Fertility for Patients of South Asian Heritage

Success Rates and Nuances for Patients of South Asian Heritage

Video Lesson

Written Lesson

A Word About Characterizing Patients

In this lesson, we’ll showcase a number of studies that incorporate data (often from the U.K. or U.S.) comparing Caucasian, “Asian”, "Indian", and “South Asian” populations.

We should point out that the approach is inherently challenged for a few reasons.

First, by and large, most studies only categorize groups according to female heritage, race, or ethnicity. This approach may ignore any impact of the man providing sperm.

Next, within such racial and ethnic groupings, definitions vary. While some studies include definitions that are more specific (e.g. “Indian”), few, if any, take a more refined approach (e.g. by Indian region). What’s more, studies may classify patients as “South Asian” (without a definition or weighting of proportion) or simply “Asian”, which may include patients of Japanese or Chinese heritage, amongst others. Needless to say, this makes it difficult to determine who precisely is being studied or whether the findings are "generalizable".

Next, even when there is clarity and consistency, populations therein may be inherently different, and an over-representation of some groups may mask, overstate, or understate observations as they apply to other groups.

Next, even amongst populations of a similar ethnic heritage, the region where they were raised may play some role in their underlying hormonal milieu. The implication, if true, is that observations of a population in one region may not apply to a similar population living in a different region. To illustrate, one small study of women of Bangladeshi heritage noted varying ovarian reserve marker levels (itself a test that needs to be interpreted with caution from a fertility perspective) depending upon whether the women lived in Bangladesh, or the U.K., and if so, the age at which they emigrated.

Finally, some of the data provided here comes from patient populations studied in the United States or Europe and are published in respected, but uniformly, English-langauge journals. The degree to which the findings apply in other countries may remain an open question. Additionally, there may be a number of useful studies that have yet to appear in English-language journals and, as a result, we didn't manage to take them into consideration in this rundown.

Starting Treatment

As we’ve seen in previous lessons, and we’ll show again below, the age at which a woman begins treatment can impact the odds that treatment will work. Below is an example of pregnancy rates post IUI treatment performed at a single, large Indian clinic.

Similarly, below are examples for IVF across broader populations and larger centers in Latin America, China, Japan, and the United States.

In the U.K. and the U.S., a number of studies have shown women of South Asian or Indian heritage tend to start treatment later than Caucasian women. Some of these studies (e.g. Dhillon) reflect larger populations and their observations are of more use.

This finding, if true, may be all the more important because there's data to suggest women of Indian heritage have similar ovarian reserve levels of Caucasian women who are six years older, "suggesting ethnic differences in ovarian aging". (Please note these tests do not correlate with infertility unless someone's been given an infertility diagnosis). Amongst infertile populations, these ovarian reserve tests correlate with the likelihood fertility treatment will work.

If treatment is, indeed, delayed for patients of South Asian heritage, there may be multiple plausible explanations.

Weaker Referral Patterns

One plausible explanation is that in countries like the U.K. or the U.S., some referring doctors may not perceive women of South Asian heritage to be in need of treatment. For example, in a small survey of 155 general practitioners in the American midwest, less than 1% identified “Asian-American” women to be the ethnic group most in need of care. Rather, 82% (incorrectly) cited women of European ancestry. Whether this observation is generalizeable to doctors in regions who see more patients of South Asian heritage is up for debate.

Overarching Barriers to Women's Health Resources

Many studies in the U.K., Canada, and the U.S. reveal a broader trend that women of South Asian heritage receive lower levels of testing and care (e.g. pap testing, clinical breast exams) than similarly matched women in the broader population.

For instance, one U.S. study of South Asian women in New York State reported dramatically lower rates of pap testing despite the sample size's relatively elevated socio-economic status (90% had health insurance, 45% had a household income of over $80,000, and 42% had a masters-or-higher degree of education). Factors like how long a woman had lived in the United States were tightly correlated with odds of receiving a pap test.

Patient’s Own Perceptions of Fertility & Treatment

Finally, women and couples may delay treatment for personal reasons. They may remain optimistic about their ability to conceive naturally or find their current challenges difficult to acknowledge.

We’ve yet to see hard data that indicates South Asian patients are any more likely to harbor these feelings than other groups. However, when we speak with patients, therapists, and doctors of South Asian heritage (as you'll see in our lesson on mental health), many share with us a feeling that prospective patients in these cultures may be more likely to ascribe self-blame for their challenges or grow up in environments where topics like intercourse, reproduction, and fertility were less likely to be broached. In "Asian American Communities and Health", Trinh-Shevrin and Islam arrive at a similar conclusion for patients of Asian heritage broadly and consider this to be a major disintermediator between female patients and doctors.

IVF

There have been a number of studies (mostly originating from the U.K.) comparing IVF outcomes between “South Asian” and Causcasian women. Many have been at single centers, have enrolled fewer patients, and yet most studies show a trend (though not always meeting “statistical significance”) pointing towards South Asian women having lower odds of success.

To overcome the “lower powered” nature of such studies, investigators use a technique called “meta-analysis” that pools the study volume (number of patients) and results from separate studies. Met-analysis has many shortcomings (e.g. challenges in harmonizing disparate studies, judgment on which studies to include, and how to weigh their influence).

Below you can see that in a meta-analysis of the above studies, it appears women of South Asian heritage do indeed record lower IVF success rates at a statistically significant rate. When the same investigator looked through UK CARES databases (where heritage, age, and outcomes are recorded), Dhillon noticed that the odds of success for South Asian patients seem to be lower, once one corrects for a few variables.

Response to Injectable Hormones

When trying to ascertain a possible cause of lower IVF success rates, some studies suggest that South Asian women produce fewer embryos during the IVF process, possibly hampering rates of success. However, a number of studies did not record similar findings.

Fresh vs Frozen Embryo Transfers

Fresh Transfers

If a disparity does in fact exist, another possible explanation is that transfers (using comparably good embryos) are less likely to result in a live birth for patients of South Asian heritage. To illustrate the possibility, let's look at a small study from investigators at Stanford and UCSF in California. In this case, investigators compared live birth rates amongst patients who produced comparably high quality, “blastocyst” embryos.

What investigators saw was that patients of "Indian ethnicity" were less likely to have their embryos “implant” into the uterus, which carried over into lower pregnancy rates. Given the odds of miscarriage was not statistically signifcant between the two groups, ultimately, live births per transfer were dramatically lower in the "Indian ethnicity" population.

Frozen Transfers

In the the previous studies showing lower IVF success rates for South Asian patients, most transfers were probably conducted using “fresh” embryos.

During a “fresh embryo transfer", a woman’s body has only 3—7 days to recover from the injectable hormones given leading up to the egg retrieval. As a result, estrogen levels may remain high and the uterus may be less “receptive” to allowing an embryo to embed in the uterine wall.

However, when embryos are frozen before a transfer, a woman’s body is given a month or more to recover, estrogen levels typically drop, the uterus tends to become more receptive, and implantation rates sometimes rise.

To illustrate the point, let’s look at another small study out of Stanford—the same clinic that produced the results above. In this study, transfers of only frozen embryos were used. As you can see, implantation rates, pregnancy rates, and live birth rates pulled even with what Caucasian patients experience.

While interesting, we need to be careful in interpreting the findings. First, few studies like this exist and so more data is needed to draw any firm conclusions. Next, as with any single center study, one needs to be careful not to overgeneralize the results. The outcomes may be driven by idiosyncracies of the clinic's patient base or how that clinic practices medicine. For example, not all clinics available to a patient may be equally as skilled at growing embryos to "blastocyst" stage, freezing them, and then thawing them. When patients weigh their options, it can be important to calibrate the abilities and track record of the clinic's laboratory (see our lesson here).

Endometriosis, PCOS, & Other Disease States

Endometriosis

There’s data to suggest fertility patients of South Asian heritage are more likely to suffer from specific disease states than other groups.

One example would be endometriosis, for which we have a detailed course you may want to consult here.

Polycystic Ovarian Syndrome (PCOS)

The higher “incidence” of PCOS shows up in many (but not all) of our studies that compare fertility patients of South Asian heritage and those who are Caucasian. We should note, many of these studies were retrospective, single center studies and not designed to identify if a diagnosis like PCOS is more common across populations.

Polycystic Ovarian Syndrome (PCOS) is a group of disorders all of which result from an interruption in a woman's endocrine (or hormone) system. From a fertility perspective, women with PCOS often ovulate an egg irregularly or not at all, making the ability to conceive without assistance difficult, and sometimes, impossible.

Challenges in Diagnosis

Unfortunately, primary care doctors, OBGYNs and fertility doctors on a global basis do a poor job in discerning which women have PCOS. One 2010 study calculated that only 70% of women who truly have PCOS were ever diagnosed by a doctor and over a third of women given a PCOS diagnosis did not in fact have it.

Technically, for a woman to be diagnosed with PCOS, she must meet two of three criteria.

Androgen Excess: A woman has uncommonly high amounts of hair growth on her face or back as well as acne or alopecia. The reality is “uncommonly high” can vary by race or ethnicity or can be hard to detect if the patient treats it. As a result, blood levels can be taken to detect levels of testosterone to make this diagnosis.

Ovulatory Dysfunction: If a woman gets her period more frequently than every 21 days, or less frequently than every 35 days, this qualifies. However, some women can have ovulatory dysfunction and yet still have a “normal cycle”.

High Follicle Count, or Volume, Within Ovaries: A woman qualifies if she has 12 follicles growing/resting in one ovary as detected by ultrasound. Alternatively, if either ovary has a 10mL volume, this qualifies. Some doctors refer to this phenomenon as “polycystic ovaries” (hence the name Polycystic Ovarian Syndrome) but that is a misnomer: the hallmark here is a high number of follicles, not cysts.

Equally important in the diagnosis of PCOS is to rule out any issues driven by an abnormal thyroid or prolactin levels as well as adrenal gland conditions.

PCOS is a highly heterogenous diagnosis, which presents itself in many different forms and phenotypes. Candidly, there is not a "one size fits all" treatment approach, and the best path can often depend on which features (e.g. metabolic factors, low or elevated weight) are more prominent.

PCOS Implications for Fertility Treatment



Value of Diet and Exercise for Some Patients

Generally speaking, weight loss helps PCOS patients who have a high body mass index (BMI) to restore normal ovulatory function (if that is an underlying issue) and ultimately conceive. We should note, many women of South Asian heritage who have PCOS have lean PCOS and for women with lean PCOS, much of the diet / exercise data we'll describe doesn't apply.

Strategies for weight loss often incorporate both diet modification (calorie restriction) and exercise (increased physical activity). Even under intensive weight restriction programs, less than one-third of PCOS patients with a high BMI lose 10% of their body weight. Yet, the data shows that pursuing a weight loss strategy can be effective for PCOS patients with a high BMI who are trying to conceive.

Let’s look at one study conducted in the United States on mostly Caucasian women who have PCOS and a high body mass index. The data showed women who took oral medication like Clomid managed to improve their odds of success when they incorporated dietary improvements and exercise.

Having established that diet and exercise help for women who have PCOS, are anovulatory, and have an elevated BMI, the next key question is whether it’s so helpful that it warrants delaying fertility treatment to try and lose weight.

Amongst younger women with a high BMI with no other indication of infertility (e.g. poor egg quality or sperm), the answer appears to be yes. In comparing two U.S. National Institutes of Health studies, amongst women who underwent 16 weeks of diet and exercise before advancing to oral medication for ovulation induction, success rates were far higher than amongst similar women who skipped diet and exercise and proceeded directly to oral medication.

However, this may not be true for women with a condition where IVF is likely necessary (e.g. women with poor egg quality, who are relying upon poor quality sperm, or have a tubal blockage). Time is especially of the essence for these women if they are older, since IVF success rates on a per-cycle basis quickly diminish after age 35. For many of these patients, it’s not worth the trade-off of lost months (or years) to see if they can reduce their body weight.

Ovulation Induction: Clomid or Letrozole

Most PCOS patients trying to conceive will suffer from ovulatory dysfunction. If a woman is not able to ovulate an egg she won’t be able to conceive naturally.

For these patients, a first line of medical treatment is to take ovulation induction drugs like Clomid or letrozole (Femara) and to time intercourse to coincide with ovulation. Ovulation induction drugs are easy to take (oral) and relatively inexpensive versus other fertility treatment drugs.

Generally speaking, the research suggests letrozole (Femara) is the superior choice as shown by the data below in PCOS patients with fertility challenges. According to this New England Journal of Medicine study an especially large difference was recorded amongst women with a higher body mass index.

Smaller, single center studies in India, Iran and Egypt have suggested that letrozole (Femara) is likely equivalently effective, if not more likely to be effective, than Clomid.

IUI

IUI with ovulation induction (e.g. letrozole or Clomid) is no more effective than ovulation induction on its own. For that reason, unless the PCOS patient also is using poor quality sperm (see our lesson on the semen analysis here), there is not much added benefit to adding an IUI to a letrozole or Clomid cycle.

Alternatively, IUI success rates when accompanied by gonadotropin (a more potent, expensive, injectable hormone) are dramatically higher than ovulation induction alone or ovulation induction with IUI. You will recall in the previous studies four cycles of letrozole achieved roughly 20%—30% cumulative success rates. As you can see below, a single IUI with gonadatropin produces similar results.

However, a third of these pregnancies involved twins or triplets which, for many, is an unacceptably high level of risk to take on. As a result, many doctors steer patients away from this route. If a PCOS patient does pursue IUI with gonadotropins, she must be monitored closely and be prepared for her doctor to start and cancel multiple cycles in trying to find a gonadotropin dose that is likely to be safe and effective. It's critical patients talk with their doctor about the risk of accompanying an IUI with gonadotropins, but the issue is especially pressing if a woman may have PCOS.

IUI gonadotropin PCOS

IVF

Women with PCOS have seemingly comprable, or higher rates, of success with IVF as most other patients. Below you can see the live birth rates after one IVF cycle for U.S. patients with ovulatory dysfunction (many are likely to have PCOS) and those of similar ages with a uterine factor or diminished ovarian reserve.

When Indian investigators from a single center looked at four years of IVF success data amongst PCOS patients, they noted no significant difference between patients put on the "long agonist" drug protocol or the "antagonist" protocol. A broader meta-analysis of 10 studies revealed a similar finding but that PCOS patients suffered lower rates of hyperstimulation on the antagonist protocol because it features a Lupron-only trigger.

Updated PCOS Protocols

Amongst PCOS patients treated in China, investigators noted in the New England Journal of Medicine higher rates of success from "frozen" transfers rather than "fresh" transfers. In this case, patients also suffered lower rates of hyperstimulation.

New PCOS Fresh vs Frozen