1 PAPER J Forensic Sci, November 2013, Vol. 58, No. 6 doi: / Available online at: onlinelibrary.wiley.com PATHOLOGY/BIOLOGY; TOXICOLOGY Nancy Hardt, 1 M.D.; Tit D. Wong, 2 M.P.H.; Martha J. Burt, 3 M.D.; Ross Harrison, 4 B.S.; Will Winter, 5 M.P.H.; and Jeffrey Roth, 6 Ph.D. Prevalence of Prescription and Illicit Drugs in Pregnancy-Associated Non-natural Deaths of Florida Mothers, * ABSTRACT: Abuse of prescription and illicit drugs has been rapidly increasing. This study examines the prevalence of drug use in the nonnatural deaths of pregnant or recently pregnant women. Records from Florida s Pregnancy Associated Mortality Review conducted between 1999 and 2005 (n = 415) were linked to 385 toxicology reports obtained from Florida medical examiners offices. The final study sample consisted of 169 drug-positive, pregnancy-associated non-natural deaths. Of these, 86 were positive for both blood and urine, 64 were positive for blood only and five for urine only, and the remainder were positive for some other specimen. Among these deaths, 91 cases (54%) involved prescription drugs, 78 cases (46%) involved illicit drugs, and 69 cases (41%) involved alcohol. Opioids constituted the majority of deaths associated with prescription drugs. Substantial co-use of opioids and benzodiazepines was seen. Pregnant or recently pregnant women may have more interactions with healthcare providers, which may present more opportunities for intervention and prevention. KEYWORDS: forensic science, pregnant women, substance abuse, opioid, prescription drugs/poisoning, overdose/mortality With the exception of alcohol and marijuana, prescription drugs are now the most commonly abused psychotropic agents in the United States (1). Opioid painkillers have been identified as a major driver of the observed increase in prescription drugrelated mortality (2 9). In one study, opioids were encountered in 93.2% of pharmaceutical drug overdose fatalities (4). In at least one state, the majority of drug overdose-related deaths were attributable to the abuse of prescription opioids (10). Unlike the illicit drug epidemics of the 1970s that were seen as concentrated in urban centers, the rate of increase in drug poisoning mortality in rural areas is three times greater than what has been observed in metropolitan areas (5). Prescription drug abuse also has significant associated morbidity that has also seen a sharp increase recently (11). Between 2004 and 2009, the number of 1 Departments of Pathology and Obstetrics/Gynecology, University of Florida, Box , Gainesville, FL Infectious Disease Epidemiology Program, Division of Surveillance and Disease Control, West Virginia Bureau for Public Health, 350 Capitol Street, Room 125, Charleston, WV Department of Pathology, University of Florida, Box , Gainesville, FL College of Medicine, University of Florida, Box 10081, Gainesville, FL Department of Pediatrics, Shands Teaching Hospital, University of Florida, Box , Gainesville, FL Department of Pediatrics, University of Florida, Box , Gainesville, FL *Presented in part at the 17th Annual Maternal and Child Health Epidemiology Conference, December 14 16, 2011, in New Orleans, LA; and the 35th Annual Conference of the Association for Medical Education and Research in Substance Abuse, November 3 5, 2011, in Arlington, VA. Received 4 Dec. 2011; and in revised form 19 July 2012; accepted 25 Aug emergency department visits related to misuse or abuse of prescription drugs surpassed the number of visits related to illicit drug use, with the largest increases in drug abuse or misuse coming from opioids and anxiolytics (12). Overdose deaths have important public health implications: for every one overdose death, there are nine abuse treatment admissions, 35 emergency room visits for misuse or abuse, 161 people with abuse/dependence, and 461 nonmedical users (13). A pattern of multiple drug abuse has been noted among prescription drug abusers, with opioid abusers being more likely to abuse other medications such as benzodiazepines (4,6). In Florida, similar trends are being observed (14 16). From 2003 to 2009, the annual number of deaths in Florida involving lethal drug concentrations increased 61.0%, while the death rate increased from 10.6 to 15.7 per 100,000 individuals a 47.5% increase (14). This observed trend is almost entirely attributable to prescription drugs. During the same period, the prescription drug overdose death rate increased by 84.2%, while the illicit drug over dose death rate decreased by 21.4% (14). Other studies from Florida support this shift from illicit to prescription drugs as a significant source of mortality (15). By 2009, the deaths involving prescription drugs were four times as common as deaths involving illicit drugs such as heroin and cocaine (14) (See Fig. 1). Inappropriate prescribing practices at pain clinics commonly referred to as pill mills are contributing to the prescription drug abuse epidemic in Florida (15 22). The increases observed in the overdose death rates of the commonly abused opioid oxycodone and the benzodiazepine alprazolam 264.6% and 233.8% between 2003 and 2009, respectively seem to indicate that pill mills are a contributing factor to the situation in Florida (14). Until recently, the state lacked both a prescription drug American Academy of Forensic Sciences
2 HARDT ET AL.. DRUGS IN PREGNANCY-ASSOCIATED UNNATURAL DEATHS 1537 FIG. 1 Annual drug overdose death rates for selected prescription and illicit drugs - Florida, Source: Centers for Disease Control and Prevention (CDC) (14). monitoring program and legislation against inappropriate prescribing practices (22,23). According to data supplied to Florida s Department of Children and Families by Florida s Agency for Health Care Administration, there has been more than a 500% increase in newborns treated for drug withdrawal between 2005 and 2010 that has been anecdotally attributed to maternal use of prescription drugs (24,25) (See Fig. 2). Given the rise in prescription drug abuse and infants requiring treatment for drug withdrawal, there is reason to believe that Florida s pregnant women are abusing prescription drugs. The purpose of this study was to examine the role of prescription drug abuse in the non-natural deaths of Florida s pregnant or recently pregnant women. While there has been substantial investigation into the relationship between substance abuse and pregnancy outcome, there is limited research into how drug abuse, especially prescription drug abuse, may be related to pregnancy-associated non-natural death. Methods Case Identification and Inclusion Criteria Florida s Department of Health has conducted a Pregnancy- Associated Mortality Review (PAMR) since 1996 (26). Pregnancy-associated death is defined by PAMR as a woman s death from any cause, while she is pregnant or within 1 year of termination of the pregnancy, regardless of duration, outcome, and site of the pregnancy. of pregnancy-associated death were identified by linking maternal death certificates, Healthy Start Prenatal Risk screenings, birth certificates, and fetal death records by Florida Department of Health (DOH), Bureau of Vital Statistics. The PAMR team provided researchers at the University of Florida with a dataset of all pregnancy-associated deaths between 1999 and 2005 where the manner of death was anything but natural (homicide, suicide, accident or undetermined, herein referred to as non-natural ). Medical examiners reports, including toxicology, autopsy, and case history information, were obtained through requests to district medical examiner. Each case of a pregnancy-associated death was matched to a medical examiner s report and then entered into Microsoft Office Access 2007 database. Complete information on all variables of interest was available for 415 pregnancy-associated non-natural deaths between 1999 and Three cases were identified as natural deaths and removed from the dataset. where a toxicology report was unavailable were also removed from the cohort (n = 27). that had a negative toxicology report (n = 167) were also removed. Positive toxicology reports that contained only caffeine, carbon monoxide/carboxyhemoglobin, or atropine/lidocaine were also excluded (n = 31). Positive toxicology for carbon monoxide or carboxyhemoglobin is not considered indicative of drug abuse, but rather is commonly associated with fire-related accidents. Caffeine is ubiquitous throughout our culture and was not considered a drug that generally poses serious harm to health. Atropine/lidocaine is used in resuscitation and usually administered as part of a resuscitation protocol. These deletions reduced the dataset to 187 cases of a pregnancy-associated death with a positive toxicology report. Eighteen additional exclusions were made for toxicology reports indicating the presence of only over-the-counter medications, including nicotine, acetaminophen, salicylates (aspirin), and diphenhydramine (antihistamine). Two cases with negative toxicology were included because they were delayed deaths from acetaminophen toxicity. The final cohort consisted of 169 drugpositive, pregnancy-associated non-natural deaths. The construction of the study sample is summarized in Fig. 3. Case History Review For cases that matched the inclusion criteria for our cohort, the following information was extracted from medical examiners reports: age, race, cause of death, manner of death, and drugs found in toxicology analyses. Information was unavailable on the socioeconomic status of the women. Similarly, in cases of positive toxicology involving prescription drugs, the source of the drugs was not indicated. FIG. 2 of neonatal withdrawal syndrome in Florida, Source: Florida Agency for Health Care Administration and Florida Department of Children and Families. Toxicologic Testing The postmortem toxicology data collected for this study were obtained from the toxicology reports submitted by the individual medical examiner offices and included quantitative drug data for
3 1538 JOURNAL OF FORENSIC SCIENCES blood, vitreous humor, and/or urine. Because this study s aim was evaluating the prevalence of use (and not dose/concentration), a case was considered positive for a drug/toxin if it was detected in any body fluid sample, whether or not it was quantified. Toxicology reports with presumptively positive (nonconfirmed) results were not included. The toxicology data were collected from the reports generated by a number of different laboratories. The state of Florida is divided into 23 Medical Examiner Districts; each has its own policies and procedures regarding how toxicology testing is performed, but in general, most offices utilize an accredited toxicology laboratory, such as UF and Wuestaff, and others utilize local or regional hospital laboratories for screening, with confirmation and quantification performed selectively at a specialized laboratory. Several large medical examiner districts have their own, in-house accredited laboratories, such as Miami-Dade County. The methodologies used were also varied and included gas chromatography, gas chromatography mass spectrometry, high-performance liquid chromatography, thin-layer chromatography, ELISA, and immunoassays. For these reasons, the toxicology data are heterogeneous in the manner in which they were reported and included confirmed positive, presumptive positive, and quantified drugs. Because we are interested in exposure of this population to drugs, both illicit and prescription, we chose to include cases with both quantified and nonquantified, but confirmed positive results. For the purposes of this paper, this is the definition of a positive toxicology report. Of the 169 cases included in this study, 86 had both blood and urine positive for drug(s), 64 had 415 Pregnancy Associated Mortality Review (PAMR) Records PAMR records Linkage of PAMR records to Medical Examiner (ME) Reports 385 Linked PAMR+ME Reports 3 Natural deaths removed 27 No toxicology report 167 Negative toxicology report only blood positive for drug(s), and five had only urine positive for drug(s). The remainder (14) had some other specimen positive for drug(s), such as vitreous humor, gastric contents, bile, brain, liver, or decomposition fluid. Classification of Drugs Drugs encountered in this study were broadly classified as either prescription or illicit. Prescription drugs were subcategorized as opioids (morphine, hydrocodone, methadone, hydromorphone, oxycodone, propoxyphene, fentanyl, tramadol, and codeine), benzodiazepines (oxazepam, nordiazepam, temazepam, alprazolam, diazepam, midazolam, benzodiazepine, and clonazepam), and antidepressants (sertraline, venlafaxine, nortriptyline, citalopram, amitriptyline, doxepin, wellbutrin, and fluoxetine). A general other category was also used to group lessfrequently encountered prescription drugs in the toxicology reports (gabapentin, promethazine, barbiturate, butalbital, olanzapine, phenytoin, benzonatate, cyclobenzaprine, cimetidine, and anxiolytic not otherwise specified). Morphine is difficult to categorize as prescription or illicit, given that morphine is the major metabolite of heroin. Without either substantial investigative information indicating heroin use, or the detection of heroin and/or 6-monoacetylmorphine in postmortem samples, the source of the morphine cannot be definitively ascertained. For the purposes of this study, we chose to place those positive for morphine without heroin or heroin metabolites in the prescription drug category because of the far greater accessibility to prescription opioids and the relatively low availability of heroin. Results Table 1 lists the major groups of causes of death for the 169 decedents included in this study. These were grouped into categories based on mechanism of death, such as drug toxicity, motor vehicle crash, and sharp force injury. The largest groups of causes of deaths were drug toxicity (both single and mixed) and motor vehicle crashes, each accounting for approximately one-third of the deaths. Gunshot wounds were listed as the cause of death in 24 of the 169 deaths, or 14%. The remainder of the causes of death each accounted for <10%. Table 2 indicates that at least one prescription drug was found in 91 of the 169 cases (54%) of drug-positive, pregnancy-associated non-natural deaths; 78 cases (46%) were positive for at least one illicit drug, and alcohol, whether detected alone or in combination with other substances, was detected in 69 cases (41%). 218 Linked PAMR+ME Reports 187 Linked PAMR+ME Reports 169 Final study sample 31 Positive toxicology report for caffeine, carbon monoxide, or atropine 18 OTC drug findings FIG. 3 Construction of final study sample: 169 pregnant or recently pregnant women who died and who had a positive toxicology report. TABLE 1 Causes of death as reported by the medical examiner on the death certificate. Cause of Death Number % Drug toxicity Single drug toxicity Mixed drug toxicity Motor vehicle crash Gunshot Blunt trauma NOS Hanging Strangulation/asphyxia Sharp force injury Other* Total *Other: Homicide NOS (2), carbon monoxide (1), drowning (1).
4 HARDT ET AL.. DRUGS IN PREGNANCY-ASSOCIATED UNNATURAL DEATHS 1539 TABLE 2 Incidence of prescription and illicit drugs, plus alcohol detected and frequency co-detected with other substances in pregnant and recently pregnant women who died, Florida, (N = 169). Substance(s) Detected Positive Toxicology Reports Percentage Among Pregnant and Recently Pregnant Women Who Died Prescription drugs, +/ other Prescription drugs, alone Prescription drugs and illicit drugs Prescription drugs and alcohol 14 8 Prescription drugs, alcohol, 12 7 and illicit drugs Illicit drugs, +/ other Illicit drugs, alone Illicit drugs and prescription drugs Illicit drugs and alcohol 11 6 Illicit drugs, alcohol, and 12 7 prescription drugs Alcohol, +/ other Alcohol Alcohol and illicit drugs 11 6 Alcohol and prescription drugs 14 8 Alcohol and illicit drugs 12 7 Table 3 indicates that prescription opioids were detected alone or in conjunction with other drugs in 50 cases (30% of toxicologypositive cases). Table 4 indicates that benzodiazepines were the second most frequently detected class of prescription drug with 42 cases (25%) positive for benzodiazepines alone or in conjunction with other drugs. Evidence of co-use/co-abuse with other drugs was detected. Twenty cases (12%) were positive for both opioids and benzodiazepines. Of cases involving benzodiazepines, 18 were also positive for illicit drugs. Table 5 lists the type and frequency of illicit drugs detected with/without involvement of other drug types. Illicit drugs were involved in 69 (41%) of the 169 cases of pregnancy-associated non-natural deaths. Table 6 indicates that 32 of the 55 toxicology-positive decedents (58%) were pregnant at the time of their death. Toxicology reports indicated that 11 of the 32 decedents (34%) had prescription drugs in their systems at the time of their death. Sixteen cases (50%) showed evidence of illicit drug use, and twelve cases (32%) evidence of alcohol use. Because there are numerous challenges in determining intent in cases of overdose, accidental and suicidal overdoses were considered together. Table 7 indicates that 47 of the 169 deaths (28%) were identified as due to the direct toxic affect of drugs. Of these, single or multiple prescription drugs were attributed as the cause of overdose in 33 cases (70%). In six additional cases, involvement of illicit drug use was also detected. Single or multiple illicit drugs alone accounted for 18 cases of overdose (38%). Two other cases of overdose were detected; one overdose was attributed to alcohol toxicity. The other cause of overdose was determined to be acetaminophen toxicity, although opioids were also detected. Table 8 indicates that alcohol was the drug most commonly found in the toxicology reports of pregnant or recently pregnant women who died from non-natural manners (69 of 169 cases or 41%). Approximately two-thirds of those involved the admixture of alcohol with prescription drugs and one-third with illicit drugs. Discussion Our study represents the first investigation exploring the relationship between prescription and illicit drug use and, TABLE 3 Frequency of cases involving prescription opioids with/without involvement of other drug types. Prescription Opioids Detected, with/without Other Substances Percentage of Opioids, without other drugs Opioids, with benzodiazepines* Opioids, with antidepressants* Opioids, with >1 other type of drug 8 16 Opioids, with illicit drugs* Opioids, total cases involving *With/without involvement of other prescription drugs. TABLE 4 Frequency of cases involving benzodiazepines with/without involvement of other drug types. Benzodiazepines Detected, with/without Other Substances Percentage of Benzodiazepines, without other drugs Benzodiazepines, with opioids* Benzodiazepines, with antidepressants* 7 17 Benzodiazepines, with >1 other type of drug 7 17 Benzodiazepines, with illicit drugs* Benzodiazepines, total cases involving *With/without involvement of other prescription drugs. TABLE 5 Type and frequency of illicit drugs detected with/without involvement of other drug types. Illicit Drugs Detected* Percentage of Cocaine Cannabis Methamphetamine/amphetamine 4 6 Heroin 4 6 Phencyclidine 1 1 c-hydroxybutyric acid 1 1 Illicit drugs, with alcohol Illicit drugs, with prescription drugs Illicit drugs, total cases *Single case may be positive for >1 drug/group of drugs. TABLE 6 Substances detected in women who were pregnant at the time of their death (N = 32). Substance(s) Detected in Pregnant Decedents * Percentage of Prescription drugs Opioids 4 13 Benzodiazepine 2 6 Antidepressants 4 13 Other 4 13 Illicit drugs Cocaine 8 25 Cannabis 8 25 c-hydroxybutyric acid 1 3 Alcohol Total pregnant decedents *Single case may be positive for >1 drug/group of drugs. pregnancy-associated non-natural death, keeping in mind that pregnancy-associated death indicates a death in a woman who was pregnant or recently pregnant at the time of her death. Also important to note is that just because a drug is categorized in the
5 1540 JOURNAL OF FORENSIC SCIENCES TABLE 7 of pregnancy-associated accidental and intentional overdose (N = 47). Drug Type Attributed to Overdose Percentage of Prescription drugs Single prescription drug class Multiple, with other classes of prescription drugs Multiple, with illicit drugs 6 13 Single or multiple illicit drugs* Other 2 4 Total Overdoses use. *Includes cases where toxicology report also indicated prescription drug TABLE 8 Frequency of cases involving alcohol with/without involvement of other drug types. Alcohol Detected, with/without Other Substances Percentage of Alcohol, without other drugs Alcohol, with opioids* Alcohol, with benzodiazepines* Alcohol, with antidepressants* 8 12 Alcohol, with other prescription drugs* 4 6 Alcohol, with >1 type of prescription drugs 9 13 Alcohol, with illicit drugs* Alcohol, total cases involving *With/without involvement of other prescription drugs. prescription drug group does not mean it was prescribed to the decedent. Prescription drugs were detected in a majority (91 of 169 or 54%) of toxicology-positive cases of pregnancy-associated nonnatural death from Florida between 1999 and Opioids and benzodiazepines were the most frequently encountered prescription drug classes: 50 total cases were positive for opioids, and 42 total cases were positive for benzodiazepines. In cases of drug-positive overdose, without regard to overdose intent, prescription drugs were the most common drugs encountered. Substantial co-use of opioids and benzodiazepines was seen. Sixteen cases were positive for both benzodiazepines and opioids. There are several significant limitations in the ascertainment of prescription and illicit drug abuse during and in the year after pregnancy. Most notably, this study investigated a very narrowly defined population: cases of pregnancy-associated non-natural death with positive postmortem toxicology or investigative information directly linking the death to a specific drug or toxin. This study is not able to capture those individuals whose bodies may have completely metabolized any recently ingested drugs, nor able to identify occasional or binge use of drugs and medications. It is possible that some of those cases positive for morphine (without detectable heroin and/or 6-MAM) were from exposure to heroin rather than a prescription opioid. However, given the historically low use of heroin throughout the general population and the easy access to prescription forms, we chose to group morphine-positive cases with prescription opioids. Even if we took the opposite approach and assumed that ALL morphine detected in our population sample originated from heroin, a staggering number of cases positive for some other opioid remain. This method of categorizing heroin and morphine deaths is similar to that of the Florida Medical Examiner Commission in their annual drug surveillance reports (\ such that our data can be directly compared and correlated with statewide medical examiner data. The statewide data reported by medical examiners show that within the group of all opioids, heroin and morphine together make up a small fraction of opioid-positive deaths, both in this study and across the state of Florida: in 2005, 369 of 1747 opioid-positive deaths, or 21% of opioid-positive deaths, were positive for heroin or morphine combined, as compared to 1378 of 1747 opioid-positive deaths, or 79% that were positive for any other opioid drug. For 2010, the numbers are even more staggering: 699 of 6358 opioid-positive deaths (11%) were positive for heroin or morphine, compared with 5659 of 6358 deaths (89%) that were positive for an opioid other than morphine or heroin. This represents a more than 300% increase in prescription drug exposure in the entire, statewide medical examiner population. The data in our study sample of pregnant and recently pregnant women are similar to that reported by the Florida Medical Examiner Commission: of the 50 cases that were positive for any opioid, only 8 deaths, or 14%, were positive for morphine without any other prescription opioid. Thus, even if we assumed all the morphine detected in these decedents came from heroin, it would not change the bottom line prescription opioid use and abuse is epidemic in our population. The prevalence of opioid exposure in our study population of non-natural deaths in mothers is similar to that in the general medical examiner population. In this comparison of two groups suffering non-natural deaths during the same time frame, roughly 12% were opioid positive. Of note, in 2010, the proportion of opioid-positive non-natural deaths in Florida was 44.5%. This is consistent with the observed overall increase in use and misuse of opioids. Based both on this data and on the rising incidence of neonatal abstinence syndrome, we infer that women are continuing to use opioids during pregnancy. Further study of the more recent time period may be of interest. The Centers for Disease Control recently reported that the number of deaths related to prescription opioids rose nearly fourfold between 1999 and 2008 (27). Comparison studies in states with prescription drug control legislation would be useful to evaluate the efficacy of prescription drug monitoring programs and establish best practices. Other limitations of this study include sparseness of socioeconomic data. Most of the women in the study population were White; however, their socioeconomic status was not reported. Ethnic or socioeconomic difference in drug use may limit the applicability of these data to non-white women, even those who are or recently were pregnant. Limited data prevented the ascertainment of the source of prescription drugs detected. There was no way of determining the extent of prescription drug diversion from Florida s pain clinics in the study population. Some medical examiners reporting on cases of homicide during the study period were not made available to the investigators because they are currently under criminal investigation and access to these files was very limited. One factor worth emphasizing is that this study population is quite unique in that it is composed of relatively young women (of reproductive age), and because they were pregnant or recently pregnant at the time of their death, they would have been expected to have more interactions with healthcare providers and more opportunities for intervention and prevention of high-risk behaviors. However, as shown in this study, they have very similar exposures to both prescription and illicit drugs and are dying from their toxic effects. These cases may represent missed opportunities for counseling and prevention. Another possibility is that women who die of trauma are frequently
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Tallahassee, FL: Substance Abuse and Mental Health Program Office, \ us/programs/ samh/substanceabuse/docs/countynewbornwithdrawaldiagnoses2010.pdf 26. Hernandez L, Sappenfield W, Burch D Florida pregnancyrelated mortality report: why are Florida mothers continuing to die? Tallahassee, FL: Florida Department of Health, Centers for Disease Control and Prevention (CDC). Vital signs: overdoses of prescription opioid pain relievers United States, MMWR 2011;60(43): Additional information and reprint requests: Nancy Hardt, M.D. Professor, Pathology and Obstetrics/Gynecology College of Medicine University of Florida PO Box Gainesville, FL