A Tale of 2s: Optimizing Maternal–Child Health in the Context of Antenatal Maternal Depression and Antidepressant Use

Not a week goes by without new studies reporting on depression during pregnancy and outcomes following exposure to prenatal SSRIs. Recent public and scientific attention has focused on interpreting contrasting reports of increased risk for congenital anomalies—particularly vascular and cardiac defects¹ and the apparent lack of risks related to SSRI exposure.^2–4 Reports of neurobehavioural disturbances associated with prenatal SSRI exposure^5,6 contrast with other studies that find no increased developmental vulnerability.^1,7 This constantly evolving literature raises scientific⁸ and public^9,10 concern about managing mood disorders during pregnancy¹¹ and conceptualizing the responsible inclusion of pregnant women in medical research.^12,13

In this issue of The Canadian Journal of Psychiatry, 2 key papers address this pressing question.^14,15 The paper by Dr Dan Rurak and colleagues (see Shea et al¹⁴) highlights key factors that influence fetal drug exposure, and presumably influence the long-term developmental consequences of prenatal drug exposure. Given the variable outcomes associated with pharmacotherapy, the paper by Dr Sherryl H Goodman and Dr Sona Dimidjian¹⁵ offers a developmental psychopathology perspective and promising evidence for psychosocial interventions to treat depression during pregnancy. These 2 perspectives offer ways to optimize antenatal mental health treatment and pharmacotherapy to minimize fetal drug exposure.

As clinicians, we are frequently faced with questions about how best to promote optimal care for mothers and support development and behaviour in the children of mothers who were depressed during pregnancy. As antenatal maternal mood disorders themselves influence infant and child behaviour,^16,17 we are challenged to provide appropriate and timely care when both antenatal SSRI and maternal mood effects are often indistinguishable. To appreciate the impact of these prenatal exposures, we recognize the interplay of 3 key features influencing child development in this setting. This is a story of interplay between the 2s: 2 environmental pathogens—exposure to depressed–anxious maternal mood and SSRI ADs; 2 time periods—spanning pre- and postnatal periods; and 2 highly interrelated individuals, spanning 2 generations—the mother and her infant. Accounting for the ongoing interplay between these factors is essential, but our current understanding of the impact, both of SSRI medications and of psychiatric disorders, on early human development limit our ability to distinguish between the impact of disease and treatment.

The incidence and period prevalence of MDDs during pregnancy are 7.5% and 12.7%, respectively.¹⁸ Although MDD is common, only 1 in 5 Americans receive any guideline-concordant intervention, and most are inadequately treated.⁶ Treatment rates for mood disorders are even lower for pregnant women (14%) than in the general population of women (26%).⁷ Pregnancy frequently results in discontinuation of both psychotherapy and pharmacotherapy, and women do not resume care in the postpartum period.⁸ Most women do not receive prescriptions for ADs beyond 6 weeks of gestation. Pregnant women who discontinue ADs proximate to conception have a higher risk for relapse (68%), compared with those who maintain treatment (26%).¹⁹ Although psychotherapy is the preferred treatment of most women,⁶ it is neither available in all practice settings nor accessible for some mothers.

Low treatment rates are juxtaposed against mounting evidence that MDD increases multiple risks for the pregnant woman and fetus. Gestational MDD is associated with risk directly related to the physiological sequelae of psychiatric illness as well as secondary to associated maternal behaviours, such as smoking, poor nutrition, substance abuse, inadequate obstetrical care, and interpersonal isolation and suicide.²⁰ MDD incurs an increased risk for maternal obesity, small for gestational age²¹ and LBW infants, and PTB.^10,21 The offspring of women with gestational MDD are at risk for insecure attachment,¹¹ and sleep and eating disorders.¹⁶ Severe stress during pregnancy, especially early during gestation, results in delayed fetal maturation, disrupted emotional regulation, impaired cognitive performance during infancy, and decreased brain volume in areas associated with learning and memory in children aged 6 to 8 years.²² Gestational MDD is the strongest predictor of postpartum MDD.²³ The relation between maternal MDD and child developmental adversity is a continuum that often begins in pregnancy.

In a meta-analysis, Grote et al²⁴ found that depression or clinically significant depressive symptoms during pregnancy were associated with an increase in the relative risks for PTB by 39%, for LBW by 49%, and for intrauterine growth restriction by 45%. Several direct and indirect causal pathways have been suggested, such as dysregulation of the hypothalamic–pituitary–adrenal axis, which is one of the most consistent biological findings in patients with MDD. Increased uterine artery resistance in response to perceived stress, which results in placental hypofusion, has been reported.^25,26 The immune activation characteristic of depression may also contribute to PTB.²⁷

SSRIs are often considered for antenatal therapy,²² with the goal of improving maternal mental health during pregnancy.²⁸ However, AD treatment resulted in remission of MDD after optimal dosing of citalopram in only 37% of patients in the initial treatment phase of the National Institute of Mental Health–funded national Sequenced Treatment Alternatives to Relieve Depression (commonly referred to as STAR*D) trial. After additional intervention steps, the overall cumulative remission rate was 67%.²⁹

Similarly, a substantial number of pregnant women remain partially or fully symptomatic after treatment.^30,31 Dynamic changes in the pharmacokinetics of SSRIs during pregnancy, which often require changes in drug doses to achieve optimal therapy, may reduce the efficacy of antenatal treatment.³²

Failure to achieve remission leaves mothers’ mood disturbances (and inherent confounding factors, such as smoking, alcohol, and socioeconomic status) and antenatal SSRI exposure to continue incurring consequences for mothers, and cognitive and emotional child development.¹⁷ Thus mothers and clinicians must balance the potential consequences of untreated, or poorly treated, mental illness against risks of antenatal psychopharmacotherapy.

Understanding how antenatal maternal mood and SSRIs influence early brain development can provide critical clues to how early adverse life experience programs developing neural systems that may contribute to health risks, such as depression, later in life. Given that both prenatal maternal mood disturbances and SSRIs affect levels of the key neurotransmitter 5-HT during critical periods of neurodevelopment, it is conceivable that altering levels of 5-HT, secondary to SSRI exposure, may change fetal brain development and subsequent 5-HT-related behaviours.^22,33,34 To date, no gross SSRI-related neuroteratogenic effects have been identified, yet evidence of subtle functional behavioural disturbances associated with fetal SSRI exposure have been reported.³⁵ While some outcomes reflect a main effect for the SSRI exposure,³⁶ beyond infancy, childhood development appears typical⁷ or predicted by ongoing life with a mother with disturbances.³⁷ Neonatal behavioural disturbances may be associated with cord drug levels and neurotransmitter alterations,³⁸ and genetic variables play a moderating role, though not all alleles carry the same risk.³⁹ Why some children are affected by prenatal SSRI exposure and others are not remains a pressing question. It is possible that SSRI exposure and maternal mood interact with genetic factors to affect levels of 5-HT during development^38,39 and influence disease susceptibility later in life via altered early levels of central 5-HT, suggesting fetal serotonergic programming.³⁴ It is also likely that successful maternal SSRI treatment reduces the multiple biopsychosocial impacts of MDD on fetal (and later) development; in fact, this possibility is an aspect of the potential benefit in the risk–benefit decision-making process.

In this issue, Dr Rurak and colleagues¹⁴ outline key factors that influence fetal drug exposure and clarify our understanding of an emerging story of developmental risk, vulnerability, resiliency, and recovery. Appreciating the numerous metabolic and molecular factors that influence 5-HT levels during gestation is central to understanding differences in developmental risk in this setting. In our search for an understanding of the impact of prenatal medication exposure, we need to apply a broader developmental lens through which to examine developmental outcomes that extend beyond the newborn period. Prenatal changes in central neurotransmitters during periods of neural growth may lead to subtle functional effects and central nervous system vulnerability extending from fetal–neonatal periods to well into childhood. As 5-HT regulates arousal, memory, mood, and attention, alterations in such behaviours may not be readily apparent at birth. In this sense, the altered developing neural system function may only manifest in varying ways, owing to the changing functions or demands on the system.²³ With this perspective, affected behaviours of interest may only emerge with time as they may be masked (or sleeper) effects in yet-to-emerge capacities.⁴⁰ This is particularly true of domains, such as executive functions, that regulate attention and arousal and come online when a child reaches the developmental stage where the capacity is required. Moreover, as a potential behavioural teratogen, the effects of SSRI exposure may only affect functioning in a temporary or transitory manner. Case in point, neonatal withdrawal symptoms may only appear for a short time, then disappear, but could subsequently be antecedent to other altered behaviours later in childhood.⁴¹

Importantly, emerging evidence supports key nonpharmacological options to manage mood disorders during pregnancy. As Dr Goodman and Dr Dimidjian¹⁵ argue, using a developmental psychopathology perspective, treatment should include attention to the continuum of depression, from subclinical to severe MDD, appreciating an individual woman’s pattern of risk and resilience factors, careful recognition of the potential benefits of treating a couple’s relationship, the mother’s qualities of parenting, and the infant’s and (or) child’s mental health needs, and including a detailed understanding of the developmental pathways leading to antenatal depression.

In summarizing our current knowledge, 3 themes emerge that should guide clinical practice. First, this is not a story in which outcomes can easily be attributed to one causal factor (for example, maternal mood, the drug, genetics, the placenta, and maternal pharmacological factors), but rather outcomes in this setting represent an interplay of psychological, pharmacological, genetic, and social factors related to both the mother and her child. This is, indeed, a setting where nature meets nurture and niche.⁴⁰ Second, while SSRIs are prescribed with the anticipation of improving maternal and neonatal health, maternal pharmacotherapy may not result in MDD remission, and both mothers and their children remain at risk. Finally, in this context of developmental vulnerability and resilience, identifying mothers who will benefit from prenatal SSRI treatment remains a pressing question. Longitudinal study designs that integrate a maternal and infant–child developmental perspective will help us move away from regarding maternal mood, prenatal SSRI exposure, or even specific genotypes as bad or harmful and rather to look at these as adversity- or risk-related factors that heighten or lessen vulnerability.

From a maternal–child health perspective, our task is to recognize risks arising from both the maternal disease and its treatment, and find ways to stack the deck in favour of optimal health in the context of family well-being. The decision to initiate SSRI treatment during pregnancy rests with the mother and her physician carefully weighing the risks and benefits.⁴¹ In providing care, we need to recognize risk characteristics that are inherent to an individual and focus on the urgent need to effectively diagnose and address maternal and child needs with all available pharmacological and nonpharmacological options. This should include addressing the well-being of the entire family and its social context, ensuring access to affordable and appropriate health care, and providing lay community support. Addressing barriers to identifying and treating maternal perinatal mood disturbances should be an urgent public health concern that will benefit mothers and children alike.⁴²

What is critical is that we recognize that multiple and ongoing environmental influences that require surveillance and timely interventions. This fascinating and complex conundrum has much to teach us about the basic science of maternal and child development and offers clues that will help promote health across the 2s.

Abbreviations

5-HT

serotonin

AD

antidepressant

LBW

low birth weight

MDD

major depressive disorder

PTB

preterm birth

SSRI

selective serotonin reuptake inhibitor