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Antidepressants during pregnancy and risk of persistent pulmonary hypertension of the newborn

by Meg Fluharty @MegEliz_

This blog originally appeared on the Mental Elf site on 2nd July 2015.

Persistent pulmonary hypertension of the newborn (PPHN) is associated with increased morbidity and mortality of infants and occurs in 10-20 per 10,000 births.

Those who survive face chronic lung disease, seizures, and neurodevelopmental problems as a result of hypoxemia and aggressive treatment (Walsh-Sukys et al 2000; Farrow et al 2005; Clark et al 2003; Glass et al 1995).

Based on a single study in 2006, the FDA issued a public health advisory that late pregnancy exposure to SSRIs may be associated with an increased risk of PPHN (FDA 2015; Chambers 2006). However, a review yielding conflicting findings led the FDA to conclude that they were premature in their conclusion.

This is the background to a new study by Huybrechts et al (2015), which sets out to investigate SRRI and non-SSRI antidepressants and the associated risk of PPHN in late stage pregnancy.

PPHN 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.

Methods

Cohort and data

Participants were drawn from the Medicaid Analytic eXtract (MAX) cohort, which holds the health records of medicate beneficiaries in the United States.

Antidepressants

If women filled 1 antidepressant prescription 90 days before delivery, they were considered ‘exposed.’ Antidepressant medications were classified as either SSRIs (Selective Serotonin Re-uptake Inhibitors) or non-SSRIs. Women exposed to both types of antidepressant were excluded from the analysis. A reference group of women was created, whom had not been exposed to either SSRI or non-SSRIs at any time during pregnancy.

Persistent Pulmonary Hypertension of the Newborn (PPHN)

PPHN was defined by the ICD-9 diagnostic criteria for persistent foetal circulation or primary pulmonary hypertension in the first 30 days following delivery.

Analysis

A sensitivity analysis was conducted to control for possible misclassification, with exposure status defined as filling 2 prescriptions during 90 days before delivery, and outcome redefined as only severe cases of PPHN (respiratory assistance, extracorporeal membrane oxygenation, or inhaled nitric oxide therapy).

This very large (3.8 million pregnant women) population-based study included mothers in the US on low income and with limited resources.

Results

Within 3,789,330 pregnancies, 3.4% of women used antidepressants in the 90 days before delivery, of which 2.7% were SSRIs and 0.7% were non-SSRI antidepressants.

Antidepressant versus non-use

  • 31.0 (95% CI, 28.1 to 34.2) per 10,000 infants exposed to antidepressant use had PPHN
  • 20.8 (95% CI, 20.4 to 21.3) per 10,000 infants not exposed to antidepressant use had PPHN

SSRI versus non-SSRI antidepressant use

  • 31.5 (95% CI 28.3 to 35.2) per 10,000 infants exposed to SSRIs had PPHN
  • 29.1 (95% CI 23.3 to 36.4) per 10,000 infants exposed to non-SSRIs had PPHN

Depression diagnosis

After restricting to a diagnosis of depression:

  • 33.8 (95% CI, 29.7 to 38.6) per 10,000 infants exposed to SSRIs had PPHN
  • 34.4 (95% CI, 26.5 to 44.7) per 10,000 infants exposed to non-SSRIs had PPHN
  • 14.9 (95% CI 23.7 to 26.1) per 10,000 infants not exposed to antidepressant use had PPHN

Sensitivity analysis

  • Women who filled 2 prescriptions in the 90 days before delivery did not have stronger associations
  • Changing the definition for PPHN did not alter associations in either SSRIs or non-SSRIs

The chances of a baby getting PPHN when its mother was not taking an SSRI are around 2 in 1,000, compared to around 3 in 1,000 when the mother had taken an SSRI in the last 90 days of pregnancy.

Discussion

Overall, the authors found evidence that SSRI exposure in the last 90 days of pregnancy may be associated with an increased risk of PPHN. However, the magnitude of risk observed is less than has previously been reported. Furthermore, sensitivity analyses did not amplify these risks.

The authors conclude by suggesting clinicians should take the increase of risk of PPHN into consideration when prescribing these drugs during pregnancy.

Limitations

There are a few limitations in this study to be noted:

  • Possible misclassification of the exposure or outcome, (e.g. filling a prescription does not guarantee it was taken as prescribed) which may bias the results. However, the authors did conduct a sensitivity analysis in order to control for this.
  • The baseline characteristics varied between women taking antidepressants and those who did not, with women prescribed antidepressants more likely to be older, white, taking other psychotropic medicines, be chronically ill, be obese, smoke, and have health care issues. While the SSRI and non-SSRI groups were more comparable, non-SSRI women had higher overall illness, more comorbidities, and co-medication use. Additionally, the participant population was drawn from a relatively low-income group, in which comorbid illness is likely to be higher than general populations, which may account for the difference in risk of previous studies.

This evidence would suggest that the benefits of antidepressants taken during pregnancy outweigh the risks of rare events such as PPHN.

Professor Andrew Whitelaw, Professor of Neonatal Medicine at the University of Bristol, said of the study:

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.

Links

Primary paper

Huybrechts K, Bateman B, Palmsten K, Desai R, Patorno E, Gopalakrishnan C, Levin R, Mogun H, Hernandez-Diaz S. (2015) Antidepressant Use Late in Pregnancy and Risk of Persistent Pulmonary Hypertension of the Newborn. 2015: 313(21). [Abstract]

Other references

Walsh-Sukys MC, Tyson JE, Wright LL et al. (2000) Persistent pulmonary hypertension of the newborn in the era before nitric oxide: practice variation and outcomes. Pediatrics. 2000;105(1 pt 1):14-20. [PubMed abstract]

Farrow KN, Fliman P, Steinhorn RH. (2005) The diseases treated with ECMO: focus on PPHN. Semin Perinatol. 2005;29(1):8-14. [PubMed abstract]

Clark RH, Huckaby JL, Kueser TJ et al. (2003) Clinical Inhaled Nitric Oxide Research Group.  Low-dose nitric oxide therapy for persistent pulmonary hypertension: 1-year follow-up. J Perinatol. 2003;23(4):300-303. [PubMed abstract]

Glass P, Wagner AE, Papero PH et al. (1995) Neurodevelopmental status at age five years of neonates treated with extracorporeal membrane oxygenation. J Pediatr. 1995;127(3):447-457. [PubMed abstract]

US Food and Drug Administration. (2006) Public health advisory: treatment challenges of depression in pregnancy and the possibility of persistent pulmonary hypertension in newborns.

Chambers  CD, Hernández-Diaz  S, Van Marter  LJ,  et al.  Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. N Engl J Med. 2006;354(6):579-587. [PubMed abstract]

– See more at: http://www.nationalelfservice.net/treatment/antidepressants/antidepressants-during-pregnancy-and-risk-of-persistent-pulmonary-hypertension-of-the-newborn/#sthash.kEFM7Ik8.dpuf

Financial incentives for smoking cessation in pregnancy

By Meg Fluharty @MegEliz_

This blog originally appeared on the Mental Elf site on 11th March 2015.

shutterstock_90615607

Smoking during pregnancy is thought to cause approximately 25,000 miscarriages per year in the United Kingdom (Health and Social Care Information Centre, 2010).

Additionally, smoking while pregnant is attributable to 4-7% of stillbirths (Flenady et al., 2011), and 3-5% of infant deaths (Gray et al., 2009) with these rates even higher in deprived areas, where remaining a smoker during pregnancy is more common (Gray et al., 2009).

In 2009, 24% of women attending antenatal appointments in Scotland were smokers (NHS, 2009). However only 1 in 10 reported using cessation services, and 3% were abstaining by four weeks (Tappin et al., 2010).

A recent Cochrane systematic review suggested financial incentives may be beneficial in helping pregnant women stop smoking, although it concluded that further evidence was needed (Chamberlain et al., 2013). Tappin et al (2015) investigated the effectiveness of shopping vouchers in addition to NHS Stop Smoking Services to aid quit attempts in pregnant women.

Nearly 1 in 4 women attending antenatal appointments in Scotland were smokers (NHS, 2009).

Methods 

The authors conducted a randomised controlled trial of 609 pregnant smokers recruited from NHS Greater Glasgow and Clyde. Women were randomly allocated to routine smoking cessation care (control group) or to routine care and up to £400 in shopping vouchers if they engaged with services and successfully quit smoking (incentives group).

Routine care

Routine specialist pregnancy care involved an initial meeting to discuss quitting smoking and set a quit date. This was followed by 4 weekly telephone calls, and free nicotine replacement therapy for 10 weeks.

Incentives group

The incentives group received £50 in shopping vouchers for attending the initial meeting to set a quit date. If participants were smoke-free 4 weeks later, they would receive another £50 voucher, and if smoke-free at 12 weeks, participants received £100 in gift vouchers. Between 34-38 weeks gestation, women were once again asked smoking status, and those who had quit received a final £200 voucher. In all instances, smoking status was verified by a carbon monoxide breath test. 

Women who successfully quit smoking in this study received up to £400 in shopping vouchers.

Results 

  • More women successfully quit smoking in the incentives group (22.5%) than the routine care group (8.6%).
  • There was a higher quit rate at 4 weeks in the incentives group compared to the routine care group.
  • 12 months after quit date, there was still large difference in self-reported quit rates (15% incentives, 4% control).
  • Women lost to follow-up were assumed to be smokers, which was validated by analysing residual routine blood samples for cotinine.

shutterstock_56322052

Summary

This study demonstrated that financial incentives with routine care could be beneficial in motivating quit attempts in pregnant smokers, as well as aiding them in continuing to abstain up to 12 months after their quit date. Furthermore, the quit rates reported in this trial were larger than many pharmaceutical (Coleman et al., 2012) or behavioural (Chamberlain et al., 2013) intervention trials in pregnant women. Although, it should be noted that women in the control group had higher nicotine addiction scores than those in the incentives group.

While the evidence from this study suggests using financial incentives may be beneficial in helping pregnant smokers to stop, there may be practical and ethical issues in implementing this as an intervention.

Additionally, other studies are needed to determine the generalizability and possible cost effectiveness of this intervention, as well as what cessation services are best suited to pair with financial incentives. However, it will be interesting to see how this study may be used to inform future policy.

Links

Tappin D, Bauld L, Purves D, Boyd K, Sinclair L, MacAskill S et al. Financial incentives for smoking cessation in pregnancy: randomised controlled trial (pdf). BMJ 2015; 350:h134

Health and Social Care Information Centre, Infant feeding survey 2010 (pdf). HSCIC, 2012. www.hscic.gov.uk/pubs/ifs2005.

Flenady V, Koopmans L, Middleton P, Frøen JF, Smith GC, Gibbons K, et al. Major risk factors for stillbirth in high-income countries: a systematic review and meta-analysis. Lancet 2011;377:1331-40. [Abstract]

Gray R, Bonellie SR, Chalmers J, Greer I, Jarvis S, Kurinczuk J, et al. Contribution of smoking during pregnancy to inequalities in stillbirth and infant death in Scotland 1994-2003: retrospective population based study using hospital maternity records. BMJ 2009;339:b3754.

Information Services Division, NHS National Services Scotland. Births and babies: smoking and pregnancy, 2009. www.isdscotland.org/isd/2911.html.

Tappin DM, MacAskill S, Bauld L, Eadie D, Shipton D, Galbraith L. Smoking prevalence and smoking cessation services for pregnant women in Scotland. Subst Abuse Treat Prev Policy 2010;5:1.

Coleman T, Chamberlain C, Davey MA, Cooper SE, Leonardi-Bee J. Pharmacological interventions for promoting smoking cessation during pregnancy. Cochrane Database Syst Rev 2012;9:CD010078. [Abstract]

Chamberlain C, O’Mara-Eves A, Oliver S, Caird JR, Perlen SM, Eades SJ, et al. Psychosocial interventions for supporting women to stop smoking in pregnancy. Cochrane Database Syst Rev 2013;10:CD001055

– See more at: http://www.thementalelf.net/mental-health-conditions/substance-misuse/financial-incentives-for-smoking-cessation-in-pregnancy/#sthash.upeNCXSE.dpuf

Exercise for the prevention and treatment of antenatal depression

By Meg Fluharty

This blog originally appeared on the Mental Elf blog on 19th September 2014

shutterstock_59173807

Depression occurring during pregnancy, known as antenatal depression, is very common; affecting 10-13% of women (Gavin et al, 2005), which can result in premature labour, low birth weight, and a compromised mother-child relationship (Li et al, 2009; Mancuso et al 2004).

The current treatments include antidepressants and psychotherapy (Field et al, 2009; Rethorst et al 2009). However, antidepressant use may result in adverse effects during pregnancy and psychotherapy often has lengthy waiting lists (Einerson et al 2010, Parker et al; 2008).

Exercise is also recommended as a treatment option for mental and physical health during pregnancy, by NICE (NICE, 2006), the Royal College of Obstetricians and Gynaecologists (RCOG, 2006) and the American College of Obstetricians and Gynaecologists (Artal & O’Tool, 2006).

This study is the first systematic review and meta-analysis of randomised controlled trials (RCTs) investigating the effectiveness of exercise as a treatment option in antenatal depression (Daley et al, 2014).

Exercise balls are a popular training aid and also a soft place to grab a few minutes sneaky shut-eye.

“Balls to exercise” Insert exclamation mark or question mark as you see fit.

Methods

The authors conducted a literature search of multiple electronic databases, and studies were selected for inclusion if they were RCTs which compared exercise with usual care, a control group or another comparator. Studies were also included which recruited non-depressed, at risk, and depressed participants as the review focused on both prevention and treatment of antenatal depression. Studies were excluded if the intervention was less than 6 weeks (Daley et al, 2014).

The primary outcome was change in depression score between baseline and final antenatal follow-up. The means and standard deviations of the different depression scores were extracted, or calculated if necessary. The standardised mean different (SMD) was calculated in order to summarise the effects across the trials. For the meta-analysis, a random effects model was used, with subgroup analyses in depressed vs. non-depressed patients and aerobic vs. non-aerobic exercise conditions (Daley et al, 2014).

Results

Included studies

Six out of a total of 919 papers were chosen for inclusion in the review and analysis. Studies were primarily excluded if they were not RCTs, did not measure depression, or compared exercise interventions.

All six studies investigated exercise as an intervention versus a control:

  • 2 studies used standard prenatal care
  • 2 used a waiting list
  • 1 used social support
  • 1 used parent education sessions as the control groups

The interventions ranged from 8-12 weeks and were categorised as either aerobic exercise or non aerobic.

In total, there were 406 pregnant women, whose ages ranged from 14-38 and were recruited from 16 weeks gestation.

One study included non-depressed women, and 5 studies included either at risk or participants depressed at baseline (Daley et al, 2014).

Meta-analysis results

  • There was a reduction in depression scores in the exercise groups versus the comparator groups (SMD -0.46, 95%CI -0.87 to 0.05, p=0.03, I2= 68%)
  • There was no difference between women who were:
    • Non-depressed at baseline (SMD -0.74; 95% CI -1.22 to -0.27, p=0.002)
    • Depressed at baseline (SMD -0.41; 95% CI -0.88 to 0.07, p=0.09, I2=70%)
  • There was no difference between:
    • Aerobic exercise interventions (SMD -0.74: 95% CI -1.22 to -0.27 p=0.002)
    • Non-aerobic exercise interventions (SMD -0.41; 95% CI -0.88 to 0.07, p=0.09, I2 =70%)

Exercise during pregnancy may be effective at reducing depression, but bigger and better RCTs are needed before we can be sure of this finding.

Exercise during pregnancy may be effective at reducing depression, but bigger and better RCTs are needed before we can be sure of this finding.

Discussion

Daley et al (2014) present the first meta-analysis of trials investigating the effectiveness as a treatment for antenatal depression. NICE (NICE, 2006), Royal College of Obstetricians and Gynaecologists (RCOG, 2006), and the American College of Obstetricians and Gynaecologists (Artal & O’Tool, 2006) have all stated that women should consider exercise during pregnancy for mental health benefits, and this review provides evidence to support those guidelines.

However, there are a number of limitations that should be considered:

  • The results show a small to moderate effect size, based on a small number of low to moderate quality studies
  • The studies varied greatly and contained large confidence intervals, which may result in imprecise estimates
  • 5 of the 6 studies were based on women with depression, so the authors cannot conclude whether exercise can be used to prevent depression in pregnancy
  • Tests of subgroup differences in exercise category were based on a single trial, therefore future studies should examine a larger range of exercises (aerobic and non-aerobic)
  • No studies reported on adverse events
  • Publication bias was not investigated due to the small number of trials

Future research should be based on a larger sample, include a wider range of exercise categories, investigate possible adverse events, and include non-depressed women.

While we're waiting for the new research into antenatal depression, don't forget that exercise in pregnancy has all sorts of other important benefits.

While we’re waiting for new research to be published, don’t forget that exercise in pregnancy does of course have all kinds of other undeniable benefits.

Links

Daley AJ, Foser L, Long G, Paler C, Robinson O, Walmsley H, Ward R. The effectiveness of exercise for the prevention and treatment of antenatal depression: a systematic review with meta-analysis. BJOG 2014; DOI: 10.1111/1471-0528.12909 [PubMed abstract]

Gavin NI, Gaynes BN, Lohr KN, Meltzer-Brody S, Gartlehner G, Swinson T. Perinatal depression: a systematic review of prevalence and incidence. Obstet Gynecol 2005;106:1071–83. [PubMed abstract]

Li D, Liu L, Odouli R. Presence of depressive symptoms during early pregnancy and the risk of preterm delivery: a prospective cohort study. Hum Reprod 2009;24:146–53.

Mancuso RA, Schetter CD, Rini CM, Roesch SC, Hobel CJ. Maternal prenatal anxiety and corticotropin-releasing hormone associated with timing of delivery. Psychosom Med 2004;66:762–9. [PubMed abstract]

Field T, Deeds O, Diego M, Hernandez-Reif M, Gauler A, Sullivan S, et al. Benefits of combining massage therapy with group interpersonal psychotherapy in prenatally depressed women. J Body Mov Ther 2009;13:297–303. [PubMed abstract]

Rethorst CD, Wipfli BM, Landers DM. The antidepressive effects of exercise: a meta-analysis of randomized trials. Sports Med 2009;39:491–511. [PubMed abstract]

Einerson A, Choi J, Einerson TR, Koren G. Adverse effects of antidepressant use in pregnancy: an evaluation of fetal growth and preterm birth. Depress Anxiety 2010;27:35–8 [PubMed abstract]

Parker GB, Crawford J, Hadzi-Pavlovic D. Quantified superiority of cognitive behavioural therapy to antidepressant drugs: a challenge to an earlier meta-analysis. Acta Psychiatr Scand 2008;118:91–7 [PubMed abstract]

Royal College of Obstetricians and Gynaecologists. Exercise in Pregnancy. Statement No. 4. London: RCOG, 2006.

Antenatal and postnatal mental health: Clinical management and service guidance. NICE CG45, Feb 2007.

Artal R, O’Toole M. Guidelines of the American College of Obstetricians and Gynecologists for exercise during pregnancy and the postpartum period. Br J Sports Med 2003;37:6–12. [PubMed abstract]

– See more at: http://www.thementalelf.net/mental-health-conditions/depression/exercise-for-the-prevention-and-treatment-of-antenatal-depression/#sthash.oDvrzRsY.dpuf