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Intravenous drug use is associated with alloimmunization in pregnancy
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Intravenous drug use is associated with alloimmunization in pregnancy Q17
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Justin R. Lappen, MD; Sydney Stark, ; Kelly S. Gibson, MD; Mona Prasad, DO, MPH; Jennifer L. Bailit, MD, MPH
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BACKGROUND: Anecdotal evidence has suggested an association of
intravenous drug abuse with alloimmunization; however, published data are limited to case reports. OBJECTIVE: The purpose of this study was to determine whether women with a history of intravenous drug abuse have an increased risk of alloimmunization. STUDY DESIGN: A retrospective cohort study was performed with the use of data from a single-center blood bank and perinatal database from 2008e2014. Blood bank data were used to identify women with alloimmunization, which was defined as a positive antibody screen in pregnancy not because of a naturally occurring antibodies, agglutinins, autoantibodies, or Rh immunoglobulin administration. Intravenous drug abuse was ascertained from a comprehensive database that has captured all drug abuse in pregnancy since 2008. For women who contributed >1 pregnancy to the database, only the most recent affected pregnancy was included. The rates of alloimmunization among women with a history of intravenous drug abuse and general obstetric populations were calculated and compared with the use of the chi-squared test. The distribution of alloantibody types, proportion of Rh-group alloantibodies, and patient Rh status were assessed for intravenous and noneintravenous drug abuseeassociated alloimmunization. Characteristics and outcomes between intravenous and noneintravenous drug abuseeassociated alloimmunization were assessed for women with clinically significant alloantibodies. RESULTS: Alloimmunization was more common in women with a history of intravenous drug abuse (11/305 women; 3.6%) compared
A
lloimmunization typically arises after exposure to foreign red blood cell antigens as the result of pregnancy, transfusion, or transplantation. In pregnancy, fetal-maternal hemorrhage represents the primary exposure that results in alloimmunization through clinical events such as induced or spontaneous abortion, ectopic or molar gestation, invasive procedures such as amniocentesis or chorionic villus sampling, antenatal hemorrhage, placental
Cite this article as: Lappen JR, Stark S, Gibson KS, et al. Intravenous drug use is associated with alloimmunization in pregnancy. Am J Obstet Gynecol 2016;:. 0002-9378/$36.00 ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2016.03.019
with women with no history of intravenous drug abuse (288/16,022 women; 1.8%; relative risk, 2.00; 95% confidence interval, 1.11e3.62). Needle-sharing was present in 7 and suspected in 4 women with an intravenous drug abuse history. Among women with a history of intravenous drug abuse, none had a history of transfusion or traditional risk factor for alloimmunization. The distribution of alloantibodies was different between intravenous drug abusee and noneintravenous drug abuseeassociated alloimmunization. Rh group alloantibodies and Rh-negative status were more common in women with a history of intravenous drug abuse. Among Rh-negative women with a history of intravenous drug abuse, 50% of RhD alloimmunization cases occurred in nulliparous women. The rate of multiple alloantibodies was not different between intravenous drug abusee and noneintravenous drug abuseeassociated alloimmunization. CONCLUSION: Maternal history of intravenous drug abuse is associated with an increased risk of alloimmunization. Approximately 1 in 30 intravenous drug abuse women may be diagnosed with an alloantibody in pregnancy. Given the current US opioid epidemic, increased vigilance in screening is required. Needle-sharing represents a possible mechanism for intravenous drug abuseeassociated alloimmunization; however, limited obstetric care, failure to obtain Rh immunoglobulin, or failure to identify early pregnancy loss cannot be excluded. Key words: alloantibodies, alloimmunization, hemolytic disease of the
fetus and newborn infant, intravenous drug use, pregnancy
abruption, or maternal abdominal trauma.1 Apart from these typical risk factors, injection with needles that are contaminated by foreign red blood cell antigens has been implicated as a risk factor for alloimmunization. Initially reported in 1973, the literature contains a small number of case reports or series on intravenous drug use (IVDU) and needle-sharing that leads to rhesus (Rh) alloimmunization and, in some cases, adverse fetal outcome as the result of hemolytic disease of the fetus and newborn infant (HD).2-7 In total, 15 cases have been reported in the literature to date. However, these studies have not used a control group, assessed for potential confounding factors, assessed non-Rh antigens, or characterized the magnitude of the association
between IVDU and alloimmunization in pregnancy. Notably, over the past 2 decades, the diversion and abuse of prescription drugs, particularly opioid pain relievers, has increased markedly in the United States. Between 2002 and 2011, approximately 25 million people initiated nonmedical use of opioid pain relievers, which included many women of reproductive age.8 Furthermore, the opioid epidemic has resulted in an increase in heroin abuse and heroin-related morbidity and death.9 Consistent with this trend, observational studies have documented a 5-fold increase in maternal opioid use in pregnancy and a 3-fold increase risk in neonatal abstinence syndrome over the past 15 years.10,11
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The routine administration of prophylactic antenatal and postpartum rhesus immune globulin (RhIG) has made Rh alloimmunization a rare encounter in clinical practice in the United States. However, the recent exponential increase in opioid addition and heroin abuse among women of reproductive age may create a new epidemic of alloimmunization and HD should a link between IVDU and alloimmunization exist. Given the paucity of literature on the association of IVDU and alloimmunization in the context of the current opioid epidemic, our primary objective was to determine the presence and magnitude of the association between IVDU and alloimmunization. We also planned to characterize other pertinent clinical factors of IVDU-related alloimmunization that may be distinct from historic alloimmunization.
Materials and Methods A retrospective cohort study was performed with data from the blood bank and perinatal database at MetroHealth Medical Center in Cleveland, OH, from 2008-2014. To generate a cohort of women with alloimmunization in pregnancy, which was defined as all women with a red cell alloantibody, institutional blood bank data were used to identify all women of reproductive age (10-50 years old) with alloantibodies on a type and screen during the study epoch. To ensure all significant red blood cell alloantibodies were maintained, the following exclusion criteria were applied to the blood bank dataset: positive antibody screen because of documented RhIG administration, cold and warm agglutinins or autoantibodies, white blood cell antibodies, and samples for which no clinically significant antibody was identified. This group of women with alloantibodies was then merged against the MetroHealth Medical Center perinatal database from the same epoch to generate an alloimmunized cohort of pregnant women. The MetroHealth Medical Center perinatal database contains validated medical, obstetric, and neonatal outcome data for all patients who delivered at the MetroHealth
Medical Center since 1974. Obstetric data are entered prospectively into the computerized perinatal database by trained data entry personnel and verified against each patient’s electronic medical record by an independent reviewer. For women who contribute >1 pregnancy to the database, only the most recently affected pregnancy was included. Finally, for all women with naturally occurring antibodies (such as anti-M or anti-N), charts were reviewed, and women were excluded if chart assessment failed to identify an exposure that could result in sensitization. In response to the opioid epidemic in Northeast Ohio, MetroHealth Medical Center initiated a Mother and Child Dependency Program in 2008. This program involves a coordinated, multidisciplinary approach to perinatal care that includes maternal fetal medicine, neonatology, nursing, and social work. Detailed social histories are attempted on all patients who are involved in the program that include specific information regarding the type and route of illicit drug use, sexual history, and needlesharing. An attempt is made to obtain urine toxicology screening at the initial clinical presentation and at delivery on all patients in the program. Since the inception of the program, a separate comprehensive database that captures all substance abuse in pregnancy has been maintained. The substance abuse in pregnancy database served as the source to identify women with the exposure of IVDU in pregnancy. For the purposes of this study, needle-sharing was considered to be present if (1) a specific history was documented in the database (obtained by patient history) or if (2) women had a history of both IVDU and hepatitis C or HIV seroconversion. The latter definition was included given that parenteral exposure is the most effective mechanism of (HCV) transmission and that previous epidemiologic evidence has reported that approximately 75% of patients with IVDU in the United States have HCV.12 Therefore, seroconversion with IVDU most likely represents needlesharing. Needle-sharing was considered “suspected” among women with a
history of IVDU and new alloantibodies if there was not documentation of needle-sharing and serostatus for HIV and HCV was negative. Chart review was performed on all women with IVDU and alloimmunization to validate exposure and substance abuse history. Based on the underlying pathophysiologic mechanism that IVDU and needle-sharing results in potential exposure to all foreign red cell antigens, we first assessed the overall rates of alloimmunization in the IVDU and general obstetric populations. The distribution of alloantibody types, proportion of Rh-group alloantibodies, and patient Rh status were assessed for IVDU- and noneIVDU-associated alloimmunization. Additional analysis was then performed on the subgroup of women with clinically significant alloantibodies, which was defined as those implicated in HD. For this subgroup analysis, all cases of alloimmunization because of antibodies that were not associated with HD were then excluded.13 Charts of all patients with clinically significant alloantibodies were that were abstracted included detailed data on maternal pregnancy and obstetric history, risk factors for alloimmunization that included invasive fetal testing (CVS, amniocentesis, multifetal pregnancy reduction), history of trauma or transfusion, maternal alloantibody titers, paternal zygosity testing, and antenatal testing and/or fetal transfusion. Neonatal data included initial hemoglobin and the diagnosis and treatment for HD that included neonatal transfusion. Maternal and neonatal characteristics and outcomes between IVDU- and noneIVDU-associated alloimmunization were compared. Categoric variables were analyzed with the use of chi-squared or Fisher’s exact test, where appropriate. Continuous variables were analyzed with the use of unpaired t-tests and Wilcoxon Rank Sum, as appropriate. Analysis was performed with Stata software (version 13.1; Stata Corporation, College Station, TX). Institutional review board approval was obtained before study initiation (IRB#15-00302, approved June 14, 2015).
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279 280 281 Flow diagram of study population 282 283 Antibody Positive T&S Results for Reproductive Age Women, 2008-2014 284 N=5,251 285 286 287 Exclusion Criteria N 288 Warm/Cold Agglutinins and Autoantibodies 205 No Clinically Significant Antibody Identified 897 289 White Blood Cell Antibody 7 290 Documented RhIG Administration 1330 Duplicate entries 2196 291 292 293 294 Deliveries at MetroHealth, 2008-2014* 295 Patients with Alloantibodies N=16,327 296 N=616 297 298 299 300 301 Non-Alloimmunized Women Final Alloimmunized Cohort 302 N=16,028 303 N=299 304 305 306 307 308 History IVDU No History IVDU 309 No History IVDU History IVDU N=11 N=288 310 N=15,734 N=294 311 312 * Duplicate entries eliminated and most recent delivery maintained in database 313 . The asterisk indicates duplicate entries that were eliminated and the most recent delivery Q9 314 maintained in the database. 315 IVDU, intravenous drug use; RhIG, rhesus immune globulin; T&S, type & screen. 316 Lappen et al. Intravenous drug abuse and alloimmunization. Am J Obstet Gynecol 2016. 317 318 319 When the cohort was restricted to risk of having a critical titer (1:16) on 320 patients with clinically significant allo- presentation (50.0% vs 19.2%; P ¼ .06) 321 antibodies, the association of IVDU with or at any point in pregnancy (40.0% vs 322 alloimmunization remained statistically 23.3%; P ¼ .10) was evident in IVDU 323 significant (8 of 305 women [2.6%] vs compared with non-IVDU alloimmu324 120 of 16,022 women [0.7%]; P < .001). nization. There were no differences in 325 Clinical characteristics and pregnancy treatment or neonatal outcomes, which 326 outcomes between IVDU and none included the risk of HD. However, 50% 327 IVDU-associated alloimmunization for of the women with IVDU were HCV 328 women with clinically significant allo- positive, which potentially limited the Q7 329 antibodies are presented in Table 2. use of PUBS. ½T2 330 Women with IVDU were more likely to 331 be white and seropositive for hepatitis C, Comment 332 to initiate prenatal care late, and to have Based on data from this single-center 333 3 alloantibodies. No difference in the retrospective cohort, maternal history 334 FIGURE 1
web 4C=FPO
223 Results 224 During the study epoch, after the 225 exclusion of the women who contributed 226 multiple pregnancies to the database and 227 the maintenance of only the most recent 228 pregnancy, 16,327 women delivered at 229 MetroHealth Medical Center of whom 230 305 women (1.9%) were identified to 231 have a history of IVDU. Blood bank data 232 identified 5251 women of reproductive 233 age with a positive antibody screen 234 from 2008-2014. Application of exclu235 sion criteria and generation of the final 236 cohort of women with alloimmunization 237 238 ½F1 in pregnancy is depicted in Figure 1. Alloimmunization was more 239 common in IVDU (11 of 305 women; 240 3.6%) compared with women with no 241 IVDU (288 of 16,022 women; 1.8%; 242 relative risk, 2.00; 95% confidence 243 interval, 1.11e3.62). The distribution of 244 alloantibodies was different between 245 IVDU- and noneIVDU-associated 246 alloimmunization (Figure 2). Antibody ½F2 247 characteristics and Rh status for 248 the cohort are outlined in Table 1. ½T1 249 Rh-negative status and Rh-group allo250 antibodies were more common in 251 women with IVDU. Four Rh-negative 252 women with a history of IVDU had 253 anti-Rh group alloantibodies, all of 254 which were anti-D. However, 50% of 255 these 4 Rh-D alloimmunized women 256 were nulliparous. The rate of multiple 257 alloantibodies was not different between 258 IVDU and non-IVDU alloimmunization 259 (27.2% vs 8.0%; P ¼ .06). Chart review 260 confirmed that needle-sharing was pre261 sent in 7 and suspected in 4 women with 262 IVDU. Notably, no women with IVDU 263 had a history of transfusion or other 264 common risk factor for alloimmuniza265 tion (eg, abruption, fetal maternal 266 hemorrhage, invasive procedure in 267 pregnancy). Urine toxicology screening 268 obtained either at initial presentation to 269 care or delivery was obtained on 283 of 270 305 women (92.8%). Of the women with 271 toxicology screening, results were posi272 tive for opiates in 155 (54.8%), for 273 methadone or buprenorphine in 141 274 (49.8%), for benzodiazepines in 61 275 (21.6%), for tetrahydrocannabinol in 276 41 (14.5%), and for cocaine or other 277 drugs in 59 (20.9%). 278
Original Research
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Original Research FIGURE 2
Alloantibody distribution in intravenous drug usee and noneintravenous drug useeassociated alloimmunization IVDU
Non-IVDU
60.0%
*p<0.001
50.0%
ProporƟon
print & web 4C=FPO
335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390
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40.0% 30.0% 20.0% 10.0% 0.0%
D
c
C e Antibody Type
E
K
LEA
Other
Other: JKA, JKB, CW, COA, FYA, LUB, M, P1, PP1Pk, S, U, SDA * Comparison using Fisher’s Exact Test Q10
. The asterisk indicates that the comparison used the Fisher’s exact test.
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c, ; C, ; D, ; e, ; E, ; K, ; LEA, . Lappen et al. Intravenous drug abuse and alloimmunization. Am J Obstet Gynecol 2016.
of IVDU is associated with an increased risk of a pregnancy that is complicated by alloimmunization. Notably, approximately 1 in 30 women with IVDU will have an alloantibody in pregnancy. Needle-sharing represents a possible mechanism for IVDU-associated alloimmunization because these women were less likely to have typical obstetric risk factors for alloimmunization. However, given the increased prevalence of Rh-alloantibodies in women with IVDU, limited obstetric care, failure to obtain RhIG, or failure to
identify early pregnancy loss cannot be excluded. With the current US opioid epidemic, increased vigilance in screening and the early initiation of prenatal care among women with IVDU is required. The primary strength of this study is that it is the first to assess for the presence and magnitude of an association between IVDU and alloimmunization in a large obstetric cohort with the use of an appropriate comparison group. The published literature on IVDU-related alloimmunization is limited to case
TABLE 1
Characteristics of women with intravenous drug useerelated and noneintrauterine drug useerelated alloimmunization for the primary study cohort
Variable
Intravenous drug use (n ¼ 11), n (%)
No intravenous drug use (n ¼ 288), n (%)
P valuea
Women with Rh-group alloantibodies
8 (72.7)
84 (29.2)
.004
Rh-negative women
5 (45.5)
27 (9.4)
.003
Rh-negative women with Rh-group alloantibodyb
4 (80.0)
14 (51.9)
.34
Women with multiple alloantibodies
3 (27.2)
23 (8.0)
.06
a
b
Calculation with the use of chi-squared or Fisher’s exact test, as appropriate; All 4 Rh-negative women with Rh-group alloantibodies and a history of intravenous drug use had anti-D antibodies. Lappen et al. Intravenous drug abuse and alloimmunization. Am J Obstet Gynecol 2016.
reports, primarily secondary to Rh-D alloimmunization.2-7 The assessment of all alloantibody types, and not simply Rh-D or clinically significant antibodies, strengthens the association between IVDU and alloimmunization because the exposure of IVDU should not discriminate between red blood cell antigen types. Given the inclusion of all obstetric patients with and without alloimmunization who delivered at our urban, tertiary care center, our results should be generalizable to other diverse obstetric populations of high-risk women. The fact that women with IVDU-associated alloimmunization were less likely to have traditional risk factors for alloimmunization increases the possibility of needle-sharing as a plausible mechanism for alloimmunization in this population. Although the immune response to red blood cell antigens varies by antigen type and between individuals, previous studies have demonstrated that intravenous injection of as little as 0.1 mL of RhD-positive red blood cells can sensitize RhD-negative individuals.14 Previous assessment of syringes that were collected after IVDU have determined that up to 0.26 mL could be leftover for transfer to the next user,15 which indicates that needle-sharing may contain a red blood cell inoculum large enough to produce sensitization. Our study is not without limitations, which includes the retrospective study design. The use of a validated perinatal database, comprehensive substance abuse in pregnancy database, and blood bank data along with chart review minimizes ascertainment and classification bias. However, nondisclosed history of IVDU among the general obstetric population cannot be excluded. The fact that opioid abuse and/or withdrawal is typically clinically evident makes this possibility less likely. The inclusion of all women with a history of IVDU and alloantibodies in our cohort, and not just women with documented needle-sharing, may overestimate the association between IVDU and alloimmunization. However, the definitions of documented and suspected needlesharing that were used were strict. In
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addition, pregnant women with a history of substance abuse may be embarrassed or remorseful of their actions and may not be comfortable disclosing all high-risk behaviors to their providers. As such, under-ascertainment of needlesharing among the IVDU population would be present. The fact that women with IVDU had a higher likelihood of Rh alloantibodies could represent limited obstetric care or failure to obtain Rh immunoglobulin. The fact that 50% of the Rh-D alloimmunization cases among women with IVDU occurred in nulliparous women makes this possibility less likely. However, undocumented early pregnancy losses in a vulnerable population of women who are less likely to initiate prenatal care early cannot be excluded. As such, larger studies of women with a history of IVDU are needed to confirm our findings. Furthermore, differences in both Rh-negative status and the presence of Rh alloantibodies may reflect the statistically significant difference in racial composition between groups, because Rh-negative blood type is more common among white women compared with African American women.13 Among women of reproductive age in our region, the opioid epidemic has impacted predominantly white women; therefore, the differences between groups accurately reflects our patient population. Last, unlike traditional alloimmunization, IVDU-related alloimmunization theoretically could result in both sensitization and HD in nulliparous women by repeated antigen exposure before and throughout pregnancy. We could not assess the impact of nulliparity on the risk of alloimmunization, given the definition of our cohort, because data were available for only the most recent pregnancy for multiparous women. Needle-sharing and repeated antigen exposure may represent a mechanism that could increase the risk of achieving a critical titer in pregnancy and thereby impact the risk of HD and neonatal outcomes. Although this study did not demonstrate a difference in neonatal outcomes, the direction of the findings deserve further investigation with larger
Original Research
TABLE 2
Clinical characteristics and pregnancy outcomes between intravenous drug usee and noneintravenous drug useeassociated alloimmunization among women with clinically significant alloantibodies Intravenous drug use (n ¼ 8)
Clinical factor Mean age, y SD
27.6 3.8
No intravenous drug use (n ¼ 120)
P value
28.7 6.2
.64a
Q12
.01b
Race, n (%) White
8 (100)
59 (49.2)
Non-white
0
61 (51.8) .02b
Initiation prenatal care, n (%) 1st Trimester
1 (12.5)
73 (60.8)
2nd Trimester
4 (50)
29 (24.2)
3rd Trimester
2 (25)
8 (6.7)
Unknown/none
2 (25)
10 (8.3) .05b
RhD, n (%) Negative
4 (50)
21 (17.5)
Positive
4 (50)
99 (82.5) 0
<.01b
Hepatitis C, n (%)
4 (50)
Previous transfusion, n (%)
0
20 (16.7)
.63b
Risk factor composite, n (%)c
0
28 (23.3)
.12b
2
3 (37.5)
17 (14.2)
.11b
3
2 (25)
2 (1.7)
.02b
On initial screen
4 (50)
23 (19.2)
.06b
In pregnancy
4 (40)
28 (23.3)
.10b
25.0 5.6
.88d
Alloantibodies, n (%)
Critical titer, n (%)
Mean gestational age at initiation of MCA, wk SD PUBS, n (%)e
25.3 6.5 0
Mean delivery gestational age, wk SD Mean birthweight, g SD
37.1 (2.6) 2798.9 722.2
Hemolytic disease of the newborn infant, n (%)
2 (25)
5 (4.2) 37.0 (3.9) 2850.0 834.8 8 (6.7)
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1.0b
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.49d .87a .12b
Unpaired t-test; b c2 or Fisher’s exact test, as appropriate; c Composite: history of transfusion, CVS, amniocentesis, multifetal reduction, external cephalic version, antepartum bleeding, abruption, trauma, IUFD; d Wilcoxon rank sum; e 3 of 4 women in the intravenous drug use group with a critical titer were hepatitis C positive. Lappen et al. Intravenous drug abuse and alloimmunization. Am J Obstet Gynecol 2016. a
studies. Among the subgroup with clinically significant alloantibodies, women with IVDU were more likely to have 3 alloantibodies. Recent data by Markham et al16 suggest that women with multiple red cell alloantibodies have a higher risk for the development of HD. Although there was not a difference in
HD between IVDU and noneIVDUalloimmunization in our cohort, our study is underpowered to assess this outcome. In summary, maternal history of IVDU is associated with an increased risk of a pregnancy that is complicated by alloimmunization. The 2-fold
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magnitude of this risk in the setting of the current US opioid epidemic should prompt recommendations for increased screening and the early establishment of prenatal care for women with a history of or ongoing IVDU. Given the implications of alloimmunization on obstetric and neonatal outcomes and transfusion medicine, ongoing studies to confirm our findings and to assess maternal and neonatal outcomes of IVDU-associated alloimmunization are warranted. n References 1. Moise KJ. Management of rhesus alloimmunization in pregnancy. Obstet Gynecol 2008; 112:164-76. 2. Vontver LA. Rh sensitization associated with drug abuse (letter). JAMA 1973;226:469. 3. McVerry BA, O’Connor MC, Price A, et al. Isoimmunization after narcotic addition. BMJ 1977;1:1324-5. 4. Chin-Yee I, Dietz GE, Marshall JV. Alloimmunization and intravenous drug abuse. CMAJ 1989;141:1160-1. 5. Bowman JM, Manning FA, Harman CR. Alloimmunization and intravenous drug abuse (letter). CMAJ 1990;142:439. 6. Bowman J, Harman C, Manning F, Menticoglou S, Pollock J. Intravenous drug
abuse causes Rh immunization. Vox Sang 1991;61:96-8. 7. Dimer JA, David M, Dudenhausen JW. Intravenous drug abuse is an indication for antepartum screening for RH alloimmunization: a case report and review of literature. Arch Gynecol Obstet 1999;263:73-5. 8. Results from the 2011 National Survey on Drug Use and Health: summary of national findings. (NSDUH series H-44,HHS publication no. (SMA) 12-4713.) Rockville (MD): Substance Abuse and Mental Health Services Administration; 2012. 9. Muhuri PK, Gfroerer JC, Davies MC. Associations of nonmedical pain reliever use and initiation of heroin use in the United States. CBHSQ Data Rev. Aug. Available at: http://www.samhsa. gov/data/sites/default/files/DR006/DR006/non medical-pain-reliever-use-2013.htm. Accessed: . 10. Patrick SW, Schumacher RE, Benneyworth BD, Krans EE, McAllister JM, Davis MM. Neonatal abstinence syndrome and associated healthcare expenditures. JAMA 2012;307:1934-40. 11. Kellogg A, Rose CH, Harms RH, Watson WJ. Current trends in narcotic abuse in pregnancy and neonatal outcomes. Am J Obstet Gynecol 2011;204:259.e1-4. 12. Nelson PK, Mathers BM, Cowie B, et al. Global epidemiology of hepatitis B and hepatitis C in people who inject drugs: results of systematic reviews. Lancet 2011;378:571.
13. Moise KJ. Hemolytic disease of the newborn. In: Creasy RK, Resnik R, Iams JD, eds. Maternal-fetal medicine principles and practice, 7th ed. Philadelphia: Saunders; 2013: 558-68. 14. Zipursky A, Israels LG. The pathogenesis and prevention of Rh immunization. Can Med Assoc J 1967;97:1245-57. 15. Hoffman PN, Larkin DP, Samuel D. Needlestick and needle-share: the difference. J Infect Dis 1989;160:545-6. 16. Markham KB, Rossi KQ, Nagaraja HN, O’Shaughnessy RW. Hemolytic disease of the fetus and newborn due to multiple maternal antibodies. Am J Obstet Gynecol 2015;213:68. e1-5.
Author and article information From Division of Maternal Fetal Medicine, MetroHealth Q8 Medical Center (Drs Lappen, Gibson, and Bailit), Case Western Reserve University ( Stark) School of Q3 Medicine, Cleveland, OH; and Ohio State University College of Medicine and Mt. Carmel Medical Center, Columbus, OH (Dr Prasad). Received Dec. 8, 2015; revised Feb. 26, 2016; accepted March 10, 2016. The authors report no conflict of interest. Presented as a poster at the Society for Maternal Fetal Medicine 36th Annual Meeting, Atlanta, GA, February Q4 , 2016. Corresponding author: Justin R. Lappen, MD. [email protected]
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Intravenous drug use is associated with alloimmunization in pregnancy Q17
Q1
Justin R. Lappen, MD; Sydney Stark, ; Kelly S. Gibson, MD; Mona Prasad, DO, MPH; Jennifer L. Bailit, MD, MPH
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BACKGROUND: Anecdotal evidence has suggested an association of
intravenous drug abuse with alloimmunization; however, published data are limited to case reports. OBJECTIVE: The purpose of this study was to determine whether women with a history of intravenous drug abuse have an increased risk of alloimmunization. STUDY DESIGN: A retrospective cohort study was performed with the use of data from a single-center blood bank and perinatal database from 2008e2014. Blood bank data were used to identify women with alloimmunization, which was defined as a positive antibody screen in pregnancy not because of a naturally occurring antibodies, agglutinins, autoantibodies, or Rh immunoglobulin administration. Intravenous drug abuse was ascertained from a comprehensive database that has captured all drug abuse in pregnancy since 2008. For women who contributed >1 pregnancy to the database, only the most recent affected pregnancy was included. The rates of alloimmunization among women with a history of intravenous drug abuse and general obstetric populations were calculated and compared with the use of the chi-squared test. The distribution of alloantibody types, proportion of Rh-group alloantibodies, and patient Rh status were assessed for intravenous and noneintravenous drug abuseeassociated alloimmunization. Characteristics and outcomes between intravenous and noneintravenous drug abuseeassociated alloimmunization were assessed for women with clinically significant alloantibodies. RESULTS: Alloimmunization was more common in women with a history of intravenous drug abuse (11/305 women; 3.6%) compared
A
lloimmunization typically arises after exposure to foreign red blood cell antigens as the result of pregnancy, transfusion, or transplantation. In pregnancy, fetal-maternal hemorrhage represents the primary exposure that results in alloimmunization through clinical events such as induced or spontaneous abortion, ectopic or molar gestation, invasive procedures such as amniocentesis or chorionic villus sampling, antenatal hemorrhage, placental
Cite this article as: Lappen JR, Stark S, Gibson KS, et al. Intravenous drug use is associated with alloimmunization in pregnancy. Am J Obstet Gynecol 2016;:. 0002-9378/$36.00 ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2016.03.019
with women with no history of intravenous drug abuse (288/16,022 women; 1.8%; relative risk, 2.00; 95% confidence interval, 1.11e3.62). Needle-sharing was present in 7 and suspected in 4 women with an intravenous drug abuse history. Among women with a history of intravenous drug abuse, none had a history of transfusion or traditional risk factor for alloimmunization. The distribution of alloantibodies was different between intravenous drug abusee and noneintravenous drug abuseeassociated alloimmunization. Rh group alloantibodies and Rh-negative status were more common in women with a history of intravenous drug abuse. Among Rh-negative women with a history of intravenous drug abuse, 50% of RhD alloimmunization cases occurred in nulliparous women. The rate of multiple alloantibodies was not different between intravenous drug abusee and noneintravenous drug abuseeassociated alloimmunization. CONCLUSION: Maternal history of intravenous drug abuse is associated with an increased risk of alloimmunization. Approximately 1 in 30 intravenous drug abuse women may be diagnosed with an alloantibody in pregnancy. Given the current US opioid epidemic, increased vigilance in screening is required. Needle-sharing represents a possible mechanism for intravenous drug abuseeassociated alloimmunization; however, limited obstetric care, failure to obtain Rh immunoglobulin, or failure to identify early pregnancy loss cannot be excluded. Key words: alloantibodies, alloimmunization, hemolytic disease of the
fetus and newborn infant, intravenous drug use, pregnancy
abruption, or maternal abdominal trauma.1 Apart from these typical risk factors, injection with needles that are contaminated by foreign red blood cell antigens has been implicated as a risk factor for alloimmunization. Initially reported in 1973, the literature contains a small number of case reports or series on intravenous drug use (IVDU) and needle-sharing that leads to rhesus (Rh) alloimmunization and, in some cases, adverse fetal outcome as the result of hemolytic disease of the fetus and newborn infant (HD).2-7 In total, 15 cases have been reported in the literature to date. However, these studies have not used a control group, assessed for potential confounding factors, assessed non-Rh antigens, or characterized the magnitude of the association
between IVDU and alloimmunization in pregnancy. Notably, over the past 2 decades, the diversion and abuse of prescription drugs, particularly opioid pain relievers, has increased markedly in the United States. Between 2002 and 2011, approximately 25 million people initiated nonmedical use of opioid pain relievers, which included many women of reproductive age.8 Furthermore, the opioid epidemic has resulted in an increase in heroin abuse and heroin-related morbidity and death.9 Consistent with this trend, observational studies have documented a 5-fold increase in maternal opioid use in pregnancy and a 3-fold increase risk in neonatal abstinence syndrome over the past 15 years.10,11
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The routine administration of prophylactic antenatal and postpartum rhesus immune globulin (RhIG) has made Rh alloimmunization a rare encounter in clinical practice in the United States. However, the recent exponential increase in opioid addition and heroin abuse among women of reproductive age may create a new epidemic of alloimmunization and HD should a link between IVDU and alloimmunization exist. Given the paucity of literature on the association of IVDU and alloimmunization in the context of the current opioid epidemic, our primary objective was to determine the presence and magnitude of the association between IVDU and alloimmunization. We also planned to characterize other pertinent clinical factors of IVDU-related alloimmunization that may be distinct from historic alloimmunization.
Materials and Methods A retrospective cohort study was performed with data from the blood bank and perinatal database at MetroHealth Medical Center in Cleveland, OH, from 2008-2014. To generate a cohort of women with alloimmunization in pregnancy, which was defined as all women with a red cell alloantibody, institutional blood bank data were used to identify all women of reproductive age (10-50 years old) with alloantibodies on a type and screen during the study epoch. To ensure all significant red blood cell alloantibodies were maintained, the following exclusion criteria were applied to the blood bank dataset: positive antibody screen because of documented RhIG administration, cold and warm agglutinins or autoantibodies, white blood cell antibodies, and samples for which no clinically significant antibody was identified. This group of women with alloantibodies was then merged against the MetroHealth Medical Center perinatal database from the same epoch to generate an alloimmunized cohort of pregnant women. The MetroHealth Medical Center perinatal database contains validated medical, obstetric, and neonatal outcome data for all patients who delivered at the MetroHealth
Medical Center since 1974. Obstetric data are entered prospectively into the computerized perinatal database by trained data entry personnel and verified against each patient’s electronic medical record by an independent reviewer. For women who contribute >1 pregnancy to the database, only the most recently affected pregnancy was included. Finally, for all women with naturally occurring antibodies (such as anti-M or anti-N), charts were reviewed, and women were excluded if chart assessment failed to identify an exposure that could result in sensitization. In response to the opioid epidemic in Northeast Ohio, MetroHealth Medical Center initiated a Mother and Child Dependency Program in 2008. This program involves a coordinated, multidisciplinary approach to perinatal care that includes maternal fetal medicine, neonatology, nursing, and social work. Detailed social histories are attempted on all patients who are involved in the program that include specific information regarding the type and route of illicit drug use, sexual history, and needlesharing. An attempt is made to obtain urine toxicology screening at the initial clinical presentation and at delivery on all patients in the program. Since the inception of the program, a separate comprehensive database that captures all substance abuse in pregnancy has been maintained. The substance abuse in pregnancy database served as the source to identify women with the exposure of IVDU in pregnancy. For the purposes of this study, needle-sharing was considered to be present if (1) a specific history was documented in the database (obtained by patient history) or if (2) women had a history of both IVDU and hepatitis C or HIV seroconversion. The latter definition was included given that parenteral exposure is the most effective mechanism of (HCV) transmission and that previous epidemiologic evidence has reported that approximately 75% of patients with IVDU in the United States have HCV.12 Therefore, seroconversion with IVDU most likely represents needlesharing. Needle-sharing was considered “suspected” among women with a
history of IVDU and new alloantibodies if there was not documentation of needle-sharing and serostatus for HIV and HCV was negative. Chart review was performed on all women with IVDU and alloimmunization to validate exposure and substance abuse history. Based on the underlying pathophysiologic mechanism that IVDU and needle-sharing results in potential exposure to all foreign red cell antigens, we first assessed the overall rates of alloimmunization in the IVDU and general obstetric populations. The distribution of alloantibody types, proportion of Rh-group alloantibodies, and patient Rh status were assessed for IVDU- and noneIVDU-associated alloimmunization. Additional analysis was then performed on the subgroup of women with clinically significant alloantibodies, which was defined as those implicated in HD. For this subgroup analysis, all cases of alloimmunization because of antibodies that were not associated with HD were then excluded.13 Charts of all patients with clinically significant alloantibodies were that were abstracted included detailed data on maternal pregnancy and obstetric history, risk factors for alloimmunization that included invasive fetal testing (CVS, amniocentesis, multifetal pregnancy reduction), history of trauma or transfusion, maternal alloantibody titers, paternal zygosity testing, and antenatal testing and/or fetal transfusion. Neonatal data included initial hemoglobin and the diagnosis and treatment for HD that included neonatal transfusion. Maternal and neonatal characteristics and outcomes between IVDU- and noneIVDU-associated alloimmunization were compared. Categoric variables were analyzed with the use of chi-squared or Fisher’s exact test, where appropriate. Continuous variables were analyzed with the use of unpaired t-tests and Wilcoxon Rank Sum, as appropriate. Analysis was performed with Stata software (version 13.1; Stata Corporation, College Station, TX). Institutional review board approval was obtained before study initiation (IRB#15-00302, approved June 14, 2015).
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279 280 281 Flow diagram of study population 282 283 Antibody Positive T&S Results for Reproductive Age Women, 2008-2014 284 N=5,251 285 286 287 Exclusion Criteria N 288 Warm/Cold Agglutinins and Autoantibodies 205 No Clinically Significant Antibody Identified 897 289 White Blood Cell Antibody 7 290 Documented RhIG Administration 1330 Duplicate entries 2196 291 292 293 294 Deliveries at MetroHealth, 2008-2014* 295 Patients with Alloantibodies N=16,327 296 N=616 297 298 299 300 301 Non-Alloimmunized Women Final Alloimmunized Cohort 302 N=16,028 303 N=299 304 305 306 307 308 History IVDU No History IVDU 309 No History IVDU History IVDU N=11 N=288 310 N=15,734 N=294 311 312 * Duplicate entries eliminated and most recent delivery maintained in database 313 . The asterisk indicates duplicate entries that were eliminated and the most recent delivery Q9 314 maintained in the database. 315 IVDU, intravenous drug use; RhIG, rhesus immune globulin; T&S, type & screen. 316 Lappen et al. Intravenous drug abuse and alloimmunization. Am J Obstet Gynecol 2016. 317 318 319 When the cohort was restricted to risk of having a critical titer (1:16) on 320 patients with clinically significant allo- presentation (50.0% vs 19.2%; P ¼ .06) 321 antibodies, the association of IVDU with or at any point in pregnancy (40.0% vs 322 alloimmunization remained statistically 23.3%; P ¼ .10) was evident in IVDU 323 significant (8 of 305 women [2.6%] vs compared with non-IVDU alloimmu324 120 of 16,022 women [0.7%]; P < .001). nization. There were no differences in 325 Clinical characteristics and pregnancy treatment or neonatal outcomes, which 326 outcomes between IVDU and none included the risk of HD. However, 50% 327 IVDU-associated alloimmunization for of the women with IVDU were HCV 328 women with clinically significant allo- positive, which potentially limited the Q7 329 antibodies are presented in Table 2. use of PUBS. ½T2 330 Women with IVDU were more likely to 331 be white and seropositive for hepatitis C, Comment 332 to initiate prenatal care late, and to have Based on data from this single-center 333 3 alloantibodies. No difference in the retrospective cohort, maternal history 334 FIGURE 1
web 4C=FPO
223 Results 224 During the study epoch, after the 225 exclusion of the women who contributed 226 multiple pregnancies to the database and 227 the maintenance of only the most recent 228 pregnancy, 16,327 women delivered at 229 MetroHealth Medical Center of whom 230 305 women (1.9%) were identified to 231 have a history of IVDU. Blood bank data 232 identified 5251 women of reproductive 233 age with a positive antibody screen 234 from 2008-2014. Application of exclu235 sion criteria and generation of the final 236 cohort of women with alloimmunization 237 238 ½F1 in pregnancy is depicted in Figure 1. Alloimmunization was more 239 common in IVDU (11 of 305 women; 240 3.6%) compared with women with no 241 IVDU (288 of 16,022 women; 1.8%; 242 relative risk, 2.00; 95% confidence 243 interval, 1.11e3.62). The distribution of 244 alloantibodies was different between 245 IVDU- and noneIVDU-associated 246 alloimmunization (Figure 2). Antibody ½F2 247 characteristics and Rh status for 248 the cohort are outlined in Table 1. ½T1 249 Rh-negative status and Rh-group allo250 antibodies were more common in 251 women with IVDU. Four Rh-negative 252 women with a history of IVDU had 253 anti-Rh group alloantibodies, all of 254 which were anti-D. However, 50% of 255 these 4 Rh-D alloimmunized women 256 were nulliparous. The rate of multiple 257 alloantibodies was not different between 258 IVDU and non-IVDU alloimmunization 259 (27.2% vs 8.0%; P ¼ .06). Chart review 260 confirmed that needle-sharing was pre261 sent in 7 and suspected in 4 women with 262 IVDU. Notably, no women with IVDU 263 had a history of transfusion or other 264 common risk factor for alloimmuniza265 tion (eg, abruption, fetal maternal 266 hemorrhage, invasive procedure in 267 pregnancy). Urine toxicology screening 268 obtained either at initial presentation to 269 care or delivery was obtained on 283 of 270 305 women (92.8%). Of the women with 271 toxicology screening, results were posi272 tive for opiates in 155 (54.8%), for 273 methadone or buprenorphine in 141 274 (49.8%), for benzodiazepines in 61 275 (21.6%), for tetrahydrocannabinol in 276 41 (14.5%), and for cocaine or other 277 drugs in 59 (20.9%). 278
Original Research
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Original Research FIGURE 2
Alloantibody distribution in intravenous drug usee and noneintravenous drug useeassociated alloimmunization IVDU
Non-IVDU
60.0%
*p<0.001
50.0%
ProporƟon
print & web 4C=FPO
335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390
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40.0% 30.0% 20.0% 10.0% 0.0%
D
c
C e Antibody Type
E
K
LEA
Other
Other: JKA, JKB, CW, COA, FYA, LUB, M, P1, PP1Pk, S, U, SDA * Comparison using Fisher’s Exact Test Q10
. The asterisk indicates that the comparison used the Fisher’s exact test.
Q11
c, ; C, ; D, ; e, ; E, ; K, ; LEA, . Lappen et al. Intravenous drug abuse and alloimmunization. Am J Obstet Gynecol 2016.
of IVDU is associated with an increased risk of a pregnancy that is complicated by alloimmunization. Notably, approximately 1 in 30 women with IVDU will have an alloantibody in pregnancy. Needle-sharing represents a possible mechanism for IVDU-associated alloimmunization because these women were less likely to have typical obstetric risk factors for alloimmunization. However, given the increased prevalence of Rh-alloantibodies in women with IVDU, limited obstetric care, failure to obtain RhIG, or failure to
identify early pregnancy loss cannot be excluded. With the current US opioid epidemic, increased vigilance in screening and the early initiation of prenatal care among women with IVDU is required. The primary strength of this study is that it is the first to assess for the presence and magnitude of an association between IVDU and alloimmunization in a large obstetric cohort with the use of an appropriate comparison group. The published literature on IVDU-related alloimmunization is limited to case
TABLE 1
Characteristics of women with intravenous drug useerelated and noneintrauterine drug useerelated alloimmunization for the primary study cohort
Variable
Intravenous drug use (n ¼ 11), n (%)
No intravenous drug use (n ¼ 288), n (%)
P valuea
Women with Rh-group alloantibodies
8 (72.7)
84 (29.2)
.004
Rh-negative women
5 (45.5)
27 (9.4)
.003
Rh-negative women with Rh-group alloantibodyb
4 (80.0)
14 (51.9)
.34
Women with multiple alloantibodies
3 (27.2)
23 (8.0)
.06
a
b
Calculation with the use of chi-squared or Fisher’s exact test, as appropriate; All 4 Rh-negative women with Rh-group alloantibodies and a history of intravenous drug use had anti-D antibodies. Lappen et al. Intravenous drug abuse and alloimmunization. Am J Obstet Gynecol 2016.
reports, primarily secondary to Rh-D alloimmunization.2-7 The assessment of all alloantibody types, and not simply Rh-D or clinically significant antibodies, strengthens the association between IVDU and alloimmunization because the exposure of IVDU should not discriminate between red blood cell antigen types. Given the inclusion of all obstetric patients with and without alloimmunization who delivered at our urban, tertiary care center, our results should be generalizable to other diverse obstetric populations of high-risk women. The fact that women with IVDU-associated alloimmunization were less likely to have traditional risk factors for alloimmunization increases the possibility of needle-sharing as a plausible mechanism for alloimmunization in this population. Although the immune response to red blood cell antigens varies by antigen type and between individuals, previous studies have demonstrated that intravenous injection of as little as 0.1 mL of RhD-positive red blood cells can sensitize RhD-negative individuals.14 Previous assessment of syringes that were collected after IVDU have determined that up to 0.26 mL could be leftover for transfer to the next user,15 which indicates that needle-sharing may contain a red blood cell inoculum large enough to produce sensitization. Our study is not without limitations, which includes the retrospective study design. The use of a validated perinatal database, comprehensive substance abuse in pregnancy database, and blood bank data along with chart review minimizes ascertainment and classification bias. However, nondisclosed history of IVDU among the general obstetric population cannot be excluded. The fact that opioid abuse and/or withdrawal is typically clinically evident makes this possibility less likely. The inclusion of all women with a history of IVDU and alloantibodies in our cohort, and not just women with documented needle-sharing, may overestimate the association between IVDU and alloimmunization. However, the definitions of documented and suspected needlesharing that were used were strict. In
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addition, pregnant women with a history of substance abuse may be embarrassed or remorseful of their actions and may not be comfortable disclosing all high-risk behaviors to their providers. As such, under-ascertainment of needlesharing among the IVDU population would be present. The fact that women with IVDU had a higher likelihood of Rh alloantibodies could represent limited obstetric care or failure to obtain Rh immunoglobulin. The fact that 50% of the Rh-D alloimmunization cases among women with IVDU occurred in nulliparous women makes this possibility less likely. However, undocumented early pregnancy losses in a vulnerable population of women who are less likely to initiate prenatal care early cannot be excluded. As such, larger studies of women with a history of IVDU are needed to confirm our findings. Furthermore, differences in both Rh-negative status and the presence of Rh alloantibodies may reflect the statistically significant difference in racial composition between groups, because Rh-negative blood type is more common among white women compared with African American women.13 Among women of reproductive age in our region, the opioid epidemic has impacted predominantly white women; therefore, the differences between groups accurately reflects our patient population. Last, unlike traditional alloimmunization, IVDU-related alloimmunization theoretically could result in both sensitization and HD in nulliparous women by repeated antigen exposure before and throughout pregnancy. We could not assess the impact of nulliparity on the risk of alloimmunization, given the definition of our cohort, because data were available for only the most recent pregnancy for multiparous women. Needle-sharing and repeated antigen exposure may represent a mechanism that could increase the risk of achieving a critical titer in pregnancy and thereby impact the risk of HD and neonatal outcomes. Although this study did not demonstrate a difference in neonatal outcomes, the direction of the findings deserve further investigation with larger
Original Research
TABLE 2
Clinical characteristics and pregnancy outcomes between intravenous drug usee and noneintravenous drug useeassociated alloimmunization among women with clinically significant alloantibodies Intravenous drug use (n ¼ 8)
Clinical factor Mean age, y SD
27.6 3.8
No intravenous drug use (n ¼ 120)
P value
28.7 6.2
.64a
Q12
.01b
Race, n (%) White
8 (100)
59 (49.2)
Non-white
0
61 (51.8) .02b
Initiation prenatal care, n (%) 1st Trimester
1 (12.5)
73 (60.8)
2nd Trimester
4 (50)
29 (24.2)
3rd Trimester
2 (25)
8 (6.7)
Unknown/none
2 (25)
10 (8.3) .05b
RhD, n (%) Negative
4 (50)
21 (17.5)
Positive
4 (50)
99 (82.5) 0
<.01b
Hepatitis C, n (%)
4 (50)
Previous transfusion, n (%)
0
20 (16.7)
.63b
Risk factor composite, n (%)c
0
28 (23.3)
.12b
2
3 (37.5)
17 (14.2)
.11b
3
2 (25)
2 (1.7)
.02b
On initial screen
4 (50)
23 (19.2)
.06b
In pregnancy
4 (40)
28 (23.3)
.10b
25.0 5.6
.88d
Alloantibodies, n (%)
Critical titer, n (%)
Mean gestational age at initiation of MCA, wk SD PUBS, n (%)e
25.3 6.5 0
Mean delivery gestational age, wk SD Mean birthweight, g SD
37.1 (2.6) 2798.9 722.2
Hemolytic disease of the newborn infant, n (%)
2 (25)
5 (4.2) 37.0 (3.9) 2850.0 834.8 8 (6.7)
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1.0b
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.49d .87a .12b
Unpaired t-test; b c2 or Fisher’s exact test, as appropriate; c Composite: history of transfusion, CVS, amniocentesis, multifetal reduction, external cephalic version, antepartum bleeding, abruption, trauma, IUFD; d Wilcoxon rank sum; e 3 of 4 women in the intravenous drug use group with a critical titer were hepatitis C positive. Lappen et al. Intravenous drug abuse and alloimmunization. Am J Obstet Gynecol 2016. a
studies. Among the subgroup with clinically significant alloantibodies, women with IVDU were more likely to have 3 alloantibodies. Recent data by Markham et al16 suggest that women with multiple red cell alloantibodies have a higher risk for the development of HD. Although there was not a difference in
HD between IVDU and noneIVDUalloimmunization in our cohort, our study is underpowered to assess this outcome. In summary, maternal history of IVDU is associated with an increased risk of a pregnancy that is complicated by alloimmunization. The 2-fold
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magnitude of this risk in the setting of the current US opioid epidemic should prompt recommendations for increased screening and the early establishment of prenatal care for women with a history of or ongoing IVDU. Given the implications of alloimmunization on obstetric and neonatal outcomes and transfusion medicine, ongoing studies to confirm our findings and to assess maternal and neonatal outcomes of IVDU-associated alloimmunization are warranted. n References 1. Moise KJ. Management of rhesus alloimmunization in pregnancy. Obstet Gynecol 2008; 112:164-76. 2. Vontver LA. Rh sensitization associated with drug abuse (letter). JAMA 1973;226:469. 3. McVerry BA, O’Connor MC, Price A, et al. Isoimmunization after narcotic addition. BMJ 1977;1:1324-5. 4. Chin-Yee I, Dietz GE, Marshall JV. Alloimmunization and intravenous drug abuse. CMAJ 1989;141:1160-1. 5. Bowman JM, Manning FA, Harman CR. Alloimmunization and intravenous drug abuse (letter). CMAJ 1990;142:439. 6. Bowman J, Harman C, Manning F, Menticoglou S, Pollock J. Intravenous drug
abuse causes Rh immunization. Vox Sang 1991;61:96-8. 7. Dimer JA, David M, Dudenhausen JW. Intravenous drug abuse is an indication for antepartum screening for RH alloimmunization: a case report and review of literature. Arch Gynecol Obstet 1999;263:73-5. 8. Results from the 2011 National Survey on Drug Use and Health: summary of national findings. (NSDUH series H-44,HHS publication no. (SMA) 12-4713.) Rockville (MD): Substance Abuse and Mental Health Services Administration; 2012. 9. Muhuri PK, Gfroerer JC, Davies MC. Associations of nonmedical pain reliever use and initiation of heroin use in the United States. CBHSQ Data Rev. Aug. Available at: http://www.samhsa. gov/data/sites/default/files/DR006/DR006/non medical-pain-reliever-use-2013.htm. Accessed: . 10. Patrick SW, Schumacher RE, Benneyworth BD, Krans EE, McAllister JM, Davis MM. Neonatal abstinence syndrome and associated healthcare expenditures. JAMA 2012;307:1934-40. 11. Kellogg A, Rose CH, Harms RH, Watson WJ. Current trends in narcotic abuse in pregnancy and neonatal outcomes. Am J Obstet Gynecol 2011;204:259.e1-4. 12. Nelson PK, Mathers BM, Cowie B, et al. Global epidemiology of hepatitis B and hepatitis C in people who inject drugs: results of systematic reviews. Lancet 2011;378:571.
13. Moise KJ. Hemolytic disease of the newborn. In: Creasy RK, Resnik R, Iams JD, eds. Maternal-fetal medicine principles and practice, 7th ed. Philadelphia: Saunders; 2013: 558-68. 14. Zipursky A, Israels LG. The pathogenesis and prevention of Rh immunization. Can Med Assoc J 1967;97:1245-57. 15. Hoffman PN, Larkin DP, Samuel D. Needlestick and needle-share: the difference. J Infect Dis 1989;160:545-6. 16. Markham KB, Rossi KQ, Nagaraja HN, O’Shaughnessy RW. Hemolytic disease of the fetus and newborn due to multiple maternal antibodies. Am J Obstet Gynecol 2015;213:68. e1-5.
Author and article information From Division of Maternal Fetal Medicine, MetroHealth Q8 Medical Center (Drs Lappen, Gibson, and Bailit), Case Western Reserve University ( Stark) School of Q3 Medicine, Cleveland, OH; and Ohio State University College of Medicine and Mt. Carmel Medical Center, Columbus, OH (Dr Prasad). Received Dec. 8, 2015; revised Feb. 26, 2016; accepted March 10, 2016. The authors report no conflict of interest. Presented as a poster at the Society for Maternal Fetal Medicine 36th Annual Meeting, Atlanta, GA, February Q4 , 2016. Corresponding author: Justin R. Lappen, MD. [email protected]
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