Saturday 4 May 2019

The Price of Hope

I received some disappointing fertility news last night.  The way I deal with things is to explain them to (mostly unwilling) people (who are trying valiantly to be polite) so, as my reluctant captive audience, you might want to pause here to get a drink and make yourself comfortable.

I’ll start with the general and move to the specific.

The first IVF (so-called “test tube” although conception actually takes place in a Petri dish, much more romantic) baby, Louise Brown, was born in Manchester in 1978.  The second was born in India, which, frankly, surprises me, as the last thing India needs is help increasing its population.  Oddly, the third was born in Glasgow and the fourth in Melbourne, which makes the British Empire IVF pioneers.  The sun never sets on British fertility?

The original purpose of IVF was to help couples in their 20s and 30s who could not conceive the old-fashioned way.  Brown’s mother had blocked tubes, and other early adopters of the procedure had low sperm count.  IVF was emphatically not established to address age-related infertility.  In fact, as its commercialisation spread (over 5 million IVF babies had been born worldwide by 2012), most clinics had a cut-off age of mid-30s.

But age at first birth has been rising, with women delaying motherhood to pursue higher education, careers, financial stability, and to find an appropriate partner.  Also, some women who had children young are remarrying and wanting to have a child with their new partner.  (There is much that could be said about the economic and relationship factors that push women to delay childbearing, not least a discussion of student loans, parental leave, cost of childcare, and the career penalty of the “mommy track”, but I’ll leave that for another post.)

IVF clinics are in the business of making money, and they make loads of it (get it, loads…never mind). A single IVF cycle can cost upwards of $25K in the U.S., and it’s typical for women to endure up to 7 cycles before getting pregnant or (more likely) giving up.  Clinics have responded to the demand for services by women in their 40s by raising their age limits.  But, since they rely on success rates to lure new clients, and IVF success over age 42 is unlikely, they face a conundrum:  Do they take people’s money, when they know the chances of a live birth are essentially zero, and lower their stats, or turn away potentially lucrative clients who will ignore the statistics in their desperation to have a baby? In some cases, regulators have stepped in, with some countries setting an age limit on IVF.  Insurance will not cover it over a certain age, usually somewhere between 39-42.  But the main solution clinics have found is the use of donor eggs (and, in cases where male infertility is a factor, or the woman is single or gay, donor embryos).

Age is no barrier when eggs from younger women are utilized.  Assuming she is otherwise healthy enough to sustain a pregnancy and give birth, an 80-year-old woman could bear a donor-egg child.  IVF success rates with OE (own egg) drop dramatically over age 35, and become essentially zero after age 42, but there is no decrease in success rates with DE (donor eggs).
For women who choose to use donor eggs, and who have no fertility issues besides egg quality, success is virtually guaranteed.  But some women don't want to use donor eggs.  These women are on the cutting edge of IVF, pushing doctors and clinics to use their own eggs despite the odds.  So far, success has been elusive.  Egg quality is the problem.

It’s ALL about the egg.

Whereas men are continually producing sperm (always a good excuse to get out of housework, “Sorry, honey, busy making sperm right now.  I can paint the garage or we can have a baby, your choice.”), a woman is born with all the eggs she will ever have.  Yes, it sounds somewhat ironic, that we are making all of our eggs when we ourselves are still foetuses.  Female fertility commences at puberty, when hormones stimulate the follicles in which those eggs reside to begin maturing.  Fertility declines as that reserve of eggs dies (follicular atresia) and some get used up via ovulation.  Of the 1-2 million eggs present at birth, about 90% will have died off by age 30. By age 50, most women are nearly out of eggs.
Why does it matter that so many die off?  We have plenty to spare:  Since a woman ovulates one egg per month for about 40 years, she uses less than 500 of that million-egg stash.  The issue is egg quality.  Even if a woman ovulates religiously every month into her 50s, her chances of a viable pregnancy decline rapidly after age 30 and precipitously after age 40.  The reason for this drastic decline in fertility is an increase in chromosomal abnormalities in the eggs.  In your 20s, one out of 10 eggs that you ovulate will be chromosomally abnormal.  In your 40s, all 10 will be abnormal.

These DNA hiccups don’t always prevent conception from occurring but, in the days following conception, as the aneuploid blastocyst divides, it is nonviable.  An aneuploid blastocyst either fails to implant or fails so soon after implantation that the woman gets her period as normal and has no idea that conception occurred.  This very early pregnancy failure happens in about 70% of all pregnancies, even in young women, but is usually invisible.  With the invention of super-sensitive home pregnancy tests that can detect the weakest rise in hCG, impatient women who are desperately hoping to conceive obsessively test early, get a positive result, and then are gutted when they get their period.  It's smart to wait until your period is late rather than test early and be disappointed by these extremely common early failures.  But most women whose biological clocks are ticking loudly and thus are desperate that this has to be the month don't have that kind of patience and take advantage of the new early tests only to be let down when their period arrives on schedule despite a positive pregnancy test.

Cruelly, some chromosomal abnormalities take longer to manifest.  The woman misses her period, celebrates a positive pregnancy test, perhaps even tells her partner or announces it to the world, and the early pregnancy progresses normally, but then the aneuploid (abnormal) embryo reaches a point in foetal development where it fails.  This causes a miscarriage usually within the first 5-12 weeks of pregnancy.  Later miscarriages, and stillbirths, are also caused by these chromosomal abnormalities. A 49-year-old woman who conceived naturally has a 99% chance of miscarriage in the first trimester.  That percentage goes down only slightly in the second, with the chances of stillbirth so high in the third that there is overall a less than 1% chance of a woman who conceived naturally at 49 having a live birth.

In some cases, the chromosomal abnormalities are not incompatible with life and are discovered via in utero testing.  So, the few women who don’t miscarry end up needing abortions when abnormalities are detected in utero.  (Some women choose not to get tested, or to carry to term even when tests have shown that their foetus is abnormal.  I find that unconscionable but that is a subject for another post.)

Conventional wisdom says that these abnormalities occur because the eggs are “old”.  But that’s a misleading view.  Men have the same problem:  Male fertility declines slightly in the 30s and dramatically in the 40s and 50s due to chromosomal abnormalities in sperm.  A miscarriage in a woman in her 40s is just as likely to be a result of an abnormality in her partner’s sperm as in her egg, unless he is considerably younger. Since sperm are made fresh every day, it isn’t the age of the sperm themselves that is the problem.  It is not known why abnormalities in both sperm and eggs increase with time but it’s the same with all the cells of our bodies, and may be due to environmental, lifestyle, nutrition, or other factors we haven’t discovered yet.  The point is errors in meiosis increase with age and, whilst they may not prevent conception, they prevent viable pregnancy.  If you get pregnant over 40, you are almost guaranteed to have a miscarriage, not a live baby, at the end of it.

IVF could change all that. In a normal cycle, one egg matures and is released at ovulation.  If it’s a dud, you have to wait a month for another go.  The IVF process involves hyper-stimulating the ovaries with drugs to mature multiple eggs at once, the more the merrier.  I don't want to do it; it’s gruelling, disruptive, and risky:  the woman must inject hormones into her abdomen daily, which have both unpleasant and potentially dangerous side effects, and endure repeated invasive and undignified procedures, including surgical retrieval of however many eggs she has succeeded in maturing.  (The male role in all this is to watch some porn and jerk off in a cup, but no-one said life was fair).

Once the eggs are fertilized in the aforementioned Petri dish (most labs play Ravel’s “Bolero”, but some have reported higher success rates with Prince), they can be genetically tested before implantation.  The more embryos you have to test, the higher the chance that one will be chromosomally normal (euploid).

So why are clinics steering women over 40 to egg donation?  Two reasons:

1)   It’s common in women over 40 for a retrieval of 10 eggs to result in 10 aneuploid embryos. It can take many exhausting and expensive IVF cycles to get even one euploid embryo, and then you have to factor in implantation success rates, which are quite low for all age groups.
2)   In order for the IVF drugs to stimulate multiple eggs to mature, a woman must have a reserve of eggs available.  Reproductive endocrinologists (REs) assess ovarian reserve in two ways:  By counting follicles during an ultrasound and by measuring the blood levels of a hormone called AMH (Anti-Müllerian Hormone—Attorney General Barr seems to produce an excess, but that’s another story…rimshot).  AMH is excreted by developing follicles.  It peaks at puberty and decreases until menopause, when there are no more developing follicles.  The desired level is 1.0-2.5.  Levels of 0.7-0.9 give you some chance, but levels below 0.6 are considered an indication that your ovaries are running out of eggs and have closed up shop.  At this AMH level, via ultrasound one can usually see them displaying little “retired, moved to The Algarve” signs.  Even the most aggressive IVF protocol won’t result in any mature eggs for retrieval in women with low AMH because there aren’t enough eggs left.

The pressure to use donor eggs is egregious.  Most REs refuse to treat any woman over 42 who wants to use her own eggs.  But that is changing.  A few years ago, one clinic in Illinois agreed to treat women up to age 45. Others have followed, with one infamous clinic in upstate NY treating women up to age 49.  Success rates have been low so far:  The oldest baby born to a woman using OE IVF was 47, a record achieved in 2018, beating the previous record of 45, set in 2014.  But success rates may be low in part because the number of women trying to use their own eggs is still low.  As more women delay childbearing, and more clinics become willing to let them try OE IVF, expect to see success rates rise.  Many women also go abroad, because foreign clinics are much less expensive and don’t care about success rates—they are eager to take desperate women’s money.  There is now a clinic in Cyprus that will do OE IVF up to age 50.  (They originally said 55 but the legal age limit is 47 and a crackdown made them lower it to 50.  They're allowed some wiggle room because of the money IVF tourism brings into the country.)

This is where we move from the general to the specific:  I want my own biological child, and I just turned 50 last Sunday.  I delayed trying to conceive until I turned 40, at which point the ticking of the biological clock trumped financial and relationship considerations.  I had one early miscarriage at 42 but no other conceptions (that I know of).  I don’t have the money for IVF but the existence of that clinic in Cyprus is tantalizing.  I realise they are peddling a fantasy: I am a social scientist; I understand statistics. But the desire for your own biological child pushes all realistic assessment of numbers from your mind.

A birthday is a time to assess where you are in life and make a plan for filling any gaps between where you are and where you want to be.  This includes one's health.  To that end, I've made appts for a variety of routine health screenings, including a fertility assessment.  There is only one RE in my (rural) area.  Luckily, he takes my insurance.  My last attempts to see an RE, at ages 42 and 46, went poorly when they flat-out refused to treat me based on my age alone.  I was a nervous wreck thinking this guy was going to laugh me out of his office. Yet, strangely, I also had a good feeling about him, and that was justified.  He listened to my story, my hopes about the clinic in Cyprus, and he didn’t waste my time belaboring statistics I already know or trying to convince me to go the DE route.  When he heard about my PSVT, he further impressed me by immediately referring me to a cardiologist he respects.  That’s not under his purview so he didn’t have to take an interest.

In the end we agreed to the following:  He would test my AMH levels that same day.  At my age, every month counts; you cannot waste even one cycle.  In two days, I would come back for a mid-cycle ultrasound.  IF my AMH was high enough and IF my ovarian reserve and everything else looked good, he’d take me on.  At this point, he leaned across the desk and declared that, if he did take me on, “it would make a full-court press look like a walk in the park”.  I liked his attitude but there is one thing I didn’t tell him:  If he were to initiate this aggressive egg priming protocol, I don’t have the money to go to Cyprus.  But perhaps I could freeze eggs for use years hence when I can afford it.

I initially thought the ultrasound went well:  The tech saw follicles, with a burst one indicating ovulation had occurred, and she said everything looked normal. But the RE had a totally different interpretation.  He saw only 3 total follicles (they like to see at least 10), at least two functional cysts (which are benign and common, occurring when the follicle that has ovulated reseals and fills with fluid; the problem is that a follicle can sometimes fill with fluid without releasing its egg first—the former type has no bearing on fertility, the latter type obviously does) and he found a birth defect known as a septate uterus, where a membrane that is supposed to disappear during foetal development still divides the uterus down the centre.  It is very common and often causes miscarriage; a woman usually cannot carry a pregnancy to term unless the membrane is cut—a procedure that would be routine in a younger woman planning to have children, but which has never been done in someone my age.  RE will likely be of the impression that I have no chance of pregnancy so no point in correcting the defect.  Since it's elective—there are no health implications; it is purely to restore fertility—I don't know if my insurance would cover it.

As for the AMH, late last night, after I was already in bed preparing to sleep, an email popped up from the lab:  My AMH results were in, and my level was an abysmal 0.3.  That is waaaaay below the minimum level for treatment.  I was shocked and disappointed.

But I am not giving up.  I have been reading about ways to improve AMH levels, and even induce the ovaries to make new eggs from stem cells.  I am going to propose that I try these methods for 4 months and re-test in Sept.  RE can’t say no to letting me re-test then, and maybe I’ll be in better financial shape.  But I can’t deny that this AMH lab result and ultrasound were a major disappointment.  I am NOT willing to forego having my own biological child; that is a crucial part of life.  I’ve been feeling as grim as our rainy weather today, and trying to keep my hope, and spirits, up.