Fertility Drug Risk Factors
As a woman faces the reality that her child-bearing years are about to expire, it is quite understandable that she would seek out fertility drugs as a quick fix to her dilemma – especially after a lengthy effort to conceive without success. When it happens, she is usually sent home with a prescription for Clomid (clomiphene citrate). The drug, which is taken orally – not by injection – is the preferred starter for ovulation induction because it is easy to use and has fewer side effects than Pergonal (human menopausal gonadotropin) and other injectables. This has led to the unfortunate view that Clomid is relatively harmless, with little to be concerned about beyond multiple births and an occasional episode of ovarian hyperstimulation syndrome. Many use the drug as a means of regulating ovulation, even though it has only been approved by the FDA for inducing it in women with ovulatory dysfunction. Controlling the time of ovulation, of course, makes it easier to conceive.
This lax view about the safety of Clomid is fostered by the perception of many fertility specialists and OB/GYNs that the drug poses no threat to the resulting embryo. They argue, among other things, that Clomid is ingested 4-5 days before conception; so how could there be a risk to the baby. They also point to a statement in the package insert that the incidence of birth defects during the premarket clinical studies was the same as the rate in the general population.
Studies show, however, that Clomid has a very long half-life. It can be biologically active for up to 54 days after taking the last tablet and accumulates with each successive cycle of treatment. As for the pre-approval studies, they likewise cannot provide an assurance of safety for the simple reason that they were never designed to assess the risk of birth defects. I know, because I personally took the deposition of the doctor who designed and oversaw the studies. Indeed, the vast majority of the clinical investigators in the study did not even deliver the babies and had no personal knowledge about the outcome of those deliveries.
Over the years, the FDA has done little to bring to the attention of the general public – or even to the medical profession, for that matter - that there is a higher risk of congenital anomalies in pregnancies induced by Clomid. FDA language about such a risk, approved in 1983, has never been included in the product labeling (package insert) for the drug, and the regulatory agency has yet to enforce its mandated amendment. Anyone interested, might want to read my Ezine article on the subject [http://ezinearticles.com/?Fertility-Drugs-and-Birth-Defects---The-Tragedy-of-a-Useless-Package-Insert&id=1304163]. Yet there are numerous incriminating studies which have yet to be included or referred to in the labeling.
Earlier this year the Harvard School of Public Health reported that the use of fertility drugs to induce ovulation (including clomiphene citrate) increased the risk of autism spectrum disorder in the offspring by 91%. Studies demonstrating a higher risk of birth defects have also been published, including a 280% increased risk of craniosynostosis (abnormally-shaped cranium); a 10-fold increased risk of spina bifida; and a 508% increased risk of severe hypospadias. On July 2, 2008, the CDC reported on the results of its research, drawn from the National Birth Defects Prevention Study, at the annual convention of the Teratology Society in Monterrey, California. They found that the offspring of Clomid users had a 170% increased risk of being born without a brain (anencephaly); a 140% increased risk of being born with shortened limbs; a 200% increased risk of being born with a closed esophagus (esophageal atresia); and a 110% increased risk of being born with a urethra exiting at the base of the penis (hypospadias). Anencephaly is a neural tube defect (NTD) in which the cranium does not fully close; spina bifida an NTD where the spinal column does not fully close. There are several other studies, as well.
A little known – but critically important fact – is that Clomid is a CHOLESTEROL REDUCING DRUG. It acts on enzymes in the body to reduce cholesterol, similar to the action of statin drugs, such as Lipitor and Pravachol. In 1993 it was learned that depriving an embryo of an adequate amount of cholesterol can cause birth defects. That’s when it was discovered that babies born with Smith-Lemli-Opitz syndrome suffer their classical set of birth anomalies because of a defective enzyme impairing the production of this vital product. Not only is cholesterol a component of every cell in our body, there are certain genes in our body that must bind with it to properly form a specific set of organs. This is why the labeling on all statin drugs warns that women of child-bearing age use birth control methods while using the drugs.
There is, however, GOOD NEWS on the horizon. With knowledge that many birth defects are caused by a deficiency in cholesterol – be it caused by a drug or naturally – we are positioned to take protective measures that can reduce or eliminate thousands of birth defects every year. Published studies conducted with laboratory animals have demonstrated that administering cholesterol to a pregnant mother, while on a cholesterol-reducing drug, can eliminate the birth defects that would otherwise occur absent the supplementation. Human studies are needed to confirm these animal studies and to establish the ideal level of total cholesterol during pregnancy to minimize or eliminate the risk. This will occur, however, only when medical science acknowledges the risk from fertility drugs and is sufficiently motivated to see that these studies take place. www.TerenceMix.com.
After a fertility specialist has thrown up his hands following an unsuccessful run with Clomid (clomiphene citrate), Pergonal (human menopausal gonadotropin or hMG) is often next up for consideration. Unlike clomiphene, Pergonal is administered by injection in a doctor’s office. It is generally followed by an additional injection of human chorionic gonadotropin (hCG) to trigger ovulation. The combo is usually referred to as gonadotropin therapy. As one might expect, this method is more potent and has a higher incidence of side effects than the oral medication.
Among these adverse reactions is ovarian hyperstimulation syndrome (OHSS). This condition – unique to fertility drugs – is classified by 3 different levels of severity: mild, moderate and severe. With mild OHSS the ovaries are enlarged 5-12 cm, accompanied by abdominal bloating, slight discomfort in the ovaries, nausea, diarrhea and a slight weight gain. A moderate form of the condition involves further enlargement of the ovaries, mild ovarian pain, weight gain of greater than 2 pounds per day, increased abdominal swelling, vomiting, diarrhea, darker and decreased urine and excessive thirst. In its severe form, OHSS generally requires hospitalization and on rare occasions can be fatal. There is significant ovarian pain, severely enlarged ovaries, fullness/bloating above the waist, abdominal bloating or distention (protrusion from pressure), ascites (fluid accumulation in abdomen and/or lungs), shortness of breath, significantly darker or cessation of urination, calf and chest pains, and risk of thrombosis (blood clots) and kidney failure.
The incidence of mild OHSS following gonadotropin therapy is about 8-23%, depending upon the nature of the infertility problems of the patients. For example, women with polycystic ovary syndrome (PCOS) are at a greater risk. The same therapy causes a 1-7% incidence of moderate OHSS in patient users and a 0.25-5% rate in its severe form. If promptly treated, the symptoms will usually disappear within 1-2 weeks. If pregnancy should occur, the condition can worsen and last much longer. The occurrence of OHSS in association with the use of clomiphene is significantly lower than with gonadotropin therapy.
Multiple births are another risk factor when using the Pergonal/hCG combination of treatment. As many as 20% of all such pregnancies involve more than one conception – including about 5% which are triplets or a higher order (e.g., quadruplets, etc.) of pregnancy. By comparison, only 8-10% of Clomid pregnancies are multiple births, with instances of triplets and higher very rare. Multiple births resulting from fertility drugs generally involve two or more eggs; namely fraternal twinning. Multiple-birth conceptions, of course, involve their own set of complications, including prematurity and low birth weight. This issue will be discussed later in a separate posting.
It will come as a surprise to some, but there is also an increased risk of spontaneous abortions (miscarriages) in association with the use of Pergonal/hCG treatment to induce ovulation. The spontaneous abortion (SA) rate has always been considered high with gonadotropin therapy. As far back as the published study by Hack, et al. (1970) they reported an incidence of 29% - almost one out of every three pregnancies. Those that challenge the drug’s causal relationship argue that the high rate is due to the underlying infertility condition; namely that the hCG trigger is expelling a long-overdue egg that is defective. What they choose to ignore, among other things, is a study published by Boue’, et al. (1973) only three years later. The peer-reviewed study reported that first trimester SAs following pregnancies induced by gonadotropins and clomiphene had a significantly higher incidence (83-86%) of abnormal chromosomes than first trimester SAs that occurred after natural pregnancies in fertile patients (60%) and infertility patients (61%) who conceived two or more cycles after last using ovulation-inducing drugs. Such oversight has been facilitated by omission of the study in the product labeling for the drugs – a warning required of the manufacturer of Clomid by the FDA in 1983 that has yet to be put in print.
There are, however, other published studies that implicate gonadotropin therapy. Several later papers, looking at SAs following the use of gonadotropins, found that the rate of the miscarriages in induced pregnancies was around 29%, whereas the SA rate in infertility patients who conceived without the use of drugs had an incidence of approximately 9%. When pregnancies occur in association with OHSS, the numbers climb even higher. SA rates as high as 50-55% have been reported in association with severe OHSS. When broken down by the level of severity, studies have shown that milder forms of OHSS have a lower SA rate than the severest class of the side effect.
The importance of this phenomenon is revealed by the strong correlation between hyperstimulation of the ovaries and the incidence and severity of OHSS, the incidence of multiple eggs/multiple births and the level of estrogen produced; namely, the greater the stimulation, the higher the incidence and severity of OHSS, the higher the incidence of multiple eggs/multiple births and the higher the elevation of estrogen. In vitro (test tube) studies have shown that abnormal levels of estrogen (high or low) can damage or alter chromosomes. This would explain how fertility drugs can cause first trimester SAs, which have a high incidence of chromosomal anomalies and abnormalities of the embryo. It would also provide an explanation for the study by Oakley, et al. (1972), in which they found twice the expected frequency of Down syndrome, when they combined the premarket studies of Pergonal and Clomid. Down syndrome is 100% related to abnormal chromosomes. This became known as the Mix Hypothesis after I presented the theory to the FDA in 1975.
Finally, gonadotropin therapy has the ability to malform the human embryo via its capacity to suppress cholesterol levels very early in pregnancy. Studies have established that following hyperstimulation of the ovaries by the Pergonal/hCG package, the resulting elevated estrogen during the luteal (post-ovulation) phase of the cycle suppresses the level of total cholesterol. In fact, there is an inverse correlation between concentrations of estrogen and the level of total cholesterol: the higher the level of estrogen, the lower the concentration of total cholesterol. As indicated in my prior posting, adequate levels of cholesterol are vital to the proper formation of organs.
Many women, desperate to conceive, will rush into the use of fertility drugs – including gonadotropins – with little thought about the consequences to the resulting baby. Unfortunately, many prescribing doctors add to this problem by not informing their patients about all of the mentioned risks. It is hoped that this posting will fill that void and motivate anyone contemplating the use of fertility drugs to step back and give it some thought before moving forward. An informed choice is the only true choice. www.TerenceMix.com.
Multiple Birth Risks
When a couple contemplates the prospect of using fertility drugs, the first thing that comes to mind is the risk of having multiple births. Not only is it common knowledge that twins and higher order multiples occur in association with the use of ovulation inducing drugs, it is something that the prescribing doctor will thoroughly discuss with his or her patient. Most patients – eager to push forward with the treatment – will embrace the idea of twins. Hey, we get two with one pregnancy. What could be so bad? Of course, it could turn out to be triplets. How about quads? Although with IVF there is more control via the placement of a specific number of embryos in the uterus, with fertility drugs alone there is a more random risk based upon the number of eggs produced and the chance impregnation by the sperm. But beyond the possibility of ending up with more than one baby, what are the real risk factors of having two or more in the oven?
The most common event arising out of multiple conceptions is premature delivery. More than 50% of twins and 90% of triplets are born preterm (less than 37 weeks), compared to about 9% in singletons; and 14% of twins and about 40% of triplets are born very early in gestation (less than 24 weeks), compared to approximately 2% in singletons. Babies weighing less than 2,500 grams (5½ pounds) are generally considered premature. Preterm births thus often result in a lower birth weight. But there are more significant problems that can arise as a result of being early.
When a baby’s delivery is appreciably short of full term, his or her organs have not had an adequate opportunity to develop. As a consequence, serious complications can occur. Among the many potential problems are Respiratory Distress Syndrome (harsh and irregular breathing); pneumonia; infections; reduced heart rate; jaundice (yellowish skin) resulting from a build-up of bilirubin; and intraventricular hemorrhage (IVH). IVH involves bleeding in the brain due to immature blood vessels. It can lead to cerebral palsy, mental retardation and learning disabilities; and occurs in about one third of the babies delivered at 24-26 weeks of gestation. Immaturity of the gastrointestinal tract can result in an inability to absorb nutrients from normal feedings. These are just a few of the complications – there are many more. When they occur, they not only threaten the long-term health of the baby, but often involve extended hospital stays and their attendant costs.
Does the twinning process produce maternal conditions that are hostile to developing embryos? Actually, the evidence is quite overwhelming that naturally occurring multiple births also carry a higher risk of birth defects. Indeed, the higher the order of multiple births, the greater the frequency of birth defects. Li and colleagues (2003) found in a study of 922,791 singletons and 24,032 infants from multiple births that singletons had an incidence of congenital anomalies of 4.8%; twins an incidence of 9.2%; triplets an incidence of 13.0%; and quadruplets and higher an incidence of 22.2%. And there are other studies with similar results. Kato and Fujiki (1992) found a birth defect rate in singletons of 1.47%; twins at 2.17%; and triplets at 3.70%. Calculated from a different perspective, Olson, et al. (2005) recorded a 29% increased risk for twins and a 112% increased risk for triplets over singleton pregnancies.
But do twins following fertility drugs have a higher incidence of birth defects than naturally conceived twins? This very question was explored by Kuwata, et al. (2004), who calculated the incidence of congenital anomalies following three distinct procedures used in Assisted Reproductive Technology (ART) – namely Intracytoplasmic Sperm Injection (ICSI), Gamete Intrafallopian Transfer (GIFT) and conventional In Vitro Fertilization (IVF) – along with ovulation induction without ART (fertility drugs alone), and compared the birth defect rates to the incidence occurring with naturally conceived twins. The answer was a resounding “yes.” After making epidemiologic adjustments for maternal age, they found an increased risk for all four categories using fertility drugs, namely an incidence of 13.1% for ICSI; 8.4% for GIFT; 7.4% for IVF; and 4.9% for fertility drugs alone, compared to 2.1% for twins conceived without the use of drugs.
As can be seen, the risk of multiple births should never be viewed as just a possible two-for-one deal. Although more often than not the parents will bring home a healthy set of twins, or even triplets, serious complications do in fact occur. And when they do, the consequences can be devastating, both emotionally and financially. This is only to suggest that before you dive into the pond that you know what is below the surface of the water. www.terencemix.com.
Ovarian Cancer Risks
A serious concern about a relationship between fertility drugs and ovarian cancer first reared its ugly head during the early 1990s and gained momentum following a study published by Rossing, et al. in 1994. They followed 3,837 infertile women, comparing those who had used ovulation inducing drugs against those who had not sought the aid of fertility drugs. When looking at the overall rate, they found a 150% increased risk. But when the researchers assessed only Clomid (clomiphene citrate) in women who had used the drug for one year or longer, the numbers got rather scary – they found in excess of a ten-fold increased risk. As you might imagine, this spawned a series of similar studies over the years that have continued to the present day. The end result: more confusion than resolution – some studies finding an association between the use of fertility drugs and ovarian cancer, and others concluding that there was no association.
As the mist from conflicting studies continues to obscure the issue, one drug – namely Clomid – seems to be rising to the surface as a true risk factor for ovarian cancer. So much so, that at least as early as 2001, the FDA has required the following language on the drug’s labeling: “epidemiology data suggest that prolonged use of clomiphene may increase the risk of a borderline or invasive ovarian tumor.”
Later studies appear to justify this concern; even studies concluding that there was no association between the use of fertility drugs and ovarian cancer. For example, one such study by Brinton, et al. (2004), found that when they followed patients for 15 or more years after treatment, there was a 48% increased risk of ovarian cancer for Clomid and a 146% increased risk for gonadotropin therapy (Pergonal and hCG). Similarly, they found a 54% increased risk for clomiphene patients with either 12 or more cycles of exposure; although no increase was found for the long-term use of gonadotropins. Even though the numbers were not “statistically significant” – because of an inadequate number of patients studied – they strongly suggest the need to follow patients for an extended period of time due to the slow development of this type of cancer. It is also important to look at the long-term use of Clomid.
A recent study by Jensen, et al. (2009) was not reassuring. Although finding no association with other fertility drugs, the risk of the most common type of ovarian cancer (serous) was significantly increased after the use of clomiphene – namely a 67% increased risk. The increase in risk was found mainly among women followed for 15 years or more after first use of clomiphene when compared with those never using the drug. For less than 5 years there was a 22% increased risk; 5-9 years, 76%; 10-14 years, 23%; and 15 years or longer, 117%. The authors acknowledged an important limitation of the study. “Even though we had a relatively long follow-up period, the median age at the end of follow-up (47 years) was below the usual peak age (early 60s) for ovarian cancer, which might have weakened our estimates.”
Ovarian cancer is one of the most deadly
carcinomas among women. When caught early (confined to the ovaries), there is
about a 90-95% cure rate. But if caught late in its advanced stages (III and
IV), only about 17-30% survive five years post-diagnosis. The problem is that
because of the location of the ovaries and vagueness of the symptoms, early
detection is difficult. Most women are thus diagnosed after the cancer has
metastasized. With a lifetime risk of only 1.8% for ever developing ovarian
cancer, women considering the use of Clomid should give this risk factor
serious consideration. Long-term use – beyond one year – should never be an
option, and cutting it off after six cycles of treatment would be my strong
recommendation. Suffice to say, the Clomid package insert expressly cautions: “Long-term
cyclic therapy is not recommended beyond a total of about six cycles.” www.terencemix.com.