Birth Defects and Fertility Treatment - Good News or Bad?

Many infertile patients are rightfully concerned that the risk of birth defects might be increased among children conceived using fertility treatments, especially in vitro fertilization (IVF). Here are the titles of the first five articles that popped up when I did a Google search yesterday using "fertility treatment birth defect" as the search terms:

"Common fertility treatments raise birth defect risk, study finds"

"Birth-Defect Risk Higher With Fertility Treatments, Study Shows"

"Infertility Treatments May Raise Birth Defect Risk"

"Fertility Treatments May Raise Risk for Birth Defects: Study"

Bad news? Of course. If I were an infertile patient, headlines like these would be enough to make me consider cancelling my appointment to the fertility clinic. These news items all refer to a study recently published in the New England Journal of Medicine entitled, " Reproductive Technologies and the Risk of Birth Defects". (Here is a link to the original research article: http://www.nejm.org/doi/pdf/10.1056/NEJMoa1008095.)

The good news? The study actually showed that most fertility treatments do not appear to increase the risk of birth defects. In fact, here is the last paragraph of the second story listed above (from the New York Times):  

"“We can now state that a cycle of a single fresh embryo transfer with I.V.F. and, if necessary, followed by the transfer of a frozen embryo will result in no significant additional risk above that of a spontaneous conception,” [the lead author of the study] said." (My emphasis added)

So why the inconsistency? There are several studies that show the prevalence of birth defects is higher among children conceived using fertility treatments than in the general population. If you look hard enough, you can even find a couple of papers that implicate clomiphene in birth defects (a scary thought given that this is the most commonly used fertility drug in the US; in 1991, more than 700,000 clomiphene prescriptions were filled, and I'm confident the number is higher now.) The problem with these studies is that it is not appropriate to compare infertile women with women in the general population. Women who conceive without infertility treatment are generally younger and have different socioeconomic, ethnic, and work backgrounds, and infertile women who conceive are more likely to have never had a baby before. One never knows whether it is the fertility treatment or the underlying differences among the infertile women that are responsible for the observed effects. Ideally, we should compare the birth defect rates among children of women who conceive using fertility treatment to those who conceive spontaneously. The problem with such a study is obvious - infertile women don't often conceive spontaneously, so it is hard to find suitable controls. (And even then, infertile women who conceive spontaneously are probably different from infertile women who conceive using fertility treatment - they tend to be younger, for one thing.)

But the investigators in the study cited above did just that, linking a South Australian registry of over 300,000 births to registries of assisted conception treatment, birth defects, and fertility clinic data.  They compared the rates of birth defects in the children of fertile women to those of infertile women who had conceived spontaneously or using a variety of infertility treatments. They also attempted to adjust the risks based on factors thought to be associated with adverse pregnancy outcomes. Here are the factors they accounted for: "parity, fetal sex, year of birth, maternal race or ethnic group, maternal country of birth, maternal conditions in pregnancy (preexisting hypertension, pregnancy-induced hypertension, preexisting diabetes, gestational diabetes, anemia, urinary tract infection, epilepsy, and asthma), maternal smoking during pregnancy, socioeconomic disadvantage on the basis of the postal code of the mother’s residence (according to the Socio-economic Indexes for Areas), and maternal and paternal occupation".

 

And here is the conclusion of the study: "The increased risk of birth defects associated with IVF was no longer significant after adjustment for parental factors. The risk of birth defects associated with ICSI remained increased after multivariate adjustment, although the possibility of residual confounding cannot be excluded."

In other words, the observed increase in birth defects seen after IVF (about 1.5 times the baseline) was due to patient characteristics rather than the IVF procedure itself. Good news for prospective IVF patients! But what about the increased risk with intracytoplasmic sperm injection (ICSI)? I think this is most likely due to patient confounding, too, as ICSI is frequently done for male factor infertility, and in couples where the husband (who is often much older than the wife) has had a vasectomy. Older men are slightly more likely to father children with certain birth defects (which is why the recommended age limit for men to donate sperm is 39).  Unfortunately, the investigators had no information about the age of the man in this study, so they couldn't control for that variable. (And shame on them for not getting this information.)

Also, the condition of male infertility may itself by linked with other conditions that might increase the risk of birth defects. One example of this is cystic fibrosis. Men carrying the gene for cystic fibrosis may have absence of the vas deferens, and these men typically require sperm aspiration with ICSI to father a pregnancy. (In fact, the relationship between congenital absence of the vas deferens and cystic fibrosis was first recognized only after cystic fibrosis was frequently noted among offspring conceived using IVF after sperm aspiration). 

There were a few other findings in this study worth noting:

- The birth defect rate among the general population was almost 6% - higher than most people (including most physicians) realize, but consistent with other studies. This is your baseline risk and is (mostly) independent of age. I tell patients to expect a 3% major and 3% minor birth defect risk in any birth, regardless of how the child was conceived.

- There was no particular syndrome that stood out among children conceived using IVF or ICSI (this is reassuring that the procedure itself is probably not inducing a birth defect).

- The birth defect rates were the same in children conceived using fresh and previously frozen embryos.

- "Medically supervised ovulation induction" was not associated with an increased birth defect rate, but "clomiphene citrate at home" was associated with a threefold increase in birth defects, even after controlling for other variables.  The authors had no explanation for this, and the number of births was small, so it may just be a spurious finding.  (I'm not sure what "clomiphene at home" means, anyway.)

So there is both good and bad news about birth defects and infertility. The good news is that fertility treatment (except maybe ICSI) does not increase the risk of birth defects.  The bad news is that infertile women are more likely to have underlying problems that do increase that risk, regardless of how their child is conceived.  I think the bottom line is: Get as healthy as possible before you get pregnant, and don't do ICSI unless your doctor thinks you really need it to achieve fertilization in your IVF cycle.  In fact, I think you shouldn't do any fertility treatment unless there is some reasonable data to support that doing it will improve your chances of conceiving.

And don't believe everything you read in the the news.

mps 

  

Does a hysterosalpingogram make you more fertile? Update

If you have read my earlier posts, you know I believe that using Ethiodol (oil-based contrast medium) for a hysterosalpingogram increases the post-procedure pregnancy rate. Unfortunately, the only US source for Ethiodol announced in March of 2010 that they were shutting down production "for marketing reasons". Since then, limited supplies of a similar product (Lipiodol Ultra-Fluide) have been made available in the US by FDA-approved importation from a French manufacturer; the current distributor is Guerbet USA. I called up Guerbet today to see if I could buy some Lipiodol Ultra-Fluide, but alas, it is only being made available for use in "life-saving medical procedures", and even if they would sell it to me, one 10 mL ampoule would cost $590 (ouch!).

The company rep said they hope to have Ethiodol back on the market within a year.

mps

Insulin sensitizers and polycystic ovary syndrome

I've recently received some requests to address the role of insulin sensitizers for the treatment of polycystic ovary syndrome, in particular D-chiro-inositol. Here are my thoughts as of 7-23-2012.

Many women with PCOS have insulin resistance, and there are a variety of drugs which improve insulin sensitivity. These drugs include metformin, troglitazone, rosiglitazone, pioglitazone, D-chiro-inositol, and myo-inositol. Their actions on insulin release and action are rather complex, but it is useful to just consider them all as acting to improve the effect of insulin in the body.

Now, I think there is fairly good evidence that treatment with an insulin sensitizer improves ovarian function in women with PCOS. (Yes, I did participate in one of the largest trials of metformin for PCOS ever performed, which showed no benefit of metformin, but please hear me out.) Metformin is by far the most commonly used insulin sensitizer in PCOS patients. My take on the medical literature is that metformin is most beneficial in PCOS patients who are obese. (The study I participated in wasn't sufficiently powered to show this, but in that study the ovulation rate in PCOS patients with BMI over 34 who were on clomiphene was improved by adding metformin) . It does promote weight loss in these women, which probably ameliorates the syndrome a bit, but it also has some action independent of weight loss. In particular, metformin may improve the response to clomiphene in obese PCOS patients (and that is the patient for whom I most commonly prescribe metformin). However, clomiphene is much more likely to induce ovulation and pregnancy in PCOS patients than metformin. I often start obese PCOS patients on metformin for a couple of months and then add clomiphene if they are not ovulating on the metformin alone.

There is much less known about the effects of the other insulin sensitizers on PCOS, but they probably have some benefit, too. I don't use them, though. The published data on the inositol derivatives is limited and contradictory. There is even one paper that claims D-chiro-inositol worsens egg quality in infertile women. More worrisome is that some insulin sensitizers have been shown to have serious side effects, and this information didn't come to light until the drugs were widely prescribed. Troglitazone (Rezulin) is a good example. Years ago, it was held up as the "next generation metformin", with better efficacy and fewer side effects. It did work some on PCOS, but it was also found to cause liver failure and was pulled from the market. Pioglitazone (Actos) can cause heart failure.

For now, the only insulin sensitizer I use is metformin, and I don't use it all that often.

mps

Thyroid problems

Thyroid disease has been linked to menstrual irregularity, infertility, and miscarriage (as well as many other medical problems). I think that anyone with difficulty conceiving, irregular menses, or a history of miscarriage or preterm delivery should have TSH, free T4, and thyroid peroxidase antibody levels checked. Be careful if your doctor or nurse says your TSH level is OK, because even levels in the high-normal range (greater than 2.5) probably need to be treated.

Iodine is necessary for normal thyroid function, and more than one third of reproductive-age women in the US don't get enough iodine. In my opinion, all women attempting pregnancy should take a prenatal vitamin that contains at least 150 mcg of iodine (and 220 mcg may be better). The iodine in the vitamin should be not be derived from kelp, as the levels of iodine in kelp vary dramatically. I recently made a trip to the CVS pharmacy, and I was disappointed to see that fewer than half of the prenatal vitamins contained iodine, and some of ones that did listed kelp as the iodine source. The only over-the-counter prenatal vitamin I found at CVS that had 220 mcg of iodine was Centrum Specialist Prenatal. (I have no financial ties to the company that makes this vitamin.) By the way, prescription prenatal vitamins are no more likely to have iodine than over-the-counter brands.

Creepy Internet flattery?

Someone recently pointed out that one of the other fertility treatment providers in the area had set up a Web site with a name very similar to ours, that had "... Alabama fertility specialists..." embedded in the home page of the site. I contacted my son-in-law, who does Internet search engine optimization for a living. He said, "They're certainly targeting your branded traffic." I checked to see if they were doing the same trick with another fertility clinic in town - nope, just us.

My son-in-law said to just ignore it, but my colleagues at work were upset (especially my nurse practitioner, who pointed out that they had posted some patient instructions she had written years ago). I think it's a compliment, in a creepy sort of way, but I'm mostly sad about the matter. The reputation of the infertility treatment business is already bad enough, what with the octomom and the physician who secretly used his own sperm for inseminations (for the record, that wasn't a board-certified reproductive endocrinologist, but rather someone who just proclaimed himself as "specializing in infertility treatment". But I digress.) I think fertility specialists really need to be operating at the highest level of professionalism, both in real life and on the Internet.

I'm not going to post the link to the site, but you can find it by typing our name into a search engine and looking down the page. If the site has "principal investigator" misspelled, you're there. If you find it's spelled correctly, it means they probably read this blog.

But I hope you won't find it at all.