Use of Antidepressants, Nicotine in Pregnancy Linked to Childhood Difficulties

Megan Brooks

May 04, 2010

May 4, 2010 — Prenatal nicotine exposure may increase the risk of sleep problems in children through adolescence, whereas prenatal exposure to selective serotonin reuptake inhibitors (SSRIs) may increase the risk of behavior problems at the age of 3 years, although the risk may be moderated by the serotonin transporter promoter gene, SLC6A4.

These are the findings of 2 studies appearing in the May issue of Archives of Pediatrics and Adolescent Medicine.

These 2 studies, note the coauthors of an accompanying editorial, focus on compounds that are "at the eye of the storm of current concerns" regarding potential adverse effects of drug and chemical exposure on the developing fetus.

"In both instances, the new studies offer refined methods to further our understanding of these complex questions," write Gideon Koren, MD, and Irena Nulman, MD, of the Division of Clinical Pharmacology, Hospital for Sick Children, Toronto, Ontario, Canada.

Smoking and Sleep

In the first study, Kristen C. Stone, PhD, of the Brown Center for the Study of Children at Risk, Women and Infants Hospital, Providence, Rhode Island, and colleagues examined ties between sleep problems and prenatal exposure to nicotine, cocaine, opiates, marijuana, and alcohol in 808 children; 422 had prenatal nicotine exposure, whereas 346, 58, 173, and 487, respectively, had prenatal exposure to cocaine, opiates, marijuana, and alcohol.

After multivariate adjustment for relevant factors, including socioeconomic status, marital status, physical abuse, prenatal medical care, and postnatal cigarette smoke exposure, prenatal nicotine exposure was the only significant predictor of sleep problems (P = .01), the researchers found.

"Children whose mothers smoked cigarettes during pregnancy had more problems sleeping at night for the first 12 years of life," Dr. Stone told Medscape Psychiatry.

"It is important to note that most (83.2%) of the mothers in our study who smoked during pregnancy also used at least 1 other substance during pregnancy — either alcohol, cocaine, marijuana, opiates, or a combination of these. But of all these substances, only prenatal nicotine exposure was associated with difficulty sleeping during childhood," said Dr. Stone.

Each additional cigarette smoked per day during pregnancy was associated with a 0.074 increase in the child's index score of sleep problems, indicating more difficulty falling and staying asleep.

Dr. Stone suggests that "early and careful attention to sleep patterns and routines, as well as an emphasis on basic behavioral sleep education, could serve children [with prenatal nicotine exposure] and their families well by targeting and treating — in some cases preventing — problems falling and staying asleep, which will likely lead to better daytime functioning as well."

Dr. Koren and Dr. Nulman offer in their commentary on the study that the term "nicotine is questionable, as the mothers were asked about smoking and environmental tobacco smoke emits 1400 toxins in addition to nicotine."

They also caution against concluding from this study that it is the intrauterine nicotine exposure that caused the sleeping problems because "many psychosocial characteristics of smoking women may account for the measured differences in their children."

SSRI Use and Behavior

Turning to the second study, Tim F. Oberlander, MD, FRCPC, and colleagues at University of British Columbia, Vancouver, note that the effect of prenatal SSRI exposure on child development remains unclear; studies in this regard have been limited by the difficulty in accounting for prenatal and postnatal maternal mental health.

With this in mind, the researchers correlated indexes of child behavior at the age of 3 years with measures of prenatal and postnatal maternal anxiety and depression, SSRI use, and child status of a biologically relevant gene (SLC6A4). They studied 75 mothers and their children; 33 of the children had prenatal SSRI exposure and 42 did not. Parents provided information on their child's behavior, and maternal mood was assessed during the third trimester and at 3 months and 3 years post partum.

The researchers say they found evidence that both prenatal SSRI exposure (P = .05) and higher current maternal anxiety (P = .04) contributed to increased internalizing behaviors (withdrawal, anxiety, and depression) in the children. Increased levels of externalizing behaviors were also observed, and they were associated with both current maternal anxiety (P = .04) and depressive symptoms (P = .01).

This study, Dr. Oberlander's team notes, suggests that "even with prenatal maternal SSRI treatment, mothers continue to be symptomatic, and child behavior at 3 years of age continues to be at risk."

It also appeared that the impact of third trimester maternal anxiety on child mood was moderated by the child SLC6A4 genotype. Children with 2 copies of the short allele (ss genotype), resulting in reduced levels of serotonin transporter protein and potentially reduced serotonin reuptake, whose mothers were anxious in the third trimester, were seen as more anxious or depressed (internalizing) themselves, even after controlling for prenatal SSRI exposure, perinatal risk, and 3-month and 3-year maternal mood.

Children with the ss genotype may receive a higher "effective" prenatal "serotonin dose" during fetal brain development, secondary to reduced serotonin transporter, which may increase their risk of anxiety or depression symptoms during childhood, the researchers suggest.

In contrast, children with 2 copies of the L (long) allele, presumably yielding increased serotonin reuptake, coupled with late gestational maternal mood disturbance, were seen as having more aggression and externalizing behaviors.

In their editorial, Dr. Koren and Dr. Nulman conclude, "Because pregnant women will never be randomized to exposure to antidepressants or recreational drugs, high-quality observational investigations, such as those by Oberlander and colleagues and Stone and colleagues, will be critical in distinguishing associations from causation in the field of maternal-fetal toxicology."

Dr. Stone and colleagues, Dr. Oberlander and colleagues, and Dr. Koren and Dr. Nulman have disclosed no relevant financial relationships.

Arch Pediatr Adolesc Med. 2010;164:444-456, 494-495.


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