Pregnancy Hypertension

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Chandler Marrs
Every now and again I have the great pleasure of stumbling upon a brilliant piece of research; research that shakes the very core of medical science. Sadly, this is not one of those times. No, with the research I write about here, I cannot help but wonder why? Why was this study conducted? Why was it funded? Why was it published in such a prominent journal? And perhaps most importantly, why are there 15, well-credentialed, and likely, very highly accomplished individuals, lending their names to such a weak piece of research? Did they not read the study?

Just last month, published in the esteemed The New England Journal of Medicine, whose impact factor (54) far exceeds most journals in the space by a factor of 10, published a purportedly seminal piece on pregnancy hypertension: Less-Tight versus Tight Control of Hypertension in Pregnancy. The study was a huge, presumably well-funded (through a grant from the Canadian government), multi-center, international, randomized controlled trial set to investigate the important topic how best to treat pregnancy hypertension.

Pregnancy Hypertension

Hypertension during pregnancy is a growing problem that brings with it substantial risk to maternal and fetal health. How to treat pregnancy hypertension is of critical importance but not a single anti-hypertensive medication on the market currently has been tested for safety on pregnant women. Few data exist to evaluate the risks of taking such medications on short-term maternal or fetal health and no data exist to identify long term consequences. Not even the most basic of studies, those that evaluate drug pharmacokinetics and delineate appropriate dosing have been conducted for pregnancy (or any other complex hormonal environment).

Drug disposition and metabolism are altered significantly by pregnancy when hormone concentrations, plasma volume, enzymes, binding proteins, liver and kidney function change radically. These changes impact drug dosing and safety. Without proper consideration for these variables during pregnancy, the potential for overdosing and mis-dosing is significant, increasing the possibility of evoking serious maternal and/or fetal ill-effects. Setting aside the question of whether medications should be given at all during pregnancy (I don’t think they should be), I think we can all agree that when medications are necessary, safety and efficacy data must exist prior to administration.

It is from this perspective, that I approached the current study; a long overdue investigation about the safety and efficacy of anti-hypertensive drugs during pregnancy. Boy was I disappointed. In fact, the authors state: “We did not collect information on common adverse effects of anti-hypertensive medications…”  In fairness, however, other important outcome data were collected, but the design of the study was so arbitrary that any potential insight these outcomes might have contributed, was lost.

Study Details

The current study asked whether controlling maternal blood pressure strictly within a pre-defined range of parameters provided better or worse maternal or fetal outcomes compared to a more flexible approach with a broader range of accepted blood pressure metrics. For the tight control group, the goal was to maintain diastolic blood pressure at or below 85 mm Hg. For the less tight group, diastolic pressure was to be maintained at or below 100 mm Hg. The study accepted medicated and non-medicated hypertensive women (n = 987, 56-58% were medicated from each group prior to entering the study), who were anywhere from 14 weeks of pregnancy through 33 weeks pregnancy (mean = ~23 weeks).

Once participants were enrolled into the study, decisions regarding whether to medicate (if not previously medicated), which medication to use, and at what dosages, were left to the providing obstetrician’s discretion. The study excluded women who, at the time of admission into the study, showed signs of pre-eclampsia, demonstrated high systolic blood pressure (>160 mm Hg), had pre-gestational diabetes, renal disease or were utilizing ACE inhibitors (angiotensin-enzyme-converting enzyme inhibitors). If these conditions developed subsequently, patients remained in the study.

The primary outcome variables included: pregnancy loss (miscarriage, ectopic pregnancy, elective termination, perinatal death), high level of neonatal care for greater than 48 hours, gestational age and weight at delivery and a range of neonatal complications. Secondary outcome variables, measured at a much more rigorous statistical significance level (p>.001) compared to the primary variables (p>.05) included: serious maternal complications (uncontrolled hypertension, transient ischemic attack or stroke, pulmonary edema, renal failure and transfusion), placental abruption, severe hypertension (>160 mm Hg systolic or >110 mm Hg diastolic blood pressure), pre-eclampsia or abnormal labs indicative of incipient pre-eclampsia.

Results

The reported results of this study were as follows:

  1. There were no between group differences in either maternal or fetal complications.
  2. Women in the less tightly controlled group had higher blood pressure.

So for all of the money and time spent, we learned that anti-hypertensives do, in fact, reduce blood pressure, and that how intensely one uses these medications has no statistical bearing on this particular set of outcomes. This is not to say that there were not negative outcomes. There were plenty in both groups of participants; from severe maternal hypertension, pulmonary embolism and pre-eclampsia, to serious neonatal complications and fetal death. There were simply no statistically identifiable differences in the rates of these complicatiosn between the two groups. In other words, both groups had similar rates of negative outcomes.

Flaws in Study Design

Why weren’t there any statistically relevant differences between the two groups?  The answer to this question involves study design and herein we have a number of problems. First, the participant pool was largely hypertensive and medicated before entry into the study, providing no real control group from which the assess differences between blood pressure and outcomes in unmedicated versus medicated women. Elevated blood pressure is a significant risk factor for a number of maternal complications but so too are medications. What is the risk/benefit calculus that determines when the inherent risks of medications during pregnancy are outweighed by the risks of maternal blood pressure? In other words, when should we medicate to control hypertension?  Delineating between the dangers of the blood pressure versus those of the medication would have been more telling. Admittedly, such a study would present ethical considerations and quite possibly could have only been done retrospectively. Nevertheless, without these types of data, it is impossible to discern either the safety or efficacy of any therapeutic intervention; effectively nullifying the results from the onset.

A second methodological problem is the failure to address statistically pre-existing health conditions and environmental variables that confound results. That is, we don’t know what portion of the overall negative outcomes might be attributable to pre-existing or even extraneous maternal health issues versus medication use or blood pressure control. For example, a good percentage of the women in both groups were not only medicated prior to entry into the study but were significantly overweight pre-pregnancy, smoked and/or had additional health considerations. These variables would independently impact maternal and fetal outcomes, but also, could additively or synergistically influence blood pressure and other maternal risk factors. Although the mean data for both groups were presented, no analyses that might provide a richer understanding of the relationship between blood pressure and perinatal outcomes was given.

Perhaps the most problematic aspect of this study was the failure to analyze data regarding the types and dosages of medications relative to the negative outcomes. Though the researchers collected medication data and reported some of those data in the supplementary appendices (number of women per group who took a particular type of medication absent dosages was reported), there were no analyses presented. This made it impossible to identify whether certain medications were more dangerous than others and would account for the observed negative outcomes in either group. Neither did this report tell us about the dose-response relationship relative to effective blood pressure management versus adverse reactions – a very basic calculation – nor did they tell us about the role of medication interactions in the observed negative outcomes.

What Value is This?

From the standpoint of a practicing physician, a researcher or a patient, what use is a study on medication safety and efficacy during pregnancy, if there are no analytics delineating dose-response relationships by medication(s) and risk factor?  Is one medication safer than the others? Does a particular medication work better or worse for a specific group of women? Are there anti-hypertensive medications that are more or less effective during pregnancy at managing blood pressure? Or even more basically, are the dosages we currently use correct? With such a large study group, we could have learned which medications could be used safely during pregnancy, at what dosages, and with which groups of women. It is likely that some women should absolutely not be given medications due to confounding health conditions.

To answer any of these questions would have been highly useful and added significantly to the body of scientific research on pregnancy hypertension. In its current form, however, this study adds little, if anything, to our understanding of the pregnancy hypertension, the use of medications to control hypertension during pregnancy or their potential negative side effects. All this study tells us is that blood pressure medications tend to lower blood pressure and evoke complications in some women. Well, of course they do. That is not novel. We knew that already.

There are so many missed opportunities here. Not parsing the medication, dosage data was an egregious omission; one that makes me wonder why it was funded and why it was published in such an esteemed journal. And with 15 authors attributed to this study, why did no one on the masthead push to expand the analytics beyond what was presented? Pregnancy hypertension can be deadly and there is a striking lack of research in this area. Why are we not asking the big questions?

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