Dr. Moser: One issue that came up in the process of preparing guidelines addressing the treatment of hypertension in pregnant women is that the obstetrics and gynecology (OB/GYN) community is becoming more sensitive to the risks of systolic hypertension. In the last few years, diastolic blood pressure (BP) has been the prime focus. However, people who deal with pregnant women are becoming more aware and concerned about the implications of systolic hypertension.
That’s one of the reasons we’re having this conversation. One of the more controversial issues in medicine has been that of hypertension in pregnant women. The guidelines have not changed much in the last 50 years, although some effort to update these guidelines has been made recently. Today, we discuss the following: (1) The definition of elevated BP in pregnancy: is it too complicated? (2) Indications for therapy; should you wait until the BP increases to levels of 160/105 to 110 mm Hg? Is there any danger in allowing the systolic BP to remain elevated for a few months in a pregnant woman? (3) The indications for interruption of pregnancy; should we begin treatment earlier and continue to use the drugs that have been suggested over the years? During pregnancy, hypertension is typically classified as chronic hypertension (pre-existing or onset prior to 20 weeks gestation), gestational hypertension, preeclampsia, or preeclampsia superimposed on chronic hypertension.
I’m Dr. Marvin Moser, Clinical Professor of Medicine at Yale. We have with us Dr. Phyllis August, Professor of Research and Medicine and OB/GYN at Cornell Weill Medical College; Vesna Garovic, a Professor of Medicine at the Mayo Clinic who has done a great deal of work on hypertension in pregnancy; and Dr. Carl Rose, Associate Professor of Maternal-Fetal Medicine at the Mayo Clinic, to discuss this controversial subject.
Dr. August, let’s start with you. What about the definition of hypertension? We have a very complicated list of definitions of hypertension in pregnancy; do you want to review some of those? Should we simplify the criteria for clinicians?
Dr. August: I think we need to distinguish between the diagnostic category and the definition of hypertension. The definition of hypertension for the general, non-pregnant population is not very different from that for pregnant women. Obstetricians speak about mild hypertension in pregnancy, which they define as a systolic pressure of 140 to 150 mm Hg and diastolic pressure of 90 to 109 mm Hg, and then severe hypertension. There are 2 categories for hypertension: severe hypertension is a pressure of 160/110 mm Hg and above, and mild to moderate hypertension is a pressure below that level. The diagnosis of hypertension is made at a pressure of 140/90 mm Hg and above, so really, it’s not very different from Stages 1 and 2 of essential hypertension outlined in the last Joint National Committee report.1
Preeclampsia, preeclampsia superimposed on chronic hypertension, chronic hypertension alone, and gestational hypertension are the diagnostic categories within which you can have either mild to moderate or severe hypertension.
Dr. Moser: Do we need all these designations? I know that the pathophysiology of preeclampsia is different from that of essential hypertension, but are the definitions helpful for the clinician? What’s the difference, for example, if you have someone with chronic hypertension who becomes pregnant? What if you have someone with pre-eclampsia superimposed on chronic hypertension, and you have these 4 categories. Are they helpful? Does this definition affect therapy?
Dr. August: They are helpful because what we really need to identify is the condition of the woman who, because of the pregnancy, is either developing new hypertension, or that of a woman who had hypertension before, but because of the pregnancy, her hypertension is worsening. That situation can change quickly, leading to serious maternal vmorbidity and fetal morbidity. This also helps to identify women who really need to be watched closely and addressed in a different way from someone who, at the beginning of pregnancy, had a pressure of 150/100 mm Hg and has the same pressure even at mid-pregnancy. I think the diagnostic categories are useful, and the fact that they’ve been used for many decades supports their effectiveness. They’re not perfect, but they are useful.
Dr. Moser: Dr. Rose, do you want to add to that?
Dr. Rose: As an obstetrician, I would suggest that these categories allow us to communicate with one another using common terminology that we collectively understand. It also influences the obstetric management of these patients.
Dr. Garovic: It is likely that young women who don’t see a physician and present with a BP of 150/100 mm Hg when they are pregnant, have had hypertension for a longer period, which has been asymptomatic and subclinical and that it has been brought to the attention of the clinician only due to the pregnancy.
Having said that, I’m not sure that it helps that much with respect to treatment because target levels at which BP treatment is started are decreasing, especially in the tertiary centers. My approach is to treat a pregnant woman with a documented systolic BP of 150 mm Hg on at least 2 occasions, whether symptomatic or asymptomatic and at risk for preeclampsia or not.
Dr. Moser: In the last American Society of Hypertension recommendations,2 it was clearly stated that the level of the BP should guide treatment and the decision of when to interrupt or deliver the pregnancy. So, if it is the level of BP that the clinician is following, why do we need sub-designations? In other words, if the woman has chronic hypertension to start with, you’re obviously going to try and keep the systolic BP below 140 mm Hg. If she develops hypertension in the first trimester or second trimester, which is a rare occurrence, you’re going to reduce the BP. If she develops hypertension in the third trimester with or without proteinuria, for example, you’re going to treat it. So, why don’t we simplify this and treat the BP without 4 or 5 definitions? Of course, if the BP rises and there is proteinuria in the third trimester, other options will also need to be considered. Also, proteinuria in the second trimester is an indication of preeclampsia.
Dr. August: In my experience, if you have a patient who has a BP reading of 120/80 mm Hg at the start of pregnancy, and then at 20 weeks, the BP is 150/100 mm Hg, even with no proteinuria, you have to be very worried about the patient because she’s developing either superimposed preeclampsia or gestational hypertension, until proven otherwise. That’s different from a BP of 150/100 mm Hg that was stable and started out that way at 8 weeks of pregnancy, and then at 20 weeks, it still is 150/100 mm Hg. There has been no change, and no evidence for an evolving process that is potentially dangerous to the mother and fetus, so I would disagree that it’s just a number.
Dr. Moser: How would you treat the patient differently, Dr. August?
Dr. August: If a woman had a clear, well-documented pressure of 110 to 120/70 to 80 mm Hg early in pregnancy and then in the second trimester and developed mild to moderate or Stage 1 hypertension, I would make sure to check all her laboratory data and rule out preeclampsia, but I would be very worried that she was developing a pregnancy-related disorder like pre-eclampsia or gestational hypertension, and I would examine her very frequently.
Dr. Moser: But would you treat her BP?
Dr. August: I would probably treat her BP if it was 150/95 to 99 mm Hg. Even though the guidelines say 160 mm Hg, 150 mm Hg is close to 160 mm Hg and since the patient’s pressure is currently at 150 mm Hg, it may increase to 160 mm Hg in an hour from now when the patient is a little more stressed and uncomfortable; therefore, 150 mm Hg is my cutoff.
Dr. Moser: Consider this: the normal systolic pressure of a pregnant woman is 110 mm Hg, 120 mm Hg, or even lower sometimes, and even in the second and third trimester, it shouldn’t be more than 120 mm Hg, and 130 mm Hg at the most. Now, if a woman’s pressure exceeds the 140/90 mm Hg cutoff of hypertension, why do obstetricians wait until the level increases to 150 mm Hg, or as you said, 160 mm Hg?
Dr. August: They wait because they think lowering the BP too much might compromise the placental perfusion.
Dr. Moser: Dr. Garovic or Dr. Rose, can you comment on the concept that an elevated systolic pressure for a couple of months in pregnancy isn’t going to do any harm?
Dr. Rose: I agree with Dr. August that the pathophysiology of the processes is different. In other words, I do not believe that we should simply treat hypertension and categorize all the accompanying processes as a similar prenatal complication. If a mother develops new-onset hypertension late in pregnancy, certainly this represents a different clinical scenario from one who develops hypertension at 18 weeks of gestation, although implications for the pregnancy may ultimately be similar.
Dr. August: But I would argue that a woman who develops hypertension at 18 weeks and didn’t have it at 12 weeks is at a more serious risk for preterm birth than the woman who develops hypertension in the third trimester.
Dr. Moser: Let me argue on the other side again. Such patients are at risk, but what are you going to do about the risk? You’re going to check some enzymes and chemistries, etc, but what is the only thing that you might do to reduce the risk of progression of hypertension or a small placenta, which may be a result of infarcts from elevated BP? I’m trying to determine whether just lowering the BP, even though the pathophysiology is different, might prevent progression of hypertension. I know it may not prevent the progression of preeclampsia, but early treatment might prevent or delay interruption of pregnancy, based upon the criteria of an elevated BP.
Dr. Garovic: I just want to clarify the point that I was discussing earlier. A BP of 150/100 mm Hg at 21 weeks’ gestation may represent a significantly elevated BP, as the patient’s BP, at that time of pregnancy, should be even lower than her pre-pregnancy levels. I would not treat somebody with a BP of 150/100 mm Hg based on a single office reading for the same reason that we may not treat hypertension based on a single office reading in the general population. However, if I have enough evidence that a patient has sustained hypertension, especially in the second trimester when the BP should be lower than non-pregnant levels, I will treat that patient. Treatment is given after a 6-hour BP reading or nurse-monitored BP readings over a 30-minute to 1-hour period to generate enough evidence to show that BP is certainly steadily elevated.
I would like to discuss a recent patient: she was a 36-year-old woman with a BP of 150/100 mm Hg. It was her first pregnancy, and she was approximately 12 weeks pregnant. She was referred to us from one of the regional clinics close to Rochester. She underwent a retroperitoneal ultrasound, which showed bilateral renal artery stenosis/fibromuscular secondary to fibromuscular dysplasia. So, she had a BP of 150/100 mm Hg, but by the time she saw us, her systolic pressure was 160 to 170 mm Hg and diastolic pressure was in the 100s range. Dr. Rose and I aggressively treated her with 300 mg labetalol twice a day and nifedipine once a day; her BP effectively was reduced to 120 to 130 mm Hg systolic pressure and 70 to 80 mm Hg diastolic pressure, and she delivered a full-term baby boy at 38 gestational weeks.
Dr. August: Let me ask you a question: did she really have renovascular hypertension? Was she successfully revascularized and did her blood pressure normalize after revascularization?
Dr. Garovic: At 6 months post-partum, she underwent a renal angiogram with bilateral angioplasties with a subsequent normalization of her BP. She remains normotensive, when off BP medications.
Dr. Moser: Do you believe that if we treat elevated BP early, we might delay or prevent iatrogenic preterm deliveries?
Dr. August: Yes, I think your point is that if somebody in the third trimester has preeclampsia or gestational hypertension and severe hypertension, and you lower their BP and, if all other parameters are normal, the baby is fine, and the mother’s platelet count is normal, you can prevent her from having a preterm birth. You can extend the pregnancy by preventing the BP from reaching levels that are too dangerous and thus require delivery.
Dr. Moser: Dr. August, you mentioned a concern regarding a reduction in placental blood flow possibly affecting the birth weight, etc. What’s the evidence against treating a woman whose pressure is above 140/90 mm Hg, which you defined as hypertension? Why not treat her at that level, because that’s a high level for a pregnant woman? It should be lower at approximately 110 or 120 mm Hg. So, why not treat the patient when the pressure is at 140/90 mm Hg? Is there strong evidence to show that lowering the BP slowly is detrimental to the fetus?
Dr. August: I don’t think there’s any such strong evidence, but there are several issues to consider. One is that you need to weigh the risks and benefits. We don’t have convincing data on the effects, except the hemodynamic effects, of the drugs on the baby’s neurologic development and organ development. We have certain drugs that we think are safe, but have they been rigorously evaluated? Can we say with a 100% certainty that these drugs have absolutely no adverse effects on fetal growth and development? No, we can’t.
During pregnancy, we avoid exposure to any drug. The question is “what are the risks of treating mild hypertension and what are the benefits?” The treatment benefits to the mother maybe fairly small at 140/90 mm Hg. The risks to the baby are not fully known yet. Hemodynamically, we don’t know that the placental blood flow is being compromised. The data that suggest that smaller babies are a result of lowering the BP are very poor. However, you have to think that it’s probably better to use as few medications as possible during pregnancy for those reasons. Dr. Rose, I’d like to hear your opinion on this.
Dr. Rose: I would concur with Dr. August. Although Peter von Dadelszen’s 2002 metaanalysis3 suggests an association between BP control and fetal growth restriction, the more recent systematic review from Abalos4 suggests that treatment of chronic hypertension during pregnancy for lowering the BPs to thresholds lower than historically considered for therapy, should have a very small effect on neonatal birth weight.4
Dr. Moser: Maybe, some newborns born of hypertensive women are smaller because of the placental infarcts.
Dr. August: It is entirely plausible that hypertension contributes to placental pathology; The question of which is worse—mild hypertension or antihypertensive therapy—has simply not been adequately studied either. It’s just the general principle of whether you can avoid using a medication during pregnancy; if you can, you avoid it, whatever be the medication.
Dr. Garovic: I don’t know whether Dr. Rose and Dr. August would agree, but that meta-analysis3 has one important limitation that is hardly ever addressed. It was published in 2002; so, basically, it included studies published before 2000 when doctors were even more reluctant to treat hypertension. Who was getting treated then? It was likely severely hypertensive women and those with diabetes and other risk factors that are associated with an increased risk for intrauterine growth restriction from the beginning of their pregnancies. So, there may have been an initial selection bias about whom to treat. Therefore, intrauterine growth restriction in these women is likely, at least in part, related to their underlying comorbidities.
Dr. August: I completely agree with Dr. Garovic about that, and yes, I think you make a very good point.
Dr. Moser: To summarize this particular part of the discussion, all of you would agree that treating a patient with a BP > 140/90 mm Hg, even though that’s the definition of hypertension, may not be a good idea because the use of any medication in pregnancy is to be avoided, if possible. I believe that 140/90 mm Hg is an abnormal BP in a pregnant woman, whether it’s at the beginning of pregnancy or later on at 20 weeks or 30 weeks of gestation. I would favor treatment and lowering of BP slowly, because I don’t think the evidence showing fetal harm is very strong. The general consensus, however, of the experts thus far is that they are reluctant to treat a patient until the pressure reaches 150/100 or 155/100 mm Hg.
Dr. August: Well, it’s toward 150 mm Hg. One thing I can say with certainty is that we don’t have good data. We don’t have data to indicate that that treating a pressure of 140/90 mm Hg is harmful, nor do we have good data to show that treating mild hypertension is beneficial.
Dr. Garovic: I don’t know whether current theories would agree with that, but if a young patient (say about 28 years old) without any risk factors has a steady elevation of BP above 140/90 mm Hg, and I see her when she is 12 weeks pregnant, ie, early in pregnancy, I will treat her and follow-up her BP closely.
Dr. August: I agree with that.
Dr. Garovic: Again, I don’t think that it is a wise decision to treat hypertension based on a single BP reading. For me, a steady BP above 140/90 mm Hg in a young patient is an indication for treatment. We are trying to identify these patients very early and keep their BPs at 130/80 mm Hg throughout their pregnancies.
Dr. August: I would agree with that.
Dr. Moser: Would all of you agree that if a woman came in pregnant with chronic hypertension on medication, the medication should be continued, except for agents that effect the renin-angiotensin system, with the caveat that in the first trimester, you might have to lower the dosage because the pressures may be lower?
Dr. August: Most of the time, we do that. We don’t stop all the medications. We follow-up the patients closely. We see if the pregnancy has caused a decrease in BP. If the patient’s BP is 110/70, we would consider reducing the BP medications; we keep many women on medications during pregnancy, as long as they’re safe under them.
Dr. Moser: But you’d keep them on a diuretic or calcium channel blocker?
Dr. August: I would choose nifedipine because there’s more data about nifedipine.
Dr. Garovic: I agree with that.
Dr. August: I think amlodipine is safe, but unfortunately, there aren’t a lot of data on it. I have used verapamil; there are some data on it, although not comparable to the data on nifedipine.
Dr. Garovic: Verapamil also acts faster than amlodipine: it starts working earlier.
Dr. Moser: What about the continual use of diuretics, for example?
Dr. August: I continue administering them, particularly in patients with salt-sensitive hypertension. It is often possible to lower the dose during pregnancy if blood pressure decreases. I stop spironolactone but not hydrochlorothiazide. I don’t think there are a lot of data on chlorthalidone in pregnancy.
Dr. Moser: Dr. Rose, would you agree that if a person with known hypertension came in on medication, you tend to continue it, with the caveat, as Dr. August said, that if the pressure reduced, which it does in the first trimester, you might have to adjust the dosage downward, and, of course, never continue an angiotensin-converting-enzyme inhibitor, angiotensin receptor blocker, or renin inhibitor because of damage to the fetus?
Dr. Rose: Absolutely. During the second trimester, when the physiologic fall in BP occurs, one may need to discontinue medications in some patients, anticipating that therapy will be resumed later in gestation during the third trimester when BPs begin to rise.
Dr. Moser: Just a quick comment about the work that you’ve been doing on the potential problems with systolic pressure that remains high for just a few months. For many years, physicians said that a systolic pressure of 150 or 160 mm Hg for 3 or 4 months in a young woman is nothing to worry about, and there are no obvious signs of trouble. Do you agree with that?
Dr. Garovic: We are now trying to conduct a population-based study and see the effects of that “short” duration of hypertension in pregnancy with respect to cardiovascular risk later in life. Chances are that hypertension of any duration may induce vascular damage. For example, magnetic resonance imaging studies of the brain in women with eclampsia showed vasogenic edema involving the posterior circulation, which, with neurological signs and symptoms, was consistent with the diagnosis of posterior reversible encephalopathy syndrome. Follow-up studies of these patients have suggested that permanent cerebrovascular damage of the brain may occur in some of them.5,6 These changes may have some long-term effects on their neurological health and cognitive functioning later in life.
Dr. Moser: So, you’re convinced that a BP of 150 or 160 mm Hg, even for just 4 or 5 months in a young woman, might produce some long-term vascular changes?
Dr. Garovic: I think that there is a high possibility for that. Again, we don’t have data to support it, but the absence of evidence is not the evidence of absence. I would be delighted to see a study following up these women after their affected pregnancies. A paper published in the Journal of American College of Obstetrics and Gynecology7 indicated that women with a history of eclampsia have self-reported poor cognitive functioning years after their pregnancies. So, preeclampsia and brain neurological deficit are concerning conditions, and we don’t know whether they are related to only the BP or some other mechanisms. For example, endothelial dysfunction, which is a systemic condition in pre-eclamptic pregnancy, may actually facilitate any kind of vascular damage induced by high BPs.
Dr. Moser: There is evidence of endothelial dysfunction in hypertension too. Drs. August and Rose, would you agree or disagree that systolic BPs of 150 or 160 mm Hg for 4 or 5 months can produce permanent vascular changes?
Dr. August: I wouldn’t rule it out. It could happen in some people, and maybe there’s some heterogeneity; some might be able to tolerate it with impunity, but it may be more dangerous in people with other vascular risk factors or older individuals. High BP for 4 to 6 months is not very good.
Dr. Rose: I would agree. I think that at this point, we don’t have substantive data that speak one way or the other. But, it certainly seems very reasonable.
Dr. Moser: Yes, in some of the hypertension studies done in pregnant women, it would appear that if you treat early, the benefit is greater. But as you say, the data are certainly not compelling.
Since we don’t completely agree on when you should start treatment, although I think there’s a tendency toward earlier intervention, perhaps we should discuss what medicines should be used now. Obstetricians have been using alpha methyldopa and hydralazine for many years, because they’re comfortable with them and because studies have shown that they’re well tolerated. All of us in the hypertension field, however, know that these may not be the most effective drugs, and if you use them and the pressure keeps increasing, there’s a tendency for pregnancy interruption. What about changing the treatment algorithms, even though, as Dr. August has pointed out many times, there is little evidence of long-term outcomes with some of the newer drugs. Except for the angiotensin-converting–enzyme inhibitors and the angiotensin receptor blockers, there is very little evidence of fetal problems with beta blockers, although there is a report of smaller babies, but that was questionable as obstetricians are reluctant to use beta blockers, calcium channel blockers, or diuretics, partly because of lack of experience and possible litigation.
Dr. Rose: We are a relatively conservative group.
Dr. August: We use labetalol a lot. I think everybody’s happy with labetalol, which is an alpha-beta blocker. It’s reasonably effective, so I think that’s become the drug that everybody reaches for first, to treat hypertension in pregnancy, and I would say the next is nifedipine. I just got an E-mail today from a patient who I started administering nifedipine to, and she’s already complaining of swollen ankles and headache. You tend to get more side effects from nifedipine than labetalol, even though it may be more effective. Methyldopa is not the best drug, but it does work in pregnancy. There’s some evidence that sympathetic nervous system activity is part of the pathogenesis of preeclampsia, and I’ve seen methyldopa work. It makes people tired, which means that they don’t do much and spend a lot of time resting which is not necessarily bad.
Dr. Moser: Oh, yes, and depressed.
Dr. August: But, I’ve written a few prescriptions for methyldopa in the last 12 months. It’s not my first choice; I’d say it’s my third. I don’t initiate diuretics for preeclampsia or gestational hypertension. However, I might start somebody with chronic hypertension on a diuretic.
Dr. Moser: What about the effect or concern for litigation? You deliver babies, and those who deliver babies are very concerned about this because any drug, as Dr. August mentioned, has a potential for doing something, and some lawyer somewhere is going to find a reason to say it’s a terrible drug to use. Do you think that plays a role in obstetricians’ activities?
Dr. August: I think the legal profession has ruined the field of OB/GYN. They’ve decimated it. They’ve made it impossible; I don’t know what Dr. Rose has to say about it, but I think it’s one of the great tragedies of the last 30 years in medicine.
Dr. Rose is a hero for persisting in this environment and actually taking the risks to be involved in the process of delivering babies when it is such a hostile environment. I feel strongly about it because I’ve seen it, and I’m sure Dr. Rose does too.
Dr. Rose: Additionally, dosing frequency perhaps should be a consideration in the treatment of hypertension, with any type of medication requiring more frequent dosing intervals, the subsequent compliance rates are much lower. Thus, when I consider any type of medication that I'm prescribing more than twice a day, I'm not sure how realistic it is to expect good compliance.
Dr. Moser: I’m going to ask each of you to imagine that you were the chairperson of a new committee and summarize the definitions of hypertension and decide when to treat and how to treat. Would you make any major suggestions that are different from the present guidelines that have been used for so many years?
Dr. Rose: Currently, the American Congress of Obstetricians and Gynecologists recommends instituting medical therapy for patients with chronic hypertension at threshold values of 150–160/100–110 mm Hg and at diastolic values of 105–110 mm Hg for patients with preeclampsia.8
Dr. Moser: What about the drugs that we use? Would you expand the recommendations, as Dr. August mentioned, to include calcium channel blockers, drugs like labetalol, and diuretics?
Dr. Rose: Yes.
Dr. Garovic: With respect to medications, I completely agree with what other speakers have said. In general, young women, especially those with either severe hypertension in the absence of a family history or with features of secondary hypertension (such as an abdominal bruit) should be ruled out for secondary hypertension, optimally before pregnancy.
Dr. August: I would argue for a clinical trial similar to, but not exactly the same as, the Systolic Blood Pressure Intervention Trial (SPRINT), in non-pregnant people, where you could at least establish the safety of lowering BP to a normal BP (eg, 120/80 mm Hg) in women with chronic hypertension. I think one of the problems with studies like Action to Control Cardiovascular Risk in Diabetes (ACCORD), and maybe SPRINT, is that there are certain patients in whom you should not force the BP to 120/80 mm Hg. If you have to combine 3 or 4 drugs, it’s probably not worth it. So, I think the design of such a study would have to be carefully considered. But, I would like to know whether it’s safe; should we keep women at approximately normal BPs during pregnancy and look at the outcomes that are more pregnancy-related as well as maternal?
Dr. Moser: Is it advisable not to wait until their pressure gets as high as presently supported by guideline committees, just because there is no evidence and no definitive studies to prove otherwise?
Dr. August: Yes. But a large, cooperative, collaborative, multi-center study would need to be conducted to prove this.
Dr. Moser: I thank you all very much.
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