Methamphetamine dependence is an escalating problem across the United States. Methamphetamine (N-methyl-1-phenyl-propan-2-amine) is the only illegal drug that can be easily made from legally obtained ingredients, in particular over-the-counter cold medications or decongestants. Available in crystal form or as a white, odorless powder, methamphetamine can be swallowed, smoked, injected, or inhaled. It has high bioavailability: 62.7% oral, 79% nasal, 90.3% smoked, 99% rectally, and 100% intravenously, with a half life of 9–15 hours. A powerful stimulant, methamphetamine increases the release of catecholamines and dopamine and also inhibits the degradation of neurotransmitters.1,2
The drug can be detected unchanged in a person's urine or blood for up to 3 days. A recent report suggests many users are addicted after a single exposure as a result of its long euphoria of up to 24 hours, ease of production, and relatively low cost.3 The Center for Substance Abuse Research's Infant Development, Environment, and Lifestyle (IDEAL) study reported that 5.2% of women in particularly high methamphetamine prevalent regions of the United States used methamphetamine at some point during their pregnancy.4 Despite the increasing use of the drug, knowledge of actual effects in pregnancy is limited.5,6
A remarkable increase in the incidence of methamphetamine-exposed pregnancies and related complications have been anecdotally reported. However, there is a paucity of reports specific to methamphetamine and human pregnancy. This study was thus undertaken to validate the hypothesis that methamphetamine exposed pregnancies have greater perinatal morbidity.
MATERIALS AND METHODS
A single-site review of medical records of hospitalized patients was conducted for the period from January 2000 through March 2006. St. Joseph's Hospital and Medical Center is a 697-bed tertiary care, urban, academic, not-for-profit medical center. This study was approved by the Institutional Review Board for Human Research of St. Joseph's Hospital and Medical Center (#06OB039, April 20, 2006) in Phoenix, AZ.
Administrative data were used for patient identification. International Classification of Diseases, 9th Revision code 648.3x (drug dependence complicating pregnancy, childbirth, or the puerperium) was used to screen all patient medical records for detailed review. Analysis of records identified on initial screening was then performed to select methamphetamine users.
The specific inclusion criteria required either a positive urine drug screen for methamphetamine or by patient statement of methamphetamine use during pregnancy. In this institution, all patients are routinely asked if illicit drugs have been used. A urine drug screen was also performed in patients with apparent substance abuse or in certain presenting circumstances at admission in the hospital chemistry laboratory (Triage Drugs of Abuse Panel; Biosite Inc., San Diego, CA). These records were then analyzed for perinatal complications, and outcomes, along with neonatal outcomes.
The maternal charts were evaluated for the following demographic data: maternal age, ethnicity, employment status, education, marital status, domestic violence, smoking, and prenatal care. The neonatal charts were evaluated for the following: gestational age, Apgar score, site and mode of delivery, disposition of the neonate, and neonatal mortality.
These data were compared with a general control population of women presenting for obstetric care to this institution during this same period. Statistical analysis was performed using the χ2 test. Statistical significance was defined as P<.05.
Two hundred seventy-six patients responsible for 273 live births were identified as methamphetamine users and pregnant. Although control comparison data were not available for all demographic and outcome parameters, as a result of sparse data recording in routine uncomplicated births, the following results are noteworthy regarding the methamphetamine-exposed patients.
The study institution experienced a remarkable increase in the number of patients using methamphetamine in pregnancy: 22 patients in 2001, 43 in 2004, and 77 patients in 2005.
Only 19 of 276 (7%) reported being employed, and 79 of 141 (56%) had an 11th grade education or less. Furthermore, there was an unusual preponderance of non-Hispanic white (152 of 276 [55%]) patients in the methamphetamine population compared with the general hospital population demographic. Distribution of ethnicity was as follows: 35% Hispanics, 5% African Americans, 3% Native Americans, and 2% other or unknown.
These findings were inconsistent with our anecdotal experience among patients presenting for care at this institution, which serves a predominantly employed Hispanic married community. Furthermore, the majority, 213 of 275 (78%), were active tobacco smokers, 39 of 275 (14%) consumed alcohol on a regular basis, 168 of 275 (61%) tested positive for illicit substances at the time of presentation to the hospital, and 66 of 275 (24%) tested positive for multiple illicit substances (methamphetamine and tetrahydrocannabinol [n=47], opiates [n=14], cocaine [n=13], phencyclidine [n=2], and more than one other illicit drug [n=11]).
These patients had high-risk pregnancies for multiple reasons: 133 of 265 (50%) had preterm birth (52 had birth at 35–36 weeks, 44 had birth at 33–34 weeks, and 37 had birth at 20–32 weeks of gestation). In 11 cases, gestational age at delivery could not be verified. Most of the preterm deliveries were idiopathic. Thirty-two of 265 (12%) had intrauterine growth restriction,7 48 of 274 (17%) had a hypertensive complication not related to diagnostically classic preeclampsia, 25 of 272 (9%) had placental abruption, and 25 of 275 (9%) were hospital-to-hospital transport. The majority of patients delivered through spontaneous vaginal delivery (195 of 276 [71%]). Alarmingly, domestic violence during pregnancy was reported by 51 of 225 (23%).
Table 1 illustrates statistically significant differences in maternal demographics between patients using methamphetamine and a nonmethamphetamine-exposed control population (n=34,055). Clearly the methamphetamine group represented a cohort of women who were generally older, did not avail themselves of the usual prenatal care, and were substantially less likely to be legally married.
Statistically significant differences between patients using methamphetamine and a nonmethamphetamine-exposed control population with regard to perinatal outcomes is shown in Table 2. Although these pregnancy outcomes clearly suggest more preterm birth in patients using methamphetamine with what is likely associated lower initial Apgar scoring, the incidence of neonatal mortality is high.
Additionally, the following outcomes were also noted: 15 of 276 (6%) had an unattended out-of-hospital delivery (car, toilet, home, ambulance) and 87 of 215 (40%) of these pregnancies ended in initial mother and infant separation (adoption 45%, Child Protective Services or foster care 45%, primary care giver other than mother 10%), which included planned adoptions (23 of 215 [11%]). More concerning clinically, there is a suggestion of a need for much higher acuity care in patients with methamphetamine use.
Finally, the record review strongly suggested substantially increased demands on nursing staff (neonatal abstinence protocols, collection of specimens for drugs of dependance, management of withdrawal symptoms, lack of parental involvement in care), but this was a subjective observation and difficult to quantify in a reliable manner. Also of note were the anomalies found in this neonatal population, which included anencephaly, ambiguous genitalia, cleft lip, and diaphragmatic hernia, although not statistically significant as a result of low overall incidence.
The study institution has experienced a remarkable increase in the number of patients using methamphetamine in pregnancy. A recent U.S. study reported that in 1994, methamphetamine accounted for 8% of admitted pregnant women with substance abuse, rising to 24% by 2006. The majority of methamphetamine admissions occurred in the West (73%) among white (64%) unemployed (88%) women.8 Similar year-to-year increases have been noted internationally, particularly in Pacific rim countries such as New Zealand and Thailand.9,10 In a study of methamphetamine use patterns during pregnancy, among 191 users, the prevalence of methamphetamine use decreased over the three trimesters of pregnancy (84.3% compared with 56.0% compared with 42.4%), and decreased frequency was observed among users from the first trimester to the third (3.1 compared with 2.4 compared with 1.5 days per week).11
This patient population has many characteristics that led to a high-risk pregnancy, including domestic violence, substance abuse, and poor prenatal care, which may be directly linked to the observed rates of hypertension, placental abruption, and maternal and neonatal intensive care unit admission.
Methamphetamine use is associated with a risk of acute death, often as a result of hypertensive events such as cerebrovascular accident.12 Studies have also shown physical effects in rats, including histologically apparent brain alterations and evidence of oxidative DNA damage.13 Likewise, retrospective human studies have shown methamphetamine is negatively associated with gestational age, birth weight, length, and occipitofrontal circumference.14 Other investigators have reported on the very real impact of methamphetamine on maternal and neonatal mortality as well. Catanzarite and Stein15 submitted a case report on two maternal deaths in their institution resulting from cardiac decompensation perhaps attributable to methamphetamine use. Similarly, Stewart and Meeker16 described eight cases of fetal or neonatal death attributed to methamphetamine. However, with the exception of this study, a more generalized report of methamphetamine use in pregnancy and its attendant complications has not been published.
Perinatal complications were not solely limited to clinical outcomes but also involved an apparent dramatic breakdown of expected mother–infant bonding as demonstrated by the exceedingly high foster care and adoption rate. Animal reports, mostly focused on rat behavior, have demonstrated similar striking alterations in maternal interest in pup well-being.17,18 In fact, news reports in Phoenix, AZ, note that two thirds of child abuse and neglect cases are related to methamphetamine in some way.19 Although a substantial portion of the mother–infant separations in our study were court-ordered events, the high planned adoption rate suggests a marked alteration in typical bonding.
Other investigators have noted that methamphetamine not only freely crosses the placenta,20,21 but that direct methamphetamine effects or the presence of methamphetamine itself is measurable in animal fetal organs, including the heart and brain.22–25 Similar findings in human studies have increased the level of urgency for a better understanding of methamphetamine and its effects, particularly in children and pregnancy.26,27 In 1988, Little et al28 studied 52 methamphetamine users during pregnancy. They reported that neonatal body weight, length, and head circumference were significantly decreased compared with control newborns. Increasing evidence indicates that prenatal exposure to methamphetamine results in severe morphological changes in the brain with associated cognitive deficits.25 In fact, half of the newborns whose mothers used methamphetamine during pregnancy experienced withdrawal syndrome.
In a recent case–control study of a gastroschisis cluster in Reno, NV, gastroschisis was found to be associated with the use of methamphetamine with an odds ratio of 7.15 and a 95% confidence interval of 1.35–37.99.29 Prenatal methamphetamine exposure influences the development of the verbal memory system above the effects of prenatal alcohol exposure.26 Thus, there has been recent interest in methods to track the long-term outcomes in these neonates. Although studies have not as yet evaluated such long-term outcomes, reports would suggest an increase in behavioral disorders and difficulty achieving developmental milestones. Furthermore, methamphetamine-exposed neonates tax the hospital staff and burden the state foster care system. This increase in the cost of care, although not quantified in our data, is directly related to the high level of caregiver surveillance required by these newborns from birth until discharge and is not an insignificant problem.30,31
The data presented in this study have several limitations. Our screening method for methamphetamine users in pregnancy relied on patient admittance to using the drug or a positive urine toxicology screen. The toxicology screen is not routine, performed only after poorly described and documented circumstances as defined by individual caregivers. This informal screening process undoubtedly results in missed patients who are using methamphetamine or other substances. In addition, the possibility of a false-positive urine screen as a result of labetalol, ephedra, or other substances cannot be ruled out with absolute certainty.32 Also, with almost one fourth of methamphetamine users in our population using other illicit substances and most smoking tobacco, it is difficult to correlate the patients' acute medical issues and outcomes with only the methamphetamine use. Finally, this study includes a single urban hospital in a region with widespread methamphetamine abuse; thus, it may not be valid in rural areas or other regions with a difference in methamphetamine prevalence.
An interesting aspect of our data review was the unusual demographic characteristics of the methamphetamine-using cohort. They were fairly distinct from the typical population in the study hospital, representing as noted an older, smoking, less educated, unemployed, white non-Hispanic woman with a probable history of domestic violence. This pattern of factors was so distinct that it may allow screening in a more directed manner those patients who may be methamphetamine users. Validation of similar patient background demographics in other regions would be of great interest. In conclusion, methamphetamine use in pregnancy is complicated by more morbid maternal and neonatal outcomes when compared with the general obstetric population. The incidence of methamphetamine use is rising; attempts to identify these patients early and intervene in an effort to improve pregnancy-related outcomes are warranted.
1. Cruickshank CC, Dyer KR. A review of the clinical pharmacology of methamphetamine. Addiction 2009;104:1085–99.
2. Elkashef A, Vocci F, Hanson G, White J, Wickes W, Tiihonen J. Pharmacotherapy of methamphetamine addiction: an update. Subst Abus 2008;29:31–49.
3. Anglin MD, Burke C, Perrochet B, Stamper E, Dawud-Noursi S. History of the methamphetamine problem. J Psychoactive Drugs 2000;32:137–41.
4. Arria AM, Derauf C, Lagasse LL, Grant P, Shah R, Smith L, et al. Methamphetamine and other substance use during pregnancy: preliminary estimates from the Infant Development, Environment, and Lifestyle (IDEAL) study. Matern Child Health J 2006;10:293–302.
5. Marwick C. NIDA seeking data on effect of fetal exposure to methamphetamine. JAMA 2000;283:2225–6.
6. Salisbury AL, Ponder KL, Padbury JF, Lester BM. Fetal effects of psychoactive drugs. Clin Perinatol 2009;36:595–619.
7. Oken E, Kleinman KP, Rich-Edwards J, Gillman MW. A nearly continuous measure of birth weight for gestational age using a United States national reference. BMC Pediatr 2003;3:6.
8. Terplan M, Smith EJ, Kozloski MJ, Pollack HA. Methamphetamine use among pregnant women. Obstet Gynecol 2009;113:1285–91.
9. Wouldes T, LaGasse L, Sheridan J, Lester B. Maternal methamphetamine use during pregnancy and child outcome: what do we know? N Z Med J 2004;117:U1180.
10. Chomchai C, Na Manorom N, Watanarungsan P, Yossuck P, Chomchai S. Methamphetamine abuse during pregnancy and its health impact on neonates born at Siriraj Hospital, Bangkok, Thailand. SE Asian J Trop Med Public Health 2004;35:228–31.
11. Della Grotta S, Lagasse LL, Arria AM, Derauf C, Grant P, Smith LM, et al. Patterns of methamphetamine use during pregnancy: results from the Infant Development, Environment, and Lifestyle (IDEAL) Study. Matern Child Health J 2009 Jun 30 [Epub ahead of print].
12. Perez JA Jr, Arsura EL, Strategos S. Methamphetamine-related stroke: four cases. J Emerg Med 1999;17:469–71.
13. Jeng W, Wong AW, Ting-A-Kee R, Wells PG. Methamphetamine-enhanced embryonic oxidative DNA damage and neurodevelopmental deficits. Free Radic Biol Med 2005;39:317–26.
14. Oro AS, Dixon SD. Perinatal cocaine and methamphetamine exposure: maternal and neonatal correlates. J Pediatr 1987;111:571–8.
15. Catanzarite VA, Stein DA. ‘Crystal’ and pregnancy—methamphetamine-associated maternal deaths. West J Med 1995;162:454–7.
16. Stewart JL, Meeker JE. Fetal and infant deaths associated with maternal methamphetamine abuse. J Anal Toxicol 1997;21:515–7.
17. Slamberova R, Charousova P, Pometlova M. Maternal behavior is impaired by methamphetamine administered during pre-mating, gestation and lactation. Reprod Toxicol 2005;20:103–10.
18. Slamberova R, Charousova P, Pometlova M. Methamphetamine administration during gestation impairs maternal behavior. Dev Psychobiol 2005;46:57–65.
19. Scutari C. Two plans tackle meth in Arizona. The Arizona Republic February 14, 2006. Available at: http://www.azcentral.com/arizonarepublic/news/articles/0214meth0214.html
.Retrieved June 8, 2010.
20. Ganapathy VV, Prasad PD, Ganapathy ME, Leibach FH. Drugs of abuse and placental transport. Adv Druv Deliv Rev 1999;38:99–110.
21. Bartu A, Dusci LJ, Ilett KF. Transfer of methylamphetamine and amphetamine into breast milk following recreational use of methylamphetamine. Br J Clin Pharmacol 2009;67:455–9.
22. Stek AM, Baker RS, Fisher BK, Lang U, Tseng CY, Clark KE. Maternal and fetal cardiovascular responses to methamphetamine in the pregnant sheep. Am J Obstet Gynecol 1993;169:888–97.
23. Stek AM, Baker RS, Fisher BK, Lang U, Clark KE. Fetal responses to maternal and fetal methamphetamine administration in sheep. Am J Obstet Gynecol 1995;173:1592–8.
24. Won L, Bubula N, McCoy H, Heller A. Methamphetamine concentrations in fetal and maternal brain following prenatal exposure. Neurotoxicol Teratol 2001;23:349–54.
25. Inoue H, Nakatome M, Terada M, Mizuno M, Ono R, Iino M, et al. Maternal methamphetamine administration during pregnancy influences on fetal rat heart development [corrected]. Life Sci 2004;74:1529–40.
26. Chang L, Smith LM, LoPresti C, Yonekura ML, Kuo J, Walot I, et al. Smaller subcortical volumes and cognitive deficits in children with prenatal methamphetamine exposure. Psychiatry Res 2004;132:95–106.
27. Chang L, Cloak C, Jiang CS, Farnham S, Tokeshi B, Buchthal S, et al. Altered neurometabolites and motor integration in children exposed to methamphetamine in utero. Neuroimage 2009;48:391–7.
28. Little BB, Snell LM, Gilstrap LC 3rd. Methamphetamine abuse during pregnancy: outcome and fetal effects. Obstet Gynecol 1988;72:541–4.
29. Elliott L, Loomis D, Lottritz L, Slotnick RN, Oki E, Todd R. Case–control study of a gastroschisis cluster in Nevada. Arch Pediatr Adolesc Med 2009;163:1000–6.
30. Lu LH, Johnson A, O'Hare ED, Bookheimer SY, Smith LM, O'Connor MJ, et al. Effects of prenatal methamphetamine exposure on verbal memory revealed with functional magnetic resonance imaging. J Dev Behav Pediatr 2009;30:185–92.
31. Smith L, Yonekura ML, Wallace T, Berman N, Kuo J, Berkowitz C. Effects of prenatal methamphetamine exposure on fetal growth and drug withdrawal symptoms in infants born at term. J Dev Behav Ped 2003;24:17–23.
32. Shindelman J, Mahal J, Hemphill G, Pizzo P, Coty WA. Development and evaluation of an improved method for screening of amphetamines. J Anal Toxicol 1999;23:506–10.