Treating Depression during Pregnancy: Are We Asking the Right Questions?

BACKGROUND: Major depressive disorder (MDD) is a common complication of pregnancy. Once the diagnosis of MDD is made, the physician must assist the pregnant woman in developing a treatment plan. METHODS: In considering antidepressants, the benefit of medication treatment for maternal disease control must be balanced against the risk of the drug to the developing embryo-fetus. This is an individualized decision depending on the disease characteristics, likelihood of maternal depression response, probability of adverse fetal effects, and patient characteristics and values. RESULTS: There is no "zero risk" solution in caring for the pregnant woman with MDD; both the disorder and the medication present risks to the mother and the embryo-fetus. If the decision to use antidepressant medication during pregnancy is made, the justification is that the disease is associated with greater risk than the treatment. The goal should be remission of symptoms to maximally reduce disease risk to the mother and developing fetus. CONCLUSION: Optimization of selective serotonin reuptake inhibitor dosing during pregnancy dictates several treatment goals: (1) the drug must be at the optimal dose for the woman; that is, the dose that produces the best response with tolerable side effects; (2) a continuous measure of symptoms must be repeated and adjustments to maintain optimal antidepressant efficacy may be required, due to pharmacokinetic changes during pregnancy; and (3) the resolution of pregnancy at birth also requires dose adjustment in accord with the woman's transition to the nonpregnant, breastfeeding state. Birth Defects Research 109:879-887, 2017.© 2017 Wiley Periodicals, Inc.

Criminal Charges for Child Harm from Substance Use in Pregnancy.

Despite the opposition of medical and public health professionals, several state legislatures are considering laws that permit child abuse charges for substance use during pregnancy. We reviewed legal decisions regarding women charged with a crime against a fetus or child as a result of substance use during pregnancy. We identified 24 judicial opinions published between 1977 and 2015 in cases involving 29 women prosecuted in 19 states. Charges included child endangerment, child abuse, drug delivery, attempted aggravated child abuse, chemical endangerment of a child, child neglect, child mistreatment, homicide, manslaughter, and reckless injury to a child. The substances related to the charges included cocaine, heroin, methamphetamine, marijuana, and prescription pills. Proceedings resulted in dismissal of the charges or convictions overturned for 86.2 percent of the women. In all of the cases, the judicial decision depended on the disposition of the question of whether, for the purpose of adjudicating the criminal charges, a fetus is a child. The balance in the courts in favor of treating substance use during pregnancy as a medical problem depends on the definition of a child for the purposes of criminal statutes. Professional advocacy may best be directed at state legislatures.

A Moral or Medical Problem? The Relationship between Legal Penalties and Treatment Practices for Opioid Use Disorders in Pregnant Women.

OBJECTIVE: The relationship between use of medication-assisted treatment (MAT) in pregnant women with opioid use disorders, the standard of care, and state laws that permit child abuse charges for illicit drug use during pregnancy has not been described. METHODS: Using publicly available data on substance abuse treatment in the United States, we describe patterns in the use of MAT for pregnant women with opioid use disorders in states with prenatal child abuse laws compared with states without such laws. A binary logistic regression analysis was conducted to predict the presence or absence of MAT in the treatment plan of pregnant women using the following independent variables: state prenatal child abuse law, referral source, geographical region, and Medicaid coverage of methadone. RESULTS: In 2012, there were 8,292 treatment episodes of pregnant women with a primary opioid use disorder in the United States for which data on MAT use were available. Among states with laws that permit child abuse charges for illicit drug use in pregnancy (18 states), MAT was used in 33.15% of treatment admissions compared with 51.33% of admissions in states without a law. The following levels of the independent variables have a greater effect on the lack of use of MAT in descending order of importance: criminal justice referral, other community referral, Southern region, Medicaid coverage, drug abuse care provider referral, unknown referral, other health care provider referral, and presence of state law that permits child abuse charges. CONCLUSION: Referral source, geographic region, Medicaid funding, and prenatal child abuse laws were associated with significantly lower rates of use of MAT.

Defining and refining self-harm: a historical perspective on nonsuicidal self-injury.

Nonsuicidal self-injury (NSSI) is a newly proposed diagnostic category in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Some contemporary historiography dismisses NSSI as a fiction of modern psychiatry. Although the exact definition and psychological meaning attributed to self-harm has not been static over history, there is a clear thread that connects Western asylum psychiatrists' thinking about self-harm to the current stand-alone diagnostic category of NSSI. Nineteenth-century psychiatrists identified a clinically meaningful difference between self-harm with and without the intent to die, between self-injurers who were psychotic and those who were not, and between self-injurers who made a single, serious mutilation and those who repetitively self-injured without causing permanent bodily damage. These same distinctions are apparent in the definition of NSSI. Thus, NSSI is a formalization of long-held observations about a category of people who repetitively self-injure without suicidal intent.

Evaluation of serious adverse drug reactions: a proactive pharmacovigilance program (RADAR) vs safety activities conducted by the Food and Drug Administration and pharmaceutical manufacturers.

BACKGROUND: The Food and Drug Administration (FDA) and pharmaceutical manufacturers conduct most postmarketing pharmaceutical safety investigations. These efforts are frequently based on data mining of databases. In 1998, investigators initiated the Research on Adverse Drug events And Reports (RADAR) project to investigate reports of serious adverse drug reactions (ADRs) and prospectively obtain information on these cases. We compare safety efforts for evaluating serious ADRs conducted by the FDA and pharmaceutical manufacturers vs the RADAR project. METHODS: We evaluated the completeness of serious ADR descriptions in the FDA and RADAR databases and the comprehensiveness of notifications disseminated by pharmaceutical manufacturers and the RADAR investigators. A serious ADR was defined as an event that led to death or required intensive therapies to reverse. RESULTS: The RADAR investigators evaluated 16 serious ADRs. Compared with descriptions of these ADRs in FDA databases (2296 reports), reports in RADAR databases (472 reports) had a 2-fold higher rate of including information on history and physical examination (92% vs 45%; P<.001) and a 9-fold higher rate of including basic science findings (34% vs 4%; P = .08). Safety notifications were disseminated earlier by pharmaceutical suppliers (2 vs 4 years after approval, respectively), although notifications were less likely to include information on incidence (46% vs 93%; P = .02), outcomes (8% vs 100%; P<.001), treatment or prophylaxis (25% vs 93%; P<.001), or references (8% vs 80%; P<.001). CONCLUSION: Proactive safety efforts conducted by the RADAR investigators are more comprehensive than those conducted by the FDA and pharmaceutical manufacturers, but dissemination of related safety notifications is less timely.

Adverse effects of drugs used to treat hematologic malignancies: surveillance efforts from the research on adverse drug events and reports project.

Pharmaceuticals used to treat hematologic malignancies can lead to unexpected adverse events that involve a wide range of organ systems and physiological processes. The National Cancer Institute and National Heart Lung and Blood Institute-funded Research on Adverse Drug Events and Reports (RADAR) project-a collaboration of the Robert H. Lurie Comprehensive Cancer Center, the Department of Veterans Affairs, the Northwestern University Feinberg School of Medicine, and numerous academic institutions-identifies and evaluates unexpected adverse drug reactions associated with drugs used to treat malignant disorders. This article reviews the features of the safety program maintained by the U.S. Food and Drug Administration and the RADAR program.

Gemtuzumab ozogamicin-associated sinusoidal obstructive syndrome (SOS): an overview from the research on adverse drug events and reports (RADAR) project.

Gemtuzumab ozogamicin (GO) was approved for marketing in 2000 by the United States Food and Drug Administration (FDA) for older patients with relapsed acute myeloid leukemia (AML). Four months later, 14 phase II clinical trial participants who received novel GO-containing combination chemotherapy regimens developed an unexpected hepatic toxicity termed sinusoidal obstructive syndrome (SOS) or hepatic veno-occlusive disease (VOD). Investigators associated with the Research on Adverse Drug Events and Reports (RADAR) project reviewed safety reports for GO included in reports of clinical trials and observational studies, interim reports from an FDA mandated Prospective Observational Registry, and the Food and Drug Administration's Adverse Event Reporting System. Medline searches provided incidence estimates of GO-associated SOS and comparative rates of SOS without GO. SOS is characterized by hyperbilirubinemia, painful hepatomegaly, ascites, and sudden weight gain developing at a median of 10 days following GO administration for patients who did not undergo an allogeneic SCT procedure and 13 days following an allogeneic SCT for patients who had previously received GO. Among adult AML patients who received GO in clinical trials, SOS incidence was 3% at doses < or =6 mg/m(2) if administered as monotherapy or in combination with non-hepatotoxic agents versus 28% if administered with thioguanine and 15% when administered as monotherapy at a dose of 9 mg/m(2). Observational studies identified SOS rates between 15% and 40% if an SCT is performed within 3 months of GO administration. The FDA mandated Prospective Observational Registry of patients who receive care at 60 medical centers has identified GO-associated SOS rates of 14% if an SCT is performed and 9% otherwise. Caution is advised when administering GO in routine clinical practice, particularly if administered with other hepatotoxic agents, at doses and schedules more intensive than those approved by the FDA, or within 3 months of a SCT procedure.

Haematological malignancies developing in previously healthy individuals who received haematopoietic growth factors: report from the Research on Adverse Drug Events and Reports (RADAR) project.

Pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) and granulocyte colony-stimulating factor (G-CSF) promote haematopoietic progenitor cell maturation. We reviewed the findings for healthy volunteers/donors who developed haematological malignancies following PEG-rHuMGDF or G-CSF administration. Information was reviewed for three of 538 volunteers who received PEG-rHuMGDF in clinical trials and two of 200 donors who underwent G-CSF mobilised stem cell harvesting procedures for sibling stem cell transplants. Mantle cell, diffuse large B-cell lymphoma and chronic lymphocytic leukaemia were diagnosed 1-5 years after PEG-rHuMGDF exposure among three volunteers. For one patient, thrombocytopenia due to autoantibodies to PEG-rHuMGDF developed shortly after PEG-rHuMGDF administration and persisted until chemotherapy was administered. All three achieved complete remission, although one patient relapsed. Acute myeloid leukaemia was diagnosed 4 and 5 years after G-CSF mobilisation in two donors who underwent peripheral blood stem cell donation for sibling allogeneic haematopoietic stem cell transplantation. Following intensive chemotherapy, one died from acute leukaemia and the second is in complete remission. Controversy exists over the appropriateness of administering haematopoietic growth factors to healthy individuals. While a causal relationship with haematological malignancies cannot be demonstrated, long-term follow-up among healthy individuals who receive haematopoietic growth factors is needed.