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Effect of maternal mental

illness on pregnancy outcomes
Expert Rev. Obstet. Gynecol. 3(3), 391–401 (2008)

Katherine J Gold† Many pregnant women experience psychiatric disorders in their childbearing years. Emerging
and Sheila M Marcus research shows mental illness not only affects the mother’s well-being but may also have

Author for correspondence significant effects on fetal outcomes. This review details what is known about the prevalence
Department of Family of mental illness during pregnancy as well as how such disorders may influence pregnancy
Medicine, Department of outcomes. Maternal depression during pregnancy is an independent risk factor for low fetal
Obstetrics & Gynecology, birthweight and premature delivery, but other illnesses, such as anxiety disorders, eating
1018 Fuller Street, University disorders and psychotic illness, may also predict adverse birth outcomes. Possible behavioral,
of Michigan, Ann Arbor, genetic and neuroendocrine mechanisms for these relationships are presented. Principles of
MI 48104-1213, USA treatment for psychiatric disorders during pregnancy are also discussed, with an emphasis on
Tel.: +1 734 998 7120 the role of the obstetrical provider.
Fax: +1 734 998 7335 KEYWORDS: anxiety • depression • fetal outcome • low birthweight • mental illness • pregnancy • premature delivery
• psychiatric disorder • stress

Nearly half of Americans will have a mental ill- might use this information to provide optimal
ness in their lifetime, and one out of four experi- patient care. The review also highlights the
ences a psychiatric disorder in any given year [1,2]. current research and gaps in understanding
Since the majority of these illnesses start before relationships between mental health and preg-
or during the child-bearing years, many preg- nancy outcomes and proposes key areas where
nant women have significant psychiatric comor- additional research is needed.
bidity (TABLE 1). Most research has focused on the
impact of stress, anxiety and depression on the
developing fetus, but newer studies indicate that Maternal stress
a wide variety of mental disorders can pose a Animal research has shown that stress during
risk for adverse pregnancy outcomes. In order to pregnancy has both short- and long-term
make appropriate decisions regarding whether, effects on the offspring. For example, rats
and how, to treat psychiatric symptoms during exposed to a stress during pregnancy, such as
pregnancy, providers must understand what is bursts of noise or restraint, have higher levels
known about the impact of untreated illness on of hypothalamic–pituitary–adrenal (HPA)
the pregnancy and weigh these risks against activity and subsequent changes in the fetal
potential risks from psychiatric medications used hormonal response and offspring behavior [3].
for treatment. Non-human primates exposed to stress in the
Preterm delivery (PTD) and low birthweight form of noise show similar changes and also
(LBW) continue to be significant risk factors for have infants who are smaller than those born
fetal and infant death and complications. If to control primates [3]. Such research has
mental health affects timing of delivery or fetal shown strong relationships between stress and
growth there might be new approaches to fetal response and has heightened interest in
improving perinatal outcomes. Despite wide- understanding how stress during pregnancy
spread recognition that postpartum depression may affect fetal outcome in humans.
and postpartum psychosis present substantial In humans, studies have reported conflicting
risks for infant and child outcomes, the impact data about whether stress during pregnancy
of antenatal mental illness on the fetus is less affects outcomes. The 6-month Dutch famine
well understood. This review summarizes how of 1944–1945 and the pregnancy outcomes for
psychiatric illness during pregnancy affects fetal women who experienced the severe food short-
outcomes and how obstetrical practitioners ages provided a unique opportunity to evaluate 10.1586/17474108.3.3.391 © 2008 Expert Reviews Ltd ISSN 1747-4108 391

Review Gold & Marcus

Table 1. Estimated prevalence of selected psychiatric illness during pregnancy.

Disorder Illness Estimated prevalence (%) Ref.
Depressive disorders Major depression 13–20 [10,87]

Bipolar disorder Unknown

Anxiety disorders General anxiety disorder 8.5 [25,28]

Panic disorder 1–2

Post-traumatic stress disorder 3.5
Obsessive–compulsive disorder 0.2–1.2
Eating disorders Anorexia only 1.4 [43]

Bulimia only 1.6

Both anorexia and bulimia 0.7
Personality disorders 6.4
Psychotic disorders Unknown [35]

the adverse effect of stress on fetal well-being [4]. Data show experience depressed mood during pregnancy with nearly 13%
that during the famine, affected pregnancies had a shorter ges- having an episode that would meet the Diagnostic and Statisti-
tation and higher risk for stillbirth, with the impact most pro- cal Manual-Fourth Edition (DSM-IV) diagnostic criteria for a
nounced for pregnancies exposed in the first trimester. Con- major depressive disorder [10].
versely, babies exposed in the third trimester had the largest Maternal antenatal depression has been highly correlated
drop in birthweight. Risk for neonatal deaths rose for infants with PTD [6,11–14]. The effect may be less pronounced for
exposed in either the first or third trimester. adolescents; one study found no relationship between depres-
Measuring the impact of other types of stress has been more sion and pregnancy outcomes for teens but found that for
challenging. While some research indicates that pregnant adults, the risk of poor outcomes rose by 5–7% for each
women who report high levels of state or trait anxiety or stress point increase in their depression scale (Beck Depression
during pregnancy may have an increased risk for PTD, an Inventory) [15] . The risk of PTD has not been demonstrated
equal number of studies suggests that no such association in all studies, however, and it is important to note that stud-
exists [5–7]. A recent Brazilian study noted that, in general, ies vary widely in how they measure maternal depression
common mental disorders were independently associated with (clinical interview versus self-report), when during pregnancy
LBW and PTD in pregnant teenagers [8]. Measuring the spe- they assess and whether they control for potential confound-
cific effect of anxiety can be difficult because patients often ers such as other psychiatric disorders and socioeconomic
have other comorbid psychiatric disorders such as depression, variables [7,16].
and not all studies measure both. Similarly, depression also appears to be a significant risk fac-
This review is limited to the effect of prenatal psychiatric ill- tor for LBW [12–13,17–18]. The risk of LBW and PTD appears
ness on birth outcomes. However, it is clear that the effects of to be most pronounced in women in deprived social groups
mental illness on the fetus are far-reaching. Prenatal disorders and in poor countries, which has important implications for
can affect infant health and behaviors long after birth, adult public health [13]. In addition to these complications, depres-
chronic diseases have been linked to events during pregnancy, sion has significant associations with miscarriage, bleeding
and postpartum psychiatric disorders pose substantial risk for during pregnancy, higher uterine artery resistance and higher
infants and mothers [9]. Such topics are simply beyond the risk of operative deliveries [17].
scope of this review. Fetuses of depressed mothers have been shown to have differ-
ent in utero behaviors and biological responses. Two small stud-
ies found depressed mothers were more likely to have a fetus
Depressive disorders that was more active in the second trimester and were less
Major depression responsive to vibratory stimulation in the third trimester [19].
Research regarding the impact of major depression on fetal Such fetuses also have different fetal heart rate patterns com-
outcomes is compelling, and the widespread prevalence of pared with fetuses of nondepressed mothers [19–20]. Whether
maternal depression during pregnancy has been well-docu- such variations have a significant impact on fetal development
mented. A large meta-analysis combined data from a number or merely reflect small changes in the intrauterine environment
of high-quality studies and reported that up to 18% of women is not yet known.

392 Expert Rev. Obstet. Gynecol. 3(3), (2008)

Effect of maternan preg Effect of maternal mental illness on pregnancy outcomes Review

Bipolar disorder perinatal outcomes in a study that assigned a single perinatal

While there has been an explosion in research on stress and uni- score, and women with PTSD tend toward a higher rate of
polar depression in pregnancy, there is less information regarding preterm delivery although the association does not quite reach
the effect of other mental illnesses and subsequent pregnancy significance [28,30].
outcomes. For bipolar disorder, clinicians have recommended Pregnant women with PTSD often have other associated psy-
treatment strategies during pregnancy but there is little knowl- chiatric problems, such as substance use, panic disorder, eating
edge of whether bipolar disorder alters fetal outcomes or even disorders and depression, which may also play a role in fetal
how the disease itself may progress or change during pregnancy. outcomes [28,31,32]. Cook et al. found women with PTSD were
The few studies that exist have entirely contradictory findings five times more likely to have a major depressive episode during
concerning whether bipolar disorder worsens, improves or stays pregnancy compared with women without PTSD [31]. Addi-
the same during the prenatal course [21]. Manic episodes may be tionally, PTSD confers a higher risk of substance use including
associated with increased risky behaviors such as sexual activity tobacco, alcohol and marijuana during pregnancy and also
or substance use, which could affect health during pregnancy, increases the risk of unhealthy behaviors including risky sexual
but this has not been well documented [21]. Bipolar disorder has behaviour [31,32]. It is not known how different types of PTSD
been associated with placental abnormalities and antepartum might differentially impact pregnancy outcomes; for example,
hemorrhages but not stillbirths, fetal anomalies, birthweight or are there different outcomes for a pregnancy when the PTSD is
gestational age [22]. Finally, patients with bipolar disorder have a from a rape that caused the current pregnancy than when the
very high risk of comorbid alcohol or substance abuse disorders – PTSD is from a childhood trauma?
up to 60% in some studies – which could have direct adverse
impacts on fetal outcomes [23,24]. Obsessive–compulsive disorder
The prevalence of obsessive–compulsive disorder (OCD) in
pregnancy is estimated at 0.2–1.2% [25]. In two studies that
Anxiety disorders examined disease course in pregnancy, most women showed no
Given the research on stress and pregnancy, there is substan- change in symptoms, with the rest divided equally between
tial interest in how anxiety disorders may affect pregnancy symptom improvement or worsening [25,33,34]. No studies
outcomes; however, the findings have been mixed. examining OCD and fetal outcomes could be identified

Panic disorder Generalized anxiety disorder

A systematic review estimated prevalence of panic disorder dur- The prevalence of general anxiety disorder has been estimated
ing pregnancy to be 1–2%, with most women having either no at 8.5% in pregnancy, but there is little research on the impact
change or an improvement of symptoms during the prenatal on pregnancy outcomes [25].
period [25]. This is slightly lower than national survey findings,
which estimated the 12-month prevalence of panic disorder to
be 2.7% in the general population, but would be consistent Other psychiatric disorders
with a lower symptom burden during pregnancy [2]. A study of Personality disorders
38,000 mothers in a Hungarian birth registry reported 0.5% of One large Swedish study of 625 primiparous women found
mothers carried a diagnosis of panic and these women had a a prevalence of personality disorders to be 6.4% during
higher rate of premature labor and delivery, slightly shorter ges- pregnancy, based on both self-report and brief clinical inter-
tational age, polyhydramnios, anemia and a higher proportion views [35]. Only 15% of women received treatment during
of males, although this did not meet significance [26]. A differ- pregnancy, and the disorder was associated with a high rate of
ent study in Hungary looked at nearly 23,000 cases of live-born depression. There was no measure of fetal outcomes in women
infants with congenital anomalies and found that prevalence of with personality disorders.
mothers with panic was 0.9% in this group, compared with
0.5% in the control group with unaffected infants [27]. Psychotic disorders
The prevalence of psychotic symptoms during pregnancy is
Post-traumatic stress disorder unknown. However, studies show that compared with the gen-
In the USA, post-traumatic stress disorder (PTSD) has been eral population, women with schizophrenia report fewer total
reported as having a 3.5% 12-month prevalence rate, which lifetime pregnancies, a lower rate of live births and a high rate
appears to be consistent with the prevalence during pregnancy of losing the pregnancy [36]. Patients with schizophrenia and
[2,28]. Seng evaluated a large data set of women with public insur- schizoaffective disorders have significantly higher rates of a
ance; even after controlling for sociodemographic and economic number of chronic diseases such as hypertension and diabetes;
factors, there was a significantly higher odds of ectopic pregnancy this risk is also present in pregnancy, manifesting in higher rates
(OR: 1.7), miscarriage (1.9%), hyperemesis (OR: 3.9), and pre- of gestational diabetes [37]. In addition, approximately half of
term labor (OR: 1.4) [29]. PTSD has been associated with worse patients with schizophrenia and other psychotic disorders have 393
Review Gold & Marcus

been estimated to have a substance use disorder at some point familiar with use of these drugs during gestation. Treatment
in their lifetime. As in patients with bipolar disease, use of alco- must consider the severity and course of the disorder as well as
hol or illicit drugs could pose a significant risk for fetal well- individual patient risks. Unfortunately, some patients and even
being [24]. In terms of birth outcomes, women with schizophre- some providers only look at the fetal risk of medication, without
nia may be at increased risk for PTD, being small for gesta- factoring in risks to both the patient and fetus of an untreated
tional age, LBW and stillbirth [38,39]. A meta-analysis found a psychiatric disorder, which can be significant (BOX 1). There is
doubling of the risk of stillbirth in pregnancy outcomes to much clinical experience with psychotropic medications during
women with psychotic disorders [40]. In addition, schizophrenia pregnancy, but the research literature is often based on small,
has been associated with more placental abnormalities and case-controlled or cohort studies and lacks long-term data since
more cardiac defects, although no increase in total rate of fetal so many of the new and efficacious drugs have appeared within
anomalies has been observed [22]. the last 20 years. In addition, as with any medication used in
Patients with serious mental illness generally seek less medical pregnancy, fetal risks may vary depending on timing of expo-
care and this also appears to be true in pregnancy [37,40,41]. In sure; drugs linked to miscarriage or birth defects may be more
addition, women may avoid psychiatric care during pregnancy; risky in the first trimester while those that affect growth or neo-
one study reported two-thirds of women with active psychotic natal behavior may be more problematic with third trimester
symptoms did not have any contact with their psychiatric pro- use. Furthermore, in some cases, risks may be observed across an
viders during pregnancy [37]. Patients with psychotic disorders, entire category of drugs while for others, risks are limited to one
such as schizophrenia, are generally known to have worse health or two specific drugs within the category. New research will help
behaviors, such as lack of exercise, smoking, poor diet and sub- clarify these distinctions.
stance abuse, but it is not known whether these risks are also Since this brief article cannot possibly summarize all areas of
present during pregnancy [37,40,42]. research on psychiatric treatment, it is designed as a starting
point for those interested in the current state of knowledge. We
Eating disorders do acknowledge that there is significant controversy in this sub-
The prevalence of eating disorders can be difficult to measure ject area, even among expert researchers and clinicians in the
during pregnancy given that weight gain is normal in the ante- field. Many pregnant women choose to discontinue psychiatric
natal period. A study of nearly 15,000 women in the UK medications during pregnancy [13]. Although some women are
assessed women in the first trimester for active eating disorders able to do so without adverse effects, it has been demonstrated
and found that 1.4% of women reported anorexia nervosa, that there is a high risk of relapse among depressed women who
1.6% reported bulimia and 0.7% reported both disorders for a discontinue maintenance medications during the antenatal
total of 3.7% prevalence [43]. A study that examined the course period. In a study of 201 women with a history of depression,
of eating disorders longitudinally during pregnancy reported 68% of women who discontinued medication during pregnancy
that bulimia and purging tend to either improve or remit com- had a relapse of major depression during the pregnancy, com-
pletely during pregnancy but binge eating disorder, which is pared with just 26% of women who continued their medication
much more common, may actually have a high rate of new during pregnancy [46]. Stopping treatment for bipolar disorder
onset in the prenatal period [44]. has also been associated with disease relapse in both pregnant
A carefully designed evaluation comparing women with active and nonpregnant populations [21,47]. Cessation of treatment
bulimia with those having a prior diagnosis of bulimia but no during pregnancy for other mental illnesses is relatively unstud-
active symptoms noted that women with active disease had ied. In general, discontinuing psychotropic medications during
twice the rate of miscarriage, three-times the likelihood of PTD pregnancy may be a risky strategy for many women.
and nearly six times the odds of gestational diabetes [45]. The Although treatment of maternal psychiatric disorders generally
rate of hyperemesis gravidarum was dramatically higher in the appears to improve maternal symptoms and functioning, risk of
active bulimia group, leading the authors to hypothesize that relapse, and postpartum outcomes, few studies have specifically
hyperemesis could actually be masking an active eating disorder examined the effect on fetal outcome. Treatment studies of depres-
in many prenatal women. Patients with anorexia have been sion are particularly challenging during pregnancy since the sam-
shown to have a significantly higher risk of gestational diabetes ple cohort may be small, unrepresentative of the broader popula-
and lower birthweight infants [43]. However, the finding of tion and nonrandom, and control groups (including women with
lower birthweight disappeared once the researchers controlled mental illness but not on medication) are often omitted. In truth,
for the mother’s body mass index (BMI) prior to pregnancy. few robust studies of treatment of depression during pregnancy
have been reported. In addition, a treatment study that does not
show improvement in maternal depression could reflect lack of
Treatment considerations treatment efficacy, a population of women with more severe
While evaluation for psychiatric illness during pregnancy is depression or inadequate pharmacotherapeutic treatment; severe
essential, decisions concerning the use of specific treatment disease can be more difficult to treat, and depression is commonly
medications should be made in consultation with providers under-recognized and undertreated in clinical practice [48–49].

394 Expert Rev. Obstet. Gynecol. 3(3), (2008)

Effect of maternan preg Effect of maternal mental illness on pregnancy outcomes Review

A 2006 review of anxiety disorders in pregnancy noted there

Box 1. Treatment recommendations for obstetric
had been no reports from controlled studies of medication
providers caring for pregnant women with
treatment for panic, OCD, PTSD or generalized anxiety disor-
psychiatric illness.
der in pregnancy [25]. No controlled studies of medication treat-
ment during pregnancy were found for personality disorders, • Screen all pregnant women for depression using a standard
psychotic disorders or eating disorders. tool, such as the Edinburgh Postnatal Depression Scale (which
A large population linkage study in Canada compared can be used both during and after pregnancy)
women with depression treated with selective serotonin • Coordinate care with providers who are knowledgeable about
psychiatric illness during pregnancy, particularly for women
reuptake inhibitors (SSRIs) with untreated depressed women
with recurrent, severe or complex disease
and noted lower birthweight for the treated group [47]. How-
• When possible, incorporate nonpharmacologic treatment
ever, while the dataset was large, it did not evaluate symptoms, options such as cognitive–behavioral therapy, interpersonal
so women on medication could easily have had more severe therapy, support groups and stress education
depression. Misri reported that, in a small study, mothers with • Balance risks of psychotropic medications with the risks of
anxiety disorders who were on medication had infants who were untreated psychiatric disease, which can have significant
more likely to need transient observation immediately after adverse effects on a pregnancy
birth [51]. Interventions using cognitive–behavioral therapy may • Recognize that for some women with moderate or severe
help to reduce effects of stress and PTD during pregnancy but disease, pharmacotherapy may be the most appropriate
only in certain populations [52]. treatment to treat the disorder and prevent relapse
In terms of pharmacotherapy for women with depression, the
American College of Obstetricians and Gynecologists (ACOG)
suggests using a single medication at higher dose over multiple patients may opt to taper medications early in pregnancy and
medications when possible, in order to limit the number of drug restart later, others may switch to alternative medications, and
exposures to the fetus [53]. Medications such as SSRIs and serot- still others may need to continue the same pharmacotherapeu-
onin norepinephrine reuptake inhibitors (SNRIs) are commonly tics to prevent risk of a serious relapse. Decisions regarding how
used during pregnancy and are effective at treating maternal to manage patients with recurrent bipolar or manic episodes
depression. While these medications do not increase the risk of and those at high risk of relapse should be made in consultation
major fetal anomalies, they may slightly increase short-term fetal with experienced specialists, as investigators have found that
risks, such as respiratory distress and neonatal drug withdrawal medication discontinuation is associated with high rates of
[44,54]. Some studies suggest that first trimester exposure to SSRIs relapse in women with bipolar illness [60].
may increase PTD and restrict fetal growth [54,55]. A single retro- Many of the common antidepressant medications are also
spective study has reported an association with persistent pulmo- used in higher doses for panic and other anxiety disorders such
nary hypertension of the newborn but these results have not as OCD. Benzodiazepines are sometimes used for short-term
been duplicated [56]. Long-term effects of SSRIs and SNRIs are management of panic or anxiety symptoms in pregnancy. A
limited; however, there is one reassuring study that examines 1998 meta-analysis reported that some benzodiazepines have
neurodevelopmental effects of the SSRIs in children exposed been associated with a small risk of cleft lip or palate in
during pregnancy and lactation. In this study, children exposed case–control studies but not cohort studies. Given the conflict-
to fluoxetine or tricyclic agents appeared similar to their nonex- ing findings, some providers simply defer use until after full
posed siblings in measurement of IQ and rates of learning disor- development of the lip and palate [21,61]. A large, retrospective
ders [57]. One antidepressant – paroxetine – is not recommended study in Sweden recently reported that benzodiazepines were asso-
during pregnancy as its use in the first trimester has been associ- ciated with greater risk of PTD and LBW, particularly for infants
ated with a higher risk of major anomalies, including cardiovas- exposed late in pregnancy [62]. The same study found a small asso-
cular malformations. While these findings are controversial, the ciation between benzodiazepine exposure and pylorostenosis and
US FDA downgraded the safety rating of paroxetine for use in small-gut atresia.
pregnancy, and the ACOG proposes avoiding this medication Women with active psychotic disorders or severe bipolar dis-
during pregnancy when possible [47,53,58]. order may require antipsychotic medications. First-generation
Bipolar disorder poses a challenge to treating clinicians, as antipsychotics have been used clinically for decades, are often
this disorder causes significant morbidity in women, yet many used during pregnancy and are thought to be relatively safe.
common mood stabilizers have a higher risk of certain birth However, these medications have significant side-effects and
defects and should be used with caution and appropriate moni- may not optimally treat certain psychiatric symptoms. Second-
toring for fetal anomalies. For example, lithium is associated generation ‘atypical’ antipsychotics are also frequently used dur-
with a higher rate of cardiac malformations (although the abso- ing pregnancy, but they have been less well studied and long-
lute risk is low), valproate confers increased risk of both cardiac term effects are unknown [40]. A recent report suggests both
and neural tube defects and carbamazapime has been linked first- and second-generation antipsychotic medications cross
with spina bifida and craniofacial abnormalities [47,59]. Some the placenta, although drug concentrations vary widely among 395
Review Gold & Marcus

different medications [63]. While data are emerging regarding the human gestation [68]. A major event during pregnancy involves
safety of these atypical antipsychotics, most of the studies using changes in the maternal HPA axis. Pregnant rodents exposed to
them are too underpowered to draw any firm conclusion regard- stress (usually unexpected noise or confinement) have offspring
ing fetal safety. Given the complexity of serious psychiatric illness who over-react to stressors, secrete more cortisol than normal
during pregnancy, we recommend obstetrical providers collabo- controls and have other physiologic and behavioral changes
rate closely with the patient’s psychiatric providers to provide that persist into adulthood [3,69]. Guinea-pigs exposed to similar
optimal care of patients with psychosis and serious mental illness stressors have babies that demonstrate more anxiety and altera-
such as schizophrenia and schizoaffective disorders. tions in HPA functioning [70]. Nonhuman primates exposed to
sudden episodes of noise also show impaired HPA functioning
and babies that are smaller at birth [3].
Explaining mental health effects on birth outcomes An important consequence of HPA upregulation is higher
Although psychiatric disorders are clearly associated with levels of maternal corticotropin-releasing hormone (CRH),
adverse birth outcomes, the exact mechanism of action is elu- which leads to more maternal cortisol than in the nonpregnant
sive. Many researchers speculate that the mechanism involves state; in fact, one researcher has pointed out that cortisol levels
complex interactions between health behaviors, hormonal by the end of a normal pregnancy may be as high as those seen
regulation and genetic factors. in Cushing’s disease [71]. High cortisol is also seen in severe
Depression can lead to unhealthy behavioral changes and depression and is thought to represent a key mechanism by
depression during pregnancy is no exception. Depressed preg- which pregnancy effects maternal mood. Depression may help
nant women have a higher risk of smoking, drinking, using to stimulate the maternal HPA system, which, in turn, leads to
illicit drugs and being overweight – all factors that can increase more CRH release from both the maternal system as well as the
the risk for poor perinatal outcomes [17]. They may also be at placenta [17]. A study that measured maternal cortisol during
risk for seeking less prenatal care, having a lower appetite and routine ultrasound or during amniocentesis (which is typically
inadequate weight gain and poor self-care in general [17]. In a stressful event for parents) noted that women with high state
addition, prenatal depression has been associated with behavio- anxiety had modestly higher plasma cortisol, independent of
ral changes specific to pregnancy such as increased sick leave the fetal gestational age [72].
and hospitalizations during pregnancy, more medical visits and While CRH is associated with stress and depression, it also
greater use of epidural anesthesia during childbirth [6,64]. Less is plays an important role in human pregnancy. CRH secreted by
known concerning behavioral changes during pregnancy in the placenta has multiple effects on the extra- and intra-uterine
women with bipolar disorder. Manic episodes often increase environment including promotion of prostaglandin release
risk-taking and unhealthy behaviors; if mania leads to a preg- and stimulation of uterine activity and contractility, events
nant woman engaging in unsafe sex or risky physical activities linked with timing of labor and delivery [73]. In addition,
these could potentially pose significant risks to the fetus. Many inflammatory cytokines can activate CRH, which may be
mental disorders can adversely impact maternal sleep cycles, another mechanism contributing to preterm birth [73].
compounding the sleep difficulties already experienced by Approximately 10–20% of the maternal cortisol levels appear
many pregnant women. Conversely, impaired sleep from preg- to pass through the placenta to the fetus; although these levels
nancy can have a detrimental effect on psychiatric well-being, are small, they are still significant, and studies show a direct
and women with mental illness may be at highest risk [65]. correlation between maternal and fetal cortisol levels in both
Similarly, women with serious mental illness are likely to animal and human studies [11,68,70].
have associated behavioral changes that impact their preg- In addition, HPA changes resulting from both depression
nancy. Serious mental illness has been shown to impair a and PTSD have also been shown to stimulate the maternal
patient’s ability to seek appropriate medical care, recognize sympathetic nervous system, which leads to higher maternal
physical symptoms or warning signs, and follow-through with as well as fetal epinephrine and norepinephrine [18,28]. Infants
treatment recommendations [42,66,67]. Although auditory or born to mothers with depression during and after delivery
visual hallucinations could put a woman at high risk for harm- have been shown to have higher norepinephrine levels [74].
ing herself or her baby, there is little research on antepartum While norepinephrine does not appear to cross the placenta,
psychosis. However, given known risks in the nonpregnant it may impact the fetus through cardiovascular mechanisms,
and postpartum population, obstetric providers should cer- such as increasing uterine artery resistance and decreasing
tainly be aware of potential consequences and the importance uterine blood flow [18].
of actively managing psychotic symptoms in pregnancy. One of the most interesting aspects of the HPA activation
Pregnancy also confers significant changes in a woman’s theory is that upregulation appears to have different effects on
neuroendocrine system, which may partly explain the relation- male and female fetuses and on fetuses at different gestational
ship between maternal mental health and fetal outcomes. Most ages [3,9,71]. For example, babies of guinea-pigs exposed to ante-
existing research has been in animal models, although research- natal stress had lower levels of plasma testosterone if the mother
ers have begun to investigate hormonal mechanisms during was exposed three-quarters of the way through pregnancy but

396 Expert Rev. Obstet. Gynecol. 3(3), (2008)

Effect of maternan preg Effect of maternal mental illness on pregnancy outcomes Review

not if exposed at the end of pregnancy [70]. High maternal corti-

sol at 30–32 weeks predicted negative infant behaviors after Limitations in existing research
birth [68]. Stress at certain points can actually accelerate fetal While current discoveries linking psychiatric illness and obstet-
development; gestational hypertension, for example, can pro- rical outcomes are exciting, current studies have limitations that
mote organ development and neuromaturation [75]. Similarly, must be considered. First, given that the studies vary signifi-
maternal steroid injections are commonly used early in the cantly in reported fetal outcomes, one must question whether
third trimester to promote fetal lung development when there the illness itself is the risk factor or whether some other
is a threat of PTD. unmeasured variable would be a better predictor of patient risk.
However, very late pregnancy also appears to be a time dur- Is depression a better predictor than general stress? Does the
ing which the body can buffer many physiologic stimuli. A type of stress matter? One study found that depression scores
study of women who screened positive for depression at 35–36 from a questionnaire were not as good a predictor of fetal pre-
weeks’ gestation noted no significant increases in risk for maturity as maternal cortisol levels [11]. Other investigators
adverse obstetrical or neonatal outcomes [76]. Women who are have suggested unhealthy behaviors may be more related to
not depressed have a blunted cortisol response to stress at the fetal growth problems while stress may be a more significant
very end of pregnancy; at the time when there is the strongest factor in PTD [13]. This hypothesis is consistent with a study
correlation between maternal and fetal cortisol levels, the that noted no relationship between depression and PTD but
maternal HPA system actually shows the least response to exter- reported that negative life events, perceived racial discrimination
nal stressors [3,71]. Despite rapidly growing interest in this area, and sense of unsafe neighborhoods predicted PTD for Afri-
there is still no consensus regarding exactly when the fetus is at can–American subjects but not white-skinned individuals [77].
highest risk from maternal mood or stress [70]. Another study showed that women with higher depression
Other physiologic changes associated with psychiatric ill- scores were more likely to report fair/poor health and limita-
ness include imbalances in maternal inflammatory factors, tions in activities due to poor health, suggesting that health
such as cytokines. This has been hypothesized to explain might be a mediator in the relationship between depression and
abnormalities in maternal coagulation, risk for vasculitis and pregnancy outcomes [14].
maternal blood supply early in pregnancy that could contrib- In addition, current studies face a number of methodological
ute to risk for early pregnancy loss [17]. Women with PTSD challenges. Psychiatric illnesses have been measured using a
also have increased inflammatory cytokines, which is a poten- wide variety of instruments and methods, ranging from clinical
tial risk for preterm labor and delivery [28]. It is also possible interviews using DSM-IV criteria to retrospective analyses of
that disorders such as depression could increase release of billing data to one or two questions regarding mood and stress
vasoactive hormones and neuroendocrine transmitters which or retrospective self-assessment of anxiety [7,16,64]. Whether or
then mediate changes in the mother or fetus [17]. Others have not results are significant could feasibly be related to the quality
postulated that stress could impair the maternal immune sys- of the measurement tool itself, and different measurement
tem, placing the mother at increased risk of infection during instruments might easily result in different findings. Second,
pregnancy [12]. anxiety and depression often coexist and few studies have con-
Finally, it is clear that women with psychiatric disorders have trolled for both variables, making it difficult to separate poten-
a wide variety of pregnancy outcomes, which has led researchers tial effects from each [78]. In addition, many studies have been
to speculate some differences may be linked to genetic suscepti- unable to control for maternal illness, behaviors and important
bility. There are definitely genetic differences that appear to sociodemographic factors that might also predict poor fetal
contribute to risk for psychiatric illness, and some have sug- outcomes [18,26]. Third, studies evaluate mental health at differ-
gested that polymorphisms in the 5-HTT serotonin transporter ent points during pregnancy. As previously discussed, since the
gene may make women and their babies particularly vulnerable fetus appears to be vulnerable at certain gestational stages and
to the effect of mental illness during the perinatal period. There relatively protected at others, disparate results may simply
could also be variations – polymorphisms – in receptors for var- reflect different exposure times. Fourth, Littleton has pointed
ious glucocorticoids that could mediate different responses to out that studies with small sample size and less frequently used
maternal stress or psychiatric illness [3,71]. In rats, most of the methods of measuring anxiety more often show significant
maternal glucocorticoids are prevented from reaching the fetus findings for the relationship between anxiety and poor preg-
due to an enzyme in the placenta that inactivates the glucocor- nancy outcomes [7]. Future research will benefit from robust
ticoids [70]. If there are genetic variations in this enzyme or in studies that are able to offer validated assessments of psychiatric
fetal cortisol receptors, some fetuses could see significantly disorders, control for important comorbidities and evaluate
higher levels of maternal cortisol than other fetuses and could how timing of exposure may affect outcomes.
therefore be at higher risk for adverse outcomes, depending on Furthermore, current studies have not evaluated how mental
the time of exposure. Some investigators have even suggested illness and treatment may differentially affect planned and
that maternal diet could influence expression of the inactivating wanted pregnancies versus unplanned and/or unwanted preg-
enzyme [3]. nancies. For a planned pregnancy, a woman may seek prenatal 397
Review Gold & Marcus

counseling, make decisions prior to or early on in pregnancy

regarding psychiatric medications and treatment, and reduce Five-year view
behavioral risk factors associated with both mental illness and While providers have long suspected a relationship between men-
poor pregnancy outcomes (i.e., use of tobacco, alcohol and tal health and pregnancy outcomes, the explosion in research
illicit substances, poor diet, lack of exercise and late prenatal reports in this area has come only in the last few years. The initial
care). Depending on how these differences affect the timing focus of work was on depression as a risk factor for morbidity
and duration of fetal exposure to medication and whether or and mortality from chronic adult diseases such as heart disease,
not psychiatric disorders are adequately treated during preg- lung disease, diabetes, stroke and cancer [79–82]. Only recently
nancy could dramatically impact our understanding of how have researchers considered whether the findings in that field
mental illness, treatment and pregnancy outcomes are related. might apply during gestation.
Finally, like for many illnesses, there are probably some The next 5 years are likely to bring many more studies, hope-
women who are at particularly high risk for adverse outcomes fully with a focus on well-designed, controlled research, which
from psychiatric illness. The impacts of depression on preg- effectively measure different psychiatric symptoms and how
nancy have been most robust in studies looking at women in they impact a pregnancy at different stages in time. An impor-
poor countries and in deprived social groups [13]. Existing stud- tant focus will be to understand the periods during pregnancy
ies have examined very different populations and whether or when fetal development is at highest risk from mental disorders
not the results are significant may be partly explained by the and whether that varies among disorders. There hopefully will
baseline risk of the population. Certain groups such as Afri- be additional investigations to evaluate whether psychiatric
can–American teenagers, unmarried women and women of low interventions can affect the prevalence of poor fetal outcomes,
socioeconomic status appear to have greater risk of stress and particularly the risks of prematurity and LBW.
depressive symptoms in pregnancy even if they do not meet full Today, psychotropic medications are widely used in pregnancy,
DSM-IV criteria for specific diagnoses [52]. Women with severe and as evidence mounts detailing fetal risk of untreated mental dis-
psychiatric disease, comorbid physical illness, risky prepreg- orders, the number of women taking these medications is likely to
nancy health behaviors, or those with certain genetic variations grow. Little is known concerning the long-term risks and benefits
may be at increased risk of poor pregnancy outcomes and may of many newer psychiatric medicines, and the next 5 years is likely
yield greatest benefit from health interventions. Identifying to bring significant knowledge on this front, which will allow pro-
which women are at risk and how to best assist them will be an viders and patients alike to better assess options for psychiatric
important focus for future research. treatment, which can reduce risks to both mother and baby.
In the area of adult chronic disease, there have been multiple
hypotheses regarding how depression might affect disease out-
Expert commentary come. These include behavioral, neurological, endocrine and
Emerging research linking maternal mental health and pregnancy genetic pathways. Some of the theories could apply to pregnancy
outcomes is an exciting development in obstetrical care. While outcomes and researchers are likely to further explore these possi-
providers have focused on trying to reduce maternal morbidity bilities. For example, there is strong evidence that inflammatory
from psychiatric disorders, it is possible that fetal morbidity and factors may play an important role in cardiovascular illness, and
mortality could be equally significant. Prematurity and LBW con- these factors are also implicated in depression [83]. Inflammation
tinue to be vexing outcomes that disproportionately affect disad- has been considered as a potential risk for prematurity and LBW
vantaged women. Despite tremendous improvements in the resus- and might be one way in which maternal mood and birth compli-
citation and care of very small and very premature infants and cations could be related [84,85]. Similarly, some patients express
substantial public health efforts to improve birth outcomes among polymorphisms in a gene that regulates depression as well as nico-
at-risk groups, there has been little progress in reducing prematu- tine addiction; if this could be demonstrated in pregnant women,
rity and LBW. If mental health problems present an independent it could present a potential behavioral mechanism which contrib-
risk for these complications, it could potentially offer a new utes to adverse fetal outcomes [86]. Such work will offer important
approach for addressing these problems. contributions to an area of research with great potential to
While some associations between psychiatric disease and fetal improve obstetrical outcomes.
outcomes appear robust, it remains unclear which disorders or
symptoms present the greatest risk and whether treatment can
mitigate poor birth outcomes. Understanding potential mecha- Financial & competing interests disclosure
nisms through which mind and body impact one another is an The authors have no relevant affiliations or financial involvement with
essential step in identifying how fetal outcomes are affected by any organization or entity with a financial interest in or financial conflict
mental health disorders. New developments in this field could with the subject matter or materials discussed in the manuscript. This
elevate the importance of mental health during pregnancy and includes employment, consultancies, honoraria, stock ownership or options,
lead to dramatic changes in how providers care for women at expert testimony, grants or patents received or pending, or royalties.
risk for psychiatric problems during pregnancy. No writing assistance was utilized in the production of this manuscript.

398 Expert Rev. Obstet. Gynecol. 3(3), (2008)

Effect of maternan preg Effect of maternal mental illness on pregnancy outcomes Review

Key issues
• Many women experience symptoms of mental illness during pregnancy.
• Animals stressed during gestation have smaller offspring.
• In humans, maternal depression is associated with low birthweight, preterm delivery and other adverse pregnancy outcomes.
• For anxiety disorders during gestation, fetal impacts are unclear, with some studies suggesting a risk for poor outcomes and others
obtaining normal results.
• Psychotic disorders present a higher risk for many adverse pregnancy outcomes including stillbirth.
• Eating disorders have been associated with fetal birthweight abnormalities.
• The mechanisms for poor fetal outcomes probably involve a complex mix of neuroendocrine factors, genetic variations and maternal
behavioral changes.
• Treatment of mental illness during pregnancy is vital, and risks of medications should be weighed against risk of untreated disease,
which can be serious.
• Future research should focus on controlled trials with strong mental health measures and consideration of potential medical, social and
psychiatric comorbidities.

7 Littleton HL, Breitkopf CR, Berenson AB. depression and anxiety: a population-
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