Non-Invasive Prenatal Testing

Chromosomally derived anomalies have been with us for millenia –maintaining structural and functional integrity is obviously difficult when you think about it. We humans have 46 chromosomes that must continually divide and reproduce unerring copies of themselves as they issue unique and contextual instructions for cell development or maintenance.

The functional components of chromosomes are called genes and we have around 20,000-30,000 of them, each one built from smaller base pairs like words in a sentence. And depending on the chromosome, each strand of DNA has well over a hundred million base pairs to supervise. It doesn’t take too much imagination to realize that rearranging words in such a sentence, or letters in each word, can alter its meaning. Jumble its information – or even destroy its function…

Throughout recorded history, there has been a recognition that some individuals lacked the same intellectual or emotional attributes as the rest of the community, and yet these people still had a role in the society. They were tolerated and often cherished members of the group and contributed to the weft and warp of the social fabric. Every town had its Village Idiot, to use the ancient (and non-revisionist) term; every village had its special people…

It would seem we live in different times, however, and social values have shifted; there is an expectation of normalcy, if not perfection, in our offspring. The current thrust is early –prenatal– diagnosis of suspected anomalies so that the expectant parents can choose whether the issue lies within their comfort and capability zones.

Prenatal testing has undergone many sea-changes over the years as technology and attitudes have goaded each other. Early tests sought to detect only the most frequent genetic anomaly: Down syndrome –or trisomy 21. As time and ability progressed, more genetic abnormalities have received similar surveillance.

But accuracy of prediction has come under scrutiny of late. It is no longer acceptable merely to arouse suspicion of an abnormality. False positives (thinking the anomaly is present when it is not) and false negatives (not detecting the anomaly) each have their own consequences. Risk of error, in other words, needed to be minimized if decisions were to be reliably dependent on the results.

In Canada, there are currently three (and now four –the subject of this essay) options for prenatal screening of genetic abnormalities –still largely for trisomy 21 because it is by far the largest component of the pool of abnormalities:

  • First trimester screening –done between 11 and 14 weeks gestational age with a detection rate of 87-90% and a false +ve rate of 5%
  • Integrated prenatal screening– consisting of two parts: the first one the same as with first trimester screening and the second between 15 and 20 weeks gestational age. This has a detection rate of 87%-95% and a false +ve rate of 2 to 5%
  • Quad screening– done between 15-20 weeks but with a detection rate of only 81% and a false +ve rate of between 5 and 7%

These results are pretty good and statistically acceptable –unless, that is, a mother has to make an irrevocable decision based on them. There was a need for even more accuracy –less risk- and so technology again rose to the challenge: the Non-Invasive Prenatal Test (NIPT). This is a blood test taken from the mother that measures her baby’s DNA that is floating free in the part of her blood called plasma. It is being continually released into the maternal circulation (with a half-life of around 16 minutes), so it’s an up to date survey of the foetus. There is maternal DNA there though, and the fetal fraction of it is usually about 10% so, to be sure the result is representative, the fetal fraction measured has to be at least 4%… Confused? Well, just remember that it is most reliably measured after 10 weeks gestation and with no upper limit of gestational age; that it has a detection rate of over 98% and a false +ve rate of less than 0.3% (I’ve taken these figures from the June 2014 edition of JOGC).

There are some caveats, of course –there always are- and seemingly a variety of iterations of what can be measured. But by and large it seems close to ideal: high accuracy with minimal if any risk to mother or baby. It is still recommended that a result indicating a chromosomal anomaly be confirmed with an amniocentesis (taking a sample of fluid from around the baby in the uterus) for confirmation, however.

So why don’t we fully embrace NIPT and relegate the other tests to history –tests that were helpful in their time, but indirectly naïve on sober reflection? Well, apart from the current high cost which might preclude its equal availability to all strata of society, there are other ethical considerations. And although these same considerations obtain with any prenatal genetic test, with NIPT these are largely attributable to its accuracy; one could foresee a time when the recommendation for a corroborative amniocentesis to obviate any risk of false positivity might be rescinded, further decreasing the time available for thoughtful and reflective parental decision-making.

Autonomy is the right of an individual to make informed choices for herself. But the key word here is ‘informed’. This implies that the information that informs her is both relevant and appropriate information. And yet, by necessity, it is provided and constructed by others; it is drawn from social and political contexts that she may not share and the options it provides may reflect this. Relational autonomy is an ethical theory that considers the ramifications of those choices that are made available to her. More traditional views have tended to treat the person making decisions as an isolated unit; but in fact, she is embedded in her own -perhaps differing- culture that influences both the context and the situation in which she has to make her decision.

We do not all react the same to identical information, nor is the ability to make an informed choice simply a function of the amount of information available. Women and doctors have different data priorities. Even different message priorities. We all need time to sift through the context; we need time for processing our feelings. Our needs. Our connection to the simmering culture in which we swim.

And then there is the issue of what we want NIPT to detect. Access to fetal DNA offers boundless opportunities in the future for singling out other aspects of the chromosomes we wish to interrogate –whether with serious concerns: hereditary conditions like cystic fibrosis, for example, or with more broad-based anxieties such as concern about random mutations

Other, more frivolous concerns such as sex selection or, in the forseeable future, even searches for –and hence management of- certain genetic traits, present a growing tension between individual autonomy and societal values. For that matter, even detection of the trisomies has engendered much controversy, let alone the prospect of finding and perhaps eliminating other abnormalities not shared by the majority. What is the expectation –perceived or otherwise- after an ‘abnormal’ test? And what is abnormal? What should we accept?

I suppose, ultimately, it is for each of us to decide. Of course Shakespeare offered his opinion long ago: Love looks not with the eyes, but with the mind. But are we still that wise? Or have time and circumstance changed that as well?

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Should IVF be denied to Obese Women?

Obesity has a long and chequered history. Different cultures have both defined it and viewed it differently: in some it was a sign of wealth and was seen as desirable; in others, a sign of weakness, dysfunction, sloth. I use the past tense advisedly, given the rise of fast food outlets throughout the world and their putative role in the rise of obesity in all social strata. Adiposity wears different clothes today.

The classification of weight is now largely dependent on measurement of the Body Mass Index (BMI) -(calculated by dividing the person’s mass -weight- in kilograms, by the square of their height in meters. i.e. M/H x H). In North America, at least, ‘Normal’ weight is less than 25; Overweight is 25-30; Obese is greater than 30. The levels assigned for each category are somewhat arbitrary, however, and various countries -perhaps reflecting differences in diet, genetics, or their own studies- have defined them quite differently.

Obesity, then, is a chimera -a culturally enhanced improvisation; there is little argument about the extremes, but much debate in the middle ground, and therefore about the value at which to begin an intervention -and the resultant stigmatization- if it is solely on the basis of BMI. Not all large people are unhealthy, and neither hypertension nor diabetes, for example, are restricted to that population. So, to base important judgements -with their attendant far-reaching effects- on the measurement of BMI alone is more of a societal bias, a cultural bigotry, than a well-founded and scientifically validated decision.

I am not arguing that excess weight is healthy -or even desirable- but suggesting that to justify treatment decisions on BMI alone risks applying generalizations that are useful when dealing with large populations, but inadequate when considering individuals. No one of us is the herd. And the distinction is an important one.

For example, there seems to be a constantly-shifting move afoot to deny fertility treatments -especially in vitro fertilization (IVF)- to obese women.  Canadian MDs consider denying fertility treatments to obese women   It is based, apparently, on several factors: success rates tend to be lower in this group; the procedure is technically more challenging, and the woman is more likely to suffer complications in the pregnancy that may jeopardize both her and the foetus. The fact that in some jurisdictions, the first one or two treatments may be covered by a government subsidy, suggests that there might also be a feeling that the taxpayer’s money could be better spent on projects more likely to succeed. Or perhaps on issues that benefit more of the electorate.

I have to admit I am conflicted in this. One likes to hope that funds -be they private or public- will be well spent. That there is a reasonable likelihood of success. That the risk/benefit ratio is weighted in favor of the funder. And if this is not the case, then it should be made perfectly clear at the start; the outlook honestly explained, lest expectations trump reality.  http://www.creatingafamily.org/blog/obese-women-banned-vitro-fertilization/

But hope is often unquenchable no matter the argument, so what is an infertility clinic to do? Obviously there have to be some standards for IVF. BMI may well be one of them, but as I have suggested, this is likely only a rough guide to success and seems to have discriminatory overtones, no matter the data.

In medical ethics, decisions are often guided by a few simple principles: Autonomy -the right of an individual to make an informed decision; Beneficence -promoting the health and well-being of others and attempting to serve their best interests; and Non-Maleficence -not intentionally doing them harm (primum non nocere). It is the last of these that seems the most problematic for the IVF clinics. Should they knowingly embark upon a treatment -an elective treatment at that- which may have adverse consequences for their patient? The argument has been raised that doctors don’t apply the same values with respect to dealing with, say, smokers or alcoholics that they do with obese infertile women -all of whose problems are often considered to be self-inflicted, at least by society at large. The argument, of course is specious: the condition of infertility, however unfortunate, is not comparable with emphysema, lung cancer, or liver failure…

I think that a more reasonable approach would be to divide the risks both to the obese woman and her foetus into what I will term heedless risk and assimilable risk. It would be irresponsible, for example, to consider IVF in an older woman, obese or not, with severe, unstable and longstanding insulin-requiring diabetes with hypertension and end stage renal failure -the risks are far too great and the outcome unpredictable at best. Contrast that with a large woman -otherwise healthy- whose only risk is her weight. Yes, there may be technical challenges for the IVF, and each of these would need to be assessed on its own merit and risk; and yes, obese women do have a higher likelihood of pregnancy complications, but so do normal weight women who have, say, pre-existing hypertension, or SLE (lupus). And what about obese women who have become pregnant on their own? We struggle through pregnancies with them…

So I suppose the issue is not so much the risk as the guilt of complicity. The sin of acquiescence: collusion with the woman’s dreams of having a baby. Of actively fostering it. Stepping out of the role of omniscient parent and into the character of enabler. But to see it this way, is to be blind to the other equally important, and yet often forgotten ethical principle: Autonomy. If the risk is assimilable, does the patient not have the right to participate in the decision? Is this not also a requirement of that third principle, Beneficence: serving what she perceives to be in her best interest?

It’s a difficult issue, to be sure, and there’s likely no algorithmically valid approach to its resolution. But in the end, we’re humans, not flow charts -our minds simply do not function well that way. Decisions are not unidimensional, because we are not. Let judgements be based not on the letter of the textbooks, not on the litany of complications, nor on the statistical analyses of non-players, non-actors in the drama. As with the Law, let us consider the spirit in which it was written; details are important, but so are people. Even if they happen to be obese.

 

The Miracle (part 1): A woman’s story in 2 parts

It was still there, no doubt about it. She patted her stomach warily, as if she were afraid it would go away with too critical an examination. But it was real -or as real as any present could be inside a box- hidden away, untouchable: Schrödinger’s cat…  Some things required faith; not everything in life was a punishment.

Up till now it had been a draw. Meaning, purpose, goal -whatever one called it- was a childhood memory, or maybe a fantasy. The fabric of her life, like an often-mended blouse, was intact but barely recognizeable. Even Bill, who had promised so much at first, had not so much the power of a colored thread in any dream she wove. Nothing distinguished him from a thousand others. He was like a picture that had hung above the bed for years: describable in an instant, but noticed only when missing. He added nothing to her life, subtracted nothing. Were other men the same, she wondered, looking vacantly around the room?

She was sitting in the front room – the back room, actually, since it looked out over an ill-kept back yard of aging trees and spotty grass. It was raining as usual and the rotting boards of the patio seemed to stare blankly at the clouds like old men waiting in their beds to die. The furniture was the same, she thought, itemizing it one by one as if she were still a stock clerk after all these years. A china cabinet made of some cheap wood by her grandfather a century or so before, stood at fragile attention across the room, arthritic and brittle with age. She ticked it off mentally with a sigh, noticing the lack of dishes on its shelves. Like her, it merely occupied space.

A lot of the furniture was like that, though -the couch on which she sat, for example. Even looking at it, she was hard-pressed to name the colour. Its utter banality saved her from the need to classify it as to style or pattern. It merely was; it existed, and was allowed to, simply because it was there. No other reason. Nor did the coffee table distinguish itself, except that it was not the floor, nor was it the same color or texture as the blue-green rug. The room was an occupied space; it was not the kitchen, it was not the bedroom… The room and what it contained -including herself- could best be characterized by what they were not; some inscrutable pique of nature had defined them all by inference only.

Maybe that’s why her life had never changed: Nothing is difficult to rearrange. Until now, that is. She allowed herself a little smile and glanced at her unseen present, her secret. For a moment in her mind, it seemed to glow, the colors expanding and wavering with her breath. What did they call those color-filled boxes you held up to the light and turned? Kaleidoscopes? In the grey, unpolished world she now had a kaleidoscope of her very own.

A brief pain lanced though her lower back, followed by a burning sensation in her groin. Not yet, she thought, clenching her fists tightly against the jolt. But this wasn’t the first time she’d felt its complaint. There was also the pressure -the constant, dragging pressure that made her feel as if all her pelvic organs were going to drop out- and the bloating, to the point of nausea. All to be expected however, and she smiled again, embarrassed by her sudden wealth.

It had been a couple of months since she’d begun to feel different. At first, only the pressure and discomfort after eating -nothing major, and really only noticed because she had nothing else to notice in her life. Well, that wasn’t quite true: Bill had seemed more attentive to her. He said she was losing weight, not eating -that she was changing on him. Bill didn’t like people to change because then he never knew what to expect. But what did it matter what he thought? She could see where she was gaining weight… She was different, and that was that.

Bill seldom confronted her with the change, but she could tell he was concerned. Communication was not something he entered lightly and he often changed his mind on the brink of a sentence. Recently he had been trying to fathom the problem from a distance with inquisitive glances and a puzzled look on his face -attempts, in other words, to make her admit there was something wrong. Admit? What he really wanted was a confession. As if she had done something wrong by not being the routine, predictable Emily. She shrugged and sighed inwardly. Maybe if he just talked about it… Or about something: the weather, the supper, her hair, the time of day -anything. Maybe then it would be alright… Or a least better… But of course in a grey and toneless world, words are just passing clouds, indistinguishable after a while from everything else.

She was interrupted in her reverie by Bill -not the man (he seldom came into this room), but the voice… the command, rather. Ever since she had known him, even his questions had been commands garnished over. Then, at least he had tried to disguise them; now he seldom bothered.

“Emily, what are you doing? You’ll be late for the doctor.”

“In a minute, Bill.” Oh how she hated him sometimes. Hated? Was that true, or was it just painful when he surfaced abruptly from the background where he lived? Possibly where they both lived. Until recently she couldn’t have said where she lived, but of course all that was different now.

She rose slowly to her feet, dizziness stirring the room like pudding -but it didn’t last: things like that are not designed to last. Markers -that’s what she called them- events that rimmed a change of state: up, down, standing or sitting… She did not dwell on the thought, and the dizziness passed as quietly as it had arrived.

She ventured a few tentative steps across the carpet but towards the window and not the door as she had intended. A movement outside had caught her eye and she was captured by the damp, leaf-strewn lawn. A four o’clock wind was mindlessly poking at the balding trees that stood like a living fence around the yard. They, too, were brown, but not what had attracted her. There was also the patio, rambling and broken, where a chair leg had teased the ancient boards apart. It was brown as well. And so was the grass under the rhododendron bush that squatted like a disheveled toad in the middle of the yard, untidy, unadorned… But it was the lawn’s problem, not hers.

She sighed and looked away. But not soon enough; there, almost hidden under a yellowed leaf beside the railing of the decaying deck, she saw it. Only the tail was visible now, but a smeared, red line marked its erratic trail. While she watched, the tail twitched once. A cat, brick-still on the rail above, studied the movement for a moment, then pounced. Emily quickly shut her eyes as a wave of nausea rolled over her.

“Emily! What’s keeping you, woman?” This time it was the man who entered the room. Balding and short, he kept fingering a caterpillar-like moustache on his marshmallow face. He looked out of place in the room -like some waxen, glistening beetle that hadn’t yet scuttled out of sight. His head was perspiring and the dim light from the yard speckled it with tiny shadows. “Emily, I thought I asked you to hurry up!”

She looked at him -or rather, through him- like she had the window. “What? Oh, the doctor… I’d forgotten,” she lied.

He stared at her with unreadable insect eyes. “Forgotten?” he hissed, “You asked me to make the damned appointment in the first place. Christ woman..!” He stomped his foot in anger, but to her the gesture and the words were empty. “I can’t understand you,” he sputtered, choking on his saliva. “For a month you’re sick, and when you finally decide to do something about it besides complain, you forget.”

“I’ve never complained,” she interrupted softly.

His face grew red, and he paused long enough from fingering his moustache to wipe his forehead with his sleeve. It was a sloppy habit, she thought, and blinked twice.

“No, you never complain!” he continued. “Not you. Not in words, anyway; words I could handle. No it’s all the other things: the sighs, the groaning at night… No, you don’t complain, you torment.”

It was meant to be cruel she realized, but it had no effect. The words just disappeared into the cracks of the floor hitting nothing: water sucked down a drain.

He turned abruptly and left the room. “I’ll be in the car,” he shouted at the hallway, then vanished as if he’d never been. She could hear him fussing around by the front door, banging things or dropping them in frustration, but he might as well have been outside for all it mattered to her.

The tail was gone now, she noticed; so was the cat. She shuddered at the hidden, unfair struggle going on somewhere outside, but even as she did, it occurred to her that it probably wasn’t like that at all. Life and death likely snuck past her each day unseen… Like her life.

A sudden spasm of pain shot through her pelvis leaving her nauseated. And a horn somewhere continued its insistent complaint. She smiled as the pain eased slowly from her back. Unseen could be a wonderful thing: it was a gift not yet unwrapped.