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Original Research Relation Between Prenatal Maternal Mood and Anxiety and Neonatal Health
Shaila Misri, Tim F Oberlander, Nichole Fairbrother, Diana Carter, Deirdre Ryan, Annie J Kuan, Pratibha Reebye
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Original Research

Relation Between Prenatal Maternal Mood and Anxiety and Neonatal Health

Shaila Misri, MD, FRCPC¹, Tim F Oberlander, MD, FRCPC², Nichole Fairbrother, PhD³, Diana Carter, MD, FRCPC¹, Deirdre Ryan, MD, FRCPC¹, Annie J Kuan, BA⁴, Pratibha Reebye, MD, FRCPC⁵

In the last decade, there has been an increasing accumulation of data on the effects of selective serotonin reuptake inhibitor (SSRI) exposure in neonates (1–3). However, what remains unclear and inconclusive is how the maternal psychiatric symptomatology affects neonatal health.

Anxiety and depression are known to complicate maternal health during pregnancy and may be associated with poor infant outcome in the newborn period (4). However, the influence of maternal mood and anxiety on fetal development and neonatal adaptation cannot be easily separated from the effects of medications that are used to manage maternal psychiatric symptoms. SSRIs are frequently used to treat maternal mood and anxiety during pregnancy. While these medications appear to be safe for use in this population, there have been reports of withdrawal symptoms or transient poor neonatal adaptation in exposed newborns (1). The mechanisms that account for these findings remain unclear.

Some evidence from both animal and human studies suggests that maternal mood and anxiety, in itself and without other compounding factors, may influence newborn health status (2–11). However, this relation has not been studied in a group of women with clinical depression and anxiety who have also been exposed to psychopharmacological agents.

We recently reported that neonatal symptoms might be associated with elevated maternal and fetal levels of SSRIs at birth, particularly when exposure was combined with the benzodiazepine, clonazepam (3). These symptoms were predominantly respiratory distress that resolved within 24 hours and were not associated with any other adverse neonatal or maternal conditions (3). While pharmacologic factors may account for these findings, the concurrent influence of maternal mood and anxiety merited further exploration.

We undertook a prospective study to explore the relation between maternal mood and anxiety and transient neonatal symptoms in infants of psychiatrically treated mothers.

Methods

Participants and Procedures
With approval from the University of British Columbia Research Ethics Board and the Children’s and Women’s Health Centre of British Columbia Research Review Committee as well as informed patient or parent consent, a cohort of mothers and their infants were prospectively recruited during pregnancy as part of a larger study of the effects of psychotropic medication use during and following pregnancy (3,12).

Maternal Measures
We assessed maternal symptoms of anxiety and depression, using the Hamilton Anxiety Rating Scale (HARS) (13) and the Hamilton Depression Rating Scale (HDRS) (14), when the women entered the study during pregnancy. The treating psychiatrist assessed diagnostic status according to DSM-IV diagnostic criteria (15), using structured clinical interview. We obtained these measures at study entry. The frequency of visits to assess maternal mood varied, because women entered the study at different trimesters. We also obtained background measures of maternal age, education, marital status, social status, current obstetrical risk factors (for example, hypertension and diabetes), sexual abuse history, alcohol abuse, cigarette smoking, marijuana, cocaine use, and the presence or absence of a supportive partner. The obstetrician on the research team regularly monitored prenatal health.

Women recruited from the Provincial Reproductive Mental Health Program at the BC Women’s Hospital were referrals from family physicians and obstetricians. Inclusion criteria for the study that women be medically healthy and have received 1 or more Axis-I diagnoses during pregnancy. Women were excluded from participating if they were abusing a substance, were suffering from psychosis, were suicidal, or had been exposed to known teratogens.

Infant Outcomes
We prospectively followed infants from birth and evaluated them for symptoms of poor neonatal adaptation as defined by Chambers (1). Infant outcomes of interest included the following: gestational age at birth, growth parameters at birth, Apgar scores (that is, 1- and 5-minute scores of heart rate, respiratory effort, muscle tone, reflex irritability, and colour), evidence of transient neonatal symptoms suggesting altered adaptation in the newborn period (such as jitteriness, respiratory difficulty, hypoglycemia, lethargy, weak or absent crying, or dissatisfaction when feeding) (1), presence of major anatomical anomalies, admission for observational unit or special care nursery, and duration of hospital stay.

Statistical Analysis
We used t tests, chi-square analysis, and univariate analysis of variance and covariance to examine group differences and the potentially mediating role of clonazepam.

Results

A total of 71 women were approached for possible participation, and 46 pregnant women were included in the study. At the time of signing informed consent, all patients met inclusion criteria, but as the study progressed, 3 revealed that they were using substances such as alcohol or marijuana during pregnancy. The remaining 25 women were not eligible or declined to participate. Women were recruited to the study between 5 and 37 weeks of their pregnancy (mean 22.93 weeks, SD 8.40). The mean maternal age at study entry was 31.37 years, SD 4.67. Women reported having obtained a mean of 13.89 years of education, SD 2.60; most (91.3%) had English as their first language; and most were married (76.1%) or living common-law (15.2%) at the time of study entry. Three women were single (6.5%), and 1 was divorced. This was the first baby for 18 of the women.

Maternal Mood
All 46 women in the study suffered from clinical depression according to DSM-IV diagnostic criteria. In addition to major depression, 30 women also received diagnoses of Axis I disorders: 14 had panic disorder (with or without agoraphobia); 11 had panic disorder and obsessional thoughts or obsessive–compulsive disorder (OCD); and 5 had panic disorder, OCD, and an eating disorder. At entry, the mean HARS score was 15.88, SD 10.87, and the mean HDRS score was 17.88, SD 8.05.

Psychotropic Medication Treatment
All participants took antidepressant medication for part or all of their pregnancy (33 took paroxetine, 9 took fluoxetine, and 4 took sertraline). Mean duration of SSRI use prior to delivery was 25.97 weeks, SD 10.99. A total of 18 women also took clonazepam at some point during pregnancy. Dosages of SSRI medications are tabulated in Table 1.

Maternal Mood and Infant Outcomes
Of the 46 infants, 14 required closer observation in the newborn period: 11 for respiratory distress, 2 for reasons of birth complications, and 1 owing to prematurity (34 weeks). Symptoms for all infants resolved within 24 hours of birth. The average length of stay in the special care nursery was 3 days (mean 3.10 days, SD 3.46). With the exception of 1 infant, all infants were born at term. The mean length of gestation was 39.66 weeks, SD 1.03, for infants without complication, vs 38.83 weeks, SD 1.83, for infants with complications. Differences between the groups were not statistically significant. Infants with complications did not differ significantly from infants without complications regarding birth weight in grams (mean weight 3416.38 g, SD 427.86 vs mean weight 3536.43 g, SD 488.20), birth length in centimetres, (mean 51.77 cm, SD 2.91 vs mean 51.77 cm, SD 2.65), head circumference in centimetres (mean 34.29 cm, SD 1.27 vs mean 34.27 cm, SD 1.29), or 1-minute Apgar scores (mean score 7.28, SD 1.44 vs mean score 6.77, SD 1.24). Though the means for both groups were in the normal healthy range, infants without complications received higher 5-minute Apgar scores (mean score 8.78, SD 0.49), than did infants with complications (mean score 8.07, SD 0.98).

Infants with and without symptoms did not differ significantly regarding the type of SSRI they were exposed to (Table 2). Similarly, proportions of infants exposed to clonazepam did not differ between infant groups (Table 2). Regarding maternal background characteristics and substance use, the mothers of infants with complications were more likely to be single, to be on social assistance, and to abuse alcohol (Table 3). However, infants requiring observation were exposed to significantly higher dosages of clonazepam (Table 2). However, mothers in the 2 groups did not differ significantly with respect to maternal age; completion of Grade 12 or over; presence of obstetrical risk factors; history of maternal sexual abuse; use of marijuana, cigarettes, or cocaine during pregnancy; or presence of a supportive partner (Table 3).

The mothers of the babies who required observation reported significantly higher HARS scores at entry to study (mean HARS score 13.55, SD 8.262) than did mothers whose babies did not require observation (mean HARS score 21.08, SD 14.227) (F = 4.68, df 1,2; P = 0.036). The presence or absence of clonazepam as a covariate did not alter this relation. A total of 44% of babies of women whose HARS scores were in the moderately to severely anxious range (that is, HARS score = 18) required observation. These mothers also met criteria for proportionally more anxiety disorders than did the mothers of babies who did not require observation (Table 4).

The mothers of babies who required observation reported higher HDRS scores at study entry (mean HDRS score 16.17, SD 8.005) than did the mothers of babies not requiring observation (mean HDRS score 21.69, SD 6.993), (F = 4.595; df 1,2; P = 0.038). The presence or absence of clonazepam as a covariate did not alter this relation (P > 0.05). Among the babies of women whose HDRS scores were in the moderately to severely depressed range (HDRS = 18), 32% required observation.

Infant outcomes were also related to the number of maternal comorbid conditions. Of the mothers of infants requiring observation, 13/14 (92.86%) had 2 or more psychiatric diagnoses (Table 4), compared with 17/32 (53.13%) mothers of infants not requiring observation (c² = 10.39; P = 0.016).

Discussion

Increased levels of maternal anxiety and depression during the second and third trimesters were associated with increased risk for poor transient neonatal adaptation in the newborn period. While increased anxiety symptoms were associated with increased dosage of clonazepam, the relation between maternal anxiety and neonatal outcomes did not appear to be confounded by the presence of this benzodiazepine. Further, as the frequency and concurrence of maternal comorbid psychiatric disorders increased, the risk for poor neonatal outcomes also increased.

These data suggest that, even in the presence of pharmacologic therapy for maternal mental illness during pregnancy, maternal levels of anxiety and depression were related to adverse infant outcomes.

Every clinician who treats a pregnant woman with depression and (or) anxiety is faced with the dilemma of the relative risks of exposure to medications vs exposure to the illness itself. Previously, concerns about the potential harmful effects of SSRI exposure on the developing fetus predominated. Emerging data suggest that some of these medications may be safely prescribed during pregnancy (16,17). Several recent studies suggest that prenatal depression may itself have a direct, negative impact on neonatal health (5,6). Newport and colleagues report that depression during pregnancy may in fact be “a child’s first adverse life event” (4). The short-term effect of maternal stress and depression includes preterm labour (18), intrauterine growth retardation (6), and babies with low birth weight (7). A recent prospective study of maternal prenatal depression found a negative relation between depression and child cognitive and language development, independent of antidepressant medication exposure (2).

In addition to depression, a direct link between anxiety disorders and adverse infant health may also exist. Recent literature indicates that prenatal maternal stress is negatively related to birth outcomes and child health (7,9,19). The animal literature also supports a connection betweeen maternal anxiety and (or) stress and infant pathology (10). The hypothesis that maternal psychiatric symptoms negatively effect neonatal health remains a speculation among humans. Three mechanisms by which maternal stress influences neonatal health have been proposed: reduction of blood flow to the uterus and the fetus, transplacental transfer of maternal hormones, and increased placental corticotropin-releasing hormone (CRH) (20). Depression and anxiety in pregnant women is a complex phenomenon. For ethical and methodological reasons, prospective studies demonstrating the effect of untreated antenatal depression and anxiety on the human neonate are difficult to conduct. Therefore, data that provide information regarding the impact of prenatal psychiatric illness on human offspring are indirectly drawn from animal research and studies of untreated women with psychiatric illnesses.

In the current study, we attempted to elucidate the link between prenatal anxiety and (or) depression and infant outcome in the context of psychotropic medication exposure. Our data confirm an already-known correlation between maternal psychopathology and negative infant outcome, specifically focusing on transient neonatal outcomes when medication exposure is controlled for. Although difficult to conduct, further research comparing the infant outcomes of untreated mood and anxiety disorders in pregnancy with a control group of psychologically healthy women is needed.

Funding and Support

The work described in this review was supported by grant BCM96–0152 from the British Columbia Medical Services Foundation.

Acknowledgements

We are grateful to Mr Nicholas Misri and Mr Amir Lachman for their assistance with data entry and Colleen Fitzgerald for patient recruitment and data collection. We thank the women who participated in this project; without their help, the project would not have been possible.

References

1. Chambers CD, Johnson KA, Dick LM, Felix RJ, Jones KL. Birth outcomes in pregnant women taking fluoxetine. N Engl J Med 1996;335:1010–5.

2. Nulman I, Rovet J, Stewart DE, Wolpin J, Pace-Asciak P, Shuhaiber S, and others. Child development following exposure to tricyclic antidepressants or fluoxetine throughout fetal life: a prospective study. Am J Psychiatry 2002;159:1889–95.

3. Oberlander TF, Misri S, Fitzgerald C, Kostaras X, Rurak D, Riggs W. Pharmacological factors associated with transient neonatal symptoms following prenatal psychotropic medication exposure. J Clin Psychiatry 2004;65:230–7.

4. Newport, DJ, Wilcox MM, Stowe ZN. Maternal depression: a child’s first adverse life event. Semin Clin Neuropsychiatry 2002;7:113–9.

5. Chung TK, Lau TK, Yip AS, Chiu HF, Lee DT. Antepartum depressive symptomatology is associated with adverse obstetric and neonatal outcomes. Psychosom Med 2001:63:830–4.

6. Hoffman S, Hatch MC. Depressive symptomatology during pregnancy: evidence for an association with decreased fetal growth in pregnancies of lower social class women. J Health Psychol 2000;19:535–43.

7. Lobel M, DeVincent CJ, Kaminer A. The impact of prenatal maternal stress and optimistic disposition on birth outcomes in medically high-risk women. J Health Psychol 2000;19:544–53.

8. Lundy BL, Aaron Jones B, Field T, Nearing G, Davalos M, Pietro PA, and others. Prenatal depression effects on neonates. Infant Behav Develop 1999;22:119–29.

9. O’Conner TG, Heron J, Glover V, the ALSPAC Study Team. Antenatal anxiety predicts child behavioral/emotional problems independently of postnatal depression. J Am Acad Child Adolesc Psychiatry 2002;41:1470–7.

10. Schneider ML, Roughton EC, Koehler AJ, Lubach GR. Growth and development following prenatal stress exposure in primates: an examination of ontogenetic vulnerability. Child Dev 1999;70:263–74.

11. Buitelaar JK, Huizink AC, Mulder EJ, Robles de Medina PG, Visser GHA. Prenatal stress and cognitive development and temperament in infants. Neurobiology of Aging 2003;24:S53–S60.

12. Oberlander TF, Gruneau RE, Fitzgerald C, Ellwood A, Misri S, Rurak D, and others. Prolonged prenatal psychotropic medication exposure alters neonatal acute pain response. Pediatr Res 2002;51:443–53.

13. Hamilton M. The assessment of anxiety states by rating. Br J Med Psychol 1959;32:50–5.

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15. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. Washington (DC): American Psychiatric Association; 1994.

16. Kulin NA, Pastuszak A, Koren G. Are the new SSRIs safe for pregnant women? Can Fam Physician 1998;44:2081–3.

17. Masand PS, Gupta S. Selective serotonin-reuptake inhibitors: an update. Harv Rev Psychiatry 1999;7:69–84.

18. Majzoub JA, McGregor JA, Lockwood CJ, Smith R, Taggart MS, Schulkin J. A central theory of preterm and term labor: putative role for corticotrophin- releasing hormone. Am J Obstet Gynecol 1999;180:S232–S241.

19. O’Connor TG, Heron J, Golding J, Beveridge M, Glover V. Maternal antenatal anxiety on children’s behavioral/emotional problems at 4 years. Br J Psychiatry 2002;100:502–8.

20. Mulder EJH, Robles de Medina PG, Huizink AC, Van den Bergh BRH, Buitelaar JK, Visser GHA. Prenatal maternal stress: effects on pregnancy and the (unborn) child. Early Hum Dev 2000;70:3–14.

Author(s)

Manuscript received September 2003, revised, and accepted January 2004.

This paper was presented at the 155th annual meeting of the American Psychiatric Association; 2002 May 18–23; Philadelphia (PA).

1. Psychiatrist, Reproductive Mental Health, Department of Psychiatry, University of British Columbia, Vancouver, British Columbia.

2. Pediatrician, Department of Pediatrics, University of British Columbia, Biobehavioural Research Unit, Centre for Community Child Health Research, Research Institute For Children’s and Women’s Health, Vancouver, British Columbia.

3. Psychologist, Department of Psychiatry, University of British Columbia, Vancouver, British Columbia.

4. Research Assistant, Department of Psychiatry, University of British Columbia, Vancouver, British Columbia.

5. Infant Psychiatrist, Child Psychiatry, Department of Psychiatry, University of British Columbia, Vancouver, British Columbia.

Address for correspondence: Dr S Misri, Reproductive Mental Health Program, H214–4500 Oak Street, Vancouver BC V6H 3N1

e-mail: smisri@cw.bc.ca

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