Methotrexate For Pregnancy Termination
Methotrexate gives women the opportunity to have a termination performed as early as a week prior to missing their period up to 9 weeks from the last menstrual period. Methotrexate is not only used to stop the growth of pregnancy tissue, but it is used to treat different cancers (head and neck, breast, female genital tract, psoriasis, rheumatoid arthritis, ulcerative colitis, and other chronic diseases that affect are autoimmune disorders. It is also used to treat patients with ectopic (tubal) pregnancies which are pregnancies that implant outside of the uterus (fallopian tubes, ovaries, abdomen, liver, diaphragm, etc.). Methotrexate stops the rapidly growing embryonic and placental cells of early pregnancy from further developing.
Methotrexate used alone can cause miscarriage in close to 85% of patients that use it prior to 6 weeks or less gestation. It generally takes 3 to 4 weeks to begin having spontaneous bleeding and for the miscarriage to occur. This is why giving Cytotec (Misoprostol) approximately 48 to 72 hours after taking the Methotrexate by mouth or injection has a success rate of 92 to 98%. Cytotec causes the uterus to begin to contract and leads to bleeding similar to a normal period in most women. Some women experience a little heavier bleeding than their normal period. Patients less than 6 weeks gestation have nearly a 100% success rate with the combination of these medications. Women who do not want surgery and want their abortion experience to be more private and have the support of spouse, family member, or friend, find this method to be more comfortable from a psychological and physical standpoint.
Methotrexate is extremely safe and effective in terminating pregnancies less than 9 weeks gestation. This medication has been used in our offices for over 16 years and used around the world for over 25 years in performing Medical Abortions. Methotrexate must be avoided in patients who will be in the sun for a prolonged period of time, or have an allergy to it. Please see General Contraindication to having the medical abortion procedure performed.
Abortion is one of the most commonly performed medical procedures provided in the United States. Approximately 1.21 million abortions were performed in 2008. Each year, 2% of women aged 15 to 44 terminate a pregnancy. Almost 50% of women who terminate their pregnancy will have had at least one previous abortion. Nearly 50% of women will experience an unintended pregnancy before the age of 45 with nearly 33% of women before age 45 having an abortion. Approximately 55% of women who have abortions had used some form of contraceptive method (usually the pill or condom) during the same month of their pregnancy. On September 28, 2000, the U.S. Food and Drug Administration approved RU486 (Mifeprex, Mifepristone) for medical abortion procedures between 3 to 7 weeks of pregnancy. In 2008, 59% of abortion providers, or 1,066 facilities, provided one or more early medication abortions. At least 9% of providers offer only early medication abortion services. Abortion Pill Procedures accounted for 17% of abortions, and approximately 25% of abortions performed before nine weeks of gestation and nearly 50% at 6 weeks or less.
Surgical abortions are associated with rare complications which include uterine perforation, cervical lacerations, bowel and bladder injuries, retained tissue, heavy bleeding, and death. These complications generally occur less than 1% of the time. Maternal mortality associated with abortion is over 10 times less compared to that of a full term delivery. Medical abortions have gained in popularity since the mid-80’s. Due to the unavailability of Mifepristone (RU486) in the 90’s, only Methotrexate alone, or Misoprostol alone or the combination or Methotrexate and Misoprostol (Cytotec) were used to perform the medical abortion procedure.
Methotrexate Medical Abortion: The Facts
Methotrexate inhibits dihydrofolic acid reductase. Dihydrofolates must be reduced to tetrahydrofolates by this enzyme before they can be utilized as carriers of one-carbon groups in the synthesis of purine nucleotides and thymidylate. Therefore, Methotrexate interferes with DNA synthesis, repair, and cellular replication. Actively proliferating tissues such as malignant cells, bone marrow, fetal cells, buccal and intestinal mucosa, and cells of the urinary bladder are in general more sensitive to this effect of Methotrexate. When cellular proliferation in malignant tissues is greater than in most normal tissues, Methotrexate may impair malignant growth without irreversible damage to normal tissues.
Peak serum concentrations of Methotrexate occur 30 to 60 minutes after injection or by the oral route. The terminal half-life reported for Methotrexate is approximately three to ten hours. Renal excretion is the primary route of elimination and is dependent upon dosage and route of administration. With IV administration, 80% to 90% of the administered dose is excreted unchanged in the urine within 24 hours. There is limited biliary excretion accounting for up to 10% or less of the administered dose. Circulation of Methotrexate between the liver and intestines is possible. Renal excretion occurs by glomerular filtration and active tubular secretion. Nonlinear elimination due to saturation of renal tubular reabsorption has been observed in psoriatic patients at doses between 7.5 and 30 mg. Impaired renal function (creatinine of greater than 1.5 or other evidence of chronic renal disease), as well as concurrent use of drugs such as weak organic acids that also undergo tubular secretion, can markedly increase Methotrexate serum levels. As the urine creatinine clearance decreases, the Methotrexate levels will increase in the body and may lead to damage of the kidneys and causing acute renal failure and potentially cause maternal death.
How Does Methotrexate Terminate Pregnancy
Antifolates, such as Methotrexate, function by blocking purine metabolism and thus interfering with DNA synthesis, making actively dividing cells susceptible targets. In addition, Methotrexate also inhibits RNA and protein synthesis. Regarding early pregnancy, Methotrexate inhibits proliferation (cell division and growth) of cytotrophoblast cells in the placenta which are the undifferentiated (primitive cell) rapidly dividing cells responsible for producing syncytiotrophoblast which are the cells responsible for the production of BHCG and HPL (human placental lactogen) which in turn causes the production of the corpus luteum to produce progesterone which maintains a pregnancy (prevents miscarriages). Methotrexate destroys cytotrophoblasts which are actively dividing only in the S phase of a cell cycle. It has been shown that the cell division rate of cytotrophoblast cells, i.e., the number of cells in the cell cycle at a given time, did not decrease with advanced pregnancy. However; studies show that the time it takes a cell to complete an entire cell cycle was lengthened from the first trimester to the end of pregnancy. In essence, the cells do not divide as fast at the end of pregnancy than they do in early pregnancy. Since the time it takes a cell to go through its S phase division does not vary greatly, the longer cell cycle time would imply that the other phases have lengthened. As the number of weeks in pregnancy increase, the less number of cytotrophoblast cells in the S phase decrease reducing the number cells that Methotrexate can destroy. Thus, the reason that Methotrexate is so highly effective at 6 weeks or less has a logical explanation. It appears that there is a significant increase in cell cycle length of the cytotrophoblast cells beginning on or around day 50 of gestation and after that, Methotrexate no longer is significantly effective in terminating pregnancies alone. Studies have shown that Methotrexate alone can cause abortions up to 69% of patients who are 9 weeks pregnant or less. Combining Misoprostol with Methotrexate leads to a 94 to 99% success of terminating pregnancies between 3 to 9 weeks gestation. Terminating pregnancies before women miss their first menstrual cycle is offered by over 45% of abortion providers.
Contraindication to the Use of Methotrexate
Women who are allergic or have sensitivity to Methotrexate should not receive the medication.
Methotrexate can cause fetal death, teratogenic effects and miscarriage when administered to a pregnant woman. Pregnancy should be avoided if either partner is receiving Methotrexate; during and for a minimum of three months after therapy for male patients, and during and for at least one menstrual cycle after therapy for female patients.
For women who are breastfeeding, Methotrexate is contraindicated due to the complications it can cause infants which are similar to the ones that occur in adults with the passage of the Methotrexate metabolites in the mother’s breast milk.
For women who have blood dyscrasias (blood disorders), anemia, low platelet counts, low white and red blood cell counts) Methotrexate is contraindicated.
Methotrexate Injection and Tablet Dosage for Abortion (Termination of Pregnancy)
There are several regimens and dosages used to terminate pregnancy using the Methotrexate alone or induction medical abortion pill method form 3 to 9 weeks gestation. Methotrexate alone does not appear to work to terminate pregnancies further than 9 weeks gestation. The success rate depends on the length of the pregnancy and the dosage used as there is approximately 65% to 95% effective alone in patients who are 6 weeks or less pregnant. For pregnancies less than or equal to 9 weeks gestation, the overall success rate is 67% using Methotrexate alone. The combined addition of Misoprostol vaginally or by mouth (orally, bucally, or sublingually) has been shown in numerous studies to be more effective, though patients prefer taking the Cytotec by mouth. Misoprostol has been studied and found to be highly effective and safe for use up to 14 weeks gestation. Additionally, Misoprostol is commonly used in second trimester and late term abortions including third trimester if indicated.
Exposure of Fetus to Methotrexate in Early Pregnancy
Exposure of a fetus to Methotrexate is associated with an increase incidence of teratogenic defects and fetal abnormalities. Methotrexate-induced congenital defects are similar to those produced by another folic acid antagonist Aminopterin. Anomalies in two infants noted were: Absence of lambdoid and coronal sutures (oxycephaly), absence of frontal bone, low-set ears, depressed and wide nasal bridge, low-set ears, long webbed fingers, wide-set eyes (hypertelorism), dextroposition of heart, absence of digits on feet, growth retardation, very wide posterior fontanelle, hypoplastic mandible and other anomalies.
Side Effects and Risks with Use of Methotrexate
Methotrexate Potential Toxicity (Most Serious Reactions)
The majority of undesirable reactions include ulcerative stomatitis (ulcers with blistering in the mouth), leucopenia (low white cell counts), nausea, and abdominal and vomiting and abdominal discomfort. Other frequently reported adverse effects are tiredness, fatigue, chills and fever, lightheadedness and a higher incidence of infection.
Alimentary (Gastrointestinal) System: Gingivitis (inflamed gums), pharyngitis (sore throat), stomatitis (inflammation of mouth), anorexia (loss of appetite), nausea, vomiting, diarrhea, hematemesis (vomiting blood), melena (dark stools), gastrointestinal ulceration and bleeding, enteritis and pancreatitis.
Blood and Lymphatic System Disorders: Suppressed hematopoiesis (low blood counts) causing anemia.
Cardiovascular: Pericarditis (inflammation of pericardium), pericardial effusion (fluid within pericardium), hypotension, and thromboembolic events including arterial thrombosis (blood clot in artery) cerebral thrombosis (blood clot in brain), deep vein thrombosis, retinal vein thrombosis, thrombophlebitis, and pulmonary embolus.
Central Nervous System: Headaches, drowsiness, blurred vision, transient blindness, speech impairment including dysarthria and aphasia, hemiparesis, paresis and convulsions have also occurred following administration of Methotrexate. Following low doses, there have been occasional reports of transient subtle cognitive dysfunction, mood alteration, unusual cranial sensations, leukoencephalopathy, or encephalopathy.
Hematologic: Methotrexate can suppress hematopoiesis and cause anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, and/or thrombocytopenia. In patients with malignancy and preexisting hematopoietic impairment, the drug should be used with caution,
Hepatic: Methotrexate has the potential for acute (elevated transaminases) and chronic (fibrosis and cirrhosis) hepatotoxicity. Chronic toxicity is potentially fatal; it generally has occurred after prolonged use (generally two years or more) and after a total dose of at least 1.5 grams. In studies in psoriatic patients, hepatotoxicity appeared to be a function of total cumulative dose and appeared to be enhanced by alcoholism, obesity, diabetes and advanced age. An accurate incidence rate has not been determined; the rate of progression and reversibility of lesions is not known. Special caution is indicated in the presence of preexisting liver damage or impaired hepatic function.
Hepatobiliary: Disorders, hepatotoxicity, acute hepatitis, chronic fibrosis and cirrhosis, decrease in serum albumin, liver enzyme elevations.
Infection: There have been case reports of sometimes fatal opportunistic infections in patients receiving Methotrexate therapy for neoplastic and non-neoplastic diseases. Pneumocystis carinii pneumonia was the most common opportunistic infection. There have also been reports of infections, pneumonia, sepsis, nocardiosis, histoplasmosis, cryptococcosis, herpes zoster, H. simplex hepatitis, and disseminated H. simplex.
Musculoskeletal: Stress fracture
Ophthalmic: Conjunctivitis, serious visual changes of unknown etiology.
Pulmonary: Respiratory fibrosis, respiratory failure, interstitial pneumonitis; deaths have been reported, and chronic interstitial obstructive pulmonary disease has occasionally occurred. Pulmonary symptoms (especially a dry nonproductive cough) or a nonspecific pneumonitis occurring during Methotrexate therapy may be indicative of a potentially dangerous lesion and require interruption of treatment and careful investigation. Although clinically variable, the typical patient with Methotrexate induced lung disease presents with fever, cough, dyspnea, hypoxemia, and an infiltrate on chest X-ray; infection (including pneumonia) needs to be excluded. This lesion can occur at all dosages.
Renal: Methotrexate may cause renal damage that may lead to acute renal failure. Nephrotoxicity is due primarily to the precipitation of Methotrexate and 7-hydroxyMethotrexate in the renal tubules. Close attention to renal function including adequate hydration, urine alkalinization and measurement of serum Methotrexate and creatinine levels are essential for safe administration.
Urogenital: Severe nephropathy or renal failure, azotemia, cystitis, hematuria; defective oogenesis or spermatogenesis, transient oligospermia, menstrual dysfunction, vaginal discharge, and gynecomastia; infertility, abortion, fetal defects. Methotrexate-induced congenital defects are similar to other folic acid antagonist such as Aminopterin. Anomalies in two infants were the following: Absence of lambdoid and coronal sutures, oxycephaly which is caused by absence of the cononal sutures, absence of frontal bone, low-set ears, hypertelorism, dextroposition of heart, absence of digits on feet, growth retardation, very wide posterior fontanelle, hypoplastic mandible and multiple anomalous ribs, large anterior fontanelle, depressed and wide nasal bridge, low-set ears, long webbed fingers and wide-set eyes.
Skin: Erythematous rashes, pruritus, urticaria, photosensitivity, pigmentary changes, alopecia, ecchymosis, telangiectasia, acne, furunculosis, erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson Syndrome, skin necrosis, skin ulceration, and exfoliative dermatitis. Severe, occasionally fatal, dermatologic reactions, including toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, and erythema multiforme, have been reported in children and adults, within days of oral, intramuscular, intravenous, or intrathecal Methotrexate administration. Reactions were noted after single or multiple, low, intermediate or high doses of Methotrexate in patients with neoplastic and non-neoplastic diseases. Lesions of psoriasis may be aggravated by concomitant exposure to ultraviolet radiation. Radiation dermatitis and sunburn may be “recalled” by the use of Methotrexate.
Other rarer reactions related to or attributed to the use of Methotrexate such as nodulosis, vasculitis, arthralgia/myalgia, loss of libido/impotence, diabetes, osteoporosis, sudden death, reversible lymphomas, tumor lysis syndrome, soft tissue necrosis and osteonecrosis and anaphylactoid reactions have been reported.
Most of the Methotrexate side effects described above do not occur unless there is prolonged use. The side effects below have occurred with one dose.
Mild Side Effects
Headaches, blurred vision, chills, nausea, vomiting, rash and swelling on palms and feet, diffuse body pruritic (itchy), cystitis (inflammation of bladder), vaginal discharge, rash, constipation, diarrhea, abdominal and lower back pain, acute kidney and liver disease that normally recovers though there have been incidences where death has occurred, diffuse pulmonary alveolitis vaginal discharge, stomatitis (inflammation around mouth), folliculitis, raised skin, nodules, temporary drop in white and red blood cells.
Side Effects Solely Related To Methotrexate Medical Abortion Procedure Pregnancy Complications
Bleeding usually starts within 16 days if the Methotrexate is going to be effective. Less than 30% of abortions are complete in the first 7 days of the abortion procedure; 86% by 28 days and 91% by 35 days in studies where Methotrexate alone was used up to 56 days of pregnancy. Once the bleeding starts it normally lasts for 14 days. Bleeding may last in a few patients up to 30 days and rarely up to 60 days. The menstrual period generally returns 8 to 10 weeks after Methotrexate alone has been taken. Bleeding by itself does not indicate a complete abortion. A follow-up sonogram is mandatory.
The patient should contact the office immediately if: 1) she soaks more than two maxi sanitary pads an hour for more than two consecutive hours; 2) if she stops bleeding and suddenly experiences an onset of very heavy bleeding two weeks after taking the Misoprostol; 3) if she has bled continuously for several weeks or suddenly feels dizzy or light-headed, has tingling of the fingers, hands or toes for more than one hour; and 4) if none or only minimal bleeding has occurred 7 days after taking the Misoprostol. Blood transfusions have been necessary for heavy bleeding though the incidence is rare (1 to 3/1000).
Pain is the most common side effect which occurs in approximately 70 to 90% of patients and just before they begin to bleed, the pain and discomfort reaches its peak. Most patients do not require analgesics; however, if necessary, Non-Steroidal Anti-Inflammatories (NSAID’s) are effective the majority of the time.
Retained Pregnancy Tissue
Pregnancy tissue that remains in the uterus and not expelled may lead to persistent vaginal bleeding that may be bright red, pink or dark brown in color. There may be mild discomfort in the lower abdomen or back but most of the time there is no pain or discomfort. Patients are treated surgically or by using the Abortion Pill (Misoprostol/Cytotec) to expel the retained pregnancy tissue.
Maternal infections (Endometritis, Myometritis and Pelvic Inflammatory Disease (PID)
Infections may occur due to bacteria migrating from the vaginal area into the uterus. Retained pregnancy tissue acts as a nidus to cause the bacteria to replicate leading to infection of the lining of the Uterine wall and may penetrate the uterine muscle and eventually spread to the fallopian tubes and ovaries which leads to Pelvic Inflammatory Disease and possibly Tubovarian Abscesses if not treated aggressively with antibiotics and surgical removal of the retained pregnancy tissue.
Infection Leading to Maternal Death
A severe infection can enter the blood stream. The bacterial infection is Clostridium Sordelli. It can cause severe sepsis that affects all of the major organs in the body (kidneys, liver, heart, lung and brain) leading to maternal death in rare cases. Clostridium Sordelli has also been found to cause maternal death in patients who delivery their pregnancies by C-Section, vaginal deliveries and spontaneous miscarriages. Patients usually have an odorous vaginal discharge, severe lower back and lower abdominal pain, severe headaches, dizziness, nausea, vomiting and low grade temperature. The patient rapidly becomes weak and unable to stand up. The patient may lose consciousness rapidly. Antibiotics must be started immediately along with aggressive hydration.
A failed abortion is defined as either a pregnancy is still alive or the fetus has expired in the uterus without any indication of bleeding or contractions. The further weeks in gestation the procedure is performed, the higher the incidence of a failed abortion. There are no successful abortions with the use of Methotrexate alone after 9 weeks gestation. A surgical abortion must be performed due to the high teratogenic defects and fetal abnormalities that occur after the use of Methotrexate injection or tablets.
Methotrexate Dosage for Medical Abortion (Termination of Pregnancy)
There are several regimens and dosages used to effectively terminate pregnancy using the Methotrexate medical abortion process. The success rate depends on the length of the pregnancy and the dosage. Methotrexate Injection protocols have used 50mg/m2 or 75mg Intramuscularly or Methotrexate tablet protocols use 25mg and 50mg tablets by mouth to terminate pregnancies in patients that are 9 weeks or less gestation.
Success Rate of Methotrexate Abortion Procedure vs. Mifepristone (RU486, Mifeprex), Misoprostol/Cytotec and Tomaxifen alone or in Combination
Efficacy of Methotrexate, Mifepristone (Mifeprex, Mifepristone, RU486) and Misoprostol, and Misoprostol, Tomaxifen and Misoprostol and Misoprostol alone have a success rate ranging from 75 to 98% depending on length of pregnancy, dosages and route given, and additional techniques performed to achieve a high success rate. The earlier in pregnancy the Medical Abortion (Abortion Procedure) is performed, the higher the success rate. The medications used alone or in combination have been found to be highly safe and effective. The medications used in combination have a higher chance of success in terminating pregnancies than being used alone.
Why Choose the Methotrexate Abortion Pill Procedure vs. the Surgical Abortion Procedure?
There are many reasons why women choose to have the Abortion Pill Procedure (Non-Surgical Abortion, Chemical Abortion, Medical Abortion) which include but are not limited to the following: 1) Worries about the risks and complications of undergoing a surgical abortion; 2) Concern for how the surgical procedure may affect their risks of becoming pregnant in the future/or having complications during pregnancy; 3) Stress and anxiety associated with having a surgical procedure; 4) feeling that they are more in control of when and where the abortion procedure is performed; 5) being able to carry out the abortion pill procedure in the privacy of their home; 6) able to have a partner, friend or family member with them when they take the Misoprostol/Cytotec Medication.
Contraindications to Methotrexate Medical Abortion Pill Procedure
Allergy to Methotrexate or prostaglandins; possible ectopic pregnancy; blood dyscrasias; severe anemia; cervicitis; upper genital tract infection; Pelvic Inflammatory Disease (PID); Intrauterine Device (IUD) in the intrauterine cavity, undiagnosed vaginal bleeding, recent treatment for Sexually Transmitted Disease (Gonorrhea, Chlamydia). Other contraindications include breast feeding, kidney disease (including kidney transplant), liver disease and lung disease.
The Medical Abortion Pill Procedure is not recommended for patients who are not able to return to the office in two weeks; if they are not able to return to the office for more than two or more visits; or if they live further than 2 hours from the office or a hospital should emergency evaluation become necessary.
Where to Get Methotrexate
It is not recommended by Physicians in the United States or Healthcare organizations that Self Induced or Home Abortion Methods be used to terminate pregnancies. Women who wish to undergo any abortion procedure (medical or surgical) should be under the care of a physician. Medical Abortions are able to be performed and completed safely over 90% of the time; however, side effects can be life threatening or even fatal which is the reason for medical supervision.
In most third world countries women can get Methotrexate at pharmacies. It can be purchased over the counter without a prescription. Additionally; Methotrexate can be bought on the black market and at abortion clinics or from medical offices where women are treated under the care of a physician.
Buying Methotrexate Online
Buying Methotrexate Online can be very inexpensive. In 1997, the FDA issued a letter warning that no one purchase abortion kits online. This is primarily due to the following reasons: 1) the medications purchased online cannot be guaranteed to be safe; 2) that all patients should be under medical supervision and receive a sonogram before the procedure to determine the number of weeks gestation and to repeat the sonogram a week to 10 days after taking the Methotrexate to assure that the tissue has passed; and 3) excessive bleeding and infection must be attended to immediately by medical personnel.
Cost/Fees of Methotrexate and Misoprostol/Cytotec Medical Abortion (Abortion Pill) Clinics
The price of the Misoprostol Medical Abortion is approximately the same as the surgical abortion procedure which is usually between $300.00 to $1,000.00 depending on the location and what individual Physicians may charge from 3 to 14 weeks gestation. The further in pregnancy the patient is, the more expensive the abortion procedure will be.
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