): This medication was originally developed to treat type II diabetes and it prevents peaks and troughs of insulin thereby stabilizing insulin levels. When combined with a low carbohydrate diet Metformin is used in patients with polycystic ovarian syndrome (PCOS) and where all other fertility factors are equal it may result in a spontaneous pregnancy, but when continued through and up until 12 weeks of pregnancy, the Metformin has been shown to increase the success rate of in vitro fertilization (IVF) as well as decrease the risk of miscarriage especially in patients with PCOS.
Progesterone: This hormone is given daily as an intramuscular injection, which begins 2 days after egg retrieval or 4 to 6 days prior to embryo transfer. It is taken daily until the pregnancy tests and through 10 weeks gestation. This medication is necessary to support pregnancy. Progesterone is extracted from the Mexican yam or the soybean and this steroid hormone is the same as that produced by the ovary and placenta.
