Erin Habecker, MD

When a patient who has a preexisting medical illness seeks prenatal care, the obstetrician asks herself (himself) 2 questions:
   • What impact will the illness have on the pregnancy?
   • What impact will the pregnancy have on the illness?

Depression is both a pregnancy-associated and pregnancy­-independent illness, which, in the setting of a pregnant woman who has a depressive disorder, makes these questions particu­larly difficult to answer. In such a case, coordination of care with a mental health provider is essential.

Awareness of the obstetrical complications associated with depression during pregnancy, as well as their implications for the future health of the mother–infant dyad, is important for the entire care team. This article reviews the associations and interconnectedness of depression with complications of preg­nancy, childbirth, and the neonatal period.

Diagnosis of depression during prenatal care
The American College of Obstetricians and Gynecologists (ACOG) states that evidence is insufficient to support a rec­ommendation for universal screening for depression among prenatal patients, although such screening should be considered.¹ There is considerable variability among obstetrical pro­viders regarding the practice of depression screening; tools to be used if such screening is done; and screening frequency through the pregnancy.

Discernment of depression is difficult. Many somatic symptoms of depression overlap with common prenatal complaints and, consequentially, can be overlooked. Among a sample of 700 pregnant women, for example, 56% complained of lack of energy; 19%, of insomnia; and 19%, of appe­tite changes.² Weight change, of course, is universal.

The 10-question self-rating Edinburgh Postnatal Depression Scale has been vali­dated for use during pregnancy and post­natally. This screening instrument can be helpful for differentiating purely physical complaints from mental distress due to depressive symptoms.^2,3

When an obstetrical provider suspects a depressive disorder, or one has been diagnosed, she (he) faces the problem of what to do with that information. Women of low socioeconomic status and victims of domestic violence are at increased risk of depression during pregnancy, but barri­ers to appropriate referral can seem nearly insurmountable because they lack insur­ance and social support.^4-9

In addition, within the setting of numer­ous tasks that need attending during the relatively short prenatal period, it is com­mon for women newly given a diagnosis of depression to fail to follow up on a refer­ral to a mental health provider.

Although most providers will “check in” with a depressed or at-risk patient at each prenatal visit about her mood, any effort at follow-up can be overshadowed by tangible physical concerns, such as pre­term contractions, fetal growth restriction, and coordination of routine testing that has been delayed because of scant prena­tal care. All these physical concerns and circumstances of care are associated with maternal depression, as we will discuss.

Preterm labor and birth
Preterm labor is defined as uterine contrac­tions that lead to cervical change before 37 weeks gestational age. Preterm labor increases the risk of preterm birth; pre­term labor precedes 50% of preterm births. Preterm birth is the leading cause of neona­tal mortality in the United States, and rates of morbidity and mortality increase as ges­tational age decreases.¹⁰ Common neonatal complications related to prematurity are shown in the Figure.¹¹

Women who suffer from depression have an increased risk of preterm labor and preterm birth, as many studies of treated and untreated depressed pregnant women have shown.^12-20 The causative mechanism is unknown; it has been proposed that the increase in maternal cortisol production asso­ciated with depression and distress triggers overproduction of placental cortisol releasing hormone, which is thought to be involved in initiation of parturition.^21,22 Depression also is associated with other risk factors for preterm birth, such as low socioeconomic status, sub­stance use, and smoking.

Intrauterine growth restriction
Women who have depression during preg­nancy have an increased risk of intrauterine growth restriction (IUGR), which leads to delivery of an infant who is small for ges­tational age (SGA) or of low birth weight (LBW) (weighing <2,500 g at birth), or both.²³ Again, the basis of the association between depression and IUGR and SGA is unknown; it is theorized that increased levels of cortisol and catecholamines associated with maternal distress might, by increasing blood pressure and inducing vasoconstriction, cause placen­tal hypoperfusion.^24,25

It also is possible that the association of depression with other risk factors for IUGR, such as smoking, substance use, obesity, and poor prenatal care, puts the infants of depressed women at risk of growth restric­tion.²⁶ Several large-scale studies showed that the association between LBW and depres­sion is lost when smoking and substance use are accounted for; other studies, however, found a persistent association in untreated depressed women when smokers, substance users, and drinkers were excluded.^17,26,27

IUGR infants are at increased risk of iat­rogenic prematurity and stillbirth. Fetuses that weigh <10th percentile for their ges­tational age are delivered no later than 40 weeks; delivery can be indicated as early as 32 weeks, depending on the results of other antenatal tests. Women who have a growth-restricted infant have a higher risk of cesarean delivery because growth-restricted infants often have less reserve and poorer tolerance of labor.

Preeclampsia and eclampsia
Preeclampsia is defined as blood pressure >140/90 mm HG on at least 2 occasions, with proteinuria, that occurs later than the twentieth week of pregnancy in women who did not have hypertension or renal dysfunction at baseline. Preeclampsia is a progressive disease that can cause severe maternal morbidity, including renal failure, stroke, hepatic rupture, pulmonary edema, and heart failure.

Eclampsia refers to onset of seizures in the setting of preeclampsia. These 2 hyperten­sive disorders are the third leading world wide cause of maternal mortality.²⁸

Depressed women have an elevated risk of preeclampsia. The association between preeclampsia and depression might be caused by the presence of increased levels of inflammatory mediators^29,30; other comorbidities, such as increased body mass index, also might be involved, but the risk for preeclampsia in depressed women still is increased after controlling for obesity.³¹

The presence of preeclampsia is respon­sible for a high percentage of iatrogenic pre­term births, because the cure for the disorder is delivery—even at early or previable gesta­tional age. Complication rates for mother and infant are high.

The presence of preeclampsia is a sig­nificant risk factor for intrauterine fetal demise. Treating the mother after delivery involves administration of IV magnesium for 24 hours; often, the mother is separated from her infant for a day after birth.

Impact on prenatal care
Depression increases odds that women will have fewer prenatal visits.³² During pregnancy, women typically initiate pre­natal care during the first trimester, when pregnancy-dating ultrasonography and early screening tests for chromosomal abnormalities are performed. Prenatal vis­its occur monthly until the third trimes­ter, then every 2 weeks between 32 and 36 weeks’ gestation, increasing to weekly after 36 weeks’ gestation.

The increased number of visits in late pregnancy allows for early detection and treatment of hypertensive disorders; assesses fetal well-being; and decreases the risks of morbidity and mortality for mother and fetus.³³ Because women who suffer from depression are at increased risk of an array of adverse pregnancy outcomes, the impor­tance of regular and timely prenatal care cannot be understated.

In addition, the prenatal visit gives the obstetrician the opportunity to connect women with other specialists for manage­ment of any unmet medical needs. One study showed that, when women have adequate prenatal care (measured by the number of visits), the association between preterm birth and self-reported maternal depression was eliminated.³⁴

Substance use
Substance use and depression often co-exist.^35,36 Unlike screening for depression, screening for substance use is universal dur­ing prenatal care. Studies have shown that women who screen positive for depression are at higher risk of a number of comorbidi­ties, including substance use.^37,38 Conversely, women who use substances are more likely to screen positive for depression.

Evidence suggests that best practice might be to screen for depression in any woman who has a positive drug screen, if a provider is not routinely screening their general patient population.³⁹ Substance use in pregnancy is associated with a number of poor outcomes, including placental abrup­tion (cocaine use); dysmorphic facies and congenital anomalies (alcohol); and neonatal abstinence syndrome (heroin).

Antidepressants in pregnancy
A full discussion of the risks and ben­efits associated with pharmacotherapy for depression in pregnancy is beyond the scope of this article. Generally, antidepressant use is fraught with concerns over teratogenic­ity and adverse fetal outcomes. Although ACOG states that (1) pharmacotherapy for depression should be individualized and (2) most selective serotonin reuptake inhibi­tors (SSRIs) are not considered major terato­genic agents, many obstetricians and patients feel uncomfortable using these medications in pregnancy.⁴⁰ Often, pre-pregnancy antide­pressants are discontinued in the first trimes­ter; one large population-based study found that only 0.9% of women who had depres­sion filled their antidepressant prescription consistently throughout their pregnancy.⁴¹

It is unclear whether antidepressant use in pregnancy contributes to the risk of preterm birth seen in women who have depression. In a large population-based study, use of antidepressants in the second trimester was associated with preterm delivery but severe depression was not.¹⁸ A recent meta-analysis revealed an increased risk of preterm birth in women who used an antidepressant, com­pared with healthy women and untreated depressed women.⁴²

Research limits, unanswered questions. Regrettably, it is difficult to untangle risk factors for preterm birth among depressed women without randomized controlled studies that are not ethically feasible. It can­not be said with certainty whether antide­pressant pharmacotherapy is associated with a higher risk of preterm birth than depression alone.

Likewise, it is difficult to clarify the extent to which antidepressants contribute to infant growth restriction, if at all. Two recent meta-analyses concluded that exposure to antidepressants is associated with a statisti­cally significant risk of LBW.^42,43 However, increased severity of depressive symptoms generally is associated with exposure to anti­depressants during pregnancy, and a ran­domized controlled trial is, again, impossible to conduct for ethical reasons.

Whereas a plausible biological mecha­nism associating IUGR, SGA, and LBW with depression exists, the same cannot be said for antidepressants. In one study, exposure to maternal depression altered the expres­sion of certain placental genes but exposure to SSRIs did not cause further changes. This suggests that, on a cellular level, placental function might differ in depressed women.⁴⁴ Although antidepressants do cross the pla­centa, it remains to be seen whether fetal growth is impacted as a result. One study found decreased fetal head circumference in infants who had been exposed to antidepres­sants during pregnancy, but no increased risk for having a SGA or LWB infant.⁴⁵

Obstetrical management and mental health implications
Treated or not, women who suffer depres­sion are a high-risk group when it comes to preterm birth and a host of other pregnancy comorbidities. Women with serious compli­cations of pregnancy often are hospitalized for observation, and can undergo a pro­longed stay when close proximity to medical services or a surgical suite is required.

For example, hospitalization until deliv­ery is the standard of care for women who have preterm premature rupture of mem­branes or preeclampsia before 34 weeks’ gestation. Prolonged inpatient admis­sions and associated restriction of activity is profoundly deleterious on mood, with depression and anxiety significantly cor­related with length of stay.^46,47 Given the associations between depression and pre­term birth, it might be reasonable to con­sider screening antenatal inpatients at risk of preterm birth for depression on a regu­lar basis, so that treatment can be initiated if needed.

Depression during pregnancy is rela­tively common; an estimated 12.7% of pregnant women are affected at some time between conception and birth.⁴⁸ Not only does depression appear to have deleterious effects on pregnancy outcomes, it also plays a pivotal role in the qualitative experience of pregnancy for the mother.

Bottom Line
Awareness of obstetrical complications associated with depression in pregnancy is important for the entire care team, including the psychiatrist and obstetrician. Depression not only appears to have deleterious effects on pregnancy outcomes, it also plays a pivotal role in the qualitative experience of pregnancy for the mother. Antidepressant use generally is fraught with concerns over teratogenicity and adverse fetal outcomes.

Related Resources
• Freeman MP. Some SSRIs are better than others for pregnant women (audio interview). Current Psychiatry. 2014;13(7). http://www.currentpsychiatry.com/specialty-focus/practice-trends/article/some-ssris-are-better-thanothers-for-pregnant-women/e3adb4704e25492f3e15331fc1cc058d.html.
• Freeman MP, Joffe H, Cohen LS. Postpartum depression: Help patients find the right treatment. Current Psychiatry. 2012;11(11):14-16,19-21.

Disclosures
Dr. Habecker reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Freeman is a member of the advisory board of JDS Therapeutics, Sunovion Pharmaceuticals, Inc., and Takeda Pharmaceutical Co. She receives research grant support from Takeda Pharmaceutical Co.

When a patient who has a preexisting medical illness seeks prenatal care, the obstetrician asks herself (himself) 2 questions:
   • What impact will the illness have on the pregnancy?
   • What impact will the pregnancy have on the illness?

Depression is both a pregnancy-associated and pregnancy­-independent illness, which, in the setting of a pregnant woman who has a depressive disorder, makes these questions particu­larly difficult to answer. In such a case, coordination of care with a mental health provider is essential.

Awareness of the obstetrical complications associated with depression during pregnancy, as well as their implications for the future health of the mother–infant dyad, is important for the entire care team. This article reviews the associations and interconnectedness of depression with complications of preg­nancy, childbirth, and the neonatal period.

Diagnosis of depression during prenatal care
The American College of Obstetricians and Gynecologists (ACOG) states that evidence is insufficient to support a rec­ommendation for universal screening for depression among prenatal patients, although such screening should be considered.¹ There is considerable variability among obstetrical pro­viders regarding the practice of depression screening; tools to be used if such screening is done; and screening frequency through the pregnancy.

Discernment of depression is difficult. Many somatic symptoms of depression overlap with common prenatal complaints and, consequentially, can be overlooked. Among a sample of 700 pregnant women, for example, 56% complained of lack of energy; 19%, of insomnia; and 19%, of appe­tite changes.² Weight change, of course, is universal.

The 10-question self-rating Edinburgh Postnatal Depression Scale has been vali­dated for use during pregnancy and post­natally. This screening instrument can be helpful for differentiating purely physical complaints from mental distress due to depressive symptoms.^2,3

When an obstetrical provider suspects a depressive disorder, or one has been diagnosed, she (he) faces the problem of what to do with that information. Women of low socioeconomic status and victims of domestic violence are at increased risk of depression during pregnancy, but barri­ers to appropriate referral can seem nearly insurmountable because they lack insur­ance and social support.^4-9

In addition, within the setting of numer­ous tasks that need attending during the relatively short prenatal period, it is com­mon for women newly given a diagnosis of depression to fail to follow up on a refer­ral to a mental health provider.

Although most providers will “check in” with a depressed or at-risk patient at each prenatal visit about her mood, any effort at follow-up can be overshadowed by tangible physical concerns, such as pre­term contractions, fetal growth restriction, and coordination of routine testing that has been delayed because of scant prena­tal care. All these physical concerns and circumstances of care are associated with maternal depression, as we will discuss.

Preterm labor and birth
Preterm labor is defined as uterine contrac­tions that lead to cervical change before 37 weeks gestational age. Preterm labor increases the risk of preterm birth; pre­term labor precedes 50% of preterm births. Preterm birth is the leading cause of neona­tal mortality in the United States, and rates of morbidity and mortality increase as ges­tational age decreases.¹⁰ Common neonatal complications related to prematurity are shown in the Figure.¹¹

Women who suffer from depression have an increased risk of preterm labor and preterm birth, as many studies of treated and untreated depressed pregnant women have shown.^12-20 The causative mechanism is unknown; it has been proposed that the increase in maternal cortisol production asso­ciated with depression and distress triggers overproduction of placental cortisol releasing hormone, which is thought to be involved in initiation of parturition.^21,22 Depression also is associated with other risk factors for preterm birth, such as low socioeconomic status, sub­stance use, and smoking.

Intrauterine growth restriction
Women who have depression during preg­nancy have an increased risk of intrauterine growth restriction (IUGR), which leads to delivery of an infant who is small for ges­tational age (SGA) or of low birth weight (LBW) (weighing <2,500 g at birth), or both.²³ Again, the basis of the association between depression and IUGR and SGA is unknown; it is theorized that increased levels of cortisol and catecholamines associated with maternal distress might, by increasing blood pressure and inducing vasoconstriction, cause placen­tal hypoperfusion.^24,25

It also is possible that the association of depression with other risk factors for IUGR, such as smoking, substance use, obesity, and poor prenatal care, puts the infants of depressed women at risk of growth restric­tion.²⁶ Several large-scale studies showed that the association between LBW and depres­sion is lost when smoking and substance use are accounted for; other studies, however, found a persistent association in untreated depressed women when smokers, substance users, and drinkers were excluded.^17,26,27

IUGR infants are at increased risk of iat­rogenic prematurity and stillbirth. Fetuses that weigh <10th percentile for their ges­tational age are delivered no later than 40 weeks; delivery can be indicated as early as 32 weeks, depending on the results of other antenatal tests. Women who have a growth-restricted infant have a higher risk of cesarean delivery because growth-restricted infants often have less reserve and poorer tolerance of labor.

Preeclampsia and eclampsia
Preeclampsia is defined as blood pressure >140/90 mm HG on at least 2 occasions, with proteinuria, that occurs later than the twentieth week of pregnancy in women who did not have hypertension or renal dysfunction at baseline. Preeclampsia is a progressive disease that can cause severe maternal morbidity, including renal failure, stroke, hepatic rupture, pulmonary edema, and heart failure.

Eclampsia refers to onset of seizures in the setting of preeclampsia. These 2 hyperten­sive disorders are the third leading world wide cause of maternal mortality.²⁸

Depressed women have an elevated risk of preeclampsia. The association between preeclampsia and depression might be caused by the presence of increased levels of inflammatory mediators^29,30; other comorbidities, such as increased body mass index, also might be involved, but the risk for preeclampsia in depressed women still is increased after controlling for obesity.³¹

The presence of preeclampsia is respon­sible for a high percentage of iatrogenic pre­term births, because the cure for the disorder is delivery—even at early or previable gesta­tional age. Complication rates for mother and infant are high.

The presence of preeclampsia is a sig­nificant risk factor for intrauterine fetal demise. Treating the mother after delivery involves administration of IV magnesium for 24 hours; often, the mother is separated from her infant for a day after birth.

Impact on prenatal care
Depression increases odds that women will have fewer prenatal visits.³² During pregnancy, women typically initiate pre­natal care during the first trimester, when pregnancy-dating ultrasonography and early screening tests for chromosomal abnormalities are performed. Prenatal vis­its occur monthly until the third trimes­ter, then every 2 weeks between 32 and 36 weeks’ gestation, increasing to weekly after 36 weeks’ gestation.

The increased number of visits in late pregnancy allows for early detection and treatment of hypertensive disorders; assesses fetal well-being; and decreases the risks of morbidity and mortality for mother and fetus.³³ Because women who suffer from depression are at increased risk of an array of adverse pregnancy outcomes, the impor­tance of regular and timely prenatal care cannot be understated.

In addition, the prenatal visit gives the obstetrician the opportunity to connect women with other specialists for manage­ment of any unmet medical needs. One study showed that, when women have adequate prenatal care (measured by the number of visits), the association between preterm birth and self-reported maternal depression was eliminated.³⁴

Substance use
Substance use and depression often co-exist.^35,36 Unlike screening for depression, screening for substance use is universal dur­ing prenatal care. Studies have shown that women who screen positive for depression are at higher risk of a number of comorbidi­ties, including substance use.^37,38 Conversely, women who use substances are more likely to screen positive for depression.

Evidence suggests that best practice might be to screen for depression in any woman who has a positive drug screen, if a provider is not routinely screening their general patient population.³⁹ Substance use in pregnancy is associated with a number of poor outcomes, including placental abrup­tion (cocaine use); dysmorphic facies and congenital anomalies (alcohol); and neonatal abstinence syndrome (heroin).

Antidepressants in pregnancy
A full discussion of the risks and ben­efits associated with pharmacotherapy for depression in pregnancy is beyond the scope of this article. Generally, antidepressant use is fraught with concerns over teratogenic­ity and adverse fetal outcomes. Although ACOG states that (1) pharmacotherapy for depression should be individualized and (2) most selective serotonin reuptake inhibi­tors (SSRIs) are not considered major terato­genic agents, many obstetricians and patients feel uncomfortable using these medications in pregnancy.⁴⁰ Often, pre-pregnancy antide­pressants are discontinued in the first trimes­ter; one large population-based study found that only 0.9% of women who had depres­sion filled their antidepressant prescription consistently throughout their pregnancy.⁴¹

It is unclear whether antidepressant use in pregnancy contributes to the risk of preterm birth seen in women who have depression. In a large population-based study, use of antidepressants in the second trimester was associated with preterm delivery but severe depression was not.¹⁸ A recent meta-analysis revealed an increased risk of preterm birth in women who used an antidepressant, com­pared with healthy women and untreated depressed women.⁴²

Research limits, unanswered questions. Regrettably, it is difficult to untangle risk factors for preterm birth among depressed women without randomized controlled studies that are not ethically feasible. It can­not be said with certainty whether antide­pressant pharmacotherapy is associated with a higher risk of preterm birth than depression alone.

Likewise, it is difficult to clarify the extent to which antidepressants contribute to infant growth restriction, if at all. Two recent meta-analyses concluded that exposure to antidepressants is associated with a statisti­cally significant risk of LBW.^42,43 However, increased severity of depressive symptoms generally is associated with exposure to anti­depressants during pregnancy, and a ran­domized controlled trial is, again, impossible to conduct for ethical reasons.

Whereas a plausible biological mecha­nism associating IUGR, SGA, and LBW with depression exists, the same cannot be said for antidepressants. In one study, exposure to maternal depression altered the expres­sion of certain placental genes but exposure to SSRIs did not cause further changes. This suggests that, on a cellular level, placental function might differ in depressed women.⁴⁴ Although antidepressants do cross the pla­centa, it remains to be seen whether fetal growth is impacted as a result. One study found decreased fetal head circumference in infants who had been exposed to antidepres­sants during pregnancy, but no increased risk for having a SGA or LWB infant.⁴⁵

Obstetrical management and mental health implications
Treated or not, women who suffer depres­sion are a high-risk group when it comes to preterm birth and a host of other pregnancy comorbidities. Women with serious compli­cations of pregnancy often are hospitalized for observation, and can undergo a pro­longed stay when close proximity to medical services or a surgical suite is required.

For example, hospitalization until deliv­ery is the standard of care for women who have preterm premature rupture of mem­branes or preeclampsia before 34 weeks’ gestation. Prolonged inpatient admis­sions and associated restriction of activity is profoundly deleterious on mood, with depression and anxiety significantly cor­related with length of stay.^46,47 Given the associations between depression and pre­term birth, it might be reasonable to con­sider screening antenatal inpatients at risk of preterm birth for depression on a regu­lar basis, so that treatment can be initiated if needed.

Depression during pregnancy is rela­tively common; an estimated 12.7% of pregnant women are affected at some time between conception and birth.⁴⁸ Not only does depression appear to have deleterious effects on pregnancy outcomes, it also plays a pivotal role in the qualitative experience of pregnancy for the mother.

Bottom Line
Awareness of obstetrical complications associated with depression in pregnancy is important for the entire care team, including the psychiatrist and obstetrician. Depression not only appears to have deleterious effects on pregnancy outcomes, it also plays a pivotal role in the qualitative experience of pregnancy for the mother. Antidepressant use generally is fraught with concerns over teratogenicity and adverse fetal outcomes.

Related Resources
• Freeman MP. Some SSRIs are better than others for pregnant women (audio interview). Current Psychiatry. 2014;13(7). http://www.currentpsychiatry.com/specialty-focus/practice-trends/article/some-ssris-are-better-thanothers-for-pregnant-women/e3adb4704e25492f3e15331fc1cc058d.html.
• Freeman MP, Joffe H, Cohen LS. Postpartum depression: Help patients find the right treatment. Current Psychiatry. 2012;11(11):14-16,19-21.

Disclosures
Dr. Habecker reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Freeman is a member of the advisory board of JDS Therapeutics, Sunovion Pharmaceuticals, Inc., and Takeda Pharmaceutical Co. She receives research grant support from Takeda Pharmaceutical Co.

When a patient who has a preexisting medical illness seeks prenatal care, the obstetrician asks herself (himself) 2 questions:
   • What impact will the illness have on the pregnancy?
   • What impact will the pregnancy have on the illness?

Depression is both a pregnancy-associated and pregnancy­-independent illness, which, in the setting of a pregnant woman who has a depressive disorder, makes these questions particu­larly difficult to answer. In such a case, coordination of care with a mental health provider is essential.

Awareness of the obstetrical complications associated with depression during pregnancy, as well as their implications for the future health of the mother–infant dyad, is important for the entire care team. This article reviews the associations and interconnectedness of depression with complications of preg­nancy, childbirth, and the neonatal period.

Diagnosis of depression during prenatal care
The American College of Obstetricians and Gynecologists (ACOG) states that evidence is insufficient to support a rec­ommendation for universal screening for depression among prenatal patients, although such screening should be considered.¹ There is considerable variability among obstetrical pro­viders regarding the practice of depression screening; tools to be used if such screening is done; and screening frequency through the pregnancy.

Discernment of depression is difficult. Many somatic symptoms of depression overlap with common prenatal complaints and, consequentially, can be overlooked. Among a sample of 700 pregnant women, for example, 56% complained of lack of energy; 19%, of insomnia; and 19%, of appe­tite changes.² Weight change, of course, is universal.

The 10-question self-rating Edinburgh Postnatal Depression Scale has been vali­dated for use during pregnancy and post­natally. This screening instrument can be helpful for differentiating purely physical complaints from mental distress due to depressive symptoms.^2,3

When an obstetrical provider suspects a depressive disorder, or one has been diagnosed, she (he) faces the problem of what to do with that information. Women of low socioeconomic status and victims of domestic violence are at increased risk of depression during pregnancy, but barri­ers to appropriate referral can seem nearly insurmountable because they lack insur­ance and social support.^4-9

In addition, within the setting of numer­ous tasks that need attending during the relatively short prenatal period, it is com­mon for women newly given a diagnosis of depression to fail to follow up on a refer­ral to a mental health provider.

Although most providers will “check in” with a depressed or at-risk patient at each prenatal visit about her mood, any effort at follow-up can be overshadowed by tangible physical concerns, such as pre­term contractions, fetal growth restriction, and coordination of routine testing that has been delayed because of scant prena­tal care. All these physical concerns and circumstances of care are associated with maternal depression, as we will discuss.

Preterm labor and birth
Preterm labor is defined as uterine contrac­tions that lead to cervical change before 37 weeks gestational age. Preterm labor increases the risk of preterm birth; pre­term labor precedes 50% of preterm births. Preterm birth is the leading cause of neona­tal mortality in the United States, and rates of morbidity and mortality increase as ges­tational age decreases.¹⁰ Common neonatal complications related to prematurity are shown in the Figure.¹¹

Women who suffer from depression have an increased risk of preterm labor and preterm birth, as many studies of treated and untreated depressed pregnant women have shown.^12-20 The causative mechanism is unknown; it has been proposed that the increase in maternal cortisol production asso­ciated with depression and distress triggers overproduction of placental cortisol releasing hormone, which is thought to be involved in initiation of parturition.^21,22 Depression also is associated with other risk factors for preterm birth, such as low socioeconomic status, sub­stance use, and smoking.

Intrauterine growth restriction
Women who have depression during preg­nancy have an increased risk of intrauterine growth restriction (IUGR), which leads to delivery of an infant who is small for ges­tational age (SGA) or of low birth weight (LBW) (weighing <2,500 g at birth), or both.²³ Again, the basis of the association between depression and IUGR and SGA is unknown; it is theorized that increased levels of cortisol and catecholamines associated with maternal distress might, by increasing blood pressure and inducing vasoconstriction, cause placen­tal hypoperfusion.^24,25

It also is possible that the association of depression with other risk factors for IUGR, such as smoking, substance use, obesity, and poor prenatal care, puts the infants of depressed women at risk of growth restric­tion.²⁶ Several large-scale studies showed that the association between LBW and depres­sion is lost when smoking and substance use are accounted for; other studies, however, found a persistent association in untreated depressed women when smokers, substance users, and drinkers were excluded.^17,26,27

IUGR infants are at increased risk of iat­rogenic prematurity and stillbirth. Fetuses that weigh <10th percentile for their ges­tational age are delivered no later than 40 weeks; delivery can be indicated as early as 32 weeks, depending on the results of other antenatal tests. Women who have a growth-restricted infant have a higher risk of cesarean delivery because growth-restricted infants often have less reserve and poorer tolerance of labor.

Preeclampsia and eclampsia
Preeclampsia is defined as blood pressure >140/90 mm HG on at least 2 occasions, with proteinuria, that occurs later than the twentieth week of pregnancy in women who did not have hypertension or renal dysfunction at baseline. Preeclampsia is a progressive disease that can cause severe maternal morbidity, including renal failure, stroke, hepatic rupture, pulmonary edema, and heart failure.

Eclampsia refers to onset of seizures in the setting of preeclampsia. These 2 hyperten­sive disorders are the third leading world wide cause of maternal mortality.²⁸

Depressed women have an elevated risk of preeclampsia. The association between preeclampsia and depression might be caused by the presence of increased levels of inflammatory mediators^29,30; other comorbidities, such as increased body mass index, also might be involved, but the risk for preeclampsia in depressed women still is increased after controlling for obesity.³¹

The presence of preeclampsia is respon­sible for a high percentage of iatrogenic pre­term births, because the cure for the disorder is delivery—even at early or previable gesta­tional age. Complication rates for mother and infant are high.

The presence of preeclampsia is a sig­nificant risk factor for intrauterine fetal demise. Treating the mother after delivery involves administration of IV magnesium for 24 hours; often, the mother is separated from her infant for a day after birth.

Impact on prenatal care
Depression increases odds that women will have fewer prenatal visits.³² During pregnancy, women typically initiate pre­natal care during the first trimester, when pregnancy-dating ultrasonography and early screening tests for chromosomal abnormalities are performed. Prenatal vis­its occur monthly until the third trimes­ter, then every 2 weeks between 32 and 36 weeks’ gestation, increasing to weekly after 36 weeks’ gestation.

The increased number of visits in late pregnancy allows for early detection and treatment of hypertensive disorders; assesses fetal well-being; and decreases the risks of morbidity and mortality for mother and fetus.³³ Because women who suffer from depression are at increased risk of an array of adverse pregnancy outcomes, the impor­tance of regular and timely prenatal care cannot be understated.

In addition, the prenatal visit gives the obstetrician the opportunity to connect women with other specialists for manage­ment of any unmet medical needs. One study showed that, when women have adequate prenatal care (measured by the number of visits), the association between preterm birth and self-reported maternal depression was eliminated.³⁴

Substance use
Substance use and depression often co-exist.^35,36 Unlike screening for depression, screening for substance use is universal dur­ing prenatal care. Studies have shown that women who screen positive for depression are at higher risk of a number of comorbidi­ties, including substance use.^37,38 Conversely, women who use substances are more likely to screen positive for depression.

Evidence suggests that best practice might be to screen for depression in any woman who has a positive drug screen, if a provider is not routinely screening their general patient population.³⁹ Substance use in pregnancy is associated with a number of poor outcomes, including placental abrup­tion (cocaine use); dysmorphic facies and congenital anomalies (alcohol); and neonatal abstinence syndrome (heroin).

Antidepressants in pregnancy
A full discussion of the risks and ben­efits associated with pharmacotherapy for depression in pregnancy is beyond the scope of this article. Generally, antidepressant use is fraught with concerns over teratogenic­ity and adverse fetal outcomes. Although ACOG states that (1) pharmacotherapy for depression should be individualized and (2) most selective serotonin reuptake inhibi­tors (SSRIs) are not considered major terato­genic agents, many obstetricians and patients feel uncomfortable using these medications in pregnancy.⁴⁰ Often, pre-pregnancy antide­pressants are discontinued in the first trimes­ter; one large population-based study found that only 0.9% of women who had depres­sion filled their antidepressant prescription consistently throughout their pregnancy.⁴¹

It is unclear whether antidepressant use in pregnancy contributes to the risk of preterm birth seen in women who have depression. In a large population-based study, use of antidepressants in the second trimester was associated with preterm delivery but severe depression was not.¹⁸ A recent meta-analysis revealed an increased risk of preterm birth in women who used an antidepressant, com­pared with healthy women and untreated depressed women.⁴²

Research limits, unanswered questions. Regrettably, it is difficult to untangle risk factors for preterm birth among depressed women without randomized controlled studies that are not ethically feasible. It can­not be said with certainty whether antide­pressant pharmacotherapy is associated with a higher risk of preterm birth than depression alone.

Likewise, it is difficult to clarify the extent to which antidepressants contribute to infant growth restriction, if at all. Two recent meta-analyses concluded that exposure to antidepressants is associated with a statisti­cally significant risk of LBW.^42,43 However, increased severity of depressive symptoms generally is associated with exposure to anti­depressants during pregnancy, and a ran­domized controlled trial is, again, impossible to conduct for ethical reasons.

Whereas a plausible biological mecha­nism associating IUGR, SGA, and LBW with depression exists, the same cannot be said for antidepressants. In one study, exposure to maternal depression altered the expres­sion of certain placental genes but exposure to SSRIs did not cause further changes. This suggests that, on a cellular level, placental function might differ in depressed women.⁴⁴ Although antidepressants do cross the pla­centa, it remains to be seen whether fetal growth is impacted as a result. One study found decreased fetal head circumference in infants who had been exposed to antidepres­sants during pregnancy, but no increased risk for having a SGA or LWB infant.⁴⁵

Obstetrical management and mental health implications
Treated or not, women who suffer depres­sion are a high-risk group when it comes to preterm birth and a host of other pregnancy comorbidities. Women with serious compli­cations of pregnancy often are hospitalized for observation, and can undergo a pro­longed stay when close proximity to medical services or a surgical suite is required.

For example, hospitalization until deliv­ery is the standard of care for women who have preterm premature rupture of mem­branes or preeclampsia before 34 weeks’ gestation. Prolonged inpatient admis­sions and associated restriction of activity is profoundly deleterious on mood, with depression and anxiety significantly cor­related with length of stay.^46,47 Given the associations between depression and pre­term birth, it might be reasonable to con­sider screening antenatal inpatients at risk of preterm birth for depression on a regu­lar basis, so that treatment can be initiated if needed.

Depression during pregnancy is rela­tively common; an estimated 12.7% of pregnant women are affected at some time between conception and birth.⁴⁸ Not only does depression appear to have deleterious effects on pregnancy outcomes, it also plays a pivotal role in the qualitative experience of pregnancy for the mother.

Bottom Line
Awareness of obstetrical complications associated with depression in pregnancy is important for the entire care team, including the psychiatrist and obstetrician. Depression not only appears to have deleterious effects on pregnancy outcomes, it also plays a pivotal role in the qualitative experience of pregnancy for the mother. Antidepressant use generally is fraught with concerns over teratogenicity and adverse fetal outcomes.

Related Resources
• Freeman MP. Some SSRIs are better than others for pregnant women (audio interview). Current Psychiatry. 2014;13(7). http://www.currentpsychiatry.com/specialty-focus/practice-trends/article/some-ssris-are-better-thanothers-for-pregnant-women/e3adb4704e25492f3e15331fc1cc058d.html.
• Freeman MP, Joffe H, Cohen LS. Postpartum depression: Help patients find the right treatment. Current Psychiatry. 2012;11(11):14-16,19-21.

Disclosures
Dr. Habecker reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Freeman is a member of the advisory board of JDS Therapeutics, Sunovion Pharmaceuticals, Inc., and Takeda Pharmaceutical Co. She receives research grant support from Takeda Pharmaceutical Co.