Christina D. Chambers

Birth Outcomes in Pregnant Women Taking Fluoxetine

BACKGROUND Although fluoxetine is the most frequently prescribed antidepressant drug in the United States, its safety in pregnant women has not been established. METHODS From 1989 through 1995, we prospectively identified 228 pregnant women taking fluoxetine. We compared the outcomes of their pregnancies with those of 254 women identified in a similar manner who were not taking fluoxetine. RESULTS The rate of spontaneous pregnancy loss did not differ significantly between the women treated with fluoxetine and the control women (10.5 percent and 9.1 percent, respectively), nor was the rate of major structural anomalies significantly different (5.5 percent vs. 4.0 percent). Among the 97 infants exposed to fluoxetine who were evaluated for minor anomalies, the incidence of three or more minor anomalies was significantly higher than among 153 similarly examined control infants (15.5 percent vs. 6.5 percent, P=0.03). As compared with the 101 infants exposed to fluoxetine only during the first and second trimesters, the 73 infants exposed during the third trimester had higher rates of premature delivery (relative risk, 4.8; 95 percent confidence interval, 1.1 to 20.8), admission to special-care nurseries (relative risk, 2.6; 95 percent confidence interval, 1.1 to 6.9), and poor neonatal adaptation, including respiratory difficulty, cyanosis on feeding, and jitteriness (relative risk, 8.7; 95 percent confidence interval, 2.9 to 26.6). Birth weight was also lower and birth length shorter in infants exposed fluoxetine late in gestation. CONCLUSION Women who take fluoxetine during pregnancy do not have an increased risk of spontaneous pregnancy loss or major fetal anomalies, but women who take fluoxetine in the third trimester are at increased risk for perinatal complications.

A meta-analysis of adverse perinatal outcomes in women with asthma

Please cite this paper as: Murphy V, Namazy J, Powell H, Schatz M, Chambers C, Attia J, Gibson P. A meta‐analysis of adverse perinatal outcomes in women with asthma. BJOG 2011;118:1314–1323.

Reproductive and developmental effects of phthalate diesters in females

Abstract Phthalate diesters, widely used in flexible plastics and consumer products, have become prevalent contaminants in the environment. Human exposure is ubiquitous and higher phthalate metabolite concentrations documented in patients using medications with phthalate-containing slow release capsules raises concerns for potential health effects. Furthermore, animal studies suggest that phthalate exposure can modulate circulating hormone concentrations and thus may be able to adversely affect reproductive physiology and the development of estrogen sensitive target tissues. Therefore, we conducted a systematic review of the epidemiological and experimental animal literature examining the relationship between phthalate exposure and adverse female reproductive health outcomes. The epidemiological literature is sparse for most outcomes studied and plagued by small sample size, methodological weaknesses, and thus fails to support a conclusion of an adverse effect of phthalate exposure. Despite a paucity of experimental animal studies for several phthalates, we conclude that there is sufficient evidence to suggest that phthalates are reproductive toxicants. However, we note that the concentrations needed to induce adverse health effects are high compared to the concentrations measured in contemporary human biomonitoring studies. We propose that the current patchwork of studies, potential for additive effects and evidence of adverse effects of phthalate exposure in subsequent generations and at lower concentrations than in the parental generation support the need for further study.

The EULAR points to consider for use of antirheumatic drugs before pregnancy, and during pregnancy and lactation

A European League Against Rheumatism (EULAR) task force was established to define points to consider on use of antirheumatic drugs before pregnancy, and during pregnancy and lactation. Based on a systematic literature review and pregnancy exposure data from several registries, statements on the compatibility of antirheumatic drugs during pregnancy and lactation were developed. The level of agreement among experts in regard to statements and propositions of use in clinical practice was established by Delphi voting. The task force defined 4 overarching principles and 11 points to consider for use of antirheumatic drugs during pregnancy and lactation. Compatibility with pregnancy and lactation was found for antimalarials, sulfasalazine, azathioprine, ciclosporin, tacrolimus, colchicine, intravenous immunoglobulin and glucocorticoids. Methotrexate, mycophenolate mofetil and cyclophosphamide require discontinuation before conception due to proven teratogenicity. Insufficient documentation in regard to fetal safety implies the discontinuation of leflunomide, tofacitinib as well as abatacept, rituximab, belimumab, tocilizumab, ustekinumab and anakinra before a planned pregnancy. Among biologics tumour necrosis factor inhibitors are best studied and appear reasonably safe with first and second trimester use. Restrictions in use apply for the few proven teratogenic drugs and the large proportion of medications for which insufficient safety data for the fetus/child are available. Effective drug treatment of active inflammatory rheumatic disease is possible with reasonable safety for the fetus/child during pregnancy and lactation. The dissemination of the data to health professionals and patients as well as their implementation into clinical practice may help to improve the management of pregnant and lactating patients with rheumatic disease.

Birth outcomes in women who have taken leflunomide during pregnancy

OBJECTIVE In preclinical reproductive studies, leflunomide was found to be embryotoxic and teratogenic. Women treated with leflunomide are advised to avoid pregnancy; those who become pregnant are advised to reduce fetal exposure through a cholestyramine drug elimination procedure. The present study was undertaken to investigate pregnancy outcomes in women who received leflunomide and were treated with cholestyramine during pregnancy. METHODS Sixty-four pregnant women with rheumatoid arthritis (RA) who were treated with leflunomide during pregnancy (95.3% of whom received cholestyramine), 108 pregnant women with RA not treated with leflunomide, and 78 healthy pregnant women were enrolled in a prospective cohort study between 1999 and 2009. Information was collected via interview of the mothers, review of medical records, and specialized physical examination of infants. RESULTS There were no significant differences in the overall rate of major structural defects in the exposed group (3 of 56 live births [5.4%]) relative to either comparison group (each 4.2%)(P = 0.13). The rate was similar to the 3-4% expected in the general population. There was no specific pattern of major or minor anomalies. Infants in both the leflunomide-exposed and non-leflunomide-exposed RA groups were born smaller and earlier relative to infants of healthy mothers; however, after adjustment for confounding factors, there were no significant differences between the leflunomide-exposed and non-leflunomide-exposed RA groups. CONCLUSION Although the sample size is small, these data do not support the notion that there is a substantial increased risk of adverse pregnancy outcomes due to leflunomide exposure among women who undergo cholestyramine elimination procedure early in pregnancy. These findings can provide some reassurance to women who inadvertently become pregnant while taking leflunomide and undergo the washout procedure.

Weight Gain in Infants Breastfed by Mothers Who Take Fluoxetine

Objective. Despite the manufacturers recommendation that fluoxetine not be used by women while breastfeeding, many women choose to do so. There is little information available in the literature to suggest that this practice is or is not safe. The purpose of this study was to examine weight gain in infants who are breastfed by mothers who take fluoxetine, compared with weight gain in infants who are breastfed by mothers who do not take any psychotherapeutic medication. A secondary goal was to assess the frequency of reported side effects in infants who are breastfed by mothers who take fluoxetine. Methodology. A retrospective cohort study design was used. Subjects were identified from an ongoing pregnancy outcome study conducted through the California Teratogen Information Service and Clinical Research Program. A total of 64 women were interviewed who had taken fluoxetine during a pregnancy between the 1989 and 1997; 26 of these women breastfed their infants and continued to take the medication, and 38 breastfed their infants but did not take the medication. Postnatal weight gain was taken from pediatric records, and the frequency of side effects was measured by maternal response to the interview questionnaire. Results. Using linear regression analysis, the infants who were breastfed by mothers taking fluoxetine demonstrated a growth curve significantly below that of infants who were breastfed by mothers who did not take the drug. The average deficit in measurements taken between 2 weeks and 6 months of age was 392 g (95% confidence interval: −5, −780). Using a repeated measures analysis of covariance for those infants with more than one postnatal weight measurement available, the difference between the two groups was similar, ∼1.2 standard deviations (P = .005). In response to interview questions regarding side effects, no mother who breastfed her infant while taking fluoxetine reported any unusual symptoms that could be attributed to the medication. Conclusions. These data do not suggest that women who breastfeed while taking fluoxetine are likely to note unusual behavior in their infants that they consider related to use of the medication. However, although there was no excess of infants in the fluoxetine group with postnatal weight measurements >2 standard deviations below the mean, these data indicate that breastfeeding while taking fluoxetine is associated with reduced growth that may be of clinical importance in situations in which infant weight gain is already of concern.

Maternal fever and birth outcome: a prospective study.

Although maternal fever has been implicated as a human teratogen in several studies, no prospective study has adequately addressed the full spectrum of birth outcomes following such exposure in pregnancy. The purpose of this study was to determine whether or not maternal fever is associated with an increased risk for structural malformations, prematurity, growth retardation, or pregnancy loss. Using a prospective cohort study design, we ascertained women who had called the California Teratogen Information Service and Clinical Research Program between 1979-1996 with questions regarding fever in a current pregnancy. Of these women, 115 who reported a fever of at least 38.9 degrees C lasting for at least 24 h (high fever group) and 147 women who reported a fever of either less than 38.9 degrees C or lasting less than 24 h (low fever group) were enrolled in the cohort. An additional 298 pregnant women who reported having no fever at any time in pregnancy were enrolled in a control group. All pregnancies were followed in a similar fashion, and outcomes were compared among the three groups. The combined prevalence of all major structural malformations was increased, but not significantly so, in the offspring of women who had a high fever in the first trimester of pregnancy compared to those with a lower fever or to controls (relative risk 1.80 for high fever group compared to controls; 95% confidence interval, 0.54, 6.03; relative risk 1.21 for low fever group compared to controls; 95% confidence interval, 0.36, 4.03). However, 2/34 or 5.9% of women who had a high fever during the critical period for neural tube closure carried fetuses with anencephaly compared to none in the low fever group or controls. Specific minor defects were found more frequently in the high fever group compared to controls and were consistent with the pattern of defects previously reported in a retrospective case series. In addition, stillbirth occurred more frequently in the high fever group compared to controls (2.6% vs. 0%). These data support the conclusion that high maternal fever early in pregnancy is a human teratogen. Women who experience fevers of 38.9 degrees C or higher for extended periods of time in the first month of pregnancy should be considered at increased risk for neural tube defects and should be provided appropriate counseling.

Torticollis, facial asymmetry and plagiocephaly in normal newborns

Objective: To evaluate the incidence and characteristics of torticollis, plagiocephaly and facial asymmetry in normal newborn infants. Design: 102 healthy newborn infants were examined prospectively during their birth hospitalisation for torticollis with neck range of motion (ROM) assessment and for facial, mandibular and cranial asymmetry by photographic analysis. Results: 73% of newborns had one or more asymmetry: torticollis (16%), asymmetry of the mandible (13%), facial asymmetry (42%) and asymmetry of the head (61%). Torticollis was associated with maternal report of the fetus being “stuck” in one intrauterine position for more than 6 weeks before delivery. Moderate facial asymmetry was associated with a longer second stage of labour, forceps delivery, a bigger baby and birth trauma. Moderate cranial and mandibular asymmetries were associated with birth trauma. More than one significant asymmetry was found in 10% of newborns. Conclusions: Asymmetries of the head and neck are very common in normal newborns, and sixteen (16%) of 102 study newborns were found to have torticollis. Such newborns, especially if they sleep supine, are thought to be at risk of developing deformational posterior plagiocephaly. Identification of affected infants may allow early implementation of positioning recommendations or physical therapy to prevent the secondary craniofacial deformations that are part of an increasingly common phenomenon.

Pregnancy and reproduction in autoimmune rheumatic diseases

Despite evidence for the important role of oestrogens in the aetiology and pathophysiology of chronic immune/inflammatory diseases, the previous view of an unequivocal beneficial effect of oestrogens on RA compared with a detrimental effect on SLE has to be reconsidered. Likewise, the long-held belief that RA remits in the majority of pregnant patients has been challenged, and shows that only half of the patients experience significant improvement when objective disease activity measurements are applied. Pregnancies in patients with SLE are mostly successful when well planned and monitored interdisciplinarily, whereas a small proportion of women with APS still have adverse pregnancy outcomes in spite of the standard treatment. New prospective studies indicate better outcomes for pregnancies in women with rare diseases such as SSc and vasculitis. Fertility problems are not uncommon in patients with rheumatic disease and need to be considered in both genders. Necessary therapy, shortly before or during the pregnancy, demands taking into account the health of both mother and fetus. Long-term effects of drugs on offspring exposed in utero or during lactation is a new area under study as well as late effects of maternal rheumatic disease on children.

Updated clinical guidelines for diagnosing fetal alcohol spectrum disorders

The adverse effects of prenatal alcohol exposure constitute a continuum of disabilities (fetal alcohol spectrum disorders [FASD]). In 1996, the Institute of Medicine established diagnostic categories delineating the spectrum but not specifying clinical criteria by which diagnoses could be assigned. In 2005, the authors published practical guidelines operationalizing the Institute of Medicine categories, allowing for standardization of FASD diagnoses in clinical settings. The purpose of the current report is to present updated diagnostic guidelines based on a thorough review of the literature and the authors’ combined expertise based on the evaluation of >10 000 children for potential FASD in clinical settings and in epidemiologic studies in conjunction with National Institute on Alcohol Abuse and Alcoholism–funded studies, the Collaborative Initiative on Fetal Alcohol Spectrum Disorders, and the Collaboration on FASD Prevalence. The guidelines were formulated through conference calls and meetings held at National Institute on Alcohol Abuse and Alcoholism offices in Rockville, MD. Specific areas addressed include the following: precise definition of documented prenatal alcohol exposure; neurobehavioral criteria for diagnosis of fetal alcohol syndrome, partial fetal alcohol syndrome, and alcohol-related neurodevelopmental disorder; revised diagnostic criteria for alcohol-related birth defects; an updated comprehensive research dysmorphology scoring system; and a new lip/philtrum guide for the white population, incorporating a 45-degree view. The guidelines reflect consensus among a large and experienced cadre of FASD investigators in the fields of dysmorphology, epidemiology, neurology, psychology, developmental/behavioral pediatrics, and educational diagnostics. Their improved clarity and specificity will guide clinicians in accurate diagnosis of infants and children prenatally exposed to alcohol.