Impact of antidepressant use, discontinuation, and dosage modification on maternal depression during pregnancy.

Women tend to discontinue their antidepressants during pregnancy. This study compared the risk of depressive symptoms in the second-half of pregnancy in women who discontinue or continue with or without dosage modification their antidepressant during gestation. Women were eligible if they called MothertoBaby during 2006-2010 and within 14 completed weeks of pregnancy. A total of 367 pregnant women were included. The Edinburgh Postnatal Depression Scale (EPDS) was used to measure depression during the first and second half of pregnancy. Presence of depressive symptoms was defined as EPDS ≥13. Among participants, 149 did not use antidepressants, 38 used antidepressants at the beginning of pregnancy but discontinued before the end of second-trimester, and 180 used antidepressants continuously throughout pregnancy. Among continued users, 46 modified antidepressant dosage before the end of the second trimester, and 134 did not modify dosage. The majority of antidepressant users (150/218, 68.8%) had mild to moderate depression. Thirteen percent (13%) of women who continued antidepressant use throughout pregnancy without dosage modification remained depressed. Adjusting for potential confounders including maternal depression/anxiety before pregnancy, and compared to non-users, discontinued users were 5.95 times (95%CI: 1.54-23.02), and continued users without dosage modification 4.59 times (95%CI: 1.44-14.64) more at risk of depression in the second-half of pregnancy. Those with dosage modifications were at a similar risk of depression during pregnancy than non-users (adjusted odds ratio 0.58, 95%CI: 0.06-5.52). In conclusion, in a cohort of mild to moderate depressive pregnant women, discontinuing or continuing antidepressant use without dosage modification during pregnancy were associated with an increased risk of depression during the remaining gestational period.

Association between CYP2D6 Genotypes and the Risk of Antidepressant Discontinuation, Dosage Modification and the Occurrence of Maternal Depression during Pregnancy.

Importance: Polymorphic expression of drug metabolizing enzymes affects the metabolism of antidepressants, and thus can contribute to drug response and/or adverse events. Pregnancy itself can affect CYP2D6 activity with profound variations determined by CYP2D6 genotype. Objective: To investigate the association between CYP2D6 genotype and the risk of antidepressant discontinuation, dosage modification, and the occurrence of maternal CYP2D6, Antidepressants, Depression during pregnancy. Setting: Data from the Organization of Teratology Information Specialists (OTIS) Antidepressants in Pregnancy Cohort, 2006-2010, were used. Women were eligible if they were within 14 completed weeks of pregnancy at recruitment and exposed to an antidepressant or having any exposures considered non-teratogenic. Main Outcomes and Measures: Gestational antidepressant usage was self-reported and defined as continuous/discontinued use, and non-use; dosage modification was further documented. Maternal depression and anxiety were measured every trimester using the telephone interviewer-administered Edinburgh Postnatal Depression Scale and the Beck Anxiety Inventory, respectively. Saliva samples were collected and used for CYP2D6 genotype analyses. Logistic regression models were used to calculate crude and adjusted odds ratios (OR) with 95% confidence intervals. Results: A total of 246 pregnant women were included in the study. The majority were normal metabolizers (NM, n = 204, 83%); 3.3% (n = 8) were ultrarapid metabolizers (UM), 5.7% (n = 14) poor metabolizers (PM), and 8.1% (n = 20) intermediate metabolizers (IM). Among study subjects, 139 women were treated with antidepressants at the beginning of pregnancy, and 21 antidepressant users (15%) discontinued therapy during pregnancy. Adjusting for depressive symptoms, and other potential confounders, the risk of discontinuing antidepressants during pregnancy was nearly four times higher in slow metabolizers (poor or intermediate metabolizers) compared to those with a faster metabolism rate (normal or ultrarapid metabolizers), aOR = 3.57 (95% CI: 1.15-11.11). Predicted CYP2D6 metabolizer status did not impact dosage modifications. Compared with slow metabolizers, significantly higher proportion of women in the fast metabolizer group had depressive symptom in the first trimester (19.81 vs. 5.88%, P = 0.049). Almost 21% of treated women remained depressed during pregnancy (14.4% NM-UM; 6.1% PM-IM). Conclusions and Relevance: Prior knowledge of CYP2D6 genotype may help to identify pregnant women at greater risk of antidepressant discontinuation. Twenty percent of women exposed to antidepressants during pregnancy remained depressed, indicating an urgent need for personalized treatment of depression during pregnancy.

Methylphenidate in Pregnancy: A Multicenter, Prospective, Comparative, Observational Study.

INTRODUCTION: Methylphenidate is a central nervous system stimulant medicinally used in the treatment of attention-deficit disorder with or without hyperactivity (ADD/ADHD). Data on its use in human pregnancy are limited. The primary objective of the study was to evaluate the risk of major congenital anomalies after pregnancy exposure to methylphenidate for medical indications. METHODS: In a prospective, comparative, multicenter observational study performed in 4 participating Teratology Information Services (in Jerusalem, Berlin, Newcastle upon Tyne, and Toronto) between 1996 and 2013, methylphenidate-exposed pregnancies were compared with pregnancies counseled for nonteratogenic exposure (NTE) after matching by maternal age, gestational age, and year at initial contact. RESULTS: 382 methylphenidate-exposed pregnancies (89.5% in the first trimester) were followed up. The overall rate of major congenital anomalies was similar between the groups (10/309 = 3.2% [methylphenidate] vs 13/358 = 3.6% [NTE], P = .780). The rates of major congenital anomalies (6/247 = 2.4% [methylphenidate] vs 12/358 = 3.4% [NTE], P = .511) and cardiovascular anomalies (2/247 = 0.8% [methylphenidate] vs 3/358 = 0.8% [NTE], P = .970) were also similar after exclusion of genetic or cytogenetic anomalies and limiting methylphenidate exposure to the period of organogenesis (weeks 4-13 after the last menstrual period). There was a higher rate of miscarriages and elective terminations of pregnancy in the methylphenidate group. Significant predictors for the miscarriages using Cox proportional hazards model were methylphenidate exposure (adjusted hazard ratio [HR] = 1.98; 95% CI, 1.23-3.20; P = .005) and past miscarriage (adjusted HR = 1.35; 95% CI, 1.18-1.55; P < .001). CONCLUSIONS: The present study suggests that methylphenidate does not seem to increase the risk for major malformations. Further studies are required to establish its pregnancy safety and its possible association with miscarriages.

Is it safe to breastfeed while taking methylphenidate?

QUESTION: My patient has narcolepsy and is currently breastfeeding her 3-month-old infant. Lately she has had difficulties adjusting to caring for her baby, especially staying alert with the demands of breastfeeding. If she starts taking methylphenidate again, should I advise her to switch to formula? ANSWER: Methylphenidate is excreted in breast milk only in small amounts, and to date there have been no reports of breastfed infants demonstrating any adverse effects. Based on the available data, methylphenidate appears to be compatible with breastfeeding; however, the long-term neurodevelopmental effects have not been adequately studied.

Fluconazole exposure during pregnancy.

QUESTION: One of my patients has just learned that she is 8 weeks pregnant. She took a 150-mg dose of fluconazole 2 weeks ago for the treatment of vaginal candidiasis and she is worried about the effect on her child and pregnancy. Can I reassure her? ANSWER: Short-term and low-dose fluconazole exposure, such as that indicated in the treatment of vaginal candidiasis, is not expected to increase the overall risk of major congenital malformations.

Fluconazole use during breastfeeding.

QUESTION: I have a patient with persistent breast and nipple thrush. Other therapies have failed, so I have decided to treat her with a loading dose of 400 mg of oral fluconazole followed by 100 mg twice daily for at least 2 weeks. Is there any need for her to interrupt breastfeeding during this treatment? ANSWER: Available data regarding fluconazole use during breastfeeding are reassuring. Fluconazole is also used in the treatment of fungal diseases in infants and has a good safety profile. Therefore, there is no need to interrupt breastfeeding when a mother is treated with fluconazole.

Sugar substitutes during pregnancy.

QUESTION: I have a pregnant patient who regularly consumes sugar substitutes and she asked me if continuing their use would affect her pregnancy or child. What should I tell her, and are there certain options that are better for use during pregnancy? ANSWER: Although more research is required to fully determine the effects of in utero exposure to sugar substitutes, the available data do not suggest adverse effects in pregnancy. However, it is recommended that sugar substitutes be consumed in moderate amounts, adhering to the acceptable daily intake standards set by regulatory agencies.

Safety of tacrolimus in pregnancy.

QUESTION: I have a 30-year-old patient who had a kidney transplant 2 years ago. She is now planning a pregnancy. She has been treated with tacrolimus since her transplant. Will it be safe for the fetus if she continues to take it during the pregnancy or should she switch to a different antirejection medication? ANSWER: If your patient is stable while taking tacrolimus, there is no reason to switch. The current available information does not suggest that tacrolimus increases the risk of major congenital malformations above the baseline risk in the general population. Premature birth and low birth weight are often reported in this population; however, these effects are frequently reported in pregnant transplant patients treated with other immunosuppressant agents and probably reflect the effects of the maternal condition. As there are some reports of hyperkalemia and renal impairment in infants exposed to tacrolimus in utero, kidney function and electrolytes should be monitored in exposed neonates.

Is it safe to use inhaled corticosteroids in pregnancy?

QUESTION: A healthy woman with mild to moderate asthma came to my clinic today after learning that she was pregnant. She inquired about continuing her inhaled corticosteroid (ICS) medication and whether there would be any risks to her unborn child if she were to do so. What would you advise? ANSWER: Given the published evidence, ICSs should be continued throughout pregnancy at low to moderate doses sufficient to control asthma symptoms and prevent exacerbations. However, caution must be taken with doses greater than 1000 µg/d (chlorofluorocarbon beclomethasone equivalent), although whether such doses cause adverse effects is currently still questionable. Patient education on proper ICS administration and adherence, including during the first trimester, must be ongoing. Well controlled asthma will reduce the need for higher ICS doses and possible exposure to systemic corticosteroids, and might decrease the risk of adverse pregnancy or perinatal outcomes.

Cocaine abuse during pregnancy.

Cocaine abuse during pregnancy is a significant public health problem but is infrequently discussed between physicians and patients. The impact of in utero cocaine exposure on pregnancy and the baby has received significant media attention in preceding decades because of fears of teratogenicity, long-term health consequences, and poor cognitive and neurodevelopmental outcomes. We sought to review the medical literature examining these phenomena. We identified risks to the pregnancy and baby in women abusing cocaine during pregnancy. These include preterm birth, placenta-associated syndromes (e.g., placental abruption, preeclampsia, and placental infarction), and impaired fetal growth. Long-term neurodevelopmental and cognitive deficits include (but are not limited to) poorer language development, learning and perceptual reasoning, behavioural problems, and adverse effects on memory and executive function. However, these results should be interpreted cautiously because cocaine abuse may be accompanied by many other maternal and sociodemographic risk factors, so it is difficult to ascertain the effect of cocaine alone. Therefore, it is critical to counsel patients about potential risk, and perhaps more importantly, to treat addiction and to better understand, and advocate for improvements to, these patients' high-risk environment.

Bien que la consommation de cocaïne pendant la grossesse constitue un problème de santé publique considérable, elle ne fait que peu fréquemment l'objet de discussions entre les médecins et leurs patientes. Les effets de l'exposition in utero à la cocaïne sur la grossesse et l'enfant se sont mérités une attention médiatique considérable au cours des dernières décennies, en raison de préoccupations au sujet de la tératogénicité de la cocaïne, de ses conséquences à long terme sur la santé et de son influence sur l'obtention de piètres issues cognitives et neurodéveloppementales. Nous avons cherché à analyser la littérature médicale examinant ces phénomènes. Nous avons identifié des risques pour la grossesse et l'enfant attribuables à la consommation de cocaïne pendant la grossesse. Parmi ces risques, on trouve l'accouchement préterme, des syndromes associés au placenta (p. ex. décollement placentaire, prééclampsie et infarctus placentaire) et l'altération de la croissance fœtale. Parmi les déficits cognitifs et neurodéveloppementaux à long terme, on trouve (entre autres) des difficultés quant au développement langagier, à l'apprentissage et au raisonnement perceptif, des problèmes comportementaux et des effets indésirables sur la mémoire et la fonction exécutive. Toutefois, ces résultats devraient être interprétés avec prudence, puisque la consommation de cocaïne pourrait s'accompagner de nombreux autres facteurs de risque maternels et sociodémographiques; il est donc difficile de déterminer l'effet qui est seulement attribuable à la cocaïne. Ainsi, il est d'une importance cruciale de conseiller les patientes au sujet des risques potentiels d'une telle pratique et, ce qui est peut-être encore plus important, d'assurer la prise en charge de l'assuétude et de mieux comprendre les conditions de vie à risque élevé de ces patientes (et de promouvoir la mise en œuvre de mesures permettant de les améliorer).

Consuming non-alcoholic beer and other beverages during pregnancy and breastfeeding.

QUESTION: An increasing number of my patients are asking about the safety of consuming non-alcoholic beer and other alcohol-free versions of alcoholic beverages during pregnancy and breastfeeding, as they believe that these drinks might be a "safer" alternative to regular alcoholic beverages. What are Motherisk's recommendations regarding these products? ANSWER: Such drinks might contain higher ethanol levels than what is indicated on their labels. As there is no known safe level of alcohol intake in pregnancy, abstinence from non-alcoholic beverages would eliminate any risk of fetal alcohol spectrum disorder. Although it is likely that moderate intake of non-alcoholic beverages would pose no harm to breastfed infants, briefly delaying breastfeeding after consumption of such drinks would ensure that the infant is not exposed to alcohol.

Cost effectiveness of teratology counseling - the Motherisk experience.

BACKGROUND: While the benefits of evidence-based counseling to large numbers of women and physicians are intuitively evident, there is an urgent need to document that teratology counseling, in addition to improving the quality of life of women and families, also leads to cost saving. The objective of the present study was to calculate the cost effectiveness of the Motherisk Program, a large teratology information and counseling service at The Hospital for Sick Children and the University of Toronto. METHODS: We analyzed data from the Motherisk Program on its 2012 activities in two domains: 1) Calculation of cost-saving in preventing unjustified pregnancy terminations; and 2) prevention of major birth defects. Cost of pregnancy termination and lifelong cost of specific birth defects were identified from primary literature and prorated for cost of living for the year 2013. RESULTS: Prevention of 255 pregnancy terminations per year led to cost savings of $516,630. The total estimated number of major malformations prevented by Motherisk counseling in 2012 was 8.41 cases at a total estimated cost of $9,032,492. CONCLUSIONS: With an estimated minimum annual prevention of 8 major malformations, and numerous unnecessary terminations of otherwise- wanted pregnancies, a cost saving of $10 million can be calculated. In 2013 the operating budget of Motherisk counseling totaled $640,000. Even based on the narrow range of activities for which we calculated cost, this service is highly cost- effective. Because most teratology counseling services are operating in a very similar method to Motherisk, it is fair to assume that these results, although dependent on the size of the service, are generalizable to other countries.

Safety of the newer class of opioid antagonists in pregnancy.

QUESTION: I have a patient recently confirmed to be 6 weeks pregnant. For the past 6 months she has been treated for an opioid addiction with buprenorphine-naloxone combination. Should I be concerned about her exposure to this drug combination up to this point of the pregnancy? Should I switch her medication to methadone now that she is pregnant? ANSWER: The limited data on buprenorphine exposure during pregnancy show no increased risk of adverse outcomes in the newborn. There are limited data on naloxone exposure during pregnancy; however, oral use is not expected to be associated with an increased risk of adverse pregnancy outcomes. Physicians treating pregnant women or women who become pregnant while they are stable taking buprenorphine-naloxone treatment are advised to continue this treatment but to consider transition to buprenorphine monotherapy.

Using nitrofurantoin while breastfeeding a newborn.

QUESTION: My patient has a urinary tract infection and is currently breastfeeding. Her son is only 3 weeks old. Is nitrofurantoin a safe antibiotic for treatment? ANSWER: The use of nitrofurantoin in breastfeeding mothers is generally safe, as only small amounts transfer into the breast milk. Despite the lack of documented reports, there is a risk of hemolytic anemia in all newborns exposed to nitrofurantoin owing to their glutathione instability, especially in infants with glucose-6-phosphate dehydrogenase deficiency. Although some suggest that nitrofurantoin be avoided in infants younger than 1 month, studies have noted that glutathione stability might be established by the eighth day of life. In infants younger than 1 month, an alternative antibiotic might be preferred; however, if an alternative were not available, the use of nitrofurantoin would not be a reason to avoid breastfeeding. In any such case the suckling infant should be monitored by his or her physician.

Botulinum toxin type A in pregnancy.

QUESTION: My patient received 62 units of botulinum toxin type A (BTX-A) for facial lines. Two weeks later, she found out that she was pregnant. Will this cause any harm to her fetus? ANSWER: Botulinum toxin is not expected to be present in systemic circulation following proper intramuscular or intradermal injection. Moreover, BTX-A, which has a high molecular weight, does not appear to cross the placenta. From the 38 pregnancies reported in the literature, including women who had botulism poisoning during pregnancy, exposure to BTX-A does not appear to increase the risk of adverse outcome in the fetus.

Update on antidepressant use during breastfeeding.

QUESTION: Many of my patients who are diagnosed with postpartum depression want to continue breastfeeding. How safe are the newer antidepressant medications during breastfeeding? ANSWER: The newer antidepressants transfer into breast milk in low amounts and have not been associated with serious adverse events. Therefore, the antidepressant most effective for the woman should be considered.

Tdap vaccination during pregnancy to reduce pertussis infection in young infants.

QUESTION: What is the basis for the new recommendations to vaccinate pregnant women against pertussis after the first trimester? ANSWER: There have been outbreaks of epidemic proportions of pertussis, mostly among young infants who have not received sufficient passive immunity from their mothers. This strategy of vaccination during pregnancy aims at stopping these life-threatening epidemics.

Is caffeine consumption safe during pregnancy?

QUESTION: I have a pregnant patient who experienced a miscarriage in the past and who has asked me whether her consumption of 2 cups of coffee per day could have caused it. What should I tell her? ANSWER: There are conflicting data on the fetal safety of dietary caffeine consumption during pregnancy, particularly at levels of 300 mg/d or greater. Although it is difficult to assess the risk of spontaneous abortion with caffeine consumption, most of the data do not suggest an increased risk of adverse pregnancy, fertility, or neurodevelopmental outcomes with caffeine consumption of 300 mg/d or less from all sources. Therefore, consumption of 1 to 2 cups of coffee a day is not expected to be a concern.

Maternal cocaine use during breastfeeding.

QUESTION: In my practice several patients have struggled with cocaine abuse during their pregnancies. One woman, now postpartum, wants to breastfeed her infant. Despite being abstinent for the final few months of her pregnancy, I am concerned about the potential adverse effects on her child if she happens to relapse. What is the current evidence about the risks of cocaine exposure during breastfeeding? ANSWER: Given the substantial benefits of breastfeeding for infant health and development, there is no reason for mothers who previously abused cocaine to avoid breastfeeding. It is important for the health care team to counsel patients both on the serious potential risks of cocaine exposure for babies and on the benefits of breastfeeding, to allow for an informed choice. Additionally, attempts should be made to estimate maternal commitment to breastfeeding and discontinuation of cocaine use, and to offer addiction counseling to mitigate the potential risks of infant cocaine exposure. It is paramount to minimize the risk to the infant, which would certainly include mothers ceasing use of cocaine while breastfeeding. For mothers who elect to breastfeed and use cocaine intermittently, breastfeeding should be delayed sufficiently after cocaine use to allow for drug elimination (approximately 24 hours).

Health Canada advisory on domperidone should I avoid prescribing domperidone to women to increase milk production [corrected]?

QUESTION: I often prescribe domperidone to women as a galactagogue starting at a dose of 30 mg and increasing the dose as needed. In March of this year, Health Canada released an advisory warning of domperidone use and abnormal heart rhythms and sudden cardiac death. Should I cap doses at 30 mg or stop prescribing domperidone all together to these women? ANSWER: The Health Canada warning is based on 2 studies. The results of the studies are not directly applicable to breastfeeding and should not change the way you normally manage otherwise healthy breastfeeding women.