05:59pm Monday 25 May 2020

New study on the safety of prescribing antihypertensive drugs in pregnancy

Pregnant women with gestational hypertension are treated with antihypertensive drugs to reduce their risk of developing complications such as strokes, and kidney damage.  At the moment, while there is plenty of information for doctors on the treatment of pre-eclampsia and eclampsia, not much research has been done on treating pregnant women with moderate hypertension, or on the long-term effects of prenatal exposure to such drugs on the baby. 

Dutch researchers undertook a retrospective cohort study of children born to mothers with pregnancy induced hypertension (PIH) and pregnancy aggravated hypertension (PAH) at seven teaching hospitals and five general hospitals between 1983 and 1987.  The women were treated with labetalol or methlydopa for PIH or PAH and were compared to women with PIH or PAH who were treated with bed rest (a ‘treatment’ that was popular at the time although now very little used as it is thought to be ineffective).  The same groups of women were then approached in 1991 – 1992 when their children were between 4 and 10 years old for a follow-up study.  The children were assessed on their cognitive and behavioural development in areas like concentration, memory, IQ and gross and fine motor development. 

After reviewing 4,000 hospital records, 202 subjects who matched the study criteria were selected for analysis.  Researchers found that the children who were prenatally exposed to labetalol had a significantly higher risk of ADHD (attention-deficit hyperactivity disorder) compared to the bed rest group (odds ratio 45, 95% CI 1.2-13.9). There was non-significant trend to more sleeping problems in the children of mothers who took methyldopa compared with those of mothers prescribed bed rest (odds ratio 4.5, 95% CI 0.9 – 23.2).

Previous research has shown that babies of mothers who received labetalol when pregnant are more likely to be small-for-gestational age (SGA) due, researchers suggest, to reduced placental blood flow.  This may have consequences for neurodevelopment.     

Researchers emphasise that the methodological limitations of their study mean that the findings should be interpreted with caution.

Professor Philip Steer, BJOG editor-in-chief, said “Hypertensive diseases in pregnancy can lead to serious complications such as stroke if left untreated.  For this reason, doctors prescribe antihypertensive medication to keep blood pressure down to reasonable levels.  In the case of women with severe hypertension or pre-eclampsia (blood pressure greater than 150/100 mmHg), the benefits of taking such medication to prevent maternal and/or fetal death outweigh the possibility of less catastrophic long-term effects”.

“The results of this study are interesting although they could have occurred by chance.  Nonetheless, there are plausible reasons why antihypertensive drugs may be harmful to the functional development of the fetus, with long-term effects. One always has to balance the short-term benefits of a treatment against possible long-term consequences.  The results suggest that more large-scale studies looking at the effects of antihypertensive drugs on the baby long-term are warranted.”

In a separate commentary on the paper, Professor Michael Belfort, Department of Obstetrics and Gynecology, University of Utah Medical School, questions the findings from the paper, citing the possibility of bias in the collection of such data.  For example, the low follow-up rate of only 57% means that the respondents may not be properly representative. For example, parents of children with problems may be more likely to respond to a questionnaire if they had been given drugs during pregnancy than if they had not. 
Professor Belfort said, “These authors should be commended for their efforts, and in my opinion their findings should primarily be interpreted as a call for better designed studies on the effects of these, and other, drugs used in pregnancy. Until confirmatory data is available, however, I do not believe that this study should prompt physicians to stop prescribing these drugs to hypertensive patients when they are indicated.”
“Methyldopa and labetalol have for many years been primary agents used for control of blood pressure in pregnancy, and until such time as we have prospective trials that unequivocally show deleterious effects, we should be careful about avoiding them if they are indicated. Sometimes the avoidance of use of a drug because of a theoretical risk can lead to serious consequences as a result of under-treatment of a dangerous condition”.

“The data reflect long-term use of orally administered drugs in women with mainly chronic hypertension, and cannot, for example, be extrapolated to the acute management of severe preeclampsia with intravenous labetalol.”



BJOG: An International Journal of Obstetrics and Gynaecology is owned by the Royal College of Obstetricians and Gynaecologists (RCOG) but is editorially independent and published monthly by Wiley-Blackwell. The journal features original, peer-reviewed, high-quality medical research in all areas of obstetrics and gynaecology worldwide. Please quote ‘BJOG‘ or ‘BJOG: An International Journal of Obstetrics and Gynaecology’ when referring to the journal and include the website: www.bjog.org as a hidden link online.
To speak to Prof Belfort, please call 001-80107434707 or email [email protected].  To speak to Mr Michael Marsh, please call 020 7772 6446.

In the last CEMACH Saving Mothers’ Lives report, the number of direct deaths in the UK from pre-eclampsia and eclampsia was 0.85/100,000 maternities.  

Pre-eclampsia is a pregnancy complication where the woman has hypertension and protein in her urine.  If left unchecked, she could go on to have the life-threatening condition of eclampsia, characterised by violent seizures. Not all women go on to develop eclampsia from pre-eclampsia as doctors monitor pre-eclampsia and deliver the baby if that is necessary to prevent the condition progressing to eclampsia. 

Pasker-de Jong P, Zielhuis G, van Gelder M, Pellegrino A, Gabree¨ls F, Eskes T. Antihypertensive treatment during pregnancy and functional development at primary school age in a historical cohort study. BJOG 2010; DOI: 10.1111/j.1471-0528.2010.02568.x.

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