Study: Pre-Conception Screening with Higher Weight Women

In 2017, researchers from Harvard Medical School and the Brigham & Women's Hospital published a study on pre-conception consults with "obese" women and the outcomes of those consults. This study pointed out a couple of glaring problems with pre-conception consults for women of size, but as always, the authors ended up focusing on the wrong problem. 

Study Details

The consults were mostly done for women with fertility concerns who were seeking fertility treatment. 28% had a pre-existing diagnosis of Polycystic Ovarian Syndrome (PCOS), which often leads to sub-fertility in women of size. These consults were not with regular OBs or midwives; these consults were with Maternal-Fetal Medicine (MFM) specialists, who mainly see complicated or extra risky pregnancies. If anyone should have gotten pre-conception counseling right, it should have been these docs. But what researchers found were significant problems.

The researchers reviewed the charts of 162 consults between 2008 and 2014. They were looking for 3 main things in the records:

1. Documentation of discussion of obesity-related risks and complications
2. Documentation that lab tests were performed to be sure blood pressure and blood sugar were normal
3. Whether doctors advised weight loss before pregnancy, whether people took the weight loss advice via consults with the hospital's Weight Management Program, bariatric surgery, or other programs, and if so, how much weight was lost

Discussion of Obesity-Related Risks

Unsurprisingly, doctors talked about obesity-related risks in 96% of the MFM consults. With all the emphasis in the media and in the research about the risks of obesity in pregnancy, that's to be expected. We can only hope this was done in a neutral and fair way, rather than through scare-mongering and exaggeration, but there's not much information on how the risks were presented.

Discussion of potential risks is part of a medical professional's job, so no one is suggesting that this should not have been covered. But how they discuss risk matters. Is it done in a gloom-and-doom way, is it shaming or condescending, or is it simply information provided without judgment? Do doctors emphasize ways to mitigate risk beyond losing weight? Are risk ratios the only method used (which tends to inflate the perception of risk) or are actual numerical incidences used? Do doctors acknowledge that complications are not a foregone conclusion and that many women of size can have normal pregnancies and healthy babies?

Risk discussions about weight are difficult and can be fraught with emotions. Shaming and scolding backfire because most people stop listening and tune out. Most people of size have experienced such negative contacts with healthcare professionals that they have learned to block out the gloom-and-doom predictions. Exaggerating the risk results in people not taking the discussion seriously and not listening to the important advice that might be given on prevention.

We need a different way to discuss risk surrounding weight in pregnancy. Couch the discussion in neutral terms without being judgmental. Use actual incidence figures to give numerical context to risk ratios, and make sure patients understand the difference. Acknowledge that positive outcomes are possible, and suggest ways (beyond just focus on the scale) to mitigate the risk. This is much more empowering to women and more likely to be heard and heeded. Potential complications can be discussed, but with explanations of how such problems would be addressed whenever possible. Don't center the entire discussion around weight; encourage good habits like regular exercise without tying it to the scale.

Screening for Diabetes and High Blood Pressure

Part of every preconception consult for people of size should be measuring blood sugar and blood pressure. High blood sugar in early pregnancy is strongly tied to birth defects. High blood pressure issues in pregnancy often lead to too-small babies, premature births, and sometimes even death for mother or baby.  Discovering these conditions before pregnancy and getting them under control before conception can definitely improve outcomes.

Shockingly, only about half of obese women were screened for diabetes and high blood pressure at the MFM consult:

Screening for diabetes and hypertension occurred in 48% and 51% of consults, respectively.

This is very surprising, and a tremendous missed opportunity. While most obese women do not have diabetes or blood pressure issues before pregnancy, some certainly do, and those pregnancies are responsible for much of the less ideal outcomes from high BMI pregnancies.

A preconception consult is the perfect time to discover whether there are pre-existing problems, take action, and hopefully prevent some of the worst-case scenarios. Therefore it's stunning that MFM specialists screened only half of the people of size for these conditions ahead of time.

This is the most important finding of this study, in my opinion. Medical professionals need to be sure to test for these conditions before pregnancy whenever  possible. People of all sizes should have their blood pressure taken (with the correct-sized cuff) and a medical history taken. People who are at increased risk for diabetes (such as higher-weight people, people with PCOS, people with a strong family history of diabetes, etc.) should also have their blood sugar tested pre-conception if possible.

If your care provider does not order these tests in your regular check-ups, then you need to take matters in your own hands and arrange for them to be done. Even if you are not planning a pregnancy, many pregnancies occur unplanned. Getting regular monitoring of your blood sugar levels and blood pressure if you are sexually active is simply common sense. So is taking a prenatal vitamin regularly.

Weight Loss Advice and Follow-Through

Because most doctors are taught that weight loss is the main way to prevent complications in high BMI women, advice to lose weight before pregnancy is common. The authors state:

Ideally, an MFM consult should not only inform an obese woman of the impact of her weight on fertility and pregnancy, but also equip her with strategies for weight loss.

In fact, it is that hospital's policy that all women with a BMI over 40 who are seeking fertility treatment should be automatically referred to the hospital's Weight Management program, "which includes calorie-controlled diet and liquid diet programs in addition to other medical treatments for obesity."

With a protocol like this in place, it's understandable that the researchers were disappointed that weight loss referrals weren't universally given in the consults. Just over half of participants were documented as having received advice on diet and exercise. As BMI went up, more were given such advice, as well as referrals to bariatric surgery, but it was by no means universal even at the largest sizes.

Researchers were shocked by how few women took active measures to lose weight. In the study,

27% of patients saw a nutritionist, 6% saw a provider for a medically supervised weight loss program, and 6% underwent bariatric surgery... The median weight change was a loss of 2.0 lb, or 0.6% body weight, over a median of 12 months.... Rates of any pregnancy and of ongoing pregnancy were not associated with whether women lost ≥5% body weight.

The authors of the study acknowledge that most women, especially those facing fertility challenges, don't want to delay treatment for the elusive dream of losing weight, and that this likely was why most patients did not opt into the Weight Management or bariatric surgery programs. Most began fertility treatments within a month or so after their MFM consult.

It should also be pointed out that the median weight change was TWO POUNDS... not exactly outstanding results. Those who waited and lost more than 5% of body weight did not have more pregnancies, calling into question whether weight loss is as effective for fertility as doctors assume.

But of course doctors ignored these findings and just called for more weight loss emphasis in pre-conception consults. The authors state:

...the consults were unsuccessful in meaningfully effecting pre-pregnancy weight loss. In this study, only 19% of the participants with follow-up weights achieved ≥5% loss, and only 5% achieved ≥10% loss. We believe that increased emphasis is needed on weight loss resources, including discussion of lifestyle modification and referrals to specialty obesity treatment services, e.g. bariatric surgery. In addition, MFM providers and referring REI providers must be allied in counseling women to delay fertility treatment and conception to focus on weight loss. This recommendation is more nuanced in the case of women of advanced maternal age, when postponing fertility treatment may result in loss of the fertile window and may therefore be untenable. ...More emphasis is needed on weight loss resources and delaying pregnancy to achieve weight loss goals.

Here we go, back to the same old medical mentality. It's all about losing weight before pursuing pregnancy, even when they can see that most women are not interested in that, even when most women lost very little weight despite trying, and even when such weight loss may not make a difference in live birth rates.

It's like doctors are incapable of thinking outside the box. They know the colossal failure of weight loss programs but are in such denial they cannot admit that these basically useless. Instead, their answer is MORE emphasis on weight loss programs, with a fallback to bariatric surgery if all else fails.

It is telling that no acknowledgement was made of many people's long history of dieting ups and downs and the tremendous frustration of yo-yo dieting. Many patients are just done with radical weight loss programs because they know that they are not effective long-term and they are not willing to live like that.

Like most in the weight loss field, these researchers remained determinedly obtuse. It's weight loss above everything else, at any cost. And while some higher weight people are interested in this, many are not.

Discussion of Study

It's clear from the summary at the end of the paper that the main result of this study is going to be an increased pressure on MFM specialists to push weight loss before treatment. More pressure will be brought on doctors to refer patients to the hospital's Weight Management and bariatric surgery programs. The question is whether women will be free to accept or decline these programs at will.

It's one thing to offer someone access to weight management programs; some want this and that's their choice. It's another thing to browbeat women into these programs, and it's a completely different thing to require them. While this center did not deny higher BMI women access to fertility treatment without weight loss first, that seems to be the direction they are heading, and that's alarming.

Although these hospitals deny a profit motive, let's not forget that weight loss programs are big money-makers for hospitals, so financial incentives may also play a role. The weight loss industry is BIG BUSINESS and many doctors are utterly compromised by their ties to these programs. They may be unconsciously biased and not even recognize it. Ties to the pharmaceutical industry are treated with far more caution than ties to the weight loss industry, but money talks in the bariatric field as loudly as any other.

The biggest take-away from this study should not be that more emphasis on weight loss before pregnancy is needed. 

Instead, the most important take-away SHOULD be the fact that medical professionals are not adequately testing to make sure the woman is in reasonable health before pregnancy. 

The fact that only HALF of the women were not even tested for blood pressure and blood sugar issues, yet the study authors conclude that weight loss referral is the most pressing issue shows that medical professionals are too narrowly focused on the scale. They have blinders on and cannot see anything else.

Weight should not be used as a surrogate for whether a person is healthy. Instead, documentation of blood pressure and blood sugar and other labs should be done, and treatment of any problems initiated or adjusted if needed. That will likely have more downstream improvement of outcome than trying to ensure that all the women lose at least 10% of their bodyweight first.

That doesn't mean that lifestyle and health habits should be ignored. Instead, people's individual habits should be evaluated in a non-judgmental manner, and suggestions for improvements can be gently made to people of all sizes. Advice about nutrition doesn't have to be about restricting calories; combining proteins with carbs and limiting high glycemic index carbs may help prevent some complications without necessarily resulting in weight loss. Exercise can strongly improve outcomes, even if it doesn't lead to weight loss. Lab tests can be run to see if any particular nutrients are deficient and need boosting. Nutritional consults can be very useful if they are done right.

In the study, 27% of women were willing to see a nutritionist before pregnancy, while only 6% were willing to enroll in a Weight Management program. That means there is an opportunity here for a Health At Every Size® approach instead, which would emphasize healthy habits and food, regular exercise, and lab tests as measures of health instead of the scale. This may do more to improve outcome than trying to get women to lose 10% or more of their bodyweight.

Doctors need more tools in their maternal obesity toolbox besides weight loss. They need to think about prevention beyond just losing weight before pregnancy.

Testing for pre-existing conditions before pregnancy is a cornerstone of the toolbox. Too bad these researchers missed the bus on emphasizing this as their main message.



Reference

Fertil Res Pract. 2017 Jan 13;3:3. doi: 10.1186/s40738-016-0030-9. eCollection 2017. Preconception consultations with Maternal Fetal Medicine for obese women: a retrospective chart review. Page CM, Ginsburg ES, Goldman RH, Zera CA. PMID: 28620542  Full text here.

...The purpose of this study was to evaluate the quality and effectiveness of Maternal Fetal Medicine (MFM) preconception consults for obese women. METHODS: We performed a retrospective chart review examining 162 consults at an academic medical center from 2008 to 2014. The main outcome measures included consultation content - e.g. discussion of obesity-related pregnancy complications, screening for comorbidities, and referrals for weight loss interventions - and weight loss. RESULTS: Screening for diabetes and hypertension occurred in 48% and 51% of consults, respectively. Discussion of obesity-related pregnancy complications was documented in 96% of consults. During follow-up (median 11 months), 27% of patients saw a nutritionist, 6% saw a provider for a medically supervised weight loss program, and 6% underwent bariatric surgery. The median weight change was a loss of 0.6% body weight. CONCLUSIONS: In this discovery cohort, a large proportion of MFM preconception consultations lacked appropriate screening for obesity-related comorbidities. While the vast majority of consultations included a discussion of potential pregnancy complications, relatively few patients achieved significant weight loss. More emphasis is needed on weight loss resources and delaying pregnancy to achieve weight loss goals.

The Turkey Awards: Obesity Eugenics via Fertility Treatment Denial

We've been talking about Obesity Eugenics, when authorities try to keep people of size from reproducing through negative media campaigns, scare tactics, risk hyperbole, apocryphal stories, push for normal BMI before conception, and pressure for sterilization or termination. This incredibly insensitive and discriminatory movement is the winner of not one, but two Turkey Awards. It's time to call out these egregious practices.

If you aren't familiar with them, the Turkey Awards are the "prizes" I hand out to highlight fat-phobic treatment of people of size from care providers, biased attitudes or studies from researchers, or troubling trends in the care of fat pregnant women these days.

Last year's Turkey Award was delayed so I'm doing two years in a row now. I've already done the first half; attention to the Obesity Eugenics Media Campaign. Now it's time to highlight the egregious lack of access to fertility treatment for people of size.

In past years, we've talked about:

• #1: fat-phobic care providers
• #2: scare-mongering and shaming tactics
• #3: jumping to conclusions about risks
• #4: scorched earth tactics
• #5: prenatal weight gain extremism
• #6: fat-phobic attitudes around treatment of PolyCystic Ovarian Syndrome(PCOS)
• #7: astronomically high cesarean rates in women of size
• #8: weight bias in the treatment of lipedema 
• #9: obesity eugenics media campaigns
• #10: obesity eugenics via fertility treatment denial

We've already seen in the previous Turkey Award that many care providers believe that "obese" women have no business being pregnant. As a result, there has been a concerted public health campaign in recent years to reduce pregnancies in high BMI women. Today we talk about one of the most widely accepted and insidious ways the medical establishment promotes Obesity Eugenics ─ by denying access to fertility treatment.

Lack of Access to Fertility Treatment

Headline from The Hamilton Spectator, 2011

Denying access to fertility treatment via BMI restrictions is a widely-accepted practice in the medical community. It is driven by risk hyperbole, economics, and weight bias.

“Fat women only have babies because we can’t stop them; we’re certainly not going to help you conceive.” – Family Practice doctor to woman dealing with infertility

In many fertility clinics these days, women above a certain BMI are not permitted to access fertility treatments. In many clinics the cutoff is a BMI of 35, but in the U.K., the limit is usually a BMI of 30. Here is one story of a woman denied fertility treatment and pressured for bariatric surgery because of her weight.

The first thing out of the gynaecologist's mouth was “How much do you weigh”. 135kg [297 lbs]. “Do you realise how obese you are?” I then told her I have been working hard to lose weight through diet and exercise, thinking to cut her off before she got into her fat-bashing rant. As I explained that I had lost 15kg since January, was doing 90 minutes of cardio at the gym 5 times a week, and eating a low GI, low-fat, low-carb diet. She rolled her eyes at me in disbelief. Her reply was, “You are too fat for a baby. You need to get down to 65kg [143 lbs.] before I will help you”. At that point I should have stood up, told her to go f*** herself and walked out but I was stunned. I guess she took the stunned silence as agreement because then she whipped out the lapbanding pamphlet and told me I had to have weight loss surgery. 

Stories abound of women denied fertility treatment because of weight. One woman was told by her Reproductive Endocrinologist (RE):

Pregnancy is supposed to be beautiful and natural and it can be neither at your weight. I suggest you lose 100 pounds then come back.

Here is a story from the comments section of the defunct blog, My OB Said What?!?:

I...had an amazing RE last time, but she has since retired and the only one in town will not treat me due to my weight. He will not do any infertility treatment on you unless you have a BMI under 30!! Really? Because last time I got pregnant with injections and IUI [Intrauterine Insemination] I was 330!!! I had an amazing pregnancy and a healthy baby! Why is okay that...because I have a medical issue and disease I do not deserve to have children. UGH! I can’t even start on how this way of thinking pisses me off!!

Another woman in the same story wrote in the comments section:

We have a good ob/gyn...but we cannot find a reproductive endocrinologist who will even agree to see us.

BMI limits on fertility treatment is one of the most accepted ways doctors try to keep obese women from reproducing. It's another step on the path towards Obesity Eugenics.

The PCOS Conundrum

It's true that heavier women have higher rates of fertility problems. However, it's important to note that just because you are larger, it doesn't mean you will have trouble having a baby. Lots of plus-size women have babies without help. That includes me; I was told I would probably not conceive without fertility help, but conceived four children naturally with no problems. So don't just assume (or let your doctors tell you) that if you are fat you probably won't be able to have kids.

But it's important to acknowledge that some high BMI women do have more difficulty conceiving a pregnancy. Doctors often blame higher levels of estrogen, but the bottom line is that many fertility issues in women of size can be traced back to PolyCystic Ovarian Syndrome (PCOS), which leads to higher levels of estrogen.

In PCOS, women have a hormonal imbalance, probably because of underlying insulin resistance due to impaired insulin signaling. They have too much estrogen and testosterone, but not enough progesterone. As a result, the body ovulates sporadically, weakly, or sometimes only rarely. Ovarian follicles containing eggs either don't finish ovulating or ovulate only weakly. The ovarian cysts that are a byproduct of this process give off excess hormones, and can cause distressing symptoms like excess facial and body hair, thinning scalp hair, cystic acne, body tags, darkened skin around the back of the neck, armpits, etc. It also leads to reduced fertility.

In PCOS, the woman often experiences erratic menstrual cycles, which make it difficult to become pregnant. She may not ovulate regularly, or if she does, she may ovulate only weakly. If she does manage to conceive, she may have difficulty sustaining the pregnancy because of low levels of progesterone to support the the early weeks of pregnancy. In other words, the problem may be conceiving a pregnancy, or a high miscarriage rate afterwards, or both. While there are some women with PCOS who have the ovulatory phenotype and do not have problems conceiving (I'm one of these), many women with PCOS have fertility issues.

PCOS is one of the most common cause of fertility issues. Australian research suggests that up to 72% of women with PCOS have fertility issues, and PCOS often leads to long-term weight gain due to insulin resistance. While many people with PCOS are heavy, not all are, but the fertility effects of PCOS are independent of BMI. Thin women with PCOS experience fertility problems too, but they are able to access fertility help more easily than their heavier sisters.

There is an erroneous belief among some doctors that being fat or gaining weight can cause PCOS. This is an unproven assumption based on fatphobia and allows doctors to blame women with PCOS for their condition. It is far more likely to be the opposite ─ PCOS is most likely an inherited underlying metabolic condition that then triggers weight gain. One review states:

Familial aggregation of PCOS strongly supports a genetic susceptibility to this disorder.

Weight gain does tend to make PCOS symptoms worse, but it is likely the underlying condition that causes weight gain in the first place. Although it is not impossible to lose weight with PCOS, it is much harder. And not everyone who loses weight with PCOS finds that it helps their symptoms. Many people spend years yo-yo dieting because it is so difficult to lose weight with PCOS.

It is a cruel irony to then deny heavy women with PCOS access to fertility treatment. It is a double blow because they are the very ones who need help the most. It's simply a genetic condition that is inherited through no fault of their own, but they are being punished for that genetic inheritance.

Treatment Success Rates

Headline from The Globe and Mail, 2011

Many infertility doctors justify denying fertility treatment to obese people because they contend it is less likely to succeed at high BMIs, and the risk for complications if pregnancy occurs is too high. Let's take a look at these arguments and see if they hold up.

To be fair, there is considerable research that suggests lower rates of Assisted Reproductive Technology (ART) ) success in heavier women and a higher rate of miscarriage after fertility treatment, although not all studies agree. These results seem to confirm that health issues like PCOS play a strong role in infertility in obese women. But it doesn't mean that these women should be penalized for their genetic vulnerabilities.

It's probably true that a higher BMI has a generally lower success rate of fertility treatment to regulate menstrual cycles and help ovulation occur, but that doesn't always translate to actual live birth rates. When looking at live birth rates, some research has found very similar rates of ART success in obese women. One recent Israeli study found similar pregnancy and live-birth rates between all BMI groups and concluded:

The results of our relatively large retrospective study did not demonstrate a significant impact of BMI on the ART cycle outcome. Therefore, BMI should not be a basis for IVF [In Vitro Fertilization] treatment denial.

When funds are limited, doctors argue that fertility treatment should be limited to those most likely to achieve a pregnancy. However, even when funds are available or people pay for their own treatment, many fertility doctors withhold treatment for people of size. It's not just about saving money.

Most tellingly, doctors do not deny fertility treatments to other groups (like older women) who may have lower success rates. Only obese people are penalized like this. 

This is a form of selective discrimination. If older women have access to fertility treatment, so should high BMI people.

What About Weight Loss Before Fertility Treatment?

Image from The Unnecessarean

One of the arguments for BMI limits in fertility treatment is that losing weight first improves outcomes. The British NHS Guidelines state that "most overweight women would only need to lose 5 to 10 per cent of their body weight before they would be able to conceive without needing treatment." The advantage of this is that it could save lots of money and increase success rates. However, the evidence is not so clear.

Some research does suggest higher rates of ovulation in obese women with PCOS who lose weight before fertility treatment. This is why many doctors require that high BMI people lose weight before treatment is permitted. They figure a low-cost intervention like this is worth trying before resorting to high-cost ones. That is a logical argument.

However, while weight loss may improve ovulation and pregnancy rates, does it really result in more babies? What is most important is the final outcome, i.e. live-birth rates. And not all studies agree that weight loss improves actual live-birth rates. A 2017 review found:

The existing data from randomized trials...have failed to document improved live-birth rates after the [weight loss] intervention compared with control groups.

A study in infertility clinics across several Nordic countries found statistically similar live birth rates among obese women (BMI 30-35) who were subjected to a very-low-calorie liquid diet for 3 months before In Vitro Fertilization (IVF). Another study found that an intensive weight loss intervention before IVF actually resulted in decreased IVF success.

An important 2016 study in the New England Journal of Medicine found that live birth rates were actually slightly better in the non-weight loss group that proceeded directly to fertility treatment than in the group subjected to a 6 month "lifestyle intervention" program (i.e. weight loss) before treatment:

...The primary outcome [live births] occurred in 27.1% of the women in the intervention [weight loss] group and 35.2% of those in the control group..In obese infertile women, a lifestyle intervention preceding infertility treatment, as compared with prompt infertility treatment, did not result in higher rates of a vaginal birth of a healthy singleton at term within 24 months after randomization.

A follow-up of this study found that the lifestyle intervention in anovulatory women resulted in more spontaneous conceptions but made no difference in live birth rates.

The benefits of weight loss before fertility treatment are mixed. While some people of size do find increased success with spontaneous conception with a modest weight loss, other people of size do not. To blithely suggest that a 5-10% weight loss is all it takes to conceive is insensitive and unrealistic. It may help some; for others it may be a waste of valuable time. Weight loss can be offered to larger women if they are interested since it helps some achieve pregnancy, but the choice must be left up to them, not mandated.

Furthermore, time is a complicating issue. If women put off pregnancy to pursue weight loss, they are losing some of their most fertile years. It can take a long time to lose weight down to required BMI cutoffs. As one critic noted:

Restricting fertility treatment on the grounds of BMI would cause stigmatization and lead to inequity...Time lost and poor success of conventional weight loss strategies would jeopardize the chances of conception for many women.

Surveys suggest that very few women in their 30s are willing to delay seeking fertility treatment in order to pursue weight loss. They know that advancing age is a far more important risk factor than weight.

Others are unwilling to pursue weight loss because even a small loss often results in long-term weight gain rebound and they are unwilling to risk that, especially in pregnancy. A high drop-out rate in weight-loss-for-fertility programs is an additional problem, suggesting that many of these programs are not sustainable or practical.

As a result, there are some doctors who suggest an emphasis on good nutrition and exercise a few months before treatment is more effective than a weight loss emphasis.:

Lifestyle modifications, in particular a healthy diet and exercise during the 3-6 months before conception and during treatment, should result in better outcomes than requiring weight loss before fertility treatments.

This is compatible with a Health At Every Size® approach. Focus on lifestyle and habits, not the scale. Healthy habits are very important before pregnancy but they doesn't necessarily result in weight loss.

Perceived Risks of Obese Pregnancies

Headline from The National Post, 2016

Many fertility docs justify denying treatment to high BMI women because of the perceived risks of pregnancy at larger sizes. They are concerned that the risks of an Assisted Reproduction Technology pregnancy will magnify the risks of a high BMI pregnancy, creating an extremely unhealthy outcome. However, research shows that the two risks are generally not synergistic.

Some doctors believe that fat women are at SUCH high risk that they can't possibly have a healthy pregnancy or a healthy baby. While that's simply not true, it is a strongly held belief of many fertility doctors. Toronto fertility specialist Dr. Carl Laskin says:

“To me, it’s a medical issue. It is not a discrimination issue. [Obese] women are running risks in pregnancy, and if they’re running risks in pregnancy, why should you be helping them get pregnant?” Dr. Laskin has a BMI cut off of 35. “Mine is a brick wall,” he said. "Other clinics will go as high as 40. Some have no cut off."

Bill Ledger, a professor of Reproductive Medicine at Sheffield University in the U.K., reflects the extremism of some doctors' beliefs:

Doctors shouldn't be helping women have a pregnancy that's at a high risk of going horribly wrong. 

Many reproductive endocrinologists (REs) feel that "it would be unethical to help a fat woman get pregnant."  From a comment left on my blog in a past post:

I just went to a gynecologist this past week ...I was told, quite directly, that she would not and nor would any doctor in my HMO take me on since my BMI would make the pregnancy too high risk to myself and a fetus.

An article from 2016 has the doctor throwing down the Fat Death Card (if you get pregnant you'll probably die so we mustn't help you):

One woman recounted a fertility doctor telling her, “Gals your size, OK, mortality rates are higher. So I go ahead and intervene, help you get pregnant here. Then you go down to (a birthing ward). And then, boom! Pulmonary embolism.”

Again, this goes back to risk hyperbole. People of size are more at risk for blood clots, some of which can go to the lung (pulmonary embolism), and that is potentially lethal. But the actual incidence of such incidents is quite low. Furthermore the risk can be lowered with good care by using blood thinners when indicated, not doing cesareans unless truly needed, keeping women as mobile as possible all throughout pregnancy and afterwards, and increasing postpartum surveillance for blood clots in women at increased risk.

Furthermore, the argument about risk is a spurious argument because it is not applied equally. 

Doctors justify denying fertility treatment because women of size do have a higher rate of pregnancy and birth complications, but they weaken their argument by not applying it equitably:

...the objection is that it excludes a specific patient category on grounds that are not applied to treatment of others with comparable risks.

In other words, there are many other groups (like older women, people with certain medical conditions) that have similar or higher risks for complications but these groups are NOT denied access to fertility treatment. Only fatness is penalized in such an across-the-board way. As one review put it:

...a higher risk than the mean IVF population does not mean that it is irresponsible to take that risk. It is a question of proportionality: a higher risk can still be acceptable in light of the gain a woman can expect from treatment. Through the same reasoning IVF is thought acceptable in other women who are at increased risk of pregnancy complications because of medical conditions. Women with diabetes mellitus have an increased risk of hypertensive disorders and congenital abnormalities, macrosomia, stillbirth and premature labour...Diabetes mellitus is, however, not an exclusion criterion for fertility treatment.

Another recent review agreed:

Given that patients with, for example, diabetes or previous pre-eclampsia, who are at higher risks than many obese women, are allowed treatment on the basis of individualized and well-informed decision-making, we think there is no justification for taking a different line with regard to BMI.

Although fertility doctors like to pretend that denial of treatment is based on their concern for risks, they don't apply these rules equally among groups. The same standards are not applied to other women at higher risk for complications; only the obese are targeted. 

Research also shows that while some risks are increased in people of size, the increase in risk is moderate, and many women of size actually have perfectly healthy pregnancies and births. Furthermore, group statistics cannot predict any one person's outcome. Denying fertility treatment based only on weight limits or BMI means that many pregnancies that would have had normal and healthy outcomes will never occur.

Some experts refute the idea that BMI should be used as a surrogate for unacceptable risk levels:

Dr. Cheung plans to argue that studies also show IVF does not pose unacceptable risks for heavy women, and that BMI alone is not a good measure of which patients face the highest risks. Age, he said, is "by far the strongest indicator" of success and dangers.

An article highlighting the Canadian debate agrees:

But to Dr. Yoni Freedhoff, a specialist in weight control at the Ottawa Bariatric Medical Institute, that’s part of an “insidious” health care practice. 

“It would seem to me that this ‘you’re too fat to have IVF’ policy probably is in part started as patient safety, but ultimately it reflects weight bias,” he said. 

Freedhoff, who’s advised assisted reproduction patients needing to lose weight, doesn’t dispute that excess pounds can cause additional risks. What he doesn’t understand is why weight might exclude women from fertility treatment, but other factors that have been shown to adversely affect pregnancy — such as smoking or advanced age — are not perceived as equally damaging.

Ethics and Eugenics Questions

Headline from The Independent, 2018

Infuriatingly, in some areas, helping an obese woman with fertility is seen as malpractice and authorities forbid or strongly discourage allowing fertility docs to treat women of size. According to guidelines in the UK:

Fertility clinics should defer treating obese women until they have lost weight through dieting, exercise or surgery, according to guidelines published today. Under the recommendations, clinics are advised to begin treatment on severely overweight women only once they have reduced their body mass index (BMI) to below 35. Women under 37 years of age should reduce their weight further, to a BMI of less than 30, the guidelines state.

Here's a story from a woman in Australia:

I’ve been to two fertility specialists and neither of them will give us any fertility treatment until I have a BMI of under 35 (99kg). Nothing to do with my chances of getting pregnant; they say it’s an ethical matter, that obesity itself is enough of a health challenge for the body without adding the impact of pregnancy. Getting an obese woman pregnant would be seen as doing harm. The second OBGYN informed me it’s a state-wide guideline according to the Fertility Council which covers public & private health.

Although there are fertility docs out there who believe that it's wrong to deny fertility treatment to fat women, BMI restrictions are common in many fertility practices and some government healthcare.

In New Zealand, Australia, and Canada, there are guidelines in place/ being proposed to prevent women over a BMI of 35 from accessing fertility treatment. In the U.K., women under the age of 37 must have a BMI of no more than 30. In the U.S., guidelines are more individualized, but many clinics have policies in place that bar fertility treatment above a certain BMI, usually 35.

And now things are going even further. Some areas of the U.K. are proposing limiting fertility treatments to women whose male partners have a BMI over 30. The woman can have a "normal" BMI which would ordinarily get her IVF, but if her partner is fat, she doesn't qualify anymore. So not only can they deny treatment to fat women, but to fat men and any woman with a fat male partner.

Some fertility experts  recognize the major ethical problems with denying heavier people access to fertility treatment. An article about proposed BMI limitations on fertility treatment in Canada notes:

...It's ethically troubling," said the University of Manitoba's Arthur Schafer, director of the Centre for Professional and Applied Ethics. "In our society, the decision to procreate is left to the individual – so why would it be appropriate for the doctors to usurp those rights for women who are obese." 

Doctors would only be justified, he says, if they could "honestly, hand-on-heart say," that the safety risks are so great "that no reasonable fat woman would want to conceive a baby in this way." 

"I'm not sure the fertility industry or association can really defend a blanket exclusion on obese women having access to assisted reproduction."

Intersectional stigma applies here too. Another article from Australia notes that the impact of these policies is often discriminatory towards various racial groups and poorer people:

"They need to recognise that there's harm in doing nothing. Women who are unable to have children, there's a much higher risk of depression and anxiety and a doubling in the suicide rate. So doing nothing is not necessarily doing the best thing." 

The guidelines, he claims, can be classified as discrimination."Especially when you consider the low socio-economic group," he said. 

"The Indigenous patients have a lot higher incidents of obesity than the general population, so you're almost discriminating against those two disadvantaged groups in this particular policy. "Obviously that wasn't the original intent, but that is a potential end product of that."

Here is what one group of experts argues in response to the usual excuses for denying fertility treatment based on BMI (my emphasis):

Obesity is associated with a reduction in fertility treatment success and increased risks to mother and child. Therefore guidelines of the Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG) suggest that a body mass index exceeding 35 kg/m2 should be an absolute contraindication to assisted fertility treatment such as in vitro fertilisation IVF. 

In this paper we challenge the ethical and scientific basis for such a ban. Livebirth rates for severely obese women are reduced by up to 30%, but this result is still far better than that observed for many older women who are allowed access to IVF. This prohibition is particularly unjust when IVF is the only treatment capable of producing a pregnancy, such as bilateral tubal blockage or severe male factor infertility. 

Furthermore, the absolute magnitude of risks to mother or child is relatively small, and while a woman has a right to be educated about these risks, she alone should be allowed to make a decision on proceeding with treatment. We do not prohibit adults from engaging in dangerous sports, nor do we force parents to vaccinate their children, despite the risks. Similarly, we should not prohibit obese women from becoming parents because of increased risk to themselves or their child. 

Finally, prohibiting obese women's access to IVF to prevent potential harms such as 'fetal programing' is questionable, especially when compared to that child never being born at all. As such, we believe the RANZCOG ban on severely obese women's access to assisted reproductive treatment is unwarranted and should be revised.

Amen to that. Now if only the health authorities would listen. Unfortunately, they seem to be going in the opposite direction, getting more stringent in their weight-related restrictions, as seen in the U.K. limits on male partners too.

Summary

Headline from abc.news.au, 2017

A few brave medical professionals are speaking out about the discrimination happening in fertility treatment despite tremendous pressure from their colleagues. There have been a number of articles published recently in OB journals questioning the ethics of BMI restrictions but so far, none of the national guidelines have changed. And as noted in the U.K., things seem to have gotten even worse.

Bottom line, denying fat people access to fertility treatment is another form of keeping fat people from having children, but many doctors resist acknowledging the implications of these restrictions. They tell themselves they are protecting their patients with these guidelines. They tell themselves it's all about the risks, yet other groups with similar risks are not penalized. They refuse to acknowledge that they are infantilizing larger-bodied people and taking away their personal autonomy over crucial life decisions.

Authorities think that they are doing fat women a favor by insisting they lose weight before pregnancy, yet by insisting on such weight loss they deny women timely intervention when fertility treatments are most likely to succeed. The number of people who lose weight to a "normal" BMI and keep it off is quite small. When authorities insist on a much lower BMI as a requirement for treatment, they basically are keeping fat people from having children. Intentional or not, this is Eugenics.

Denial of treatment is based on weight bias, the assumption that all fat people voluntarily brought on their weight through poor health habits, sloth, and gluttony, and would perpetuate those bad habits to the next generation. Doctors assume that fatness is easily solved through altering health habits and exercising a little more willpower, but this argument does not hold up under scrutiny.

Research is very clear that most people are unable to lose weight and keep it off long-term, so denying treatment until someone reaches an "ideal BMI" or even a 5-10% reduction is unrealistic and delays fertility treatment until it may be too late. As some experts note;

Age trumps everything, so if your plan is going to make these women lose weight, the time that might take them if they’re older is going to be way more significant than any potential benefit in terms of weight loss.

Weight loss surgery does reduce BMI, but research shows significant trade-offs. There are reduced risks for gestational diabetes and large babies, but also increased risks of prematurity, too-small babies, and possibly neonatal mortality. There are no easy answers here.

Potential health complications is a red herring argument. The underlying reason weight has been made an automatic disqualifier is because doctors see people of size as unfit parents who will create more fat people. Sure, there are some fat people who do have poor health habits but so do many thinner women, yet they are not kept from fertility treatment. If health habits were the main concern then EVERY patient should be screened for this and used as a barrier to treatment for all sizes, yet it's only targeted to obese people.

Furthermore, many fat people have medical causes for their weight such as Polycystic Ovarian Syndrome, lipedema, hypothyroidism, etc., and these conditions can impact fertility as well. To deny people with conditions like PCOS treatment is to penalize them for their genetics. People should not be punished for their genetic vulnerabilities.

People of size should be informed of the potential risks of pregnancy at larger sizes, but in a realistic way, not through scare tactics. People of ALL sizes should be encouraged to practice healthy habits and have great nutrition, and should be counseled about their individual risks. In most cases, though, the decision on whether to proceed with fertility treatment must be the person's. The government or a group of doctors has no business controlling whether or not a person has children. It infantilizes women and takes away personal autonomy to impose such rigid guidelines.

Denying fertility treatment based on weight basically keeps a whole group of people from having children and that's always a suspicious restriction that smacks of eugenics.

Those who would deny fertility treatment based on BMI are trying to be the gatekeepers of who are "allowed" to reproduce; this is another insidious form of eugenics and must STOP.


Resources

If you are experiencing fertility issues, here is a brief set of links to resources that might be helpful:

• https://www.fertilityplus.com/faq/bbwfaq.html - an older document and website that has many tips for fertility treatment in women of size. Not entirely diet-free but generally balanced 
• Basal Body Temperature Chart - Chart your cycle to see when you are ovulating 
• Taking Charge of Your Fertility by Toni Weschler, an excellent book about using fertility awareness techniques to either conceive or avoid conception, depending on your intent 
• www.tcoyf.com - Website of the above book; tons of excellent information and aids 
• www.fertilityfriend.com - Other fertility aid charts and information

References

*The full list of references for this post are far too long to include. Instead, here are a few key references and quotes. The other references are scattered throughout the article and have links to the original sources and studies. 

Studies Critical of BMI Limits on Fertility Treatment

Should obese women's access to assisted fertility be limited? A scientific and ethical analysis. Tremellen et al. 2017 Aust N Z J Obstet Gynaecol https://www.ncbi.nlm.nih.gov/pubmed/28299785

Quote: "The absolute magnitude of the risks to mother or child is relatively small, and while a woman has a right to be educated about these risks, she alone should be allowed to make a decision on proceeding with treatment...we should not prohibit obese women from becoming parents because of the increased risk to themselves or their child...."

Should access to fertility treatment be determined by female body mass index? Pandey et al., 2010 Human Reproduction.  www.pubmed.gov/20129994

Quote: "Restricting fertility treatment on the grounds of BMI would cause stigmatization and lead to inequity...Time lost and poor success of conventional weight loss strategies would jeopardize the chances of conception for many women."

It is not justified to reject fertility treatment based on body mass index. Koning et al., 2017. Human Reproduction Open. https://academic.oup.com/hropen/article/2017/2/hox009/4049574

Quote: "Given that patients with, for example, diabetes or previous pre-eclampsia, who are at higher risks than many obese women, are allowed treatment on the basis of individualized and well-informed decision-making, we think there is no justification for taking a different line with regard to BMI."

Should overweight or obese women be denied access to ART?: Comment by: Ahmed Badawy, Middle East Fertility Society Journal, 2013. https://www.sciencedirect.com/science/article/pii/S1110569013001106

Quote: "Those who are choosing to postpone childbearing for the weight reduction should balance the negative effects of aging versus obesity on fertility and perinatal outcomes... there is no strong evidence for the association between obesity and live birth in infertile women. Thus, there is insufficient proof to refute women fertility treatment on grounds of BMI."

We need to stop discriminating against plus-size pregnant women. Raina Delisle, Today's Parent, 2017.  https://www.todaysparent.com/pregnancy/pregnancy-health/we-need-to-stop-discriminating-against-plus-size-pregnant-women/

Women with obese male partners will be denied IVF treatment, rules NHS group. Tom Embury-Dennis. Independent, 2018. https://www.independent.co.uk/news/health/women-obese-men-denied-ivf-treatment-bmi-30-bath-north-east-somerset-ccg-a8248061.html

Should high BMI be a reason for IVF treatment denial? Friedler et al., 2017 Gynecological Endocrinology  https://www.ncbi.nlm.nih.gov/pubmed/28531369 

Quote: "The results of our relatively large retrospective study did not demonstrate a significant impact of BMI on the ART cycle outcome. Therefore, BMI should not be a basis for IVF treatment denial."

Randomized Trial of a Lifestyle Program in Obese Infertile Women. Mutsaerts et al., 2016 New England Journal of Medicine https://www.ncbi.nlm.nih.gov/pubmed/27192672

...The primary outcome [live birth rate] occurred in 27.1% of the women in the intervention [weight loss] group and 35.2% of those in the control group (rate ratio in the intervention group, 0.77; 95% confidence interval, 0.60 to 0.99). CONCLUSIONS: In obese infertile women, a lifestyle intervention preceding infertility treatment, as compared with prompt infertility treatment, did not result in higher rates of a vaginal birth of a healthy singleton at term within 24 months after randomization.

Mr. Fertility Authority, Tear Down That Weight Wall! Hum Reproduction 2016 Dec;31(12):2662-2664. Epub 2016 Oct 19. Legro RS1. PMID: 27798043  Full text here

Discussion of the 2016 NEJM study above and subsequent subanalysis. Quote: "The impression from these epidemiologic studies and the smaller interventional trials is that obese women are damned if they do lose weight prior to pregnancy and damned if they don't. As the LIFEstyle study indicates, dropout rates with lifestyle modification are high (20%), the average amount of weight lost is modest (4.4 kg) and most women will not achieve the targeted weight loss (62%). Furthermore, women who participate, regardless of age, initial BMI and ovulatory status, will experience cumulative lower rates of a healthy baby... pending further studies, these cumulative data suggest that weight limits used to deny women access to fertility care are not only arbitrary, but discriminatory, and clearly not evidence-based.

  

2015 studies on d-chiro-inositol

Here are a few recent (though small) studies on d-chiro-inositol (DCI) for Polycystic Ovarian Syndrome (PCOS). They had promising results. This is good news.

However, this little taste of research on DCI only points out the gaps that still exist and sure leaves me wanting more. So here's my Christmas wish list for PCOS research.

• I would like to see some gold-standard randomized controlled studies with larger study groups. What's with all these little studies? It doesn't mean that much until it's been done with large study groups and replicated several times
• I'd like to see more research from the USA and other countries; why are the Italians the only ones really pursuing this so closely?
• I'd like to see more research done on how DCI affects metabolism, not just menstrual regularity, and whether it slows or prevents progression to Type II diabetes. It's really the metabolic implications that could have the most potential impact on people's health
• I want to know if there is any interaction between metformin and DCI
• I want to make sure DCI is safe in pregnancy and breastfeeding
• I'd like to see DCI studied in post-menopausal women too; that is a vastly understudied group for DCI. Does it impact the incidence of diabetes, heart disease, or stroke?
• I'd like to see DCI studied in close male relatives of women with PCOS. If PCOS women have a secondary messenger insulin signaling defect, wouldn't you think that our male relatives probably have it too? And that DCI might benefit them too?
• I'd like to see this question about which protocol is best (DCI vs. myo-inositol vs. both) settled with better quality research

Okay, I'm cranky and demanding, but with a PCOS medication that shows this much promise, isn't it about time we had larger, more complete, and more qualitative trials?

Come on, PCOS research community, get on the stick. Stop putting out these tiny little fluff studies and start cranking out some meaningful inositol research that starts answering the most critical questions.


References

Gynecol Endocrinol. 2015 Jan;31(1):52-6. doi: 10.3109/09513590.2014.964201. Epub 2014 Sep 30. The menstrual cycle regularization following D-chiro-inositol treatment in PCOS women: a retrospective study. La Marca A1, Grisendi V, Dondi G, Sighinolfi G, Cianci A. PMID: 25268566

Polycystic ovary syndrome is characterized by irregular cycles, hyperandrogenism, polycystic ovary at ultrasound and insulin resistance. The effectiveness of D-chiro-inositol (DCI) treatment in improving insulin resistance in PCOS patients has been confirmed in several reports. The objective of this study was to retrospectively analyze the effect of DCI on menstrual cycle regularity in PCOS women. This was a retrospective study of patients with irregular cycles who were treated with DCI. Of all PCOS women admitted to our centre, 47 were treated with DCI and had complete medical charts. The percentage of women reporting regular menstrual cycles significantly increased with increasing duration of DCI treatment (24% and 51.6% at a mean of 6 and 15 months of treatment, respectively). Serum AMH levels and indexes of insulin resistance significantly decreased during the treatment. Low AMH levels, high HOMA index, and the presence of oligomenorrhea at the first visit were the independent predictors of obtaining regular menstrual cycle with DCI. In conclusion, the use of DCI is associated to clinical benefits for many women affected by PCOS including the improvement in insulin resistance and menstrual cycle regularity. Responders to the treatment may be identified on the basis of menstrual irregularity and hormonal or metabolic markers.

Minerva Ginecol. 2015 Aug;67(4):321-5. Epub 2015 Feb 11. Myo-inositol vs. D-chiro inositol in PCOS treatment. Formuso C1, Stracquadanio M, Ciotta L. PMID: 25670222

AIM: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women in fertile age. It is an endocrine and metabolic disorder characterized by oligo-anovulation, hyperandrogenism and insulin-resistance. Various therapeutic approaches have been attempted in PCOS, including diet and the use of pharmacological agents such as oral contraceptives (OCs) or anti-androgens. Recently, the introduction of inositol in the treatment plan has proved to be as reasonable as useful in countering the endocrine-metabolic disorders of this syndrome. METHODS: The aim of our study was to compare the clinical, endocrine and metabolic response after 6 months of therapy in 137 PCOS women characterized by oligomenorrhea and/or acne and/or mild hirsutism and insulin-resistance. The patients were treated with myo-inositol or with D-chiro-inositol or with placebo. RESULTS: Our study showed that both myo-inositol (MI-PG) and D-chiro inositol (DCI-PG) treatments are able to significantly improve the regularity of the menstrual cycle, the Acne Score, the endocrine and metabolic parameters and the insulin-resistence in young, overweight, PCOS patients. CONCLUSION: Definitely, we assumed that both treatments with myo-inositol and with D-chiro inositol could be proposed as a potential valid therapeutic approach for the treatment of patients with PCOS. Additionally, further examination and for a longer period of treatment are needed.

Arch Gynecol Obstet. 2015 May;291(5):1181-6. doi: 10.1007/s00404-014-3552-6. Epub 2014 Nov 22. Evaluation of ovarian function and metabolic factors in women affected by polycystic ovary syndrome after treatment with D-Chiro-Inositol. Laganà AS1, Barbaro L, Pizzo A. PMID: 25416201

PURPOSE: To evaluate the effects of D-Chiro-Inositol in women affected by polycystic ovary syndrome (PCOS). METHODS: We enrolled 48 patients, with homogeneous bio-physical characteristics, affected by PCOS and menstrual irregularities. These patients underwent treatment with 1 gr of D-Chiro-Inositol/die plus 400 mcg of Folic Acid/die orally for 6 months. We analyzed pre-treatment and post-treatment BMI, Systolic and Diastolic blood pressure, Ferriman-Gallwey score, Cremoncini score, serum LH, LH/FSH ratio, total and free testosterone, DHEA-S, Δ-4-androstenedione, SHBG, prolactin, glucose/IRI ratio, HOMA index, and resumption of regular menstrual cycles. RESULTS: We evidenced a statistically significant reduction of systolic blood pressure, Ferriman-Gallwey score, LH, LH/FSH ratio, total Testosterone, free Testosterone, ∆-4-Androstenedione, Prolactin, and HOMA Index; in the same patients, we noticed a statistically significant increase of SHBG and Glycemia/IRI ratio. Moreover, we observed statistically significant (62.5%; p < 0.05) post-treatment menstrual cycle regularization. CONCLUSIONS: D-Chiro-Inositol is effective in improving ovarian function and metabolism of patients affected by PCOS.

PCOS Treatment: TZDs and Other Glucose-Lowering Medications

We've been discussing Polycystic Ovarian Syndrome (PCOS) and its impact on the health of women of size. It's time to discuss the use of non-metformin options in the treatment of PCOS.

If you've missed the last few posts, so far we've talked about the definition and symptoms of PCOS, how it presents, its testing and diagnosis, and its possible causes.

Currently, we are discussing common treatment protocols for PCOS, and the pros and cons of each. Unlike most resources, we are emphasizing a size-friendly, weight-neutral approach, rather than promoting weight loss for treatment.

We've already discussed metformin. Now, we discuss the TZDs, a.k.a. Actos, Avandia and related drugs, as other insulin-sensitizing agents often used in the treatment of PCOS.

Disclaimer: While the following information is based on my best understanding of the research, I am not a medical health-care professional and no medical advice should be inferred. Always do your own research and consult your healthcare provider.  

Trigger Warning: Passing mention of weight gain/weight loss side effects of some diabetes drugs.

Types of Insulin-Sensitizing Agents 

To summarize the information from previous posts, there are two main types of insulin-sensitizing agents ─ the group of drugs known as biguanides, and the group known as thiazolidinediones (which are also known as glitazones or TZDs). To repeat the summary from one website on insulin resistance:

• Biguanides. Biguanides are drugs that improve the body's sensitivity to insulin by lowering the absorption of glucose in the small intestine, decreasing the liver's production of glucose, and increasing the uptake of glucose in muscle and fatty tissues...
• Thiazolidinediones. These drugs stimulate glucose uptake in the muscles and fatty tissues by activating specific receptors in the cell nucleus. They also lower blood insulin levels in patients with hyperinsulinemia.

Of the biguanides, metformin hydrochloride (brand name: Glucophage) is the only drug still left in use. Metformin has been in use a long time, is very effective for many people, seems to prevent or reduce the risk of many poor outcomes, and has a longer safety profile than many other insulin-resistance (IR) drugs on the market. Because of this, it is the dominant insulin-sensitizing agent on the scene today, and deservedly so.

Thiazolidinediones (TZDs) were all the rage a few years ago because they seemed even more effective than metformin against IR and PCOS symptoms. However, safety concerns arose over the years and two TZDs (Rezulin and Avandia) were pulled from the market or limited in their use, while a third (Actos) remains under investigation.

In addition to metformin and TZDs, there are a few other insulin-sensitizing options for women with PCOS. Inositol (myo-inositol, d-chiro inositol, pinitol) is one option that received a lot of buzz at first and which is now experiencing a resurgence of interest. More on that in a separate post later on.

Limitations of the Data

A big limitation on our discussion here is that we do not have much information on the use of the TZDs for women with PCOS. Most of the information we have on insulin-sensitizing drugs has been done on the type 2 diabetes population only, so their effect on women with PCOS is somewhat speculative.

Furthermore, the studies we do have specifically on insulin-sensitizing drugs in a PCOS population are often short-term. And they place too much emphasis on surrogate outcomes like lower blood sugar or better insulin sensitivity, assuming that these will then translate to less morbidity and mortality down the line, but without actually examining whether or not they do.

As we shall see, drugs with short-term positive effects on risk factors don't always result in result in fewer heart attacks or deaths; sometimes they can actually worsen long-term outcomes. So it is key that we have long-term data on actual end-points, not just the effect on risk factors.

The bottom line is that data on the long-term efficacy and safety of these drugs in PCOS populations is urgently needed. Please keep that in mind as you read this post.

TZDs (glitazones)

The thiazolidinediones (known as glitazones or TZDs) include:

• troglitazone (Rezulin)
• rosiglitazone maleate (Avandia) 
• pioglitazone hydrochloride (Actos)

Basically, TZDs work mostly by improving sensitivity to insulin in muscle and fat tissue. As one resource explains:

The TZDs are a group of medicines that stimulate peroxisome proliferator-activated receptors (PPARs). There are many of these receptors, including PPAR-alpha, PPAR-gamma, and PPAR-delta...Once you stimulate the PPAR-gamma receptors, you improve insulin sensitivity not just in the liver, but everywhere in the body, especially in the adipose tissue and the skeletal muscles.

Like metformin, TZDs also inhibit hepatic (liver) glucose production. They are metabolized by the liver and excreted into the bile. They were introduced in the late 1990s.

Benefits

TZDs have been shown to markedly improve blood sugar. Some research shows that TZDs may improve blood sugar in diabetics even better than metformin.

More importantly in PCOS, TZDs seem to improve insulin sensitivity. Many researchers feel that this is key in helping address the underlying metabolic disturbances of PCOS.

TZDs restores menstrual cycles and ovulation in many women with PCOS, both by itself and when used in combination with clomiphene. It also seems to improve ovulation and pregnancy rates in PCOS women who are clomiphene-resistant and those who don't respond to metformin.

TZDs may improve lipid and triglyceride levels as well. It also seems to lessen androgen levels, improve hormone balance, and improve hirsutism.

Recent research suggests that Actos may also be associated with an improvement in depressive severity in women with PCOS.

TZDs were thought to be the next class of wonder-drugs for insulin resistance. Many women with severe PCOS responded better to TZDs than to metformin, or responded well to a combination of both a TZD and metformin. Therefore, TZDs seemed to be a major step forward for women with PCOS.

But alas, as with many drugs, population-wide use soon found that TZDs came with drawbacks as well as benefits.

Safety Issues and Side Effects

Unfortunately, a number of safety issues have arisen with TZDs.

• Troglitazone (Rezulin) was taken off the market in 2000 because it was associated with a increase in hepatotoxicity (liver problems)
• Rosiglitazone (Avandia) was taken off the market in Europe in 2010 and subjected to restrictions in the US because of a purported increase in cardiovascular events (heart problems)
• Pioglitazone (Actos) has a more favorable risk profile, but has recently been suspended in some European countries because some research suggested it might be associated with an increase in the risk for bladder cancer

At this time, TZDs are only approved for use with type 2 diabetics. Although commonly used for PCOS, this off-label use is still considered experimental.

As noted, most of the safety information we have is based on studies with diabetics and may not be the same for women with PCOS. In addition, it should be pointed out that many of the studies we do have on TZDs and PCOS are very small and short-term, and most do not meet the gold standard of randomized controlled trials.  

One of the risks of TZDs for diabetics is liver failure and/or hepatitis. Rezulin (troglitazone) was taken off the market because of its risk for liver toxicity, but all of the TZDs carry some degree of liver risk. Thus, many doctors recommend liver tests every few months when starting a TZD, and yearly thereafter. They should not be prescribed to anyone with existing liver disease.

A lesser-known risk associated with TZDs is a modestly increased risk of bone fractures and/or decreased bone density. This seems more associated with Actos than other TZDs, but data is still preliminary at this point and some research does not support an association. 

A common side effect of TZDs is edema (fluid retention). Although most who take a TZD don't experience it, edema from TZD use can lead to a significant worsening of undetected pre-existing heart failure. Therefore, weight gain and heart symptoms must be watched for closely in those on TZDs.

Although Avandia has been shown to lead to an increase in cardiovascular events and mortality in diabetic patients, there is still considerable debate over the validity of this finding. TZDs clearly increase the risk for congestive heart failure but the risk for myocardial infarction (heart attack) is less clear. Even if the risk is increased, the actual numerical risk is quite low, so many American doctors feel that the benefits of Avandia still outweigh the risks for some patients. European doctors, on the other hand, have basically discontinued its use.

Unlike Avandia, Actos has actually been shown to decrease some cardiovascular events, especially in those who have already had cardiac events. It can also decrease blood pressure and lipids. So the cardiovascular risk may depend on which TZD you take.

On the other hand, recent information also suggests that Actos could be associated with an increase in risk for bladder cancer in some users:

Although there was no increased risk of bladder cancer among Actos users overall, there was an increased risk of bladder cancer among those who had used the drug the longest. There was also a greater risk of bladder cancer among Actos users who had been exposed to the highest cumulative dose of the drug...FDA officials say in light of this new information, Actos should not be prescribed to people with bladder cancer or people with a history of bladder cancer.

Conversely, TZDs are associated with a lower risk for liver cancer and/or colorectal cancer in some studies. At this time, the relative benefit-risk ratio for each of these cancers is not available so it's difficult to weigh the pros and cons of their use.

Other side effects associated with TZDs may include upper respiratory tract infections, headaches, weight gain, anemia, muscle soreness, macular edema, and decreased effectiveness of oral contraceptives.

It should also be noted that TZDs are considered Pregnancy Class C drugs and, while effective for ovulation induction, should not be continued into pregnancy.

The bottom line is that the very significant benefits of TZDs may be balanced by significant risks.

Current Status and Future Use

While still used, TZDs have begun to fall from favor and many doctors do not consider them a first-line therapy for most people with diabetes. However, they are often still used to help lower blood sugar as diabetes progresses because they are very effective at lowering blood sugar, especially in combination with other drugs.

The use of TZDs as a mainstay treatment for PCOS is even less well-defined. Based on the evidence so far, most care providers feel that they are probably not the best first-line treatment for PCOS. However, they can be effective for those with more severe cases of PCOS, those with very high blood sugar, those with severe insulin resistance, or those who do not respond to/cannot tolerate metformin.

It should be pointed out that a recent review of the TZDs notes that the current TZD drugs comprise only the first generation of this drug class. Many times, the first generation of a drug class finds safety issues and results are improved upon in later generations of that drug class. Several recent reviews hint that the second generation of TZDs are on their way and may show significant improvements in both action and safety. However, only time will tell, since several other "next generation" TZD-related medications have been discontinued due to safety concerns.

For now, the benefits and risks of the current generation of TZDs (mostly Actos) must be weighed on an individual basis. For some, the possible risks may be offset by the considerable improvement in blood sugar and insulin sensitivity that may result. The trade-off would not be acceptable in someone with pre-existing heart disease or liver issues, however.

It is important to consult your healthcare provider carefully about the pros and cons of TZDs before incorporating them into your care, and to get frequent checks of your liver function if you decide to use them.

Combination Drugs

Metformin and a TZD are often used in conjunction for diabetes treatment. This combination seems particularly potent for lowering blood sugar in those with severe insulin resistance or those whose blood sugar does not normalize with metformin alone.

Rather than prescribing two different pills, the two medications are often combined into one pill. This makes it simpler and more convenient for the consumer, and the drug company is able to hold onto exclusive patent use longer for the drugs, thus prolonging the profit margins. As a result, these drug combinations are an increasingly popular way to prescribe diabetes medication.

Here are some common combination drugs:

• Avandamet is a combination of metformin and Avandia (rosiglitazone). It was pulled from the market for a while because of manufacturing problems, but is available again. The controversy over Avandia's cardiovascular safety makes it less popular now, but there is a generic form coming soon
• Actoplus Met is a combination of metformin with Actos (pioglitazone)

Again, the combination of metformin with either Avandia or Actos should probably be reserved for those with severe PCOS, or those whose diabetes does not respond adequately to metformin alone and who have contraindications to other diabetes medications.

Summary

Metformin is the first-line insulin-sensitizing treatment for diabetes because of its long history of usage and good safety profile, and deservedly so because it works well for many people with a relative minimum of side effects. It also seems quite effective for women with PCOS, although whether it should be used for normoglycemic women with PCOS is still debated.

However, metformin is not the only choice out there. In some people's opinion, TZDs also remain a viable choice for some women with PCOS. They are usually considered only when metformin fails to work well enough, has intolerable side effects, or when the patient has pre-existing kidney disease. They also are considered for women with severe hyperinsulinemia or hard-to-control diabetes.

There was much excitement when TZDs first came on the market, perhaps too much. Significant safety questions have arisen over the years, casting doubt on TZDs as a first-line treatment for either diabetes or PCOS. Because of restrictions, pioglitazone (Actos) remains the only real TZD available for most people these days, but it can be a powerful choice if monitored closely.

Newer-generation TZDs may be on their way, but users should remain vigilant about emerging safety research on these and other TZDs.

The potential for toxicity with these drugs is strong. Therefore, it is very important to have frequent blood monitoring before and during any trials of treatment with these drugs, including kidney tests, liver tests, blood sugar (fasting and HbA1c tests), and insulin levels.

The good news is that there are more choices than ever for dealing with the significant insulin resistance and blood sugar complications that seem to be an integral part of PCOS for most patients. The catch is that research into their safety is ongoing and the risks of newer drugs may not be fully known for some time.

Careful vigilance when using any of these drugs is obligatory.


References

General Information on Insulin-Sensitizing Agents

• http://www.inciid.org/faq.php?cat=complementarymed&id=2#106 - INCIID FAQ on PCOS
• http://en.wikipedia.org/wiki/Thiazolidinedione - Wikipedia entry on TZDs
• http://onlinelibrary.wiley.com/doi/10.1002/psb.194/pdf - information about prescribing meds for diabetes, including TZDs and their possible side effects

Overview of Various Diabetes Medications

Oral Diabetes Medications for Adults With Type 2 Diabetes: An Update [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2011 Mar. Report No.: 11-EHC038-EF.
AHRQ Comparative Effectiveness Reviews.  PMID: 21735563

...The objective of this review was to summarize the benefits and harms of medications (metformin, second-generation sulfonylureas, thiazolidinediones, meglitinides, dipeptidyl peptidase-4 [DPP-4] inhibitors, and glucagon-like peptide-1 [GLP-1] receptor agonists), as monotherapy and in combination, for the treatment of adults with type 2 diabetes. RESULTS: The review included 140 randomized controlled trials and 26 observational studies..Most medications lowered HbA1c on average by 1 absolute percentage point, but metformin was more efficacious than the DPP-4 inhibitors. Two-drug combinations had similar HbA1c reduction. Compared with metformin, thiazolidinediones and sulfonylureas had a more unfavorable effect on weight (mean difference of +2.6 kg). Metformin decreased low density lipoprotein cholesterol relative to pioglitazone, sulfonylureas, and DPP-4 inhibitors. Sulfonylureas had a fourfold higher risk of mild/moderate hypoglycemia compared with metformin alone, and, in combination with metformin, had more than a fivefold increased risk compared with metformin plus thiazolidinediones. Thiazolidinediones had an increased risk of congestive heart failure relative to sulfonylureas and bone fractures relative to metformin. Diarrhea occurred more often for metformin compared with thiazolidinedione users...Although the long-term benefits and harms of diabetes medications remain unclear, the evidence supports use of metformin as a first-line agent. Comparisons of two-drug combinations showed little to no difference in HbA1c reduction, but some combinations increased risk for hypoglycemia and other adverse events.

Risks of TZDs

• http://www.webmd.com/cancer/bladder-cancer/news/20110616/new-bladder-cancer-warning-for-diabetes-drug-actos - bladder cancer warning from FDA for certain patients taking Actos
• http://www.theheart.org/article/991339.do - information on fracture risks with TZDs

BMJ. 2011 Mar 17;342:d1309. doi: 10.1136/bmj.d1309. Comparative cardiovascular effects of thiazolidinediones: systematic review and meta-analysis of observational studies. Loke YK, Kwok CS, Singh S. PMID: 21415101

...To determine the comparative effects of the thiazolidinediones (rosiglitazone and pioglitazone) on myocardial infarction, congestive heart failure, and mortality in patients with type 2 diabetes. DESIGN: Systematic review and meta-analysis of observational studies...RESULTS: Cardiovascular outcomes from 16 observational studies (4 case-control studies and 12 retrospective cohort studies), including 810,000 thiazolidinedione users, were evaluated after a detailed review of 189 citations...CONCLUSION: Among patients with type 2 diabetes, use of rosiglitazone is associated with significantly higher odds of congestive heart failure, myocardial infarction, and death relative to pioglitazone in real world settings.

JAMA. 2007 Sep 12;298(10):1189-95. Long-term risk of cardiovascular events with rosiglitazone: a meta-analysis. Singh S, Loke YK, Furberg CD. PMID: 17848653 

...Recent reports of serious adverse events with rosiglitazone use have raised questions about whether the evidence of harm justifies its use for treatment of type 2 diabetes...Studies were selected for inclusion if they were randomized controlled trials of rosiglitazone for prevention or treatment of type 2 diabetes, had at least 12 months of follow-up, and monitored cardiovascular adverse events and provided numerical data on all adverse events. Four studies were included after detailed screening of 140 trials for cardiovascular events... CONCLUSION: Among patients with impaired glucose tolerance or type 2 diabetes, rosiglitazone use for at least 12 months is associated with a significantly increased risk of myocardial infarction and heart failure, without a significantly increased risk of cardiovascular mortality.

JAMA. 2007 Sep 12;298(10):1180-8. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. Lincoff AM, et al. PMID: 17848652

...Pioglitazone is widely used for glycemic control in patients with type 2 diabetes mellitus, but evidence is mixed regarding the influence of medications of this class on cardiovascular outcomes....A total of 19 trials enrolling 16 390 patients were analyzed. Study drug treatment duration ranged from 4 months to 3.5 years. Death, myocardial infarction, or stroke occurred in 375 of 8554 patients (4.4%) receiving pioglitazone and 450 of 7836 patients (5.7%) receiving control therapy (hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.72-0.94; P = .005)...CONCLUSIONS: Pioglitazone is associated with a significantly lower risk of death, myocardial infarction, or stroke among a diverse population of patients with diabetes. Serious heart failure is increased by pioglitazone, although without an associated increase in mortality.

BMJ. 2009 Dec 3;339:b4731. doi: 10.1136/bmj.b4731. Risk of cardiovascular disease and all cause mortality among patients with type 2 diabetes prescribed oral antidiabetes drugs: retrospective cohort study using UK general practice research database. Tzoulaki I, et al. PMID: 19959591

...To investigate the risk of incident myocardial infarction, congestive heart failure, and all cause mortality associated with prescription of oral antidiabetes drugs... CONCLUSIONS: Our findings suggest a relatively unfavourable risk profile of sulphonylureas compared with metformin for all outcomes examined. Pioglitazone was associated with reduced all cause mortality compared with metformin. Pioglitazone also had a favourable risk profile compared with rosiglitazone; although this requires replication in other studies, it may have implications for prescribing within this class of drugs.

BMJ. 2012 May 30;344:e3645. doi: 10.1136/bmj.e3645. The use of pioglitazone and the risk of bladder cancer in people with type 2 diabetes: nested case-control study. Azoulay L, Yin H, Filion KB, Assayag J, Majdan A, Pollak MN, Suissa S. PMID: 22653981

OBJECTIVE: To determine if the use of pioglitazone is associated with an increased risk of incident bladder cancer in people with type 2 diabetes. DESIGN: Retrospective cohort study using a nested case-control analysis. SETTING: Over 600 general practices in the United Kingdom contributing to the general practice research database.PARTICIPANTS:
The cohort consisted of people with type 2 diabetes who were newly treated with oral hypoglycaemic agents between 1 January 1988 and 31 December 2009. All incident cases of bladder cancer occurring during follow-up were identified and matched to up to 20 controls on year of birth, year of cohort entry, sex, and duration of follow-up. Exposure was defined as ever use of pioglitazone, along with measures of duration and cumulative dosage...Overall, ever use of pioglitazone was associated with an increased rate of bladder cancer (rate ratio 1.83, 95% confidence interval 1.10 to 3.05). The rate increased as a function of duration of use, with the highest rate observed in patients exposed for more than 24 months (1.99, 1.14 to 3.45) and in those with a cumulative dosage greater than 28,000 mg (2.54, 1.05 to 6.14). CONCLUSION: The use of pioglitazone is associated with an increased risk of incident bladder cancer among people with type 2 diabetes.

Benefits of TZDs

*See the many links within the post for further studies

Hum Reprod. 2003 Aug;18(8):1618-25. Pioglitazone and metformin in obese women with polycystic ovary syndrome not optimally responsive to metformin. Glueck CJ, et al. PMID: 12871871

...In an observational study of 13 women with polycystic ovary syndrome (PCOS) not optimally responsive to metformin diet, we assessed the efficacy and safety of addition of pioglitazone. We also compared these 13 women to 26 women with PCOS, who were responsive to metformin diet, matched by age and by pre- treatment menstrual history and not different by obesity categories...In women with PCOS who failed to respond optimally to metformin, when pioglitazone was added, insulin, glucose, IR, insulin secretion, and DHEAS fell, HDL cholesterol and sex hormone-binding globulin rose, and menstrual regularity improved, without adverse side-effects.

J Affect Disord. 2011 Jul 20. Use of insulin sensitizers for the treatment of major depressive disorder: A pilot study of pioglitazone for major depression accompanied by abdominal obesity. Kemp DE, et al. PMID: 21782251

...This study was conducted to examine the safety and efficacy of pioglitazone, a thiazolidinedione insulin sensitizer, in adult outpatients with major depressive disorder. METHOD: In a 12-week, open-label, flexible-dose study, 23 patients with major depressive disorder received pioglitazone monotherapy or adjunctive therapy initiated at 15mg daily. Subjects were required to meet criteria for abdominal obesity (waist circumference greater than 35 in. in women and greater than 40 in. in men) or metabolic syndrome. The primary efficacy measure was the change from baseline to Week 12 on the Inventory of Depressive Symptomatology (IDS) total score. Partial responders (≥25% decrease in IDS total score) were eligible to participate in an optional extension phase for an additional three months...During the current episode, the majority of participants (74%, n=17), had already failed at least one antidepressant trial. The most common side effects were headache and dizziness; no patient discontinued due to side effects. CONCLUSION: Although preliminary, pioglitazone appears to reduce depression severity and improve several markers of cardiometabolic risk, including insulin resistance and inflammation. Larger, placebo-controlled studies are indicated.

Other TZD Studies

• http://www.ncbi.nlm.nih.gov/pubmed/23517798 - debate over use of Actos
• http://www.australianprescriber.com/magazine/31/3/58/9/ - review of diabetes meds options
• http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3474645/?report=classic - PCOS meds