Hypertension in pregnancy

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Hello and welcome to the Australian Prescriber Podcast. My name is Jo Cheah and joining me today is George Mangos, who is a nephrologist at St George Hospital and an associate professor of Medicine at UNSW. Hi, George, thanks for joining me.

Hi, Jo, and thanks for having me. It's a pleasure.

That's great. So happy to have you. So your article in the Australian Prescriber is about hypertension in pregnancy. So, physiologically, how does pregnancy affect blood pressure? For example, why does blood pressure drop in the first trimester of pregnancy?

Okay. Good question to start the talk because we're talking about high blood pressure and, yes, the normal response to pregnancy is vasodilation and, therefore, a lower peripheral resistance. And that's the primary driver of the fall in blood pressure, which, generally, starts at about eight weeks gestation, and that's despite the other changes that occur during the pregnancy, which is an increase in cardiac output and an increase in circulating volume.

And in terms of throughout the rest of the pregnancy, how does the blood pressure change?

So the fall in blood pressure that occurs in the first trimester is generally maintained and reaches its lowest point in the second trimester. In the third trimester we start to see blood pressure increase in the normal pregnancy back towards the baseline blood pressure at booking. And that would generally occur at about 34 to 36 weeks. And then at term, generally, the blood pressure is as it was in a nonpregnant state.

And you've written this article about managing hypertension in pregnancy, so obviously some things might go a bit wrong or things might not be as they should be. So can you explain the different types of hypertensive disorders in pregnancy?

Yeah, of course. A woman can be diagnosed with high blood pressure or hypertension before she falls pregnant, so that's referred to as chronic hypertension. And we would call chronic hypertension an elevated blood pressure that's measured before 20 weeks gestation because some of these women have never had their blood pressure measured before. So if the blood pressure is elevated before 20 weeks gestation and it's sustained and confirmed, that's consistent with chronic hypertension.

For the other hypertensive disorders, they tend to occur after 20 weeks gestation. And those disorders include gestational hypertension and pre-eclampsia. And then, of course, if a woman has chronic hypertension, it can be complicated by pre-eclampsia, which is a systemic condition affecting multiple organs in the body. So that form of hypertension is called pre-eclampsia superimposed on chronic hypertension.

With chronic hypertension, it's divided into two main categories: primary and secondary. Now, often chronic hypertension is so-called primary or essential hypertension. And then there are other causes of chronic hypertension, such as kidney disease, adrenal disease, renal artery stenosis, polycystic kidney disease, for example, and often in pregnancy it gives us the opportunity to diagnose these conditions because, as I said, it may be the first time that a woman has had her blood pressure carefully measured and even perhaps a measurement of urinalysis.

And, I guess, pre-eclampsia is a scary term for a lot of people. Can you explain the importance of the condition and what it actually means for the pregnant woman?

So pre-eclampsia is a condition where the placenta probably releases factors into the blood that affect the mother. The interaction between the placenta and the uterus is probably not normal from early in pregnancy. So as a complication of that, this condition called pre-eclampsia develops, which is often characterised by swelling of the legs, which comes on quite suddenly, protein appearing in the urine, which can be detected by a dip stick when it's tested, and an increase in blood pressure amongst other symptoms.

It usually occurs either at term or very close to term after 36 weeks gestation, but can occur earlier. And one of the main reasons women have antenatal care is to look for this condition developing to make sure that baby is growing well, to make sure that blood pressure remains normal, that there's no protein in the urine, there are no symptoms of pre-eclampsia, for example.

It's scary because it sounds pretty nasty and it can become a serious condition. And in Australia, under good surveillance, our outcomes are very good and mothers and babies do very well. But, yes, it can be a serious problem, particularly in countries where we don't have excellent antenatal care.

And in terms of the other hypertensive disorders you just mentioned, how do you manage each of those?

In pregnancy, when we diagnose chronic hypertension, which is a blood pressure above 140 over 90 [mmHg] that's confirmed after a few readings or after 24 hour blood pressure monitoring, so when we diagnose that, it doesn't really matter whether it's primary or secondary or what's causing it. The important thing is that the blood pressure is controlled and that the kidneys and liver and other organs in the body are, essentially, functioning normally.

Management of the various different conditions that cause chronic hypertension, for example, if a woman has kidney disease, we'd keep a close eye on her kidney function. If the hypertension is due to a more rare condition, such as an adrenal problem, we might need to use slightly different medication. But, essentially, the principle is to keep the blood pressure under control because we know that if blood pressure is uncontrolled at the beginning of pregnancy, then the outcomes at the end of pregnancy are more complicated and certainly it's less safe on mum and less safe on the baby if blood pressure is not controlled well in early pregnancy.

One thing we can do for women who enter the pregnancy with chronic hypertension is to try to reduce the chance of it developing into a more complicated situation of pre-eclampsia by using two treatments: one of them is low-dose aspirin and the other is calcium supplementation. So low-dose aspirin is commenced between 12 and 16 weeks gestation, usually at a dose of 150 mg daily. And although aspirin, when you read the label, it says it's, "Not safe in pregnancy," that's when higher doses are used in the anti-inflammatory dosing. But with low-dose aspirin, with a more antiplatelet-type dosing, we've seen studies that have clearly shown a benefit in protecting women from early-onset pre-eclampsia if they enter the pregnancy at a higher risk. And that's why it's so important to get these women with chronic hypertension or, indeed, other high-risk situations, onto aspirin between 12 and 16 weeks gestation.

Calcium supplementation hasn't been proven as well as aspirin has but it's clear that women who have calcium-deficient diets have a higher rate of developing pre-eclampsia. And because calcium is such a safe mineral to take and an important mineral to take, we like to be sure that women have an adequate calcium intake and often it's easier to use some extra calcium carbonate rather than take a lot more dairy product.

So there are two things that we can do to help lower the risk of chronic hypertension becoming more complicated along with controlling the blood pressure with safe antihypertensive medication.

It's very interesting to know that outcomes can be improved if hypertension is picked up and we intervene earlier in the pregnancy than later. And you've just mentioned some safe antihypertensive drugs. So in your article there are some really good tables that our listeners and readers can refer to. But what are some of the antihypertensive drugs that are safe to use during pregnancies and which ones should be avoided?

Probably the one drug that has the highest pregnancy category listing is methyldopa and that's because it's probably the oldest and has been involved in a randomised controlled trial in the past. Most of the other drugs we use are either category B or C. So methyldopa is widely used. It's a centrally acting drug. It does tend to cause a bit of tiredness in women and some other symptoms, but it is widely used and safe and certainly safe for the fetus.

The other class of drug that we would use first line or second line would be a beta blocker. Currently we're using labetalol and often use that 100 mg twice to three times a day as a starting dose, increasing to 200 or 300 mg three times a day. Labetalol has both beta blocker and alpha blocker activity and, again, another safe drug for mother and fetus.

Nifedipine and other calcium channel blockers are increasingly used first and second line. We know they're safe. Again, they don't affect the fetus. They do tend to cause side effects. We know about the side effects of peripheral calcium channel blockers being flushing and tachycardia and leg swelling. And in a situation like pregnancy where vasodilation is already the state, then it's not unusual to see these symptoms occur in women.

And there are other agents we use second, third, fourth line, such as hydralazine and prazosin and they're also safe in pregnancy.

So first line could be methyldopa, nifedipine, labetalol, a combination of any of those three, and they're the drugs that we would generally be trying to stick to in pregnancy, including the first trimester, if necessary. And indeed even antepartum, preparing a woman during her preconception counselling and preparation for pregnancy to take at that time if we are already seeing the patient.

Oh, that's also interesting that you can start treatment in the preconception period, as well.

Mmmm.

So we've spoken about some medications, we've also spoken about some preventative therapies like aspirin and calcium. So what are some nonpharmacological methods of preventing or managing hypertension in pregnancy?

Actually, there aren't any nonpharmacological measures that have been proven to improve maternal or fetal outcomes in this situation. But it would make sense for a woman, for any pregnant woman really, not to gain too much weight, to have a healthy balanced diet and not necessarily to restrict or take any component of their diet in excess. For example, in patients who are not pregnant, there's evidence that lowering dietary sodium can lower blood pressure. We don't recommend that in pregnancy because a pregnant woman requires salt to maintain an expanded plasma volume and tends to have a salt craving. And there's been no evidence to show that lowering salt intake is a benefit to a pregnant woman.

So there are certain things that we can do outside of pregnancy that we don't recommend in pregnancy. So just a healthy, balanced diet.

Physical activity obviously is appropriate and recommended for many reasons, not just the metabolic benefits to reduce an excessive gain in weight, but also the mental health benefits. And, potentially, physical activity may have a benefit on lowering the inflammatory status inside a patient. And we don't know, but it's possible that regular gentle physical activity may have a beneficial effect on lowering the rate of pre-eclampsia, but that's not yet proven.

And are there current studies that are looking at proving or disproving these methods?

Yeah. Look, I think the real goal here is to find something that prevents pre-eclampsia. Aspirin does it to a very limited degree, generally in women at high risk and generally for preventing early-onset pre-eclampsia. What we really like to do is prevent pre-eclampsia occurring in any woman. To do that, firstly, we need to know which woman is going to get pre-eclampsia so we need a test at the beginning of pregnancy that says, "Okay, you're going to get pre-eclampsia or you're at very high risk of getting pre-eclampsia." And we're starting to get tests that show that, and then we'd need a treatment that we can implement that changes the outcome of the pregnancy. And, as I said, we've got aspirin and calcium now.

Drugs are being tested in Australia actually, to look, to see whether they can have an impact on the rate of pre-eclampsia developing. People have looked at all sorts of other complementary agents in the past and, unfortunately, they don't work. So there's a whole lot of supplements that have been tested, such as vitamin C and antioxidants and none of them seem to work. So we know what works a bit and we know what doesn't work, and there's a lot of potential in the future for pharmacological and non-pharmacological agents to work, but we don't have any further answers yet.

It's very interesting to hear that there are some diagnostic tools or maybe criteria that patients may meet early in pregnancy that can preempt whether they will experience pre-eclampsia. So what do those sorts of tools look like?

I suppose we could group that into clinical assessment. So if we see women who have certain risk factors, and there are a number of risk factors for pre-eclampsia, and that might include chronic hypertension as one. But being overweight, the traditional cardiovascular risk factors such as dyslipidaemia and diabetes, having an IVF pregnancy, a woman in her first pregnancy, a twin pregnancy, they’re risk factors for going on to develop pre-eclampsia. So we can make that assessment clinically.

We now also have ... And, of course, a woman who's previously had pre-eclampsia. So if a woman's in her second pregnancy and she didn't have pre-eclampsia in her first pregnancy, then her chance of getting it in her second pregnancy is very low, it's around 1%. Whereas if a woman's had pre-eclampsia in the first pregnancy and comes into a second pregnancy, she's at much higher risk, and that could be 15 to 25 or even 35/40% risk of getting pre-eclampsia in the second pregnancy. So those clinical aspects we can assess in the rooms.

Then there's tests. And what's become more sophisticated is the early ultrasound at around 14 weeks gestation where a number of parameters are measured, including blood pressure and some placental hormones and a Doppler measurement of uterine artery waveform. And a combination of these in an algorithm can give a prediction as to whether a woman is at high or low risk of early-onset pre-eclampsia. And we see now women having this test done and turning up with a report that says, "This woman is at increased risk of early-onset pre-eclampsia. We recommend low-dose aspirin." And often that's followed through even before the obstetric medicine team becomes involved.

And because low-dose aspirin's such a safe drug, it's good for that to happen in a way. It does mean that some women will be treated who won't end up getting pre-eclampsia anyway. So the number needed to treat might be relatively high but, because it's a safe drug, it's quite reasonable to take that approach. The algorithms that are being used to predict pre-eclampsia and to put women onto aspirin early are improving over time. And I'm sure with better Doppler measurements, all of these measurements and calculations will improve over the next few years.

And, I guess, if a woman was ticking off some of those high-risk criteria that you've just been discussing, for example, they start the low-dose aspirin, is it recommended that they're referred to a particular specialist or can they continue their treatment under, for example, their GP or other clinician?

Yeah, it all depends on the antenatal model that the woman is booked into, and increasingly GPs are becoming more involved with a high-risk pregnancy. So, I guess, what's more important than referral to a particular specialist is to categorise that woman as a high-risk pregnancy or not a high-risk pregnancy. And once that woman is considered to have a high-risk pregnancy because of either the early ultrasound and blood tests or her clinical status, then the antenatal surveillance is perhaps a little bit closer, a little bit more vigilant. And, particularly, in the third trimester, she may be attending her hospital where she's booked in a lot more regularly.

We do that at St George Hospital and many other hospitals around Australia in units, like a day assessment unit where, instead of just staying for a few minutes and having a blood pressure check and coming and going, she might stay for three or four hours, have blood tests, have a CTG to look at both maternal and fetal welfare and careful measurements of blood pressure over time. So that's more likely for women who are at high risk who need to be monitored a bit closer.

So that brings us to the end of the episode, George. Thank you so much for joining us on the podcast.

It's an absolute pleasure. Thank you very much. And may I thank and acknowledge my co-author Dr Amanda Beech, who's an endocrinologist and obstetric physician at the Royal Hospital for Women in Sydney.

Thank you, George and Amanda for the article. And that full article is available online. My name's Jo Cheah. Thanks for joining us on the Australian Prescriber podcast.

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