Methamphetamine use Increases Chances of Preeclampsia

C l i n M e d International Library Citation: Roloff KA, Stepanyan G, Valenzuela G (2015) Methamphetamine use Increases Chances of Preeclampsia. J Fam Med Dis Prev 1:011 Received: August 26, 2015: Accepted: September 16, 2015: Published: September 19, 2015 Copyright: © 2015 Roloff KA. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Roloff et al. J Fam Med Dis Prev 2015, 1:3 ISSN: 2469-5793


Introduction
Substance abuse in pregnancy is multifactorial problem, with implications for both mother and baby. Current trends show that the most commonly used illicit substance in pregnancy is methamphetamine [1,2]. Nearly a quarter of pregnant women admitted for substance abuse treatment programs in the United States indicate their primary substance of abuse is methamphetamine [3]. The reported incidence of methamphetamine use in pregnancy is varied. National epidemiological studies suggest 7.2% of pregnant women report using methamphetamine during pregnancy, compared to 7.1% of non-pregnant reproductive aged women [4]. Estimates from the Infant Development, Environment and Lifestyle (IDEAL) study, a multi-center, multi-state study, suggest that approximately 5-6% of women use methamphetamine during pregnancy [5,6]. However, a review of linked mother-infant datasets from California Vital Statistics showed only 0.4% of pregnancies were complicated by methamphetamine use [7].
Methamphetamine, in part, causes release of norepinephrine [8], which leads to increased vascular tone (alpha mediated vasospasm) and hypertension. Preeclampsia is also thought to be a disease of excess catecholamine (the fight or flight hormones -adrenaline and norepinephrine) [9]. Thus, there is biological plausibility that methamphetamine use in pregnancy can trigger preeclampsia.
Preeclampsia occurs in up to 10% of pregnancies, and is one of the leading causes of perinatal morbidity and mortality [1]. Preeclampsia is a disease unique to pregnancy that leads to high blood pressure and proteinuria. If the patient with preeclampsia is left undelivered she may develop kidney or liver failure, seizures, or stroke. In extreme cases, her baby may die. Preeclampsia has four forms, including: (1) mild preeclampsia, which is characterized by mild elevations in blood pressure and slight protein in the urine; (2) severe preeclampsia, identified when systolic blood pressure exceeds 160 mmHg, or diastolic blood pressure exceeds 105 mmHg, there are laboratory abnormalities of the blood that suggest end-organ damage of the kidney or liver, and/or signs/symptoms of cerebrovascular involvement such as a severe headache or a seizure; (3) gestational hypertension, the same a mild preeclampsia but without proteinuria; and (4) superimposed preeclampsia, which occurs when a pregnant mother with an underlying chronic hypertensive disorder develops preeclampsia of any of the above types.

Abstract
Objective: To study the effect of methamphetamine use during pregnancy on the chance of developing preeclampsia, and the morbidity due to preeclampsia.

Study design:
A single center, retrospective study was performed over an eighteen month period (January 2012 -June 2013) at a county hospital in San Bernardino, California. Methamphetamine use was defined as self-reported use or a positive urine drug screen (UDS) at admission for delivery. Preeclampsia was defined using the American College of Obstetricians and Gynecologists (ACOG) Task Force definition. 1 The incidence of preeclampsia among methamphetamine users was compared to non-users using inferential statistics. A composite outcome of morbidity due to preeclampsia was developed using abruption, eclampsia, HELLP (hemolysis elevated liver enzymes and low platelets) syndrome, elevated aspartate aminotransferase (AST) or alanine transaminase (ALT), thrombocytopenia, intensive care unit (ICU) admission, use of intravenous (IV) antihypertensive agent(s) for blood pressure control, or use of magnesium sulfate for seizure prophylaxis. This composite outcome was compared between methamphetamine users and non-users with preeclampsia.

Conclusion:
Methamphetamine use during pregnancy significantly increases the chance of developing preeclampsia, but does not increase morbidity due to preeclampsia.

Methamphetamine, Substance abuse, Preeclampsia, Pregnancy, Hypertension
Abbreviations ACOG: American College of Obstetricians and Gynecologists, UDS: urine drug screen, ARMC: Arrowhead Regional Medical Center, HELLP: hemolysis, elevated liver enzymes, low platelets, AST: aspartate aminotransferase, ALT: alanine transaminase, ICU: intensive care unit, IV: intravenous, mmHg: millimeters of mercury, OR: Odds ratio and norepinephrine is implicated in the pathogenesis of preeclampsia [2], and because acute methamphetamine toxicity is associated with severe hypertension, hypertensive crisis, cerebrovascular accident and intracranial hemorrhage [10,11], the current study examined the relationship between methamphetamine use in pregnancy and preeclampsia. We quantified the incidence of preeclampsia in methamphetamine users and non-users, using updated diagnostic criteria as set forth by the American College of Obstetricians and Gynecologists (ACOG) Task Force on hypertension in pregnancy in 2013 [1]. We also examined a composite marker for severity of preeclampsia to determine if any differences exist in morbidity due to preeclampsia between methamphetamine users and non-users.

Materials and Methods
This is a single center, retrospective review of consecutive deliveries between January 2012 and June 2013 at Arrowhead Regional Medical Center (ARMC), a tertiary care county hospital in San Bernardino, California. This study was conducted with approval from the Arrowhead Regional Medical Center Institutional Review Board.
Local data highlights that this area is known to have a high prevalence of methamphetamine abuse [3,6,5,12]. Methamphetamine use was defined as self-reported use or providing a positive urine drug screen (UDS) at any point during pregnancy. UDS was performed using a Roche Cobas system with sensitivity to detect urinary methamphetamine concentrations greater than 1000 ng/ ml. Methamphetamine is rapidly cleared via urine, and repetitive methamphetamine ingestion can result in detectable urine concentrations for up to 7 days [13]. Due to the limitations in UDS for detecting methamphetamine use, patients who reported methamphetamine use at any point in pregnancy were included in the user cohort. UDS testing was done voluntarily, and prior to initiation of anti-hypertensive therapy. All patients were screened at the first prenatal visit using the 4P's Plus© Screen for Substance Use in Pregnancy, a validated screening instrument developed specifically for assessing risk of alcohol or drug use in pregnant women [14]. Patients were screened again during the routine history/physical examination conducted at admission for delivery. Patients who did not self-report methamphetamine use and had a negative UDS or no UDS were categorized as non-users.
Preeclampsia was defined according to the ACOG Task Force on hypertension in pregnancy [1]. Patients were classified as having mild preeclampsia if they were diagnosed as having a new onset of hypertension (systolic blood pressure > 140 mmHg, or diastolic > 90 mmHg) on two separate occasions more than 4 hours apart, with a random urine protein to creatinine ratio of greater than 0.3, or urine dipstick test with 1+ proteinuria, or atypical features of preeclampsia. Patients were classified as severe preeclampsia if they had systolic blood pressure in excess of 160 mmHg or diastolic blood pressure in excess of 105 mmHg, or evidence of end organ involvement such as a severe headache, laboratory abnormalities, oliguria (low urine output), or seizure. Patients were considered to have superimposed preeclampsia if they were diagnosed with hypertension prior to 20 weeks of gestation, and had hypertensive urgency leading to delivery, worsening proteinuria, and/or other signs of severe preeclampsia. Gestational hypertension was diagnosed when the patient had new onset abnormal blood pressure as in mild preeclampsia without proteinuria.
To measure morbidity due to preeclampsia we developed a composite measure which included the presence of any of the following: abruption, eclampsia, HELLP (hemolysis elevated liver enzymes and low platelets) syndrome, elevated aspartate aminotransferase (AST), elevated alanine transaminase (ALT), thrombocytopenia, intensive care unit (ICU) admission, use of intravenous (IV) antihypertensive agent(s) for blood pressure control, or the use of magnesium sulfate for seizure prophylaxis.
Demographic characteristics and incidence of preeclampsia were compared between methamphetamine users and non-users for the whole cohort. Student t-test and Fisher's exact test were used to compare continuous and categorical variables respectively. An alpha level of < 0.05 was used for all statistical tests. Confidence intervals were reported at the ninety-fifth percentile. All analyses were performed using IBM SPSS Statistics, v22.0.0.0.

Results
We reviewed 3,721 consecutive deliveries. Two hundred (5.4%) cases of preeclampsia were identified. Ninety-nine (2.6%) patients tested positive for methamphetamine using UDSs or self-reported methamphetamine use during pregnancy. UDS was collected in 2,419 (65%) of patients. Methamphetamine users were more likely to be older, multigravid and multiparous (see Table 1 for participant demographics). There were more Caucasian methamphetamine users, and fewer Hispanic and Black methamphetamine users, but the distribution of ethnicity between methamphetamine users and nonusers was not statistically different.
Multivariate binary logistic regression was performed to determine the impact of methamphetamine use on preeclampsia controlling for known risk factors. Control variables included age, history of preeclampsia in a prior pregnancy, nulliparity, obesity, preexisting diabetes, and chronic hypertension, and smoking (smoking has been shown to be protective against preeclampsia). Table 2 shows the results of the logistic regression model. The model has a -2 Log likelihood of 80.796, with χ 2 = 81.401, suggesting goodness of fit. There  of methamphetamine users vary by geography. The rate of methamphetamine use in our study population was slightly less reported by others [6,3,4], but more than captured when California Vital Statistics data was reviewed [7]. However, these differences may be due to the mechanism for defining or screening for methamphetamine use.
One limitation of this study was that UDS was not performed on all patients. Only methamphetamine use up to one week prior to testing is detected by a UDS [13]. Therefore, we included self-reported methamphetamine use along with UDS positive screening, with the reasoning that it would be uncommon for a patient to falsely admit to illegal activity [15] . Our rate of methamphetamine use is comparable to other reports for expected use in this area [5,3,12]. Since patients are likely to under-report methamphetamine use [15], we suspect we have underestimated the number of methamphetamine users and would therefore only have underestimated the incidence of preeclampsia in users. In addition, we are unable to quantify the dose and duration of methamphetamine exposure as we relied on selfreported use or urine drug screening to define methamphetamine use. It is possible that some users had heavy use, and others had minimal use. Further research would be necessary to determine if heavier methamphetamine use, i.e. a higher dose of methamphetamine, would results in a dose related effect on the incidence of preeclampsia [16].
Despite the increased incidence of preeclampsia in methamphetamine users, results did not indicate any differences in morbidity due to preeclampsia among methamphetamine users versus non-users. However, methamphetamine users with preeclampsia had a slightly higher peak systolic and diastolic blood pressure than nonusers with preeclampsia.
Methamphetamine is a powerful central nervous stimulant and sympathomimetic, and is associated with intrauterine growth restriction, preterm birth, and childhood behavioral problems [2,5]. The results of this study indicate we should add preeclampsia to the list of complications of methamphetamine use in pregnancy. Blood pressure monitoring and a low index of suspicion for preeclampsia may be of particular importance in women who admit to methamphetamine use during pregnancy, and active methamphetamine use should prompt initiation of bi-weekly antenatal surveillance (non-stress testing with amniotic fluid index) and blood pressure checks in the third trimester.
was no significant interaction effect between methamphetamine use and any of the variables controlled for. Results show that advanced maternal age was significantly correlated with pre-existing diabetes and chronic hypertension (p = 0.027, and p = 0.033, respectively). Obesity was also significantly correlated with chronic hypertension (p = 0.013). Methamphetamine use was the only variable significantly associated with preeclampsia (p = 0.026, CI 0.166 -0.893) ( Table 2). Table 3, there were no differences in health morbidity outcomes as a result of preeclampsia between methamphetamine users and non-users. There was no difference in composite adverse outcomes in patients with preeclampsia who used or did not use methamphetamine (2.4 ± 1.3 non-users, 2.5 ± 1.0 methamphetamine users, p = 0.563, unpaired t-test). Methamphetamine users were more likely to have had a prior pregnancy with preeclampsia (p = 0.027), to be smokers (p = 0.001), and had higher peak systolic blood pressures (159 non-users; 160 methamphetamine users; p = 0.004), and diastolic blood pressures (96 non-users; 100 methamphetamineusers; p = 0.030). However the difference in both peak systolic and peak diastolic blood pressure is minimal, hence unlikely to be of any clinical significance (Table 3).

Discussion
This study shows that methamphetamine use in pregnancy is associated with a significant increase in the incidence of preeclampsia. This is of particular importance given that methamphetamine use is increasing in the United States [3,14], and up to 7.2% of women may use methamphetamine at some point in pregnancy [4].
Methamphetamine use is a known risk factor for preterm delivery [2]. In this study, we noted a significant risk of preterm birth among methamphetamine users. In fact, about one third of methamphetamine users developed preeclampsia, and one third delivered prematurely. This study was not designed to determine the reasons for premature delivery among methamphetamine users, but we speculate that preeclampsia may be a significant contributor to the higher number of infants born prematurely. Further research is needed to determine if there is a causal relationship between methamphetamine use and preeclampsia as a reason for preterm birth.
Methamphetamine users in this study were older than controls. This was a surprising finding in comparison to the extant literature, which suggests that an age of less than 20 years to be a prominent risk factor for methamphetamine use [5]. Perhaps demographics a AST=aspartate aminotransferase, b ALT=alanine transaminase Table 3: Risk factors for preeclampsia and markers of severity of preeclampsia compared between non-users and methamphetamine users. Values are mean ± standard deviation or n (%).