Recurrent pregnancy losses/repeated miscarriages - part 1

The treatment of patients with recurrent pregnancy loss is a substantial part of my practice. I would like the spend the next few posts sharing with you my philosophy and approach to the evaluation and treatment of this problem.

Miscarriages are common. In young women (say, about 30 years old), the miscarriage rate is about 20%. For women aged 35, it's about 25%; at age 40, that number rises to 40-50%, and in women 45 or older, about 90% of pregnancies will end in miscarriage. You will see different numbers quoted for these rates, and some of the difference depends on how closely you follow women who are attempting to conceive. If one does sensitive pregnancy tests before the day of expected menstruation, many more pregnancy losses can be identified; I have seen one estimate claiming that in young women about 40% of pregnancies are lost if you include those very early miscarriages. I don't look for pregnancies like that, and I don't recommend that you do it, either. For now, I'm going to use a background miscarriage rate of 20% for most of this discussion. That's the rate you will find among otherwise healthy young women who have a positive home pregnancy test and menstrual delay of a week or two. You might encounter the term "clinical pregnancy" if you read about fertility or miscarriage issues. This term is taken to mean various things, but most commonly refers to a pregnancy that can be seen in the uterus using ultrasound. There are some women who have repeated miscarriages before they even make it that far in pregnancy, and I am going to talk about that group of women later in this discussion.

By the way, the term "miscarriage" can vary a bit with the source. Most experts define a miscarriage as a pregnancy loss before 20 weeks gestation (meaning up to 20 weeks after the first day of the last menses, as pregnancy dates are traditionally given using that reference), but I recently reviewed one publication that included pregnancies lost up to 24 weeks in the definition. The term "pregnancy loss" is sometimes used interchangeably with miscarriage, as most pregnancy losses occur in the first half of pregnancy; however, loss of a pregnancy can occur at any time, even just before birth. I think there is some value to considering losses throughout the entire pregnancy, as there are some problems that can manifest as either a miscarriage or as a loss much later in pregnancy, so maybe "recurrent pregnancy loss" is really a more useful label than "recurrent miscarriages," even though you will see the latter term used more frequently.

Most miscarriages end within the first 12 weeks of pregnancy, and about half of those pregnancy losses are chromosomally abnormal, due to the loss or gain of a chromosome in the egg or sperm, or sometimes due to an extra set of chromosomes in the embryo (triploidy or tetraploidy). These chromosomal errors are usually random, and they generally arise from problems during maturation of the egg, although they can also occur from a random chromosomal error in the sperm, or in the embryo after fertilization occurs. These chromosomal errors are part (but not all) of the reason why older women have more miscarriages, and why they are more likely to have a child with a chromosome disorder like Down syndrome (which is due to having an extra chromosome 21). Most chromosomal errors found in embryos result in miscarriage, or even failure to implant in the uterus.

If you think of a group of women who have a miscarriage, there are probably some who lose the pregnancy due to a non-recurring cause, say a chromosomal error in the embryo, or an embryo that is growing poorly for some other reason. (We see this all the time in women who are undergoing in vitro fertilization (IVF) - not all embryos have the same potential for a continuing pregnancy.) I call this "bad luck", and if those women continue to attempt pregnancy, they are very likely to "get lucky" and have a baby in the next pregnancy. On the other hand, some women in that group may have a problem that increases their miscarriage risk to 40%, 50%, or even 100% in rare cases. Thus, in any group of women attempting pregnancy, the miscarriage rate will tend to rise over time as the women with bad luck leave the group when they get lucky in a subsequent pregnancy, and you are left with more and more women who have some problem. As I noted above, in the first pregnancy the miscarriage rate is about 20%, after one miscarriage it's about 25%, 40% after three miscarriages, and 60% after four miscarriages. In the older medical literature, the miscarriage rates were sometimes quoted as something like 20%/20%/20%/40%, meaning that the miscarriage rate didn't rise until after three miscarriages. Even today you can find weird numbers like that, with the miscarriage rate not being different  between women with two versus three pregnancy losses. I think all those numbers are statistical artifacts, and the majority of the medical literature supports the model I have described above.

So, the prognosis for women with recurrent miscarriages is quite good - even after three miscarriages in a row, about 60% of women will have a baby in pregnancy number 4. I believe the medical term for this is "treatment independent success", and it's important to keep this concept in mind when your neighbor tells you about some crazy treatment she tried that resulted in a baby - it might have happened even if she had done nothing. It's also why your doctor may reassure you after your first miscarriage that your chance of success in a subsequent pregnancy is good, and that you don't need any special testing to look for miscarriage problems. The recommendations for when to start looking for miscarriage problems vary with the source, but most say to start testing after two or three pregnancy losses, or maybe even after one loss if it occurs after 12 weeks of pregnancy.

It is important to keep in mind that those guidelines are meant for women who can achieve pregnancy quickly and easily. For women with a history of infertility, I don't hesitate to offer miscarriage testing after one loss - do you really want to wait for a patient to suffer three miscarriages over several years before you start looking for problems? The down side of that approach is that I am doing miscarriage testing on some women who probably don't need it. This is a price that I (and most patients) gladly accept. When to test and which tests to get is a matter of medical opinion, and this varies among doctors, even within our own clinic. In the next post, I am going to go over my approach to the evaluation of patients with repeated miscarriages, the value of looking at guidelines for medical practice, and why it's important to use guidelines for what they are (recommendations, opinions), rather than to blindly follow them.

New partners!

It's been quite a while since I posted something on this blog, but I haven't forgotten it. There is always something else to do, and since a blog post doesn't really have a deadline, it always gets pushed to the bottom of my to-do list. A lot has happened at Alabama Fertility Specialists since my last post, and the most important event is that I have acquired two new partners! Dr. Janet McLaren Bouknight and Dr. Mamie McLean joined Dr. Beth Malizia and I in September, 2017. Drs. Bouknight and McLean came to join us after a stint at UAB, a path I know well. You can read more about them here: AFS team

Dr. Malizia and I are excited to have these fine physicians be part of our team. Please consider making an appointment with one of them if you need help having a baby.

Treatment of Vaginal Agenesis using the McIndoe Procedure (in English)

The treatment of vaginal agenesis

There are two options for the treatment of vaginal agenesis:

Nonsurgical – Vaginal dilators are used (and this is the first option in the majority of cases)

Surgical – The McIndoe technique is the surgical procedure most commonly used in present day.

The McIndoe technique

… consists of performing a careful dissection between the bladder and rectum, thus producing a cavity which will be formed by inserting a vaginal mold covered with a skin graft.

For this operation, a split-thickness skin graft is used.

To obtain a split-thickness skin graft, the superficial layer of the skin (epidermis) along with a part of the underlying tissue (dermis) is used. The donor site can be any area of the body, but in the majority of the cases it is an area that can be hidden with clothing, such as the buttocks or the interior thigh.

The dermatome

A dermatome is employed to obtain a split-thickness skin graft. The dermatome powered by air or electricity is preferred due to the uniformity and size of the graft produced with this instrument.

(we see in this slide) The donor site

Once the graft is taken, a compress containing petroleum jelly is applied to the donor site and covered with a bandage.

The vaginal mold

… is constructed using a foam rubber covered by a condom. The graft is applied with the outer (epidermal) layer next to the vaginal mold. The graft is folded over the mold and sutured with interrupted stitches of synthetic absorbable 4-0 suture.

Dissection of the vaginal canal

Dissection of the vaginal canal is begun with a curved incision of the mucosa of the vaginal introitus.

(following slide)

The dissection is continued following a cleavage plane between the bladder and rectum towards the peritoneum, being careful not to injure the bladder or rectum. A gentle blunt dissection is all that is necessary to create an adequate cavity.

(The mold is inserted into the cavity)

The mold covered with the skin graft is inserted into the cavity. A sagittal view of the pelvis shows the form inserted into the new vaginal canal.

(Maintaining the mold in place)

To maintain the mold in place, the labia majora are sutured in the midline with interrupted sutures of 0-nylon without tension. The sutures are cut and the form removed for cleaning after 7 days.

Postoperative treatment

Initially, the patient keeps the mold in place during the day and night. After four weeks, she can attempt sexual intercourse. The patient continues to use the mold at night for about three months.

Treatment of Vaginal Agenesis using the McIndoe Procedure (en Español)

This is from a recent presentation I gave about my experience with the McIndoe procedure for the treatment of vaginal agenesis. The link is to a YouTube version of the Powerpoint presentation, and the text that follows is a narration of the slides. (I'll post the English version when I get a chance).

https://www.youtube.com/watch?v=P4DZIUk8eFc&feature=youtu.be

Corrección quirúrgica de la agenesia vaginal
Michael P. Steinkampf, MD

(El tratamiento de la agenesia vaginal)

Para el tratamiento de la agenesia vaginal, hay dos opciones:
No quirúrgico – se usa dilatadores vaginales (es la primera elección en la mayoría de los casos)
Quirúrgico – la técnica de McIndoe es el procedimiento quirúrgico más utilizado en la actualidad.

La técnica de McIndoe…

… consiste en realizar una cuidadosa disección entre vejiga y recto, formando así una cavidad, en la cual, acto seguido, se inserta un "molde" vaginal, recubierto con injertos cutáneos.

Se usa en esta operación El injerto de piel de grosor parcial

Para obtener un injerto de piel de grosor parcial, se utiliza la capa más superficial de la piel (epidermis) junto con una parte de la siguiente capa (dermis). El sitio donante puede ser cualquier área del cuerpo. En la mayoría de las veces es un área que se pueda ocultar con la ropa como los glúteos o la parte interior del muslo.

El dermatoma

Se emplea el dermatoma para obtener un injerto de piel de grosor parcial. El dermatoma accionado por aire o electricidad se prefiere debido al grosor uniforme y el tamaño del injerto producido.

(vemos en esta diapositiva) El sitio donante

Una vez tomado el injerto, se le coloca a la paciente, sobre el área donante, una compresa que contiene vaselina, cubierta con vendaje.

El molde vaginal …

… se construye utilizando un condón relleno de gomaespuma.  La forma vaginal se coloca en el lado epidérmico del injerto de piel de grosor. El injerto se pliega sobre la forma vaginal y se sutura a lo largo de su costura interrumpido con 4-0 sutura absorbible sintética. El exceso de injerto se recorta.

La disección del canal vaginal

La disección del canal vaginal se inicia con una incisión curva a nivel del borde mucocutáneo entre el introito vaginal y el periné.

(siguiente diapositiva)

Se continúa con una disección cortante inicial, que se cambia a disección digital, siguiendo el plano de clivaje del espacio virtual vésico-rectal hasta el peritoneo, teniendo mucho cuidado de no lesionar la vejiga y el recto. La disección roma suave es todo lo que se necesita para crear una cavidad adecuada.

(El molde se inserta en la cavidad)

El molde de la piel cubierta se inserta en la cavidad. Una vista sagital de la pelvis muestra la forma de la piel cubierta de insertarse en el nuevo canal vaginal.

(Mantener el molde)

Para mantener el molde en su lugar, los labios mayores se suturan en la línea media con interrumpidas 0 suturas de nylon sin tensión. Se extrae la forma para limpiar después de 7 días.

El tratamiento posoperatorio

Inicialmente, la paciente mantiene el molde en su lugar durante el día y la noche.
Después de cuatro semanas, ella puede tener una vida sexual.
La paciente continúa con el uso del molde en forma nocturna por tres meses.

Muchas gracias por su atención.

Treatment of Vaginal Agenesis - Part 1

Most of the patients I see have fertility problems, usually infertility or recurrent miscarriages, but I have always been interested in the treatment of birth defects of the female reproductive tract, even if they are unrelated to fertility. One such problem is vaginal agenesis.

About 1 of every 5000 women are born without a vagina. This syndrome is sometimes called MRKH (Mayer-Rokitansky-Kuster-Hauser Syndrome, named after some of the people who first described the condition). Women with vaginal agenesis have normal ovaries (and fallopian tubes), but in most cases the uterus is very small or absent. They go through puberty like any other women, but of course they never menstruate. Most of the time, the diagnosis is first considered around age 16. If you encounter a girl who has not yet menstruated two years after having breast development, this is one diagnosis to consider.

The cause of vaginal agenesis is not known, but there is probably some genetic factor involved, as women with this disorder sometimes have a family history of similar problems. I published a paper years ago about identical twins, one with vaginal agenesis, and the other with a normal vagina but virtual absence of the lower leg bones (go here to read the abstract of that paper: http://www.ncbi.nlm.nih.gov/pubmed/12969715). That case was a dramatic example of the relationship between the development of the genital tract and the skeleton. Women with vaginal agenesis may also renal (kidney) and hearing problems.

Diagnosis of vaginal agenesis

Usually, vaginal agenesis is diagnosed by a history and physical exam. I also do a pelvic ultrasound to look for other pelvic abnormalities, and I check to see that both kidneys are present. If there is some question about the diagnosis, a pelvic MRI, a chromosome test, and hormone tests might also be obtained. There are some other conditions that can mimic vaginal agenesis (like androgen insensitivity, a transverse vaginal septum, and an imperforate hymen), so if this disorder is being considered, it’s important to find a doctor who is experienced in making the right diagnosis rather than just someone who can help the patient make a vagina. I have to admit that many reproductive endocrinologists are so interested in doing fertility treatments like in vitro fertilization that they don’t have much interest in (or experience with) this problem, so if you live somewhere far from me, you may have to search around to find someone with expertise in dealing with vaginal agenesis. Often that will be at an academic medical center, but that isn’t true where I live.

Here is what vaginal agenesis looks like (the catheter is in the urethra):

 

Management of vaginal agenesis

So, what do you do if your doctor has said you have vaginal agenesis? Of course, you need to learn all you can about the condition. A good place to start is a Web site put up by Boston Children’s Hospital (http://www.youngwomenshealth.org/mrkh_teen.html). I'm sure other sources of information exist, but that is the best one I have found. Then, if you live not too far from Birmingham, Alabama, you should come talk to me. We’ll do some tests to confirm the diagnosis (and look for related issues that might need treatment, like a functioning uterine remnant) and talk about how to fix your problem.

Of course, you don’t have to do anything at all about vaginal agenesis. I saw a young couple many years ago that presented with infertility - they didn’t realize the wife was born without a vagina! It was clear from her exam they were engaging in anal intercourse (and they refused any treatment.) I have also seen one couple who had managed to dilate the woman’s urethra by repeated attempts at intercourse. I can’t say that I recommend either of these options. Basically, there are two ways to treat vaginal agenesis: use of vaginal dilators, or surgical treatment.

Vaginal dilators are used to slowly create an opening where the vagina should be. This is done by the woman pressing a dilator into the vaginal orifice 15-20 minutes at a session twice a day. It usually takes 3 to 6 months to get a functional vagina. The advantage of this technique is that surgery isn’t needed; the disadvantage is that it takes a long time, and it doesn’t always work. There have also been some reported cases of vaginal prolapse (meaning the vagina turns inside out and falls outside the body) among women who have used dilators to create a vagina. I think it is always best to try vaginal dilators first, since even if it doesn’t work, it can sometimes make the surgery a bit easier. If you read through the Web site I listed above, you may surmise that whoever wrote the material is a strong proponent of vaginal dilation, even if it takes over a year to get results. I am less enthusiastic, and if someone comes and says “no dilators, let’s do the surgery”, I’m OK with that; maybe it’s because I’ve had good results with surgical treatment, and because I sympathize with women who don’t want to work for over a year to get a functional vagina. (The twin whose case I published was having intercourse with her newlywed husband six weeks after surgery.)

There are several surgical options to make a vagina: using a split thickness skin graft (the McIndoe procedure), using a loop of small or large intestine, or using a surgically implanted device that provides a constant tension on the vaginal orifice (the Vecchetti procedure). You can use a full-thickness skin graft or a flap of tissue freed up from the upper thigh, but I think this is seldom done, in part because you get hair follicles growing in the vagina. I think that using a loop of bowel has fallen out of favor, too, since it is major surgery that requires cutting a loop of intestine. Also, women who have this procedure are said to have a chronic vaginal discharge from the intestinal segment that requires a sanitary pad to control. I have only seen one patient who had a vagina created from a loop of bowel, and I was unimpressed with the result. The vagina was very short (less than one inch deep); there didn’t seem to be a bothersome discharge, though, and the couple didn’t complain about the outcome, so I guess it was OK for them.

The Vecchetti procedure is a fairly recent development from Europe. It requires laparoscopy to insert sutures that connect a special tensioning insturment mounted on the abdomen to a plastic olive-shaped device installed at the vaginal orifice.The patient typically stays in hospital for 7 to 10 days and then undergoes another surgical procedure to remove the device. This technique is sort of a ramped-up dilator procedure. The outcomes are supposed to be good, but since the procedure is still fairly new, we don’t know as much about the long-term results as some of the other options, and it does involve some surgery. A few years ago I observed several Vecchetti procedures, but in the end I didn’t think it offered an advantage over what I currently do, which is the McIndoe procedure.

Next post: How to make a vagina using the McIndoe procedure.

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.

Testosterone treatment and male infertility revisited

Here is a nice story a local TV station did about testosterone and infertility. Many thanks to Mr. and Mrs. Ayotte for graciously agreeing to be interviewed for this story.

http://www.abc3340.com/story/16158175/doctor-warns-men-about-common-side-effect-of-testosterone-treatments

Aspirin and IVF

There was a study published about 13 years ago in which women undergoing IVF were randomly assigned to either low-dose aspirin or placebo during ovarian stimulation. The women receiving aspirin (it was 100 mg/day in the original study) had a better ovarian response (with almost twice as many eggs obtained in the treatment group) and significantly higher implantation and pregnancy rates.

When I first heard the findings presented at a fertility meeting (in Tours, France; ah, those were the days!), I was impressed - here is an inexpensive medicine that almost doubles the IVF pregnancy rate. The study seemed well designed and the results clear (but in reviewing the paper I see that although 298 patients were randomized, Table 1 in the manuscript reports the results on only 74 women). Here is the citation if you want to dig up the article yourself: Rubinstein M, Marazzi A, de Fried EP. Low-dose aspirin treatment improves ovarian responsiveness, uterine and ovarian blood flow velocity, implantation, and pregnancy rates in patients undergoing in vitro fertilization: a prospective, randomized, double-blind placebo-controlled assay. Fertility and Sterility 1999;71(5):825-829. The authors theorized that aspirin improved the blood flow to the ovaries and uterus, which led to the beneficial effects.


I suspect that within a year of this article being published, more than half the IVF patients in the US were on low-dose aspirin. Since then, at least 12 randomized controlled trials of aspirin treatment during IVF have been performed, and the conclusion is ... aspirin does nothing to improve the success of IVF. Here is a recent meta-analysis of all the studies: http://www2.cochrane.org/reviews/en/ab004832.html

It's too bad, really. It was such a nice story.

Clomiphene - part 1

Fertility clinics (and their patients) often talk about high-tech fertility treatments like in vitro fertilization, but the most successful infertility treatment is an inexpensive pill - clomiphene. For the next few posts, I'm going to go over some points about clomiphene that every infertile woman should know.

Clomiphene (marketed as Clomid or Serophene) was synthesized in the late 1950's by the chemist Frank P. Palopoli, who worked for a Cinncinnati drug firm, the William S. Merrell Company. (This company had gained some notoriety by aggressively pushing for approval to sell a new sleeping pill that was already available in Europe. A woman named Frances Kelsey who reviewed the application for the US FDA stubbornly refused to approve it until the company submitted more information about the drug's safety. The sleeping pill was thalidomide, and it was soon recognized to cause serious birth defects when used in pregnancy. It turns out the Merrell Co. had rather casually given US physicians over 1 million tablets of the new drug to try out on patients before approval. But I digress ...)


It had long before been recognized that compounds consisting of ethylene with three phenyl groups attached had interesting estrogen-like properties. A variety of these compounds were synthesized and tested; some had both estrogenic and anti-estrogenic properties. Clomiphene was one of these. The first clinical trial of clomiphene to induce ovulation was published in 1961, and it came on the market in 1967. It is often said that clomiphene was initially developed to prevent pregnancy, but I am not aware of any such clinical trials involving this drug.

Clomiphene was designed to induce ovulation in women who didn't release an egg on their own. Before clomiphene became available, the only options for ovulation induction were ovarian wedge resection (major surgery) or injectable gonadotropins. Although how clomiphene works still isn't completely understood, its major action is to block estrogen receptors in the brain, which leads to release of gonadotropin releasing hormone (by the hypothalamus), which in turns causes the release of follicle stimulating hormone (FSH) and luteinizing hormone (LH) by the pituitary gland. It is the FSH and LH which stimulate the ovary to mature an egg, but in effect, clomiphene acts like a mild ovarian stimulant, and the multiple pregnancy rates with clomiphene are lower (@5-10% of the pregnancies) than with FSH injections (@20%). More importantly, the risk of multiples greater than twins with clomiphene is only 1% compared to 5% of pregnancies with FSH injections (when used for ovulation induction; these rates are not applicable to IVF, in which the number of embryos reaching the uterus is controlled). A common misconception is that clomiphene doesn't increase the risk of triplets or higher, but that isn't so - the risk is about 100 times higher than for a spontaneous pregnancy (which is only about 1 in 10,000 births). By the way, clomiphene's multiple pregnancy risk does not seem to be related to the dose at which it is administered. Most of the multiples I've seen with clomiphene occurred with a dose of 50 or 100 mg a day (and the only set of clomiphene quintuplets I ever saw had conceived in her first cycle at 50 mg/day). Whether you get more follicles by increasing the clomiphene dose beyond what is required to achieve ovulation is questionable. I think the answer is "no".

I found this funny/sad/poignant video clip about clomiphene broadcast by the Canadian Broadcasting Company more than 40 years ago. Watch it and tell me what you think:

http://archives.cbc.ca/programs/754-15149/page/2/



MPS

Back in the Top 25/Why we are different

Someone sent me a link to a company that maintains a Web site which pulls IVF success rates off the SART Web site (which includes the statement “programs should not be compared …”), compares them, and publishes lists of the “top 25 programs” in the country. We’ve shown up on that list twice now. Of course, it’s better to be on the list than not, but the first time we were listed I pretty much ignored it. Small programs like ours are more likely have a high (or a low) success rate than bigger programs in any given year. After all, it’s possible for a good baseball player to hit three home runs in a row, but no one has ever hit 30 in a row. As numbers go up, success rates regress toward a mean. But if you show up twice, maybe there is something to it …

The first time we were listed in the “top 25”, a friend who runs a fertility clinic in another state called me. “Michael, what’s your secret? Blast transfer, 5% oxygen in the incubators, assisted hatching on everyone?” No, we don’t do any of those things routinely. I told him it was due to good staff, good patients, and good luck. I suppose there might be more to it than that, though. Here are some things that make our IVF program different from others:

1. We do IVF cases in series. This isn’t all that uncommon, but we batch our patients more than most other programs. – we only do IVF for one week every quarter. Some IVF programs are afraid they will lose “impatient patients” to other clinics by doing this, and that might be true. However, there is nothing like a short, intense run of IVF cases to focus your mind on the treatment. The lab is spotless, the culture medium is tested and fresh, and the staff can concentrate on one task. We bring in a good embryologist who works hard for one week and isn’t around afterwards to twiddle her thumbs while waiting for more IVF cases to dribble in (you other IVF program directors know what I’m talking about here). Doing IVF in series also forces our patients (and our staff) to rest a bit between cycles, and I think this is a good thing. We’ll do four series this year; next year we might do five.

There are some disadvantages to this approach, though. It puts more responsibility on me to keep up with freezing embryos at the end of a series, maintaining lab accreditation, following up on laboratory upkeep, etc.; but I have some technical staff who are good at that, and I don’t mind opening up the back of our laminar flow hood to see why it isn’t working (the damned thing is made in Denmark, and sometimes you have to call Copenhagen if you have a problem, but it’s a sweet machine – the embryology techs love it). Also, our nurse coordinator has to be able to launch people’s stimulation cycles so that the retrievals fall on the right day; and we basically use one stimulation protocol (OCP/long Lupron/FSH/Menopur) on everyone because we have gotten comfortable programming these cycles. No antagonist cycles here (and every time I look at the antagonist data, I’m convinced the protocol we are using is right for us).

2. We have a good IVF lab. If you see cheap furnishings in our waiting room, it’s because the furnishings in the IVF lab are really expensive. When we set up the lab, we got HVAC design specs from an IVF air quality guru and ordered the best equipment we could get. I originally wanted to stock the IVF lab with equipment made in the USA, but I wound up buying a laminar flow hood made in Denmark (see above), an embryo freezer made in Australia, and microscopes made in Japan (the incubators are US-made, however). I think US IVF programs are generally better than foreign ones, but some of the best IVF equipment is made outside the US. I occasionally visit or inspect other IVF labs, and I’ve never seen one nicer than ours. Our contract embryologist says the same thing. We also pay a lot of attention to getting the pH of our culture media just right; I have found that a surprising number of IVF labs don’t do this.

3. We do have a great staff. Front office, financial, nurses, lab techs, my medical assistant – they are all dedicated and caring. Most days we all eat lunch together in the break room. It may be what matters most, and it can be the hardest thing to fix if it isn’t right.

4. We let the husband be in the room during the egg retrieval. I’ve never seen another IVF program that does this. I doubt that it affects the success of the treatment, but I do think it relaxes the wife a bit to have the husband there, and it gives the husband an appreciation for what is going on. I’ve been allowing husbands to watch the retrievals for over 15 years and have never had a problem with it. Part of the reason why other programs don’t do this is they use deep sedation (basically general anesthesia) for the retrievals, and the anesthetists don’t like having the spouse around. We use lighter sedation (given by a nurse or a doctor). It works for us.

5. We don’t do ICSI (sperm injection) on everyone. If you look at US statistics, about 30% of the IVF cases are done because of a male factor, but over 60% of the cases employ ICSI, and some programs do ICSI on all their IVF cycles. While I don’t think doing ICSI necessarily lowers the success of IVF (it certainly doesn’t in our program), I am uncomfortable doing unneeded procedures. There are two things going on here: One is that some of the male fertility tests (like strict sperm morphology and SCSA) label many semen samples as abnormal when they really aren’t, so ICSI gets recommended. The other issue is that some IVF programs are fearful of having an IVF cycle end up with no fertilization, so they just ICSI all the cases. Around here ICSI adds about a thousand dollars to an IVF cycle, so why do it if it isn’t needed? (Hmm, on second thought, maybe that’s a third reason why ICSI is so popular. After all, that microinjector equipment is quite expensive.)

6. Free parking!

MPS

Please stop giving our patients testosterone!

We have had a rash of new infertility patients whose husbands had been put on testosterone by their primary care providers. The usual story is that the husband complains of fatigue, maybe during a routine visit. The doctor (or in one case the nurse practitioner) gets a testosterone level, which is just below the normal range. The man gets put on testosterone. No one bothers to ask if he is trying to father a child. The couple subsequently shows up in our office with infertility, and the semen analysis shows ... no sperm.

The other story we hear occasionally is that the husband isn't taking any prescription meds, but his friend at the gym is providing him with a "nutritional supplement", which turns out to be a testosterone-like substance. We have learned to ask about this whenever we see an abnormal semen analysis.

Testosterone isn't a great contraceptive - only about 80% of men will develop azoospermia. I wonder if there is some sort of recent drug company campaign that is leading to this recent increase in testosterone prescriptions.

My partner Dr. Malizia recently saw an even more bizarre infertility case. The wife was getting testosterone from one of those "natural hormone replacement" clinics you see advertised on TV.

Please don't take testosterone if you are trying to have a baby!

Bicornuate or septate uterus? (part 2)

OK, here's how to tell the difference between a bicornuate uterus and a septate uterus using transvaginal ultraound. Most of the photos below are taken in the sagittal plane, which the plane running from front to rear dividing the body into right and left halves. (Actually, some of the photos are parasagittal views, which are in planes parallel to the sagittal plane, but to the right or left of the midline. See here for an explanation of these planes: http://en.wikipedia.org/wiki/Sagittal_plane). Both these patients had HSGs that showed a duplicated uterine cavity (see previous post for more about how HSGs look in these patients).

Patient #1 (septate uterus): To the left of the midline, a normal uterus is seen. Arrows mark the endometrium. The cervix is off the screen in the upper left. The top of the uterus is in the lower right.










This is a midline (sagittal) view. The uterus is visible, but no endometrium is seen, because we are in the plane of the uterine septum. A cursor in the lower right of the photo marks the top of the uterus.









Moving the probe to view the right side of the uterus, the endometrium reappears.












Rotating the transvaginal probe 90 degrees to give a coronal view of the top of the uterus, we see two endometria contained within a single myometrium, confirming that this is a septate uterus.










Patient #2 (bicornuate uterus). View left of the midline. Normal uterus with endometrial stripe seen. Top of uterus on the right of the screen.











Sagittal (midline) view. No uterus seen. This is a bicornuate uterus.











Right parasagittal view. The uterus reappears (and there is a gestational sac in this side of the uterus).