June 2, 2015

expert reaction to antidepressant use and respiratory disorder in newborns

Publishing in the Journal of the American Medical Association, researchers have analysed a link between use of a particular type of antidepressant in pregnant women, and pulmonary hypertension in their children. The team report an increased risk of the disease in newborns whose mothers used the antidepressants, though the absolute risk was small.

Dr Patrick O’Brien, spokesperson for the Royal College of Obstetricians and Gynaecologists (RCOG) said:

“This is an extremely useful study, examining nearly 3.8 million pregnancies, it is the largest study on this issue to date. It has used a robust methodology and careful efforts have been made to account for any confounding factors. The findings therefore, are certainly the best evidence we currently have on antidepressant use in late pregnancy and the risk of PPHN.

“In a sense, these results are reassuring. The findings suggest a very small absolute risk. The chances of a baby getting PPHN when its mother was not taking an SSRI are around 2 in 1000, compared to around 3 in 1000 when the mother had taken an SSRI antidepressant medication in the last 90 days of pregnancy.

“Depression in pregnancy can be very serious for a woman and can also impact on the health of her baby, so we must consider the benefits of antidepressant medication in such cases.

“Our continued advice for pregnant women suffering with depression would be that the benefits outweigh the risks, however, all pros and cons should be discussed and weighed up by a woman, together with her obstetrician.”

Dr Nadja Reissland, who works on maternal stress, depression and fetal development in relation to maternal stress, is Deputy Head of Faculty of Science and Senior Lecturer, Department of Psychology, University of Durham, said:

“This very large population based study of mothers receiving Medicaid, the state insurance of the US for mothers on low income and with limited resources, controlled the effects of a number of variables other than the use of two types of antidepressant medication: SSRIs (selective serotonin reuptake inhibitors) and non-SSRI antidepressants. This study is important because of the potential risk of antidepressant use for the fetus and newborn infant. Specifically the use of SSRI antidepressants late in pregnancy has been found in some studies to be linked to diminished pulmonary blood flow and profound hypoexemia of the newborn infant. Given the debilitating effects of depression, these findings are reassuring for both mothers suffering from depression as well as the medical profession prescribing antidepressants to their patients. Findings indicate that although there is a slightly increased risk of SSRI antidepressants the non-SSRI antidepressants seem not to pose any additional risk to the newborn infant and hence seem to be safe to prescribe for mothers even late in pregnancy.”

Prof. Louise Howard, Professor in Women’s Mental Health, King’s College London’s Institute of Psychiatry, Psychology & Neuroscience (IoPPN) and Consultant Perinatal Psychiatrist at the South London and Mausdsley NHS Foundation Trust, said:

“This study is the latest in a number of studies investigating the uncertainty around risks of antidepressants in pregnancy. As with other recent studies this uses high quality methods but as with all studies in this area it is not a randomised controlled study and therefore cannot eliminate the possibility that its findings are due to bias or confounding i.e. that other factors explain the association described. As with other high quality studies it also reports smaller risks than those reported in earlier less rigorous studies and suggests there may be a very small increase in the risk of a rare (1 per 1,000) condition that can affect new-born babies lungs; persistent pulmonary hypertension of the newborn (PPHN). Reassuringly, though not stated in the abstract or the press release, the researchers did not find an association between the severe form of PPHN and any type of antidepressant use. The small increase in risk reported for the less severe forms of PPHN could be due to the effects of antidepressants, but may be due to other factors such as body mass index, smoking or the effect of depression itself.

“Women considering whether or not to take antidepressants in pregnancy need to discuss with their doctor the risks of not taking medication for their particular condition, their previous response to treatment (psychological and medication), and the severity of their condition  as well as the current evidence base on possible risks of medication.”

Prof. Andrew Whitelaw, Professor of Neonatal Medicine, University of Bristol, said:

“Treatment of depression in pregnant women is an important topic because suicide is now one of the leading causes of maternal death and postnatal maternal depression has a very bad effect on child development. There has been conflicting evidence on whether treatment with the commonest antidepressants (SSRIs) was associated with persistent pulmonary hypertension of the newborn (PPHN). This is a potentially fatal condition affecting mainly full term babies in which the blood flow to the lungs shuts down because the main arteries to the lungs constrict. It is important to distinguish between PPHN associated with anatomical abnormalities of the lung structure and PPHN on its own, known as primary PPHN. With sophisticated neonatal intensive care, PPHN is treatable but fatalities and brain injury can still occur. The diagnosis of PPHN is probably a fairly reliable statistic because of the resources required to treat.

“A previous study of 1.6 million infants in the 5 Nordic countries had used routinely collected diagnoses and had adjusted for other differences between those taking anti-depressants and those not taking them and found that the risk of PPHN was doubled by taking any of the 4 common SSRIs.

The new study was larger, involving nearly 3.8 million pregnant women, and required that the prescriptions had actually been collected after the 20th week of pregnancy, not just prescribed. The investigators were able to identify women who actually had a clinical diagnosis of depression. The study used advanced statistical analytical techniques to attempt to adjust for the striking differences between women exposed to SSRIs and those not exposed. By European standards, these American pregnant women seem to be awash with multiple medications. The women exposed to SSRI were taking three times more anticonvulsants and antipsychotics, five times more anxiolytics, benzodiazepines and lithium and twice as many other hypnotics and barbiturates as those not taking SSRI. Twice as many SSRI-takers were smokers as the non-SSRI group. Nearly a third of the SSRI group had migraine and 11,190 pregnant women were taking anticonvulsants but only 1,831 had a diagnosis of epilepsy.  This bizarre mixture  of polypharmacy and  mismatched diagnosis does make one wonder about the accuracy of the data and whether any amount of sophisticated statistical ‘adjustment’ can really make up for the obvious fact that the pregnant women taking SSRIs had a lot more drugs on board and other medical problems than just depression compared to the non-SSRI women. In addition, the non-SSRI-takers were less than 50% white whereas of the SSRI takers, 80% were white.

“The main conclusion from all the statistical processing was that there was an increase in primary PPHN  in babies of SSRI takers but the odds ratio 1.28 (confidence limits 1.01-1.64) only just achieved conventional statistical significance.  The population studied were low-income Medicaid beneficiaries with a lot of other medical problems and medications.  This contrasts with pregnant women in the Nordic countries who are generally healthy, well-educated, well-nourished and deliver a far lower perinatal mortality than the USA. As regards wellbeing of pregnant women, the British population are probably mid-way between the low-income Americans and the Nordics.

“Taking this study with the previous evidence, I conclude that there is a slightly increased risk of PPHN if a pregnant woman takes an SSRI but this only brings the risk up to 3 per 1000 births. I do not suggest that seriously depressed pregnant women should be denied SSRI treatment, but it would be wise for them to deliver in a hospital with a neonatal intensive care unit in case PPHN does occur.”

Dr Hamish McAllister-Williams, spokesman for the ECNP (European College of Neuropsychopharmacology), member of the ECNP Education Committee, and Reader in Clinical Psychopharmacology at The Institute of Neuroscience, Newcastle University, said:

“Although previous data has been inconsistent, it is generally believed that in utero exposure to SSRI antidepressants increases the risk of PPHN (persistent pulmonary hypertension of the newborn).  So although the findings are not completely new, this study by Huybrechts et al is by far the largest to date, and helps clarify the magnitude of the risk.  This risk is clearly small once all factors are taken into account.  It is estimated that the risk of PPHN is increased around 1.12 fold compared to the general population.  This is equivalent to an absolute risk increasing by just 0.026% from 21.8 to 24.4 per 10,000 births, meaning that there would be one additional case of respiratory disorder in newborns for every  5000 or so women treated for depression.

“Given the, albeit small, risks of using antidepressants in pregnancy it is important to think carefully before using them in such circumstances.  However, the risks of antidepressants need to be balanced against those of untreated depression which is also known to pose a risk to mother and child.  Therefore in more severe depression, the use of antidepressants in pregnancy is still potentially justified after careful discussion between the mother and her clinician.”

‘Antidepressant Use Late in Pregnancy and Risk of Persistent Pulmonary Hypertension of the Newborn’ by Huybrechts et al. published in JAMA on Tuesday 2^nd June. 

All our previous output on this subject can be seen at this weblink: http://www.sciencemediacentre.org/?s=antidepressant%20pregna&cat

Declared interests

Dr Patrick O’Brien, Dr Nadja Reissland, Prof. Louise Howard and Prof. Andrew Whitelaw had no interests to declare

Dr Hamish McAllister-Williams: “In the last two years I have received payments from a number of pharmaceutical companies as honoraria for speaking at meetings or attendance at advisory boards.  The companies involved are: Lundbeck, Pfizer, Eli Lilly, Ferrer, SPIMACO, Astra Zeneca, Janssen, Cerestim, Sunovian.  I have no ongoing financial arrangement with any pharmaceutical company and neither I nor members of my immediate family have shares in any pharmaceutical company.”