Jane was 40 years old and had been dealing with infertility for way to long. She and her husband finally decided to do IVF and her first pregnancy test was positive. Yet, there was a hesitation in the nurse’s voice when she said the test was positive and Jane asked if there was a problem. The nurse said that they would have liked the hCG levels to be slightly higher and the progesterone levels to be higher but it was too early to know what this all meant. They would know more when the test was repeated in 48 hours. The next test demonstrated a rise in the hCG but not by as much as it should have been and the progesterone was still low. Bloodwork was repeated one more time, but Jane was approaching the 5 ½- 6 weeks pregnant mark and the physician wanted to do an ultrasound to see what was happening.
Tragically for Jane the US failed to demonstrate an intrauterine pregnancy. The US was repeated as was the bloodwork, but there was no intrauterine pregnancy seen and the hCG levels continued to rise. Jane’s physician discussed the meaning of this with Jane, warning her that she could have an ectopic pregnancy. Her physician recommended using methotrexate (MTX), a drug used for cancer, so that Jane could avoid surgery. Understandably, Jane was devastated by this, but agreed to have the MTX. The MTX worked and Jane’s hCG declined, eventually reaching zero.
During her recovery, Jane began to question if she had done the right thing. Did she act too soon? Did she do something to cause this to happen? Did the MTX hurt her chances of having a baby? Jane went online to try to find answered to some of these questions, but her search only increased her confusion…and her worries. One article even suggested that patients treated for cancer with the MTX lost their ability to have children.
This scenario is all too common, and while the above if fictional, many patients undergo similar experiences. In this blog, I will try to answer some of Jane’s questions using the best available evidence that we presently have.
What is an ectopic pregnancy?
An ectopic pregnancy is any pregnancy that does not properly implant in the uterine cavity. Most are located in the fallopian tube (90%) but they can be in the cervix, the muscle wall of the uterus where the tubes exit the uterus, the ovary, or the abdominal cavity. Spontaneous ectopic pregnancies most commonly result from fallopian tubes that have been damaged by infection or surgery. The tube loses the ability to transport the developing embryo from the tube (where it grows for the first 2-3 days after it is formed) into the uterus where it will implant 6-7 days after it is formed. But, in IVF the embryo is placed into the uterine cavity and yet ends up in the tube. Why this happens is unknown but not uncommon. Risk factors for having an ectopic pregnancy include previous ectopic pregnancy, infection, endometriosis, pelvic surgery, current use of an IUD, and IVF. The risk of having an ectopic pregnancy in IVF is estimated to be between 2 and 5%. It is possible to have both a normal intrauterine pregnancy and a tubal ectopic pregnancy. These are called heterotopic pregnancies and can be quite dangerous because once an intrauterine pregnancy is seen on ultrasound, the assumption is made that there is no ectopic pregnancy. Today patients are electing to transfer only one embryo which makes the risk of a heterotopic pregnancy less, but transfer of two or more embryos raises the risk.
Thus the answer to one of Jane’s questions (Did I do something to cause this?) is a resounding NO. Ectopic pregnancies are an unfortunate complication of IVF and are not caused by the patient nor can they be avoided.
Why is an ectopic pregnancy dangerous?
Ectopic pregnancies are dangerous because they can rupture and cause massive, sometimes fatal, bleeding. This can happen rapidly and lead to a critical medical emergency. Ruptured ectopic pregnancies still account for as much as 15% of the maternal mortality in the USA.
How is an ectopic pregnancy diagnosed?
The diagnosis of an ectopic pregnancy relies upon the measurement of the pregnancy hormone hCG and vaginal ultrasound. The best way to establish that a pregnancy is in the uterus is to see it on ultrasound, and the most accurate ultrasound for this purpose is the vaginal ultrasound. The diagnosis begins, however, with the determination that the person is in fact pregnant. For IVF patients, this is done 10-12 days after the embryo transfer, and therefore sooner than for someone without an infertility problem who is trying to conceive naturally. The pregnancy produces hCG from the part of the pregnancy that forms the placenta, not the part that forms the fetus. That means that a person can have a positive pregnancy test and yet have no fetus in the developing pregnancy which is called a gestational sac. Frequently, this happens if the pregnancy has the wrong number of chromosomes, which can be a problem for women with eggs (oocytes) of poor quality. Commonly, hCG rises as pregnancy progresses. In the early weeks of the pregnancy the hCG should rise by >53% every 48 hours. That means that if the second pregnancy test does not rise appropriately, the pregnancy may be abnormal. At this early stage of development, it is impossible to know if the abnormal pregnancy is an intrauterine pregnancy that is abnormal and will result in a miscarriage or if it is ectopic and may put the women’s life in danger. Thus enters the ultrasound. A normal pregnancy should have a properly rising hCG and be visible on ultrasound by 5- 5 ½ weeks with an hCG of > 1,500- 2,000 IU/mL. If an intrauterine pregnancy is clearly visible on the ultrasound, then following the pregnancy with ultrasound will determine if it is developing normally or if it seems to be an abnormal intrauterine pregnancy that will inevitably result in a miscarriage.
An alternative finding is that the ultrasound clearly demonstrates an ectopic pregnancy outside of the uterus. Ectopic pregnancies are difficult to see on ultrasound until they are advanced in their development, frequently very near the time they could rupture. The third situation is the grey zone where the hCG continues to rise, most likely not normally, but nothing is seen on the ultrasound either in the uterus or in the tube. This is labeled a pregnancy of unknown location (PUL).For women with a PUL, 30% will have a normal pregnancy but the remaining 70% will have a failing pregnancy which can be either an ectopic or an abnormal intrauterine pregnancy.
The answer to another of Jane’s questions (Did I act too soon?) is no. With the modern use of hCG and ultrasound, people can be assured that a normal pregnancy was not interrupted.
How are ectopic pregnancies managed?
Before moving to this question, one must consider what to do about an intrauterine pregnancy that is abnormal and will inevitably result in a miscarriage. There are two choices; wait for a spontaneous miscarriage or do a D & C to remove the contents of the uterus. Both approaches have their risks and benefits. Many gynecologists prefer to wait to see if a spontaneous miscarriage occurs, thus avoiding surgery. For some patients however, it is critical to know if the pregnancy has the correct number of chromosomes or it the abnormal pregnancy is due to an abnormal number of chromosomes. This can be achieved by doing a D & C and assaying the tissue for the number of chromosomes. These decisions are very unique to a particular person’s situation and are best decided in a discussion between doctor and patient.
The management of the ectopic or PUL can require time, surgery or the use of a medication that is used to treat cancer called methotrexate (MTX). Sometimes, the hCG will fall without intervention and the body will heal the abnormal pregnancy without assistance. That is particularly true in IVF where the pregnancy tests are done so early in the pregnancy.
The traditional method of treating an ectopic pregnancy was to do surgery. Originally, this meant opening the abdomen and removing the tube with the pregnancy. But, due to advances in surgery, it became possible to operate using a laparoscope in a process known as minimally invasive surgery (MIS). MIS also allows the tube to be preserved if the pregnancy is not too large, by opening the tube and removing the pregnancy without removing the tube entirely. Reasons to do surgery include an ectopic pregnancy where the pregnancy has visible heart motion, an initial hCG of > 5000 mIU/Ml or an ectopic which measures > 4cm. Other reasons to do surgery are for people who refuse blood transfusions or the inability to be watched closely.
An alternative to surgery is methotrexate (MTX). MTX is a chemotherapeutic agent that is used to treat fast growing tumors. It is particularly effective against pregnancy tissue since pregnancies grow at such a fast rate. It works by preventing the pregnancy cells from making DNA. Without new DNA, the cells die. At any given time within the ovary there are two groups of egg units (follicles): one is not growing (dormant) and the other is growing and developing. MTX affects the developing group of egg units (follicles) but not the dormant group. Oocytes (eggs) take at least 5 and a half weeks to fully mature to where they can be used. The ovary is constantly bringing egg units out of the dormant stage and on the path to development. So, at any given time, there are a number of follicles in the ovary developing at different stages of maturation. Since it takes a long time for the egg to develop, if they are damaged, then the number of good eggs developing in the ovary is reduced until the ovary can replenish them with new follicles recruited from the dormant pool of follicles. A recent publication surveyed a number of articles about the effect of MTX on future fertility, and concluded that MTX did not affect the future fertility for a person.
The use of MTX is complicated because it takes time for the medication to stop the development of the pregnancy. Therefore, monitoring after using MTX is of vital importance. Sometime a second dose of the medication is needed if the hCG is not declining like it should. Surgery may still be used because the MTX failed to stop the growth of the pregnancy within a safe timeframe. Sometimes the ectopic will still rupture and emergency surgery is required with the potential need for a blood transfusion.
The answer to Jane’s final question (Did the MTX hurt her chances of having a baby?) is NO. She will have to wait a few months after the MTX until her hCG is at zero and there is no more effect of the MTX on developing follicles but then she should be OK to try again.
What about the person whose has a pregnancy of unknown location (PUL)?
The danger with this is not knowing whether the pregnancy is ectopic or not. Waiting too long may result in rupture of an ectopic and thus put the woman in danger. The practical way to mange this is to use MTX once it has been determined that there is no normally developing pregnancy in the uterus. Exposure of a developing pregnancy to MTX results in a high chance that the child will have defects and many times pregnancy termination is recommended.
The use of ultrasound and hCG has permitted a conservative approach in the treatment of ectopic pregnancies. The use of MTX has removed the need for surgery for many women with an ectopic who are candidates for MTX therapy.