Angiotensin II receptor antagonists (A2RAs)
(Date of issue: October 2015. Version: 2)
This factsheet has been written for members of the public by the UK Teratology Information Service (UKTIS). UKTIS is a not-for-profit organisation funded by Public Health England on behalf of UK Health Departments. UKTIS has been providing scientific information to health care providers since 1983 on the effects that medicines, recreational drugs and chemicals may have on the developing baby during pregnancy.
What are they?
A2RAs (azilsartan [Edarbi®], candesartan [Amias®], eprosartan [Teveten®], irbesartan [Aprovel®, CoAprovel®*], losartan [Cozaar®, Cozaar-Comp®*], olmesartan [Olmetec®, Olmetec Plus®* Sevikar®*, Sevikar HCT®*], telmisartan [Micardis®, Micardis Plus®*], and valsartan [Diovan®, Co-Diovan®*] are medicines that are prescribed to treat high blood pressure, heart failure and diabetic nephropathy (a kidney disease that can affect people with diabetes). Some products (marked in the list above with*) combine an A2RA with another type of medicine (usually a diuretic and/or a calcium channel blocker). This leaflet summarises the scientific studies relating to the effects that an A2RA might have on a baby when taken by the mother in pregnancy. Any potential effects of the additional components in the combination medicines are not discussed in this leaflet.
Is it safe to take an angiotensin II receptor antagonist in pregnancy?
Use of A2RAs in pregnancy is not generally advised but may occasionally be considered necessary for the treatment of very serious illnesses if other treatments have not worked. Any woman who is taking an A2RA and is planning a pregnancy should speak to her doctor to discuss the possibility of switching to a different medicine before trying to become pregnant. Your doctor will be able to help you to weigh up how necessary an A2RA is to your health against the possible risks to you or your baby, which will depend on how many weeks pregnant you are.
This leaflet summarises the scientific studies relating to the effects of A2RAs on a baby in the womb.
What if I have already taken an angiotensin II receptor antagonist during pregnancy?
If you have taken an A2RA in the second or third trimester of pregnancy without medical supervision it is important to let your doctor or midwife know straight away as your baby may need extra monitoring for the effects described below.
There is no scientific proof that taking A2RAs during the first trimester will harm a baby in the womb. However, you should let your doctor know that you are pregnant as soon as possible as the majority of women will be switched to another medicine for the remainder of pregnancy because of the known harmful effects A2RAs may have on a baby in the womb in the second and third trimester. It is important that your doctor also reviews all medicines that you are taking if you become pregnant to assess whether you still need them and, if so, to make sure that you are taking the lowest dose that works for you.
Can taking an angiotensin II receptor antagonist in pregnancy cause miscarriage?
It is unclear whether taking A2RAs in early pregnancy increases the chance of having a miscarriage. Two small studies both showed that women who take A2RAs or a related type of medicine during early pregnancy may be more likely to have a miscarriage than women who have not taken any medicines.
However, only 390 pregnancies were studied in total and women taking A2RAs were not studied separately from women taking other related medicines for high blood pressure. More research into the specific effects of A2RAs is therefore required to answer this question. Furthermore, A2RAs are used to treat high blood pressure and diabetes, both of which are more common in people with obesity. High blood pressure, diabetes and obesity are all thought to increase a woman’s chance of having a miscarriage. More research is also therefore needed to understand whether the increased risk of miscarriage reported in the above studies is due to the medicines the pregnant women were taking, their health problems, or a combination of both factors.
Can taking an angiotensin II receptor antagonist in pregnancy cause my baby to be born with birth defects?
A baby’s body and most internal organs are formed during the first 12 weeks of pregnancy. It is mainly during this time that some medicines are known to cause birth defects.
It is currently unclear whether taking A2RAs during early pregnancy can cause birth defects in the baby as not enough research into this subject has been carried out. There are a small number of case reports of women who used A2RAs in early pregnancy. At present, the number and types of birth defects among their babies does not give cause for concern. One study has specifically investigated whether treatment with A2RAs in early pregnancy might be linked to heart defects in the baby and found no evidence that this is so.
A large study that analysed information from a number of earlier studies also found no evidence that use of A2RAs or a related type of medicine in early pregnancy causes birth defects. However, in this study the women using A2RAs were not analysed on their own. Further scientific studies therefore need to be carried out before we can say whether A2RAs are safe to use in early pregnancy.
What problems can taking an angiotensin II receptor antagonist after the first trimester of pregnancy cause in my baby?
Taking an A2RA during the second and third trimesters can cause a number of problems in the baby, including:
• Reduced levels of amniotic fluid around the baby in the womb (oligohydramnios). Many of the problems described below are thought to occur as a result of very low amniotic fluid levels
• Kidney damage (renal tubular dysgenesis) which can lead to long-term kidney problems after birth
• Under-development of the baby’s skull bones
• Reduced growth of the baby in the womb
• Poor development of the baby’s lungs (amniotic fluid is needed to expand and develop the baby’s lungs before birth)
• The baby’s bladder being under-developed (because there is not enough amniotic fluid for the baby to ‘drink’ in the womb the baby does not produce enough urine to expand and develop the bladder)
• The baby’s skull and leg bones becoming misshapen and the baby’s facial features ‘flattened’ as a result of there not being enough amniotic fluid to ‘cushion’ the baby in the womb)
• Compression (squashing) of the umbilical cord, which may result in reduced blood flow from the mother to the baby in the womb
• A blood vessel in the baby called the ductus arteriosus not closing at birth to allow the baby’s blood to flow through its lungs once it starts breathing. Patent ductus arteriosus is the medical term used to describe this blood vessel staying open after birth
Because very few women take A2RAs during the second and third trimesters of pregnancy, no large studies have been carried out that might tell us what the chances are of a baby exposed to an A2RA during this period developing the above problems.
Some of the complications described above can be serious, which explains why there are reports of babies exposed to an A2RA during the second or third trimesters being stillborn and dying after birth. However, it is also possible that the serious illnesses for which pregnant women take ACE-inhibitors during late pregnancy may also contribute to the risks of stillbirth and the baby dying after birth.
An A2RA should only be taken after the first trimester of pregnancy under strict medical supervision. If your doctor has advised that you take an A2RA during the second or third trimester, this is likely because you have a serious illness that cannot be treated any other way. Some of the pregnancy problems discussed above (e.g. low levels of amniotic fluid) can be detected by ultrasound scans. If low amniotic fluid levels are identified early enough and treatment with an A2RA is stopped in time, some of these effects may be prevented or might be reversible but this is not always so (please see section below about kidney damage). Regular monitoring of your baby will therefore be required to allow ongoing decisions to be made about the best treatment for you and your baby’s health. Please discuss any concerns that you may have with your doctor.
Can taking an angiotensin II receptor antagonist in pregnancy cause preterm birth or my baby to be small at birth (low birth weight)?
There are a number of case reports of women who took an A2RA in pregnancy having preterm and/or low birth weight babies. This may be because early delivery was advised because of the mother’s underlying illness or because of low levels of amniotic fluid. Two studies have both shown that women who took an A2RA or a related medicine during pregnancy were more likely to give birth early (before 37 weeks of pregnancy) or to have a low birth weight baby (<2500g) than women without high blood pressure who were not taking medicines. However, the very few women in these studies were taking an A2RA and were not analysed separately. More research is therefore required before we can say whether preterm birth and low birth weight can be caused by A2RAs as it is possible that these outcomes are linked to the illness for which the mother was taking A2RAs (e.g. high blood pressure).
Can taking an angiotensin II receptor antagonist in pregnancy cause other health problems in the child?
Lasting kidney damage
There are a number of reports in the scientific literature of babies and children with decreased kidney function or kidney failure following exposure to an A2RA in the womb. In some cases the children required kidney dialysis or a kidney transplant. The mothers of some of these children had stopped taking the A2RA during pregnancy which had allowed the levels of amniotic fluid to recover. This suggests that in some cases the kidney damage in the unborn child that is caused by A2RA exposure in the womb is irreversible, even if treatment is stopped and levels of amniotic fluid increase.
Learning or behavioural problems
A baby’s brain continues to develop right up until the end of pregnancy. It is therefore possible that taking certain medicines at any stage of pregnancy could have a lasting effect on a child’s learning or behaviour.
No scientific studies have specifically investigated whether there is a link between taking an A2RA in pregnancy and learning or behavioural problems such as attention deficit hyperactivity disorder (ADHD) or autism spectrum disorder in the child. There are three case reports of children with intellectual disabilities whose mothers were treated with an A2RA in pregnancy. In all three cases the A2RA had caused low levels of amniotic fluid and problems in the baby relating to this.
Will my baby need extra monitoring during pregnancy?
Most women will be offered a scan at around 20 weeks of pregnancy to look for birth defects as part of their routine antenatal care. Because there is very little information on the use of A2RAs in early pregnancy, if you have taken an A2RA in the first trimester, your doctor may suggest a scan before 20 weeks to check how your baby is forming in the womb. Additionally, the illnesses that A2RAs are used to treat (e.g. high blood pressure, diabetes) are themselves linked to an increased risk of birth defects in the baby, so your doctor may wish to monitor your pregnancy more closely.
It is, however, harder to see birth defects earlier in pregnancy, which is why the main scan for birth defects is generally offered at around 20 weeks of pregnancy. It is important to understand that scans are not able to pick up all birth defects.
If you have taken A2RAs during the second or third trimesters, extra scans or monitoring of your baby’s wellbeing and amniotic fluid levels will be required.
Are there any risks to my baby if the father has taken an angiotensin II receptor antagonist?
We would not expect any increased risk to your baby if the father took an A2RA before or around the time your baby was conceived.
Who can I talk to if I have questions?
If you have any questions regarding the information in this leaflet please discuss them with your health care provider. They can access more detailed medical and scientific information from www.uktis.org.