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Perinatal mental health 1


Non-psychotic mental disorders in the perinatal period
Louise M Howard, Emma Molyneaux, Cindy-Lee Dennis, Tamsen Rochat, Alan Stein, Jeannette Milgrom

Mental disorders are among the most common morbidities of pregnancy and the postnatal period, and can have Lancet 2014; 384: 177588
adverse eects on the mother, her child, and family. This Series paper summarises the evidence about epidemiology, This is the rst in the Series of
risk factors, identication, and interventions for non-psychotic mental disorders. Although the phenomenology and three papers about perinatal
mental health
risk factors for perinatal mental disorders are largely similar to those for the disorders at other times, treatment
considerations dier during pregnancy and breastfeeding. Most randomised controlled trials have examined Health Service and Population
Research Department, Institute
psychosocial and psychological interventions for postnatal depression, with evidence for eectiveness in treating and of Psychiatry, Psychology, and
preventing the disorder. Few high-quality studies exist on the eectiveness or safety of pharmacological treatments in Neuroscience, Kings College
the perinatal period, despite quite high prescription rates. General principles of prescribing of drugs in the perinatal London, London, UK
(Prof L M Howard MRCPsych,
period are provided, but individual riskbenet analyses are needed for decisions about treatment.
E Molyneaux MSc); University of
Toronto and Womens College
Introduction pregnancy and 13% in the rst 3 months post partum Research Institute, Toronto,
Non-psychotic mental disorders are among the (period prevalence rates are 184% and 192%, ON, Canada
(Prof C-L Dennis PhD); Africa
commonest morbidities of pregnancy and the respectively).6 A higher prevalence of antenatal and
Centre for Health and
post-partum period (the perinatal period). Research postnatal depression (major and minor) is generally Population Studies, University
about perinatal mental disorders so far has largely reported in women in LMICs than in women in HICs.7 A of KwaZulu-Natal, Durban,
focused on depression, particularly postnatal depression. meta-analysis8 of the point prevalence of non-psychotic South Africa (T Rochat PhD);
Department of Psychiatry,
However, increasing evidence shows substantial common mental disorders (including depression,
University of Oxford, Oxford,
morbidity from other disorders. In this Series paper, we anxiety, adjustment, or somatic disorders) in LMICs UK (Prof A Stein FRCPsych);
also review the available evidence base for the reported values of 156% during pregnancy and MRC/Wits Rural Public Health
epidemiology and treatment of anxiety disorders, 198% post partum, with substantially higher8 and lower9 and Health Transitions
Research Unit (Agincourt),
post-traumatic stress disorder (PTSD), eating disorders, rates in specic countries.8 Pregnancy was traditionally School of Public Health,
and personality disorders. University of the
Witwatersrand, Johannesburg,
Key messages
Epidemiology Health-care professionals need to be aware that when
South Africa (Prof A Stein); and
Melbourne School of
Depressive disorders doing psychosocial assessments in the perinatal period, Psychological Sciences,
Depressive disorders are common during pregnancy mental disorders across the diagnostic spectrum can occur University of Melbourne,
and in the post-partum period and generally have the during pregnancy and post partum Melbourne, VA, Australia
same phenomenology as non-childbearing depressive (Prof J Milgrom PhD)
Psychological and psychosocial interventions are eective
disorders (panel 1).13 Somatic symptoms can result from treatments for postnatal depression; evidence from
Correspondence to:
Prof Louise M Howard, Health
normal physiological changes in pregnancy and the low-income and middle-income countries showed that Service and Population Research
early post-partum period, so therefore need to be these can be provided eectively by trained non-specialist Department, Kings College
assessed with care. However, these symptoms are more workers London, London SE5 8AF, UK
common in women with depression than in women louise.howard@kcl.ac.uk
Little research exists about the epidemiology or
who do not have depression in the perinatal period (with eectiveness of interventions for perinatal non-psychotic
the exception of appetite change), suggesting that they mental disorders, other than postnatal depression
might be valid markers of the disorder.3 Somatic To what extent interventions that are developed and used
symptoms are particularly frequent presentations of outside the perinatal period need modication for the
depression (and anxiety) in non-perinatal periods in perinatal period is unclear; nevertheless, practitioners
women in low-income and middle-income countries need to be aware of dierences in context when treating
(LMICs).4 In an Ethiopian cohort, there was a moderately women during this time
high correlation between perinatal total somatic Individualised risk benet analyses are needed when
symptoms and depression or anxiety scores, supporting judging use for psychotropic drugs in the perinatal period,
the importance of somatisation of mental distress in the accounting for the risk of untreated illness on the mother
perinatal period.5 and fetus or infant
A systematic review6 of studies, predominantly in Evidence for risks of psychotrophic drugs is restricted
high-income countries (HICs), estimated the point because it is based on observational studies that can only
prevalence of major depressive disorder to be between establish associations and not causality; however, absolute
31% and 49% during pregnancy and 47% in the rst risks from meta-analyses are small and residual
3 months post partum. Point prevalence including minor confounding is likely
depression (panel 1) was estimated to be up to 11% in

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post partum by comparison with rates pre-pregnancy,


Search strategy and selection criteria during pregnancy, or at the end of the rst post-partum
We searched PubMed, Embase, PsycINFO, and the Cochrane Library without language year; however, the estimates are based on the proportion
restrictions. Searches were done using the key search terms pregnancy, prenatal, of women newly seeking treatment rather than
antenatal, postnatal, postpartum, perinatal, puerperal, breastfeeding, birth, community-based measurement of incidence. Poor
weaning, childbirth, trimester, peripartum, lactation, ante-natal, post-natal, identication and measurement of depression during
postpartum, and mood disorder (exploded MeSH term), anxiety disorder (exploded pregnancy could lead to many women being misclassied
MeSH term), eating disorder (exploded MeSH term), depression, anxiety, eating with post-partum onset. Results from a US study15
disorder. These search terms were combined with the following specic terms using date suggested 33% of postnatal depression begins in
restrictions based on the amount of research output in each area: prevalence, pregnancy and 27% in pre-pregnancy. Additionally, some
incidence, relapse, course (searched for systematic reviews between Jan 1, 1993, and evidence suggests that there might be a higher
April 3, 2013; searched for epidemiological or experimental studies between Jan 1, 2008, prevalence of depressive symptoms during pregnancy
and April 3, 2013); screening, screen, identication, scale(searched for systematic than in the post-partum period.16 Women with postnatal
reviews between Jan 1, 1993, and May 16, 2013; searched for epidemiological or depression often recover within a few months from
experimental studies between Jan 1, 2008, and May 16, 2013), Amitriptyline, onset, but around 30% of women still have depression
Hydrochloride, Iproniazid, Citalopram, Duloxetine, Amoxapine, Isocarboxazid, beyond the rst year after delivery17 and there is a high
Escitalopram, Flupentixol, Butriptyline, Moclobemide, Fluoxetine L-tryptophan, risk of around 40% of subsequent postnatal and non-
Clomipramine, Phenelzine, Fluvoxamine, Mirtazapine, Desipramine, postnatal relapse.18,19
Tranylcypromine, Paroxetine, Nefazodone, Dibenzepin Hydrochloride,
Triuoperazine, Sertraline, Reboxetine, Dosulepin, Tryptophan, Dothiepin, Anxiety disorders
Hydrochloride, Venlafaxine, Doxepin, Imipramine, Iprindole, Lofepramine, Anxiety disorders in the perinatal period are often
Maprotiline, Mianserin, Nomifensine Hydrogen Maleate, Nortriptyline, Opipramol overlooked but are commoneg, a large US
Hydrochloride, Protriptyline, Trazodone, Trimipramine Maleate, Viloxazine, population-based study10 reported a prevalence of 13% in
Zimeldine Hydrochloride, Chloral Hydrate, Alprazolam, Clomethiazole, the past year of any anxiety disorder in currently pregnant
Bromazepam, Dipenhydramine, Buspirone Hydrochloride, Flunitrazepam, or post-partum women, comparable with non-pregnant
Chlordiazepoxide Hydrochloride, Flurazepam, Chlormezanone, Loprazolam, women. Similar rates of anxiety disorders are reported in
Diazepam, Lormetazepam, Ketazolam, Melatonin, Lorazepam, Methyprylone, African countries8,20 and there is substantial comorbidity
Medazepam, Nitrazepam, Meprobamate, Nitrados, Oxazepam, Promethazine, with depressive disorders.15 Little research has been done
Prazepam, Temazepam, Sardiazepam, Triazolam, Zaleplon, Zolpidem, into the course of anxiety disorders in the perinatal
Tartrate, Zopiclone (between Jan 1, 2010, and May 15, 2013), paternal, father, period; however, some evidence suggests a reduction in
fathers, men, husband, partner (between Jan 1, 2003, and May 15, 2013), the prevalence of generalised anxiety disorder, and
hormone(s), oestrogen, progesterone, estriadol, and treatment, intervention, anxiety symptoms, during the course of pregnancy and
prevention, trial, therapy, therapeutic, treat, medicine, medication, the post-partum period.16,21
prescribe, prescription (between Jan 1, 2003, and July 11, 2013). A meta-analysis22 reported a signicantly higher risk
of obsessive compulsive disorder in pregnant and
post-partum women than in non-pregnant women.
viewed as a time when women are protected against Ruminations in the post-partum period can include
depression, but the latest systematic review6 and a large ruminations of harm to the infant, but these are not
US epidemiological study10 do not report a signicant associated with actual harm (unlike the delusions in a
dierence in the prevalence or incidence of depression psychotic disorder); therefore, health-care professionals
between pregnant and non-pregnant women. However, need to distinguish obsessive ruminations from delusions.
rates of identication and treatment of depression might
be lower in pregnant than non-pregnant women,11 PTSD
contributing to the perception of reduced prevalence Increasingly, authors recognise that women can have
reported. Studies using non-childbearing comparators PTSD in the perinatal period triggered by traumatic
might also underestimate risks associated with the experiences during pregnancy or childbirth, or by
perinatal period because women who become mothers traumatic events before conception.23 Estimates of PTSD
might be mentally healthier and have a lower baseline prevalence after delivery vary but are often estimated to
vulnerability to depression than those who do not be around 12% in HICs23 with many more women
have children. experiencing subthreshold symptoms;23 a higher prev-
Whether the incidence of depression peaks in the alence is reported in LMICs (eg, 59% in Nigeria).24 Most
postnatal period has been greatly debated. A low mood is studies underestimate the total prevalence of PTSD in
common, aecting around 50%12 in the rst weeks after the postnatal period by only examining PTSD related to
delivery (so-called baby blues), but is usually mild and traumatic childbirth experiences; higher rates are noted
transient. Investigators of longitudinal studies using in pregnancy when diverse trauma experiences are
medical records have noted an increase in incidence of included (point prevalence 68%).25 Perinatal PTSD is
depression during the rst 5 months13 and 9 months14 highly comorbid with depression.25

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Panel 1: DSM-5 and ICD-10 diagnostic criteria for depression


DSM-51 ICD-102
Major depression Severe depression
At least ve symptoms present for at least 2 weeks, for most of At least seven symptoms, usually present for at least 2 weeks,
nearly every day experienced with severe intensity for most of every day
A symptom must be: All three key symptoms associated should be present:
Depressed mood Persistent sadness or low mood
Markedly diminished interest or pleasure in all or most Loss of interests or pleasure
activities Fatigue or low energy
Other symptoms: At least four associated symptoms should be present:
Substantial weight loss when not dieting or weight gain, or Disturbed sleep
increase or decrease in appetite Poor concentration or indecisiveness
Insomnia or hypersomnia Low self-condence
Psychomotor agitation or retardation Poor or increased appetite
Fatigue or loss of energy Suicidal thoughts or acts
Feelings of worthlessness or excessive or inappropriate guilt Agitation or slowing of movements
Diminished ability to think or concentrate or indecisiveness Guilt or self-blame
Recurrent thoughts of death or suicidal ideation (with or Individual unable to continue with social, work or domestic
without a specic plan) activities, except to a very restricted extent
Symptoms cause clinically signicant distress or impairment in Moderate depression
social, occupational, or other important areas of functionality At least two key symptoms and three associated symptoms
Symptoms not due to direct physiological eects of a substance should be present
or another medical condition Minor depression
The occurrence of a major depressive episode is not better At least two key symptoms and two associated symptoms
explained by schizoaective disorder or other psychotic should be present, with no symptoms present to an intense
disorders and there has never been a manic or hypomanic degree
episode With postpartum onset
Depressive episode with insucient symptoms* Disorder commencing within 6 weeks of delivery
Depressed aect and at least one other of the above symptoms ICD=international classication of diseases (published by WHO2). DSM=diagnostic and sta-
associated with clinically signicant distress or impairment tistical manual of mental disorders. *Changed from minor depression in DSM-4 (two to
four depressive symptoms experienced for at least 2 weeks, one symptom should be de-
persisting for at least 2 weeks pressed mood or loss of pleasure). Changed from with postpartum onset in DSM-4 (on-
With peripartum onset set of mood symptoms within rst 4 weeks after delivery).

Onset of mood symptoms happens during pregnancy or in the


4 weeks after delivery

Eating disorders prevalence of binge eating of 173% was reported and


Women with eating disorders have an increased rate associated with anxiety and pre-pregnancy binge
of fertility problems, although many still become eating disorder.
pregnant, sometimes with fertility treatment.26 The In a large population study,30 77 807 women were assessed
expectation of weight gain during pregnancy can be for eating disorders in the perinatal period; 3550% rates
considered healthy, and women are sometimes more of remission were recorded at 18 months post partum,
accepting of their body size at this time. However, suggesting higher remission rates in the community than
symptoms of eating disorders can persist during in clinical samples. Nevertheless, a substantial proportion
pregnancy for mothers who have had a recent of women with pre-pregnancy eating disorders have
episode.27 A Norwegian prospective population study of continuation or recurrence of symptoms post partum.30
41 157 women reported substantial remission rates The disruption in sleep and mealtimes and the need to
during pregnancy between 29% and 78% depending on adapt to the babys routines, especially around feeding,
the type of eating disorder; incident cases of eating makes it challenging for many mothers to establish and
disorder during pregnancy were rare, other than binge maintain their own eating patterns.31 The risk of postnatal
eating disorder (11 incident case per 1000 person-weeks) depression is increased in women with eating disorders by
which was associated with low socioeconomic status.28 comparison with women with a history of an eating
Binge eating can be common. In a Brazilian study,29 a disorder but not active symptoms.32

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Antenatal depression Postnatal depression

Social risk factors Domestic violence (HIC, LMIC)35 Domestic violence, previous abuse
Life stress and major/negative life events (HIC, LMIC)35,37,40
Socioeconomic status (HIC, LMIC)8,20,34 Negative life events, low social support
Exposure to trauma, negative life Low socio-economic status (LMIC, small (HIC, LMIC)8,20,36,39,40
events and stress association in HIC)8,20,34 Low partner support, marital diculties
Domestic violence Absence of social or relationship support (LMIC, small to medium in HIC)8,20,36,39,40
Migration status (HIC, LMIC)8,20,34 Migration status (HIC)43
Relationship and social support Intention to get pregnant Low socio-economic status
Reproductive intention (HIC, small to medium in LMIC)8, 20,34 (LMIC, small in HIC)8,20,40,41

Psychological risk factors Prior history of psychopathology Depression or unhappiness in pregnancy


(HIC, LMIC)8,20,34 (HIC, LMIC)8,20,36,39,40
Personality traits: Anxiety during pregnancy Anxiety in pregnancy* (HIC)36
high neuroticism (HIC, LMIC)8,20,34 History of depression
Prior psychopathology: depression, (HIC, LMIC)8,20,36,39,40
anxiety, PTSD, substance misuse Neuroticism* (HIC)36,39
Substance misuse* (HIC)37
Family history of any psychiatric illness* (HIC)8,20,36,39

Biological risk factors Young age (HIC, LMIC)8, 20,34 Increased parity (rural LMIC context)8,20,40
Multiple births* (HIC)38
Age Chronic illness or medical illness (HIC, LMIC)37
Genetic and hormonal susceptibility Preterm birth, low birth weight (HIC, LMIC)42
Chronic diseases No association with use of assisted reproductive
Medical illness technologies* (HIC)38
Pregnancy complications

Key
Risk characterised as strong if systematic evidence listed the risk factor to be strong, signicant, or top ranked
Risk characterised as medium to strong if some systematic evidence listed the risk factor to be medium, while others listed strong, or top ranked
Risk characterised as medium if systematic evidence listed the risk factor to be medium, moderate, or intermediately ranked
Risk characterised as small if systematic evidence listed the risk factor to be small association, inconsistently signicant, low ranked, or low rated

Figure 1: Risk factors for antenatal and postnatal depression: systematic review evidence
Risk factors for antenatal and postnatal depression are categorised by strength of risk in HICs and LMICs. Extent of risk indicated for HIC and LIC. HIC=high-income
countries. LMIC=low-income and middle-income countries. PTSD=post-traumatic stress disorder. *Evidence only available from one setting.

Personality disorders comorbidities. However, a history of any psychopathology


To our knowledge, only one epidemiological study has and psychosocial adversities, including the spectrum of
been done of personality disorders in the perinatal low social support and abuse, are predictors of mental
period. The prevalence of personality disorders in disorders during and after pregnancy with little
pregnancy, based on a self-report measure in a Swedish diagnostic specicity and should inform prevention,
study was 6%, but the prevalence of specic personality identication, and treatment. Figure 1 shows a summary
disorders was not reported.33 Personality disorders in of systematic review evidence of risk factors for antenatal
the perinatal period are often comorbid with other and postnatal depression8,20,3443 (which have a substantial
non-psychotic disorders, such as depression, and literature, unlike other disorders).
emerging evidence suggests that they are associated Although most risk factors are not specic to the perinatal
with an increased risk of adverse outcomes and poor period or specic disorders, some epidemiological18,44 and
response to treatment.33 experimental45 results support a reproductive subtype of
depression, characterised by a particular sensitivity to
Risk factors changes in reproductive hormones, increases in risk of
Despite substantial research into risk factors for premenstrual, postnatal, and perimenopausal depression46
perinatal disorders, particularly depressive disorders, and a personal or family history of postnatal depression.18,47
there are few systematic reviews and a paucity of Additionally, PTSD after childbirth has been associated
research using diagnostic measures, longitudinal with obstetric complications, particularly with severe
approaches, and comparison groups. Studies often morbidity, preterm birth, high subjective distress, and
exclude women with a history of mental illness or infant complications, although the evidence is incon-
particular groups of women, such as those who are sistent and quality of studies is moderate-to-low.48,49
infected with HIV or are chronically ill, which restricts Psychopathology (particularly depression and anxiety)
our understanding of overlapping risks and during pregnancy is strongly associated with an increased

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Panel 2: Assessment to detect postnatal depression by use of Edinburgh postnatal depression scale51
As you have recently had a baby, we would like to know how you 6) Things have been getting on top of me*
are feeling. Please underline the answer that comes closest to Yes, most of the time I havent been able to cope at all
how you have felt in the past 7 days, not just how you feel today. Yes, sometimes I havent been coping as well as usual
No, most of the time I have coped quite well
In the past 7 days:
No, I have been coping as well as ever
1) I have been able to laugh and see the funny side of things
As much as I always could 7) I have been so unhappy that I have had diculty sleeping*
Not quite so much now Yes, most of the time
Denitely not so much now Yes, sometimes
Not at all Not very often
No, not at all
2) I have looked forward with enjoyment to things
As much as I ever did 8) I have felt sad or miserable*
Rather less than I used to Yes, most of the time
Denitely less than I used to Yes, quite often
Hardly at all Not very often
No, not at all
3) I have blamed myself unnecessarily when things went wrong*
Yes, most of the time 9) I have been so unhappy that I have been crying*
Yes, some of the time Yes, most of the time
Not very often Yes, quite often
No, never Only occasionally
No, never
4) I have been anxious or worried for no good reason
No, not at all 10) The thought of harming myself has occurred to me*
Hardly ever Yes, quite often
Yes, sometimes Sometimes
Yes, very often Hardly ever
Never
5) I have felt scared or panicky for no very good reason*
Yes, quite a lot *Response categories are scored as either 0, 1, 2, or 3 according to increased severity of the
symptom. Items marked with an asterisk are reverse scored (ie, 3, 2, 1, and 0). The total score
Yes, sometimes
is calculated by adding together the scores for each of the ten items. Reproduced from Cox
No, not much and colleagues51 by permission of The Royal College of Psychiatrists.
No, not at all

risk of postnatal PTSD48 and might increase a womans between 12 and 13) and for antenatal major depression
distress during labour. Additional risk factors identied between 60% and 80% (cuto between 14 and 15), this
include previous traumatic experiences and low support range depends on the population, prevalence, translation,
during childbirth.48 and cuto point,52 and the diagnostic performance of the
EPDS seems quite good in most studies.53
Identication The EPDS has been translated and validated in many
Depressive disorders settings. A systematic review54 of studies in Africa
Because perinatal mental disorders can have serious suggested a pooled sensitivity of 094 (95% CI 068099)
consequences in terms of maternal morbidity and and specicity of 077 (059088) at a cuto of more
mortality and adverse infant outcomes,50 there is much than a score of eight. However, the authors emphasised
interest in improvement of identication of disorders to the low quantity of research into local understandings of
increase treatment rates. Most research and debate has perinatal depression syndromes in dierent African
focused on the identication of postnatal depression, countries.54 Although two recent studies suggested that
whether or not to use screening instruments routinely in very brief screens might be eective in identication of
the post-partum period, and which methods to use. The depression or anxiety post partum in HICs55 and LMICs,56
most frequently used screening method is the Edinburgh additional research is needed.
postnatal depression scale (EPDS),51 which is a self-report Only ve comparative studies have been published,
ten item questionnaire (including one on self-harm; which together provide low-to-moderate strength of
panel 2), validated for both antenatal and postnatal evidence57 for the clinical ecacy of screening in reduction
use.51,52 Although the positive predictive value for of morbidity in post-partum women. However, the
postnatal major depression can range between 9% and strongest evidence is for combined identication and
64% (cuto between 9 and 10) or 17% and 100% (cuto treatment programmes, mainly from three cluster

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randomised controlled trials in HICs that reported or psychological preventative interventions for postnatal
improvement in maternal mental health for women depression (all but three were undertaken in HICs).
who received integrated post-partum screening and Women who received an intervention were signicantly
management strategies by trained health professionals.5860 less likely to develop postnatal depression than were those
Although results from cost-eectiveness modelling have who received standard care (relative risk [RR] 078, 95% CI
suggested that formal identication methods for postnatal 066093). Protective interventions included intensive,
depression would not meet willingness-to-pay thresholds,61 individualised post-partum home visits provided by health
assumptions made in the model might not represent professionals (two RCTs), lay (peer)-based post-partum
present practice and two large RCTs58,62 suggest that telephone support (one RCT), and interpersonal
systematic identication with enhanced support can be psychotherapy (ve RCTS), particularly for studies
cost eective. Most women and health professionals deem focusing on women at-risk of postnatal depression
screening acceptable, although small qualitative studies (RR 066, 95% CI 050088), and for postnatal
report that women can experience screening as potentially interventions compared with interventions in the antenatal
stigmatising and intrusive.63 Although questions have period (073, 059090). However, no signicant
been raised about the appropriateness of the EPDS for preventive eect on depressive symptomatology was
some ethnic groups and the screening context (eg, rural recorded for psychological structured debrieng (ve RCTs,
LMIC setting)63,64 it is widely used internationally. n=3050; RR 057, 95% CI 031103) or cognitive
Although there is scope for harm through behavioural therapy (one RCT, n=150; RR 074, 029188).
non-identication and thus no access to eective treat- Additionally, there was no clear evidence to recommend
ment, concerns about other potential harms associated antenatal and post-partum classes, psychoeducation, or
with screening (such as misdiagnosis, labelling, and sleep strategies (although they might be benecial for
stigma) are particularly pertinent if a clinical decision other maternal outcomes). The use of oestrogens and
about the presence or absence of a mental disorder is progestins72 or dietary supplementation with selenium or
made only on the basis of a screening result. However, docosahexaenoic acid has little supportive evidence.73,74
as international guidelines emphasise, a central Treatment of women with antenatal depression might
principle is that the screening techniques are not prevent postnatal depression but this is better concep-
designed to diagnose depressive disorders, but aim to tualised as treatment rather than prevention.75
identify women for whom further comprehensive No consistency exists for the identication of women at-
psychosocial and clinical assessment is needed.65,66 risk of postnatal depression and there is no measure with
Appropriate training is therefore necessary for health acceptable predictive validity to accurately identify
professionals in the skilful interpersonal process for asymptomatic women who will later develop the disorder.76
psychosocial assessment with appropriate referral and Although several potential biomarkers have been
care pathways for identied risk factors. An evidence investigated (eg, raised corticotropin-releasing hormone
gap remains as to whether screening is clinically during pregnancy,77 genetic variants in the glucocorticoid
eective and cost eective during pregnancy, or in receptor, corticotropin-releasing hormone receptor 1,78 and
LMICs where few eective treatment resources serum leptin),79 all need replication. Future research might
are available. also benet from investigations of predictive techniques
that include psychosocial risk factors and biomarkers.
Other disorders
Many EPDS positive screens that prove false for unipolar Anxiety disorders
depression at diagnostic interview could be indicative of Much less research has been done in relation to the
another mental disorder;67 data from studies suggest prevention of perinatal anxiety than depression.
around 13% of screen positive women in pregnancy68 and Two small trials of group cognitive behavioural therapy
23% in the post-partum period15 have bipolar disorder. At (CBT; n=61 pregnant women with subclinically raised
present the evidence about screening instrument stress and anxiety levels;80 132 women with
accuracy, clinical eectiveness, acceptability, potential mild-to-moderate symptoms or at risk of developing
harms, and cost-eectiveness of screening for disorders depression or anxiety81) had methodological limitations
other than depression is inadequate. Nevertheless, there and equivocal results. Another small trial82 (n=71)
is general agreement about the desirability of training of suggested that incorporation of CBT-based prevention
front-line professionals to identify and treat disorders programme into childbirth education classes for women
other than depression in the perinatal period.65,69,70 at risk of developing OCD was associated with
signicantly lower levels of postnatal obsessions and
Prevention compulsions compared with women receiving general
Depressive disorders psychoeducation about anxiety.82 An antenatal self-guided
Not much research has investigated the prevention of workbook intervention with weekly telephone support
antenatal depression, whereas a Cochrane systematic might reduce symptoms of postnatal depression and
review71 identied 28 RCTs (n>16 000) about psychosocial anxiety,83 and prenatal parenting education could reduce

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post-partum anxiety and improve marital adjustment.84 063088). Insucient data prevented comparisons
A Cochrane review85 reported limited evidence for the between individual-based and group interventions.
eectiveness of other interventions (eight trials; n=556) Two systematic reviews assessing the eectiveness of
assessing hypnotherapy (one trial), imagery (ve trials), interventions to improve the mental health of women in
autogenic training (one trial), and yoga (one trial) for the perinatal period in LMICs showed 17 trials
prevention or treatment of anxiety during pregnancy. (undertaken in predominantly middle-income countries
such as China and Chile with only one trial in a
PTSD low-income country [Uganda])92,93 that reported a
Controversy has surrounded postnatal debrieng for the benecial eect of delivery of a psychosocial or
prevention of PTSD. The term debrieng is used to psychological intervention during routine perinatal care
describe a range of provision from the opportunity (pooled eect sizes: 038, 95% CI 056 to 021;91
to discuss childbirth experiences, particularly if they 034, 053 to 01692). The reviews show that training
were perceived to be traumatic, to highly structured is feasible for non-specialist workers, such as community
debrieng interventions. Most trials have shown no health workers or local women to deliver perinatal
evidence that formal structured debrieng is helpful, and mental health interventions including home visits or
one trial showed potential risk of harm.86 Women do facilitated group sessions with a focus on parenting,
benet from the opportunity to discuss the delivery, but maternal and child health, psychoeducation, social
formal debrieng interventions are not supported by support, or supportive listening adaopted to the
present evidence. circumstances the women who are being treated live
in. However, interventions should be adapted to the
Eating disorders circumstances in which the women being treated live.
No trials have been done on prevention in women at risk
of a recurrence of an eating disorder even though Other disorders
guidelines recommend identication of women with a Treatments for other perinatal disorders have been
history of an eating disorder. Professionals can help scarcely researched, so management largely relies on
women during pregnancy and the postnatal period to extrapolation from the evidence base established for other
maintain regular eating patterns and optimise nutritional times in womens lives such as CBT for eating disorders.
intake for the mother and fetus, and support them in The extent to which interventions need modication for
development of realistic goals for body shape. the perinatal period is unclear and needs additional
research. Restricted evidence from a case series suggests
Psychosocial and psychological treatments that intensive outpatient CBT that is modied for women
Depressive disorders with postnatal OCD could reduce symptoms.94
Because of maternal treatment preferences and potential
concerns about fetal and infant health outcomes, Pharmacological treatment
non-pharmacological treatment options are particularly The mainstay of pharmacological treatment for
important in the perinatal period. Evidence on the non-psychotic mental disorders in the perinatal period is
treatment of antenatal depression is limited to small antidepressants. Data suggests that in Europe around 3%
trials (with 3653 women) of interpersonal therapy, of pregnant women take an antidepressant at some point
culturally relevant brief interpersonal psychotherapy, and in their pregnancy, mostly selective serotonin reuptake
CBT,8789 and a Cochrane review (six trials, n=406) of other inhibitors (SSRIs), with rates of around 10% reported in
types of non-pharmacological interventions such as the USA.95 Antidepressants are eective treatments for
massage, acupuncture, bright light, and omega-3 oils depression, particularly for severe cases, and
reported inconsistent results.90 meta-analyses have shown that ecacy compared with
More evidence is available for postnatal depression, placebo increases with severity of depression.96
particularly from HICs, and a Cochrane review91 found Antidepressants are also eective for PTSD, anxiety
that psychosocial and psychological interventions were disorders, and bulimia nervosa.9799 However, partly
eective for reducing depression symptoms within the because of the diculties in undertaking RCTs in
rst year postpartum (RR 070, 95% CI 060081). perinatal women, no trials have been done for perinatal
Psychosocial interventions, such as peer support and disorders except for postnatal depression. These trials
non-directive counselling, show a decrease in depressive provide evidence of signicantly higher response and
symptomatology (ve trials, n=506; RR 061, 039094), remission rates for women taking SSRIs than for
conrmed by a recent large cluster trial58 in which placebo. A Cochrane systematic review100 pooled data
assessment and non-directive or cognitive behavioural from three studies comparing SSRIs with placebo and
counselling were delivered by health visitors compared reported signicantly higher response (RR 143 [95% CI
with standard care. CBT and interpersonal psychotherapy 103203]) and remission rate (RR 179 [108298]) for
were also benecial in reducing post-partum depressive participants taking SSRIs than in those in the placebo
symptomatology (six trials, n=602; RR 075, 95% CI group. However, the evidence-base is restricted because

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General principles of prescribing in the perinatal period: In discussions about drugs include:
It should not be assumed that it is always better to avoid psychotropic Womans level of distress from untreated symptoms
drugs Severity of previous episodes, previous response to treatment and the womans
Use the lowest eective dose preference
Use the drug which is eective for women and has the lowest known Potential eects of an untreated mental disorder on the fetus or infant (and the
risk to mother and fetus need for prompt treatment)
Prescribe the least number of drugs as possible Risks of relapse or discontinuation symptoms from stopping drug abruptly
Document all decisions Background risk of fetal abnormalities for pregnant women without a mental disorder
Ensure that the mother and partner or family are as involved as possible Uncertainty with regards to possible increased risk of harm associated with drug
in all decisions treatments during pregnancy and the postnatal period; include the risk in overdose
The possibility that stopping a drug with known risk during pregnancy might not
remove the associated risk
Absolute and relative risks should be discussed using natural frequencies and
common denominators (eg, 20 in 100 and 25 in 100, not 1 in 5 and 1 in 4)
Where possible, written material (preferably individualised) should be provided
to explain the risks

Pre-pregnancy During pregnancy Postnatal and breastfeeding

Discuss the possibility of pregnancy (including Where possible use non-drug treatments In each case, weigh up the benets of breastfeeding
unplanned) to the mother and infant against the risk of drug
Use lowest eective dose of drug if needed; avoid exposure in the infant (which is much lower than in
Avoid using contraindicated drugs eg, valproate changing drug regimen and use drugs with the utero); usually inappropriate to withhold treatment
unless only eective drug; women should be made largest up-to-date evidence of safety for the mother to allow breastfeeding when mother is at high risk
fully aware of their risks or fetus, taking previous response into account of relapse; treatment of maternal illness is the
highest priority
Carefully review need for drugs; choose drugs Titrate doses as pregnancy progresses and drug
most likely to achieve clinical stability and of handling is changed Where possible, suitable treatment options should
low risk (note risk of relapse with stopping be used for women who wish to breastfeed rather
or changing drug) Be aware of potential problems with individual than recommending avoidance of breastfeeding
drugs around the time of deliveryinform the
Consider discontinuation of treatment obstetric team of psychotropic use and possible Where a mother had taken a particular drug during
(potentially switching to psychological treatment) complications (including neonatal adaptation pregnancy, continuation with the drug while
if the woman is well and at low risk of relapse symptoms in infants) breastfeeding will usually be appropriate to
minimise withdrawal symptoms in the infant

Infants should be monitored for any adverse


eects of the drugs used, for example feeding
patterns and growth and development; premature
infants and infants with renal, hepatic, cardiac,
or neurological impairment are at high risk of
exposure to drugs

Time of pregnancy

Figure 2: Guidelines to prescribe in the perinatal period


Adapted from The Maudsley prescribing guidelines (11th edn),108 by permission of David Taylor.

the three studies were very small, underpowered, and severity of depression in the dierent study populations.
generally focus on women with mild-to-moderate However, recurrence after discontinuation consistently
postnatal depression.100 RCTs have so far not reported seems to be more likely in women with a history of several
evidence of additional improvement with addition of a episodes or a recent episode.105
psychological intervention to antidepressants,101,102 nor for As a general principle, drugs in pregnancy should be
addition of sertraline by comparison with placebo minimised, and many women with perinatal mental
for women given a psychotherapeutic intervention disorders can be treated with non-pharmacological
for postnatal depression, although the trials were under- interventions. However, drugs will be clinically indicated
powered.100 An RCT103 (n=61) reported signicant for women with more severe mental disorders in which
improvements in EPDS scores in women given there are substantial risks to the mother, the pregnancy,
17-oestradiol skin patches (with dydrogesterone tablets and the fetus or infant.50,107 Clinicians and women
for 12 days per month) compared with women given therefore need to assess the benets and risks of
placebo, but adverse events were reported and there is pharmacological interventions in pregnancy using key
therefore insucient evidence to support use of principles of prescription in the perinatal period
oestrogens for postnatal depression. (gure 2).108 Unlike other times in a womans life, risks of
Women often stop antidepressants during pregnancy104 illness versus risks of drugs do not only aect the women
and there is conicting evidence on whether discon- themselves, the fetus and infant can also be aected
tinuation is associated with an increased risk of relapse of through exposure to psychotropic drugs across the
depression,105,106 probably because of the dierent levels of placenta or through breastfeeding, and side-eects

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potentially aect the mothers ability to parent (eg, debate. Symptoms noted are usually mild and
sedative drugs). However, concerns about risks to self-limiting, but one study reported that infants who
the fetus or a failure to titrate the dose through developed PNAS were at an increased risk of
the pregnancy (to address the changes in drug social-behavioural abnormalities even though they had
concentrations) might lead clinicians to prescribe normal cognitive ability.117 Whether tapering of
subtherapeutic doses.109 antidepressants the week before expected labour would
Risks to the fetus are dicult to assess because of the reduce the occurrence of PNAS is unclear; some authors
absence of RCTs and the resultant diculties in have argued that the balance of evidence suggests that
interpretation of the evidence base. Many studies are discontinuation of clinically needed antidepressants in
small, with biased samples, low-quality study design, little women near term is unwarranted because neonatal
adjustment for important confounders (such as smoking), symptoms only occur in a small number of cases and are
and an almost invariable absence of adjustment for self-limited, but the risk to a womans mental health will
confounding by indication. Initial reports of risks have be increased.109 Evidence on how long to observe the
frequently not been substantiated or are shown to be neonate for PNAS symptoms is scarce. If no symptoms
smaller once larger studies and meta-analyses have been emerge within the rst 72 h after birth, PNAS is unlikely;
done. For example, despite early reports, a meta-analysis110 when PNAS symptoms are present it is advisable to
did not nd an increased risk of spontaneous abortion observe the infant until symptoms are resolved in case
associated with exposure to antidepressant drugs, and two supportive treatment is needed.118
large population studies111,112 (29 228 and 12 425 SSRI Some PNAS symptoms can suggest a spectrum of
exposures, respectively) have not found associations with eects with mild respiratory signs potentially showing
antenatal SSRIs and stillbirths or neonatal deaths after sub-clinical persistent pulmonary hypertension of the
adjusting for confounders. Similarly, two meta-analyses113,114 newborn (PPHN). A systematic review and meta-analysis119
showed paroxetine exposure is associated with only slightly reported an increased risk of PPHN associated with late
increased risks of cardiac malformations (odds ratio [OR] pregnancy SSRI exposure (OR 250, 95% CI 132473;
14) rather than the large ORs initially reported, and absolute risk dierence 2935 per 1000 infants).
residual confounding is possible. Confounding by Although individual studies used dierent diagnostic
indication also needs to be considereda study comparing criteria and possible moderating variables such as
outcomes in infants of women who stopped SSRIs before caesarean section, body-mass index, or preterm delivery
pregnancy and women who continued with SSRIs reported these could not be included in the meta-analysis.
a similar increased risk of cardiac malformations in both Serotonin has a role in the development and modulation
groups,115 suggesting that the association is due to of the lungs and this could be a factor in the development
depression rather than the drug itself. of PPHN. Evidence also shows that prenatal SSRIs are
Antidepressant exposure in pregnancy is signicantly associated with neurobehavioural disturbances in early
associated with gestational age at birth (pooled mean infancy including stress or pain regulation; the severity of
dierence in weeks, 045, 95% CI 064 to 025), these symptoms seems to be associated with high drug
preterm delivery (<37 or <36 weeks depending on the concentrations and pharmacogenetic metabolic factors.120
individual studies included; pooled OR 155, 95% CI Fewer data exists for long-term outcomes of infants
138174), and Apgar score at 1 min (mean dierence of exposed to antidepressants in utero. However, studies are
037 points) and 5 min (mean dierence of 018 points), similarly dicult to interpret because of methodological
although some might be of restricted clinical signicance.110 problems and the known associations between maternal
Meta-analyses have previously reported associations with depression, impaired motherinfant interactions, and
birthweight, but no signicant association with reduced adverse infant or child outcomes.50 Some studies reported
birthweight was reported in the 2013 meta-analysis when a range of normal neurodevelopmental outcomes
the comparison group was limited to depressed mothers including cognitive, behavioural, and emotional
without antidepressant exposure.110 outcomes while also noting adverse outcomes
A consistent signicant association exists between (eg, behavioural problems measured by the strengths
exposure to antidepressants during pregnancy and and diculties questionnaire121) in children exposed to
occurrence of poor neonatal adaptation syndrome maternal depression in utero in the comparison
(PNAS; OR 507, 95% CI 325790), and individual groups,122124 but others have reported small delays in
clinical signs (respiratory distress, OR 220, 181266; developmental milestones in children exposed to
tremors, 789, 3331873).116 The use of observational antidepressants in utero. A study125 using Danish
study designs means causality cannot be inferred; the National Cohort data reported that 415 children exposed
results could suggest measurement bias, selection bias, in the second or third trimester in utero to antidepressants
and confounding, but since abrupt discontinuation of sat 159 days (95% CI 68250) and walked 289 days
antidepressants in adults is associated with withdrawal (95% CI 150427) later than children who were not
symptoms, infants might be at risk after birth. Whether exposed to antidepressants (although still within the
the symptoms reect withdrawal or toxicity is under normal range of development); fewer children with

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exposure to antidepressants in utero were able to sit feeding) and citalopram (eg, poor sleep) than after
without support aged 6 months (OR 21, 95% CI exposure to other drugs.132 Respiratory depression,
123360), and fewer were able to occupy themselves hypotonia, and vomiting have been associated with the
aged 19 months (21, 109402) than children who were tricyclic doxepin. No studies have identied an increased
not exposed.125 A study of 31 infants exposed prenatally to risk of adverse long-term outcomes. Most authors
SSRIs scored signicantly lower than the 52 non-exposed conclude that if a mother was successfully treated for
infants on gross motor (p=003), social-emotional depression during her pregnancy, the same drug should
(p=004), and adaptive behaviour (p=005) subscales of usually be used in the post-partum period because
the Bayley Scale of Infant Development.126 Two nested discontinuation or switching of an antidepressant
case-control studies have reported an association between treatment could lead to relapse.
antidepressant exposure in pregnancy and autism Perinatal mental disorders are common and can
spectrum disorders,127,128 but no signicant association adversely aect the mother and infant. However, they
was shown in a large cohort study.129 are treatable and should therefore be identied early
Although most studies focus on adverse outcomes with to prevent adverse long-term eects. Where possible,
some inconsistent results, there is new evidence, albeit non-pharmacological treatments should be used but in
with small samples, that SSRI use in pregnancy could more severe cases, eective doses of antidepressants
have a positive eect. For example, prenatal antidepressant will be needed after a careful collaborative analysis of
treatment mitigates the eect of maternal anxiety on P50 the ratio of risk versus benet.
sensory gating (associated with increased vulnerability to
attentional decits),130 and infants exposed to SSRIs in Future research directions
utero show more readiness to interact during a toy session Data for the epidemiology and prognosis of perinatal
than do a non-SSRI group exposed to high levels of mental disorders excluding postnatal depression, in both
maternal depressive symptoms.131 Prenatal antidepressant high-income and low-income settings are scarce.
exposure might account for some neurobehavioural Similarly, there are few data for emerging risk factors
outcomes in early childhood, but maternal and infant (such as migration and substance misuse), prevention,
genetic and environmental factors (including maternal and how and whether treatments (both psychological
depressive symptoms in pregnancy and the postnatal and pharmacological) need to be modied in the
environment) will also shape childhood behaviours.50,120 perinatal period. The eect of antidepressants on the
Antidepressant exposure in breastfed infants is lower by infant exposed in utero and breastfeeding, particularly
ve to ten times than is exposure in utero. The milk drug with respect to long-term outcomes, needs further
concentration can be used to estimate the daily drug dose research. Future assessments of psychosocial
ingested by the infant, assuming an average milk intake of interventions should include distance, online selfhelp
150 mL/kg bodyweight per day.132 The infant dose per kg interventions and selfhelp groups (ie, groups not
can be expressed as a percentage of the maternal dose per facilitated by a health professional), the potential role of
kg and a relative infant dose of less than 10% is deemed a the father, and family-focused interventions. Finally,
negligible exposure. A review132 reported low relative trials of integrated models of service delivery including
infant doses for uvoxamine, paroxetine, sertraline, identication, prevention, and treatment in high-income
duloxetine, reboxetine, bupropion, and mirtazapine, and and low-income settings could be used to inform
an earlier review133 reported a low relative infant dose for development of perinatal mental health services, which
nortriptyline. Relative infant doses around 10%, and in are themselves in their infancy. In view of the rates of
some cases higher than 10% for citalopram, uoxetine, perinatal disorders, the potential implications for the
and venlafaxine, with somewhat lower relative infant dose mother, infant, and family, and that these disorders
for escitalopram have been reported.132 When high happen at such an important time in the infants life,
concentrations have been reported, infants have been these research initiatives need to be considered a priority.
aged younger than 34 months, when infants are still Contributors
developing hepatic function. Metabolic capacity is not well LMH, AS and JM developed the outline for the Series paper. EM did the
developed in preterm babies and those with genetically literature search. All authors contributed to the writing and editing of
the manuscript. LMH prepared the nal version of this Series paper,
determined impairment in antidepressant metabolism via which all authors approved.
cytochrome P-450 enzymes (CYP2D6 and CYP2C19).132
Declaration of interests
Reassuringly, indirect biological evidence shows that LMH is Chair of the National Institute for Health and Care Excellence
serotonin transmitters are not aected because no platelet (update) guideline on Antenatal and Postnatal Mental Health, and Chief
serotonin eects are noted in infants of breastfeeding Investigator of an National Institute of Health Research (NIHR)
mothers treated with sertraline or uoxetine.134 Programme Grant for Applied Research on the eectiveness of perinatal
mental health services (RP-RP-DG-110810012) which also supports JM.
Some adverse but non-specic events in infants LMH receives funding from an NIHR Research Professorship on
exposed to antidepressants via breast milk have been maternal mental health (NIHR-RP-R312011), and a grant from
reported in case reports and case series, more often Tommys baby charity (with the support of a corporate social
after exposure to uoxetine (eg, irritability and poor responsibility grant from Johnson and Johnson) on antipsychotics in

1784 www.thelancet.com Vol 384 November 15, 2014


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pregnancy. LMH is also supported by the NIHR Mental Health 18 Cooper PJ, Murray L. Course and recurrence of postnatal depression.
Biomedical Research Centre at the South London and Maudsley UK Evidence for the specicity of the diagnostic concept. Br J Psychiatry
National Health Service (NHS) Foundation Trust and Kings College 1995; 166: 19195.
London. The views expressed are those of the author and not necessarily 19 Wisner KL, Perel JM, Peindl KS, Hanusa BH. Timing of
those of the NHS, the NIHR, or the Department of Health. EM is depression recurrence in the rst year after birth. J Aect Disord
supported by a Medical Research Council PhD Studentship and 2004; 78: 24952.
Tommys baby charity. TR receives salary support from Grand 20 Sawyer A, Ayers S, Smith H. Pre- and postnatal psychological
Challenges Canada (Grant Number 006303), the Wellcome Trust (Grant wellbeing in Africa: a systematic review. J Aect Disord 2010;
Number 097410/Z/11/Z) and National Institute of Health 123: 1729.
(1R01HD07426701). AS has received many grants in relation to parental 21 Buist A, Gotman N, Yonkers KA. Generalized anxiety disorder: course
perinatal health and child development including from the Wellcome and risk factors in pregnancy. J Aect Disord 2011; 131: 27783.
Trust (090139), Medical Research Council UK, Barclay Foundation, 22 Russell EJ, Fawcett JM, Mazmanian D. Risk of obsessive-compulsive
Grand Challenges (Canada), and The Department of Education (UK). We disorder in pregnant and postpartum women: a meta-analysis.
J Clin Psychiatry 2013; 74: 37785.
declare no other competing interests.
23 Ayers S. Delivery as a traumatic event: prevalence, risk factors, and
Acknowledgments treatment for postnatal posttraumatic stress disorder.
We thank the anonymous reviewers, Charlotte Hanlon and Clin Obstet Gynecol 2004; 47: 55267.
Alan Gemmill for their helpful comments. 24 Adewuya AO, Ologun YA, Ibigbami OS. Post-traumatic stress
disorder after childbirth in Nigerian women: prevalence and risk
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