One Healthy Baby: The fear joy of multiples Part 1: Infertility treatments and the risk of multiples

Multiple pregnancy (i.e twins or higher) is a risk of infertility treatments that is well documented in the field as are efforts to curb its incidence. When bringing this risk up to patients, many do not see it as a risk, they see it as a bonus - "two for the price of one!" More often then not this reaction is in regard to twins which remains a high risk pregnancy state despite imagery in popular culture that might suggest otherwise. While higher order multiples (i.e 3 or more) remain a risk of infertility treatments, certain guidelines and practice patterns have evolved to reduce the number of higher order multiples in the United States. In this three part series, I will address some common questions that arise regarding multiples and the quest for fertility. Here I will review common infertility treatments and their risks of multiples.

What "infertility treatments" are we talking about?
Normally, women release one egg during their fertile "window"; have intercourse during that time and pregnancy occurs. About 40% of the time, couples who are having trouble conceiving, an egg is not being released (i.e anovulation or no ovulation). Many medications are used to overcome this and clomiphene citrate (Clomid) is the grandfather of infertility medications in the modern era. The drug is designed to trick a woman's brain into releasing a little extra of her own FSH (the hormone responsible for egg growth) and ultimately get women who don't ovulate - TO OVULATE.

HOWEVER, for women who have unexplained infertility (no obvious etiology of the infertility exists which affects 10% of couples), clomiphene citrate can be used to increase the number of eggs that a woman releases during her fertile window from 1 -> to 2 and sometimes 3. Now, the reason the natural multiple rate is low (about 3-4%), is because women only release one egg; creating a state in which you increase that yield only increases the chance of twins or more!


With clomiphene citrate the likelihood of twins is 8%; triplets is 1%  


Not everyone responds to clomiphene citrate, though and stronger medications are required. These are injectable medications and they are purified extracts of the hormones responsible for egg growth (FSH for example). Giving these medications increases the number of eggs that grow in the ovary dramatically! There are two scenarios in which patients get injectable medications: 1) controlled ovarian hyperstimulation with intrauterine insemination aka COH-IUI or 2) in vitro fertilization (IVF)


Let's talk about these treatments separately.

1. In COH-IUI, fertilization occurs in the woman's body. Patients are given injectable medications and monitored closely with frequent vaginal ultrasound and blood work (3-4x/week) for usually a 10-14 day period. When the time is right, a different hormone (HCG) is given to cause final maturation and release of the eggs that have grown up to that point and then an IUI (i.e artificial insemination) is performed. Often times there are more than 2 eggs released in order to maximize the likelihood that sperm will fertilize an egg.

With COH-IUI the likelihood of twins can be as high as 20%; triplets and higher 5%


 2. In IVF, controlled ovarian hyperstimulation is performed with certain tweaks that allow the physician to completely "control" the communication between the woman's brain and ovaries. The goal is the same: make as many eggs as possible. HOWEVER the difference in IVF vs COH-IUI is that the eggs are retrieved via a minor surgical procedure and are then fertilized in a dish in the lab. The resulting embryos are grown for 3-5 days in the lab after which time an embryo transfer is performed whereby the embryos are then placed back into the uterus. In IVF, the decision on how many embryos to place back into the uterus is controlled unlike in COH-IUI where the number of fertilization events are out of the hands of the physician/patient. 

With IVF, the likelihood of twins can vary by clinic and patient age but can be as high as 25-30%, triplets and higher are <2%

Both COH-IUI and IVF put a patient at risk for something called ovarian hyperstimulation syndrome (OHSS). The injectable medications radically stimulate the ovaries, and the ovaries naturally grow in size; however the response can be so dramatic that the ovaries become large enough to cause severe discomfort, difficulty breathing, and leakage of fluid into the abdominal cavity. Additionally, an increase viscosity of the blood can occur placing the patient at risk  for blood clots. Needless to say, severe OHSS is fortunately a rare event but milder forms of OHSS are common. See this document for a good overview.


COH-IUI has historically been the culprit behind the rise in higher order multiples over the last 20 years, and recent evidence combined with the increased improvements IVF may be rendering COH-IUI obsolete. Furthermore, the ability to limit the number of embryos transferred in IVF has helped reduce the higher order multiple rate over the last 10 years.

For patients without insurance coverage for infertility treatments often times cost plays a role in the management process. While treatment with clomiphene citrate (+/- IUI) can be approximately $400/cycle ($50 for the medication and $350 for the IUI). Treatment with COH-IUI can be as much as $3000/cycle because the injectable medications are expensive and the duration and intensity of treatment can vary widely based on the reason for the couple's infertility.

Three to four cycles of each infertility treatment are typically performed to maximize the chance of pregnancy after which time if pregnancy is not achieved the treatment is deemed a "failure" and more aggressive options are considered. IVF can cost upwards of $9000 plus approximately $3000-5000 for the cost of the medications, however there is a better chance of pregnancy (upwards of 60% in women <35 years of age) with a lower chance of higher order multiples.


The table below summarizes the approximate pregnancy, twin/high order multiple rates, and costs of common infertility treatments*  

Treatment	Pregnancy Rate	Twin Rate	Triplet or higher	Cost/cycle ($)
Clomiphene citrate (CC)	4-5%	8%	1%	50
CC + IUI	5-10%	5-10%	1%	400
COH-IUI	15-20%	20%	5%	3000
IVF	50-60%	25-30%	<2%	9000-15000

* actual costs vary widely based on clinic, reason for infertility, and insurance coverage; pregnancy rates are based on age <35 and assume that baseline fecundability of infertile couple is <1%. 

The risk of twins remains real and the risk of triplets or higher has to be in the back of both patient and physician's mind when discussing common treatments for infertility. In the next part of these three part series we will discuss the risks associated with carrying a twin or triplet pregnancy. Stay Tuned! 

Does IVF increase the risk of breast cancer

Recently, a study was published examining whether there is a link between breast cancer and infertility treatments. The study, published in Fertility and Sterility, a prominent journal that publishes infertility research, looks at all patients in Western Australia who had in vitro fertilization (IVF) between 1983-2002 and then examines how many of those patients developed breast cancer. This type of cohort study is similar in design to the study I wrote about recently that examined the link between birth defects and in vitro fertilization.

Since there is one identification/insurance number for all citizens (ie. Imagine that your social security number was the same as your health care insurance policy number), nations with "single payer" systems can easily link hospital data, cancer registry, and population data allowing researchers to perform these type of epidemiological studies.

There were 21,000 women who had an infertility diagnosis code assigned to their name between 1983-2002. The authors compared women with infertility who had IVF to those women with infertility who did not have IVF. When examining the cancer registry up to 2010, they found, among those 21,000 women, 384 who went on to develop breast cancer.

The authors concluded that there was no risk associated with infertility treatments and the overall risk of breast cancer.

Interestingly, they did find an age related risk linking young age (<24 years) of IVF treatment with breast cancer, but surprisingly did not see that same relationship with older women?

After reviewing this article, several points come to mind:
First, some well known reproductive/hormonal breast cancer risk factors:
1. early age of menarche (age of first period)*
2. late age of menopause*
3. nulliparity (i.e never being pregnant)
4. age of first pregnancy (i.e age >35 with first pregnancy is associated with an increased risk of breast cancer)
5. prolonged, exposure to elevated circulating levels of estrogen^

* These risk factors and others: family, genetic history of breast cancer, smoking, other dietary risk factors, were not included in the study...would this controlling for these confounders change the result? perhaps
^ Not surprisingly the authors provided the peak concentration of estrogen in an IVF cycle (4000 pg/mL) when comparing the estrogen concentration to the peak in a normal menstrual cycle (300 pg/mL).  IVF requires hormones that increase the concentration of circulating estrogen levels, however this is short lived (ie <2 weeks) and the average patient's peak estrogen level is usually 2000-2500 pg/mL. Patients rarely (<1%) achieve estrogen concentrations of 4000 pg/mL in an IVF cycle.

While I am reassured that the overall risk of breast cancer is not elevated in infertile women who undergo IVF compared with infertile women who do not undergo IVF, I don't know how to explain the increased risk of breast cancer among women <24 yrs old who undergo IVF compared to other infertile women  who do not undergo IVF?

Here is a formal response from the American Society of Reproductive Medicine (ASRM):

Linda Giudice, MD, PhD, President-elect of ASRM, noted, “The development of breast cancer is linked to estrogen exposure and the longer one is exposed, the greater the risk.  In an IVF cycle, there is a short, but significant elevation in circulating estrogen, and whether this is linked to the observations found in this study is not clear at this time. Women should be reassured that, overall, IVF was not associated with an increased risk for development of breast cancer.  However, as noted in the study, women in their thirties and forties still need to be aware of the increased risk of breast cancer associated with delivering one’s first child at this stage of reproductive life.  For younger women, there is the possibility that IVF is associated with increased risk, but more research is needed to confirm this.”

There is always extensive counseling between patient and physician in the infertility clinic setting and time is often spent discussing study findings like these. Obviously, this is a new finding that needs to be validated before it can be taken at face value, but patients should be informed. 

Ultimately, whenever I see studies linking infertility treatments to female cancer, I follow this logic: 

If a young women (in the case of this study <24 yrs of age) gets pregnant with IVF she is no longer nulliparous, and has a young first age of pregnancy. She has the opportunity now to breastfeed and a chance to go on and have multiple children - all things which reduce the risk of breast cancer!

I look forward to your comments