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It is estimated that 14 to 23% of women become depressed during pregnancy (Gaynes et al 2005) and relatively few receive treatment (Cox et al 2016) resulting in potentially serious adverse outcomes for the mother, fetus and child (Grote et al 2010). Factors that increase risk of perinatal depressed mood include previous history of depressed mood, medical problems, young age, financial hardship, unmarried status, lower education, being in an abusive relationship and poor social support (Lancaster et al 2010; Melville et al 2010).
Depressed mood during pregnancy is associated with poor prenatal care including not taking prenatal vitamins and prescription medications and increased rates of alcohol and illicit substance abuse (Grote et al 2010) all of which can have negative health consequences for the mother and the fetus. Of great concern, depressed mood in the perinatal period significantly increases the risk of maternal suicide (Lindahl et al 2005).
Perinatal depression increases the risk of pre-term birth and low birth weight, both of which increase the risk of health problems in the newborn and long-term developmental problems (Grote et al 2010; Szegda et al 2014). Infants of depressed mothers are more irritable, have more sleep problems, are at increased risk of delayed motor and cognitive development (Hanley and Ovelander 2012; Suri et al 2014), and have higher rates of attention-deficit hyperactivity disorder, depression and anxiety disorders (Graignic-Philippe et al 2012; Waters et al 2014; Pearson et al 2013), compared to offspring of non-depressed mothers.
Causal links between maternal depressed mood and problems in the fetus, newborn and child are mediated by complex mechanisms. Dysregulation in maternal CNS serotonin associated with depressed mood and anxiety during pregnancy is believed to interfere with normal fetal development, and following birth, may interfere with normal infant and early child development by influencing hormones regulated by the hypothalamic pituitary adrenal (HPA) axis, and increasing blood levels of several inflammatory molecules (Graignic-Philippe 2014; Glover 2014; Beijers, Buitelaar and deWeerth 2014).
Weighing risks and benefits of antidepressant use during pregnancy
It is estimated that 7% of pregnant women in the U.S. take a SSRI antidepressant (Mitchell et al 2011). Women who discontinue a SSRI during pregnancy in efforts to reduce the risk to their fetus may be at greater risk of relapsing compared to women who continue on an antidepressant however findings are mixed (Cohen et al 2006; Yonkers et al 2011).
As already noted, both depressed mood and antidepressant use during pregnancy are associated with increased risk of medical problems in the fetus and, subsequently, behavioral problems in the child. Hence it is difficult to determine to what extent complications at birth and developmental delays are caused by hormonal or behavioral consequences of depressed mood itself versus short-term and long-term toxic effects of antidepressants on the newborn and child (Yonkers 2014).
Many studies report inconclusive findings on the relative benefits and risks of antidepressant use during pregnancy for the mother, the fetus and, subsequently, for the newborn and developing child (McDonagh, Matthews, Phillipi et al 2014) however emerging findings suggest that conservative treatment strategies designed to minimize both maternal and fetal risk are prudent. Findings of two recent studies suggest that both depressed mood in the mother and fetal exposure to antidepressants through the maternal circulation significantly increase the risk of having a miscarriage (Kjaersgaard et al 2013; Anderson et al 2014) however a third study found no evidence of increased risk of miscarriage (Jimenez-Solem et al 2013). Some studies report that taking an antidepressant during pregnancy results in a modestly increased risk of pre-term birth, however most findings are inconsistent (Byatt 2013). Taking the SSRI antidepressant paroxetine during pregnancy may be associated with a significant risk of cardiac malformations in the fetus however findings are mixed (Myles et al 2013; Ban et al 2014; Huybrechts et al 2014). A meta-analysis of seven studies found that fetal exposure to an SSRI in third trimester (but not in early pregnancy) was associated with significantly increased risk of a medical and behavioral complications in the newborn including respiratory distress, seizures, neurologic disorders, irritability and problems nursing (Grigoriadis et al 2014). In most cases, side effects of SSRIs in the mother and newborn are mild and resolve in a few days (Grigoriadis et al 2013).
Findings of long-term negative consequences of antidepressant use during pregnancy on infant and child development are highly inconsistent (El Marroun et al 2014; Nulman et al 2012). Some studies report positive consequences such as increased infant attention and accelerated language acquisition (Hunter et al 2012; Weikum et al 2012), while others report negative consequences such as relatively lower gross motor activity and slowness in achieving adaptive social behaviors (Hanley, Brain and Oberlander 2013). Recent concerns have been voiced about a possible causal association between antidepressant use during pregnancy and increased risk of autism spectrum disorder (ASD) however findings are mixed (Harrington et al 2014; El Marroun et al 2014; Hviid, Melbye and Pasternak 2013; Sorensen et al 2013). Finally, there is evidence that antidepressant use in pregnancy may increase the risk of pre-eclampsia however findings are confounded by the increased rate of pre-eclampsia in depressed women who do not take antidepressants (DeVera and Berard 2012; Toh et al 2009; Palmsten et al 2013).
Because of potentially serious risks associated with conventional pharmacologic treatment, many pregnant women who are depressed prefer to use non-medication approaches including psychotherapy and complementary and alternative (CAM) modalities. Interpersonal psychotherapy and cognitive behavioral therapy (CBT) may be more effective than other kinds of psychotherapy (Stuart and Koleva 2014; Spinelli et al 2013). Transcranial magnetic stimulation (TMS) may be beneficial in some cases (Hizli Sayar et al 2014) though findings are limited. Electroconvulsive therapy (ECT) is sometimes recommended to treat severe depressed mood during pregnancy that is non-responsive to medications however ECT increases the risk of premature labor and fetal death and is thus considered only as a last resort (Leiknes et al 2015).
Complementary, alternative and integrative approaches
The findings of large population surveys suggest that many pregnant women use CAM to treat a variety of health and mental health problems while relatively few disclose CAM use to their physicians or other health care providers (Hall and Jolly 2014). Many CAM modalities are used to treat depressed mood during pregnancy, however most are not supported by robust findings. A recent review of complementary health practices widely used to treat depressed mood during pregnancy found moderate evidence for omega-3s, folate, and vitamin D, regular physical activity and yoga, and insufficient evidence to recommend supplementation with S-adenosylmethionine, selenium, zinc, magnesium, and the B vitamins riboflavin, pyridoxine and cobalamin (Reza et al 2018). The balance of this paper is offered as a concise review of research highlights on CAM modalities commonly used to treat depressed mood during pregnancy.
Natural supplements
S-adenosyl-methionine (SAMe) occurs naturally in the body and brain, is required for synthesis of serotonin and other neurotransmitters, and has important anti-inflammatory and neuroprotective effects. Numerous studies report antidepressant benefits of SAMe supplementation at doses between 400mg and 1600mg/day when used alone or adjunctively with an antidepressant (Mischoulon and Fava 2002; Bressa 1994; Papakostas et al 2010; Levkovitz et al 2012). No studies have investigated SAMe for depressed mood during pregnancy however an early study on SAMe for post-partum depression reported positive findings (Cerutti et al 1993). SAMe is generally well tolerated however some individuals experience mild adverse effects including transient dizziness, gastrointestinal distress, anxiety and irritability.
Standardized extracts of the herbal St. John’s wort (Hypericum perforatum) are widely used to treat depressed mood however findings of placebo-controlled trials are inconsistent (Linde et al 2005; Roder, Schaefer and Leucht 2004). The herbal may not be safe when taken during pregnancy because its active constituents interact with antidepressants and other medications, reducing serum levels resulting in potentially negative health consequences (Rayburn, Christensen and Gonzalez 2000; Dugoua et al 2006). All pregnant depressed women who are taking an antidepressant or another medication should consult with their physician before taking St. John’s wort.
Many studies have established the antidepressant efficacy of supplementation with the omega-3 essential fatty acids ecosapentanoic acid (EPA) and docosahexanoic acid (DHA) consistent with the finding that women who eat less fish are at increased risk of developing depressed mood post-partum (Strom et al 2009). However findings of antidepressant effects of omega-3s in pregnant women are mixed with some studies reporting positive effects and others reporting no benefits (Freeman et al 2008; Makrides et al 2010; Su et al 2008; Kaviani et al 2014).
Folate is a B vitamin that plays important roles in fetal development and healthy adult brain function. During pregnancy adequate dietary folate is essential for normal development of the fetal nervous system thus pregnant women are advised to take folic acid daily. Individuals with low serum folate levels are at increased risk of depressed mood (Beydoun et al 2010). A significant percentage of individuals who do not respond to antidepressants may have a genetic polymorphism that results in low serum levels of the enzyme needed to convert dietary folate into the active form, 5-methyltetrahydrofolate (t-MTHF) which crosses the blood-brain barrier and is essential for synthesis of neurotransmitters required for mood regulation. Studies on the efficacy of folate supplementation for depressed mood both as a stand-alone treatment and as an adjunct to antidepressants, have yielded inconsistent findings (Taylor et al 2003). Two recent studies found that daily folic acid supplementation reduces the risk of depressed mood in pregnancy (Lewis et al 2012; Yan et al 2017). More studies are needed to confirm these findings and determine optimal dosing strategies.
Low serum vitamin D levels are associated with increased risk of depressed mood (Anglin et al 2013). Pregnant women with higher vitamin D levels are at reduced risk of depressed mood (Williams et al 2016). However, findings of controlled studies on vitamin D supplementation in depressed mood are mixed (Spedding 2014; Gowda et al 2015). Although prenatal vitamins contain 400 IUs of vitamin D, a daily dose of 2000 IU may be needed to reach serum levels believed to be effective against depressed mood (Holick et al 2011). Findings of the only placebo-controlled randomized study on vitamin D supplementation in depressed mood during pregnancy reported antidepressant benefits in women who took 2000 IU daily for at least 8 weeks starting in beginning of the third trimester (Vaziri et al 2016).
There is preliminary evidence for antidepressant effects of selenium, zinc and riboflavin. Low dietary intake of the trace element selenium is associated with increased risk of depressed mood (Pasco et al 2012) however findings of placebo-controlled trials are inconsistent (Benton and Cook 1991; Rayman et al 2006; Miller et al 2013; Leung et al 2013). Low serum zinc levels may be associated with increased risk of depressed mood (Lai et al 2012) however findings of zinc supplementation in depressed pregnant women are mixed (Fard et al 2017). Adequate dietary intake of the B vitamin riboflavin may reduce depression risk. Findings of one prospective cohort study suggest that consuming foods rich in this vitamin may reduce the risk of depressed mood in pregnancy (Murakami et al 2010; Miyake et al 2006).
Bright light exposure therapy
Studies report consistent efficacy when bright light exposure therapy is used to treat both seasonal and seasonal depressed mood (Eastman et al 1998; Golden et al 2005). Findings of three small studies reported antidepressant benefits in women treated daily with one hour of early morning full spectrum bright light exposure (between 7,000 and 10,000 lux) for at least three weeks and bright light exposure was significantly more effective than placebo (dim light) (Oren et al 2002; Epperson et al 2004; Wirz-Justice et al 2011) however another (also small) study found no response difference in pregnant women exposed to bright light versus dim light (Corral et al 2007). Bright light exposure is well tolerated and rare cases of hypomania have been reported in individuals diagnosed with bipolar disorder.
Acupuncture
Acupuncture is widely used to treat many medical and mental health problems. Findings of sham-controlled studies on acupuncture for depressed mood are inconsistent (Smith, Hay and Macpherson 2010). A few studies on traditional acupuncture for depression during pregnancy yielded positive results (Manber et al 2004; Manber et al 2010). A small study found no response difference between women treated with traditional acupuncture and electroacupuncture (Chung et al 2012).
Exercise, massage and yoga
Pregnant women are encouraged by their providers to stay physically active because of established health and mental health benefits of exercise. Many studies report that depressed individuals who exercise aerobically on a regular basis, experience improvements in symptom severity (Krogh et al 2010; Mota-Pereira et al 2011) however research findings are inconsistent with some studies reporting no antidepressant effects (Chalder et al 2011). The optimal type, frequency and duration of exercise for depressed mood have not been established. Few studies have been done on exercise for depressed mood in pregnancy and early post-partum, and results are mixed (Norman et al 2010; Heh et al 2008; Armstrong and Edwards 2003; Dritsa et al 2008).
Regular massage therapy of at least 20 minutes weekly has significant antidepressant effects in depressed adults including in depressed pregnant women (Hou et al 2010; Field et al 2004; Field et al 2008). Further, regular massage during pregnancy may reduce the risk of premature birth and low birth weight (Field et al 2009).
Yoga
Findings on the efficacy of yoga for perinatal depressed mood are inconsistent with some studies reporting significant reductions in the severity of depressed mood with regular yoga practice and other studies reporting no differences in outcomes between women practicing yoga and women on a waitlist (Uebelacker et al 2016; Davis et al 2015; Muzik et al 2012; Field et al 2013; Field et al 2012; Mitchell et al 2012; Buttner et al 2015). Differences in outcome may be related to different styles of yoga, diverse samples and sample sizes and use of self-reported or non-standardized measures of mood in many studies. Future studies are needed to determine whether specific styles of yoga are more effective than others, the optimal frequency of yoga practice for antidepressant benefits, and to characterize safety considerations in pregnant women who practice yoga.
Summary and recommendations
Everyone who struggles with depressed mood has a unique genetic, social and psychological background that influences the risk of becoming depressed and determines how well they respond to treatment. ‘One size fits all’ does not apply to treating depressed mood in the general population or in pregnant women who are depressed. In all cases individualized treatment planning should examine the evidence for the range of evidence-based conventional and CAM modalities taking into account each person’s unique symptoms and preferences while carefully weighing the risks and benefits of disparate approaches. In view of the serious health consequences to both the mother and the fetus of untreated or under-treated depressed mood in pregnancy, and the risk of serious toxic effects of antidepressants on the fetus and on early childhood development, it is incumbent on the health care provider to carefully evaluate the risks and benefits of different choices before recommending a specific conventional or CAM approach. Depending on the severity of depressed mood, the level of motivation, personal preferences, and history of response to previous treatment (if any), the most appropriate treatment regimen – and the one most likely to be effective – may consist of one or more natural supplements, an antidepressant, acupuncture, bright light exposure therapy, regular aerobic exercise, yoga, or a combination of two or more modalities.
Frequent follow-up appointments should be offered to all pregnant women who struggle with depressed mood to closely track treatment response and to monitor for side effects in the mother and signs of toxicity to the fetus. Along the way, the health care provider should be flexible and open-minded, adjusting the treatment plan as needed until consistent improvement in mood is achieved.
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