DRUGS IN PREGNANCY
Obstetrical and Neonatal Outcomes of Methadone-Maintained Pregnant Women: A Canadian Multisite Cohort Study Alice Ordean, MD, CCFP, MHSc, FCFP,1,2 Meldon Kahan, MD, CCFP, FRCPC, FCFP,2,3 Lisa Graves, MD, CCFP, FCFP,2,4 Ron Abrahams, MD, CCFP, FCFP,5,6,7 Theresa Kim, BSc, MSc8 Toronto Centre for Substance Use in Pregnancy, St. Joseph’s Health Centre, Toronto ON
1
Department of Family and Community Medicine, University of Toronto, Toronto ON
2
Substance Use Service, Women’s College Hospital, Toronto ON
3
Department of Family and Community Medicine, St. Michael’s Hospital, Toronto ON
4
Perinatal Addictions, BC Women’s Hospital, Vancouver BC
5
Sheway Clinic, Vancouver BC
6
Department of Family Practice, University of British Columbia, Vancouver BC
7
School of Kinesiology and Health Science, York University, Toronto ON
8
Abstract Objective: To describe obstetrical and neonatal outcomes including neonatal abstinence syndrome (NAS) in a Canadian cohort of methadone-maintained pregnant women. Methods: We conducted a retrospective chart review at three integrated care programs in Vancouver, Toronto, and Montreal. Pregnant women on methadone maintenance treatment (MMT) who attended for care between 1997 and 2009 were included in this multisite study. Maternal and neonatal outcomes in each of the three contributing centres were compared. Results: A total of 94 pregnant methadone-maintained women were included in the final analysis: 36 from Toronto, 36 from Vancouver, and 22 from Montreal. Maternal demographics showed inter-site differences in ethnicity and marital status. Obstetrical complications were not frequent; the most frequent was antenatal hemorrhage, which occurred in 14% of the total cohort. The incidence of premature labour was significantly higher in Vancouver and Montreal than in Toronto. The mean gestational age at delivery for the entire cohort was 38 weeks; mean birth weight was 2856 grams. The average length of hospital stay for babies with NAS was 19 days, with 27% of neonates requiring pharmacological treatment for NAS. Approximately 60% of neonates were discharged from hospital to the care of their mother.
Key Words: Prenatal care, methadone, pregnancy complications, neonatal abstinence syndrome Competing Interests: None declared. Received on July 9, 2014 Accepted on October 8, 2014
252 l MARCH JOGC MARS 2015
Conclusion: Integrated care programs resulted in satisfactory obstetrical and neonatal outcomes for pregnant women on MMT. Policies promoting maternal–newborn contact, rooming-in, and breastfeeding may help to decrease the severity of NAS and the need for pharmacological treatment of NAS. We strongly recommend the development of similar programs across Canada to address gaps in services.
Résumé Objectif : Décrire les issues obstétricales et néonatales, y compris le syndrome d’abstinence néonatal (SAN), au sein d’une cohorte canadienne de femmes enceintes recevant un traitement de substitution à la méthadone. Méthodes : Nous avons mené une analyse de dossiers rétrospective au sein de trois programmes de soins intégrés à Vancouver, à Toronto et à Montréal. Les femmes enceintes recevant un traitement de substitution à la méthadone (TSM) qui ont sollicité les services de ces programmes entre 1997 et 2009 ont été admises à cette étude multisite. Les issues maternelles et néonatales constatées au sein de chacun des centres participants ont été comparées. Résultats : En tout, 94 femmes enceintes recevant un traitement de substitution à la méthadone ont été admises à l’analyse finale : 36 de Toronto, 36 de Vancouver et 22 de Montréal. Les caractéristiques démographiques maternelles ont révélé la présence de différences entre les programmes en matière d’ethnicité et d’état matrimonial. Les complications obstétricales n’ont pas été fréquentes : la plus fréquente a été l’hémorragie prénatale, laquelle a été constatée chez 14 % des femmes de la cohorte entière. L’incidence du travail prématuré était considérablement plus élevée à Vancouver et à Montréal qu’à Toronto. Pour l’ensemble de la cohorte, l’âge gestationnel moyen au moment de l’accouchement a été de 38 semaines; le poids de
Obstetrical and Neonatal Outcomes of Methadone-Maintained Pregnant Women: A Canadian Multisite Cohort Study
naissance moyen a été de 2 856 grammes. La durée moyenne de l’hospitalisation des nouveau-nés présentant un SAN a été de 19 jours, 27 % d’entre eux ayant nécessité une pharmacothérapie pour contrer le SAN. Environ 60 % des nouveau-nés ont été remis à leur mère à la suite de l’obtention de leur congé de l’hôpital. Conclusion : Les programmes de soins intégrés ont permis l’obtention d’issues obstétricales et néonatales satisfaisantes chez les femmes enceintes recevant un TSM. Les politiques favorisant les contacts entre la mère et le nouveau-né, le partage de la même chambre d’hôpital et l’allaitement pourraient contribuer à atténuer la gravité du SAN et la nécessité d’avoir recours à une pharmacothérapie pour contrer le SAN. Nous recommandons fortement la mise sur pied de programmes similaires partout au Canada afin de combler les écarts en matière de services. J Obstet Gynaecol Can 2015;37(3):252–257
INTRODUCTION
T
he prevalence of perinatal opioid use has been increasing over the past decade.1–3 Opioid use during pregnancy can lead to adverse obstetrical and neonatal outcomes, including an increased risk of intrauterine growth restriction, prematurity, and neonatal abstinence syndrome.4 Data from the Canadian Institute for Health Information have demonstrated that the incidence of NAS in Ontario increased from 1.3 to 3.2 cases per 1000 deliveries over the five-year period from 2004 to 2009.3 Increased perinatal opioid use is worrying, as it results in a growing number of babies being born with the effects of opioid exposure in utero. Methadone maintenance treatment has been the standard of care for the management of opioid use disorders during pregnancy since the early 1990s because of increasing evidence showing reductions in obstetrical and neonatal complications associated with methadone use in pregnancy.4,5 However, there is very little published information about the outcomes associated with MMT in Canada. The objective of this study was to document and compare obstetrical and neonatal outcomes in a Canadian cohort of methadone-maintained pregnant women receiving care in three major metropolitan areas. METHODS
We conducted a multisite retrospective review of the medical records of methadone-maintained pregnant women attending integrated care programs from 1997 to 2009 in ABBREVIATIONS MMT
methadone maintenance treatment
MOTHER Maternal Opioid Treatment: Human Experimental Research NAS
neonatal abstinence syndrome
T-CUP
Toronto Centre for Substance Use in Pregnancy
three cities (Vancouver, Toronto, and Montreal). The programs were the Sheway clinic in Vancouver, the Toronto Centre for Substance Use in Pregnancy, and the Herzl Family Practice Centre in Montreal. T-CUP and the Herzl Clinic are both hospital-based centres, whereas Sheway is a community-based clinic. These programs reduce barriers to care by providing comprehensive obstetric care and addiction treatment at a single-access site.6 For the study we included pregnant women who had a history of opioid use disorder and who were already on MMT pre-conception or who were eligible for MMT; they were excluded if they were only on MMT for chronic pain with no history of opioid dependence. A spreadsheet was developed and used to collect maternal demographics (age, marital status, gravidity, parity), obstetrical outcomes, and neonatal outcomes including NAS and management. Data entry was performed by one research assistant, who worked in both Toronto and Vancouver. The Montreal-based program used a different research assistant for data collection. Inter-rater reliability was established by having five charts from this site reviewed independently by both research assistants. Data were summarized using descriptive statistics. Means, standard deviations, and P values were reported. Differences in proportions and means among the three city groups were analyzed using chi-square tests, Fisher exact test (for less than 5 expected frequencies for each cell), and independent t tests. The assumption of normality was tested using the ShapiroWilk test. For non-normally distributed data, the KruskalWallis test was performed. All analyses were conducted using SPSS v. 21.0 (IBM Corp., Armonk, NY) and significance was set an alpha of 0.05. Further regression analysis was also performed to rule out confounding variables. Ethics approval for the study was obtained from the St. Joseph’s Health Centre Research Ethics Board (Toronto), the Jewish General Hospital Research Ethics Board (Montreal), and the University of British Columbia Research Ethics Board (Vancouver). RESULTS
A total of 94 women were included in this study: 36 from Toronto, 36 from Vancouver, and 22 from Montreal. We excluded eight women who attended the Toronto program but for whom documentation relating to delivery and neonatal outcome was not available for review because they delivered at an external hospital. Maternal demographic data are presented in Table 1. Significant inter-site differences were found in ethnicity and marital status. Women in Montreal were more likely to MARCH JOGC MARS 2015 l 253
Drugs in Pregnancy
Table 1. Maternal demographics Site Characteristic Mean age, years (SD)
Toronto n = 36
Vancouver n = 36
Montreal n = 22
Total cohort n = 94
P
29.3 (4.9)
29.2 (5.4)
29.8 (6.0)
29.4 (5.3)
0.902
19 (53)
23 (64)
3 (14)
45 (48)
Marital status, n (%) Single Married/Partnered
0.001 17 (47)
13 (36)
19 (86)
49 (52)
Mean gravidity (SD)
3.4 (2.1)
3.7 (2.0)
3.7 (1.8)
3.6 (2.0)
Mean parity (SD)
1.9 (1.0)
2.6 (1.4)
1.7 (0.8)
2.1 (1.2)
Ethnicity, n (%) White
0.700 0.006 < 0.001
23 (64)
14 (39)
22 (100)
59 (63)
Aboriginal
2 (5)
19 (53)
0
21 (23)
Asian
6 (17)
1 (3)
0
7 (7)
Other
5 (14)
2 (5)
0
7 (7)
Table 2. Obstetrical outcomes Site, n (%) Toronto n = 36
Vancouver n = 36
Montreal n = 22
Total cohort n = 94
P
Antenatal bleeding
8 (22)
0
4 (18)
12 (14)
0.026
Placental abruption
3 (8)
0
0
3 (3)
0.088
0
1 (3)
0
1 (1)
0.426
Postpartum hemorrhage
5 (14)
1 (3)
0
6 (7)
0.067
Premature rupture of membranes
2 (6)
3 (9)
1 (5)
6 (6)
0.784
Preterm delivery
5 (14)
12 (33)
9 (41)
26 (28)
0.052
Characteristic
Placenta previa
Type of delivery Spontaneous vaginal
0.743 26 (72)
25 (69)
15 (68)
66 (70)
Assisted vaginal
4 (11)
5 (14)
5 (23)
14 (15)
Caesarean section
6 (17)
6 (17)
2 (9)
14 (15)
have partners than those in other cities. In addition, there were more Caucasian women in Montreal and Toronto, whereas more women in Vancouver were Aboriginal. Polysubstance use was common throughout pregnancy.5 At delivery, heroin and benzodiazepine use was significantly different among the three sites, with both of these reported most commonly in Vancouver. Cocaine use also tended to be more common among the Vancouver population but did not reach statistical significance. Antenatal bleeding (including placental abruption and placenta previa) was the only significant pregnancy complication and was observed more commonly in Toronto and Montreal than in Vancouver (Table 2). A further regression analysis for antenatal bleeding showed no significant differences among other confounding variables such as maternal age and gestational age. 254 l MARCH JOGC MARS 2015
The majority of women had a vaginal delivery, with 15% requiring a Caesarean section. Approximately 28% of infants were delivered before 37 weeks’ gestational age, and only three births (all in Vancouver) occurred before 32 weeks’ gestational age. Prematurity rates varied among the three sites, with a non-significant trend towards higher rates of premature delivery in Vancouver and Montreal than in Toronto. The average gestational age at delivery was 38 weeks (Table 3). The mean length of neonates was significantly greater in Toronto than in Montreal and Vancouver. Resuscitation at birth consisting of either positivepressure ventilation or more extensive measures (e.g., intubation or chest compressions) was required for approximately 20% of neonates, with no inter-site differences. Acute neonatal complications occurred
Obstetrical and Neonatal Outcomes of Methadone-Maintained Pregnant Women: A Canadian Multisite Cohort Study
Table 3. Neonatal data and outcomes Site Characteristic Mean gestational age, weeks (SD) Mean birth weight, grams (SD)
Toronto n = 36
Vancouver n = 36
Montreal n = 22
Total cohort n = 94
P
38 (2)
38 (3)
38 (2)
38 (2)
0.203
2985 (607)
2775 (762)
2776 (509)
2856 (653)
0.322
Mean birth length, cm (SD)
50 (3)
47 (5)
48 (4)
48 (4)
< 0.001
Mean head circumference, cm (SD)
34 (2)
33 (4)
33 (2)
33 (3)
0.528
8
8
8
8
0.442
Mean Apgar score, 1 minute Mean Apgar score, 5 minutes
9
9
9
9
0.832
Need for resuscitation, n (%)
8 (22)
8 (23)
3 (14)
19 (20)
0.666
Neonatal jaundice, n (%)
8 (22)
27 (77)
14 (64)
49 (53)
< 0.001
Need for phototherapy, n (%)
3 (8)
8 (23)
10 (45)
21 (23)
0.005
0
11 (31)
0
11 (12)
< 0.001
6 (17)
5 (14)
4 (22)
15 (17)
0.767
Neonatal sepsis, n (%) Breastfeeding, n (%)
more frequently in Vancouver and Montreal than in Toronto. Neonatal sepsis and neonatal jaundice requiring phototherapy occurred most commonly in Vancouver. Breastfeeding was reported by only 17% of the total cohort. Breastfeeding rates and discharge status were not significantly different among the three programs. A logistic regression analysis was performed to ascertain the effects of age, marital status, birth location, length of hospital stay, breastfeeding, and gestational age on neonatal sepsis. The regression model determined that length of stay (OR 1.1; P = 0.008) and gestational age (OR 0.6; P = 0.008) were associated with the probability of neonatal sepsis. Outcomes related to assessment and management of NAS are presented in Table 4. Rates of NICU admission varied significantly between the three sites because of the different approaches to managing NAS. Babies in Toronto and Montreal were routinely admitted to the NICU for NAS scoring. In contrast, a rooming-in approach was used in Vancouver, and this led to a reduced rate of NICU admission. Overall, infants remained in hospital for an average of 19 days for management of NAS. For the entire cohort, approximately one third of neonates required pharmacotherapy for NAS. There were no significant differences between the sites in rates of use of pharmacotherapy or duration of NAS treatment. At the time of discharge, neonates in Vancouver had higher rates of involvement of child protection services; however, there were no significant differences in rates of neonates being taken into custody. Approximately two thirds of neonates were discharged in the care of their mother and/or family. These rates did not vary among the three programs.
DISCUSSION
These data provide an overview of obstetrical and neonatal outcomes for a national cohort of pregnant women on MMT. Differences in obstetrical outcomes are mostly related to maternal demographics and rates of maternal substance use. As previously reported,6 this sample of pregnant women used multiple substances including heroin, prescription opioids, nicotine, cocaine, marijuana, and benzodiazepines during pregnancy. This pattern of substance use is common among opioid-dependent women.5 The higher incidence of antenatal bleeding observed in Toronto compared with the other centres is surprising because women in the Toronto cohort reported higher rates of use of marijuana, benzodiazepines, and prescription opioids, which have not been associated with higher rates of hemorrhage.4,7,8 The reason for this inter-site difference remains unclear, since rates of cocaine and heroin use were higher in Vancouver. The trend towards preterm delivery may reflect polysubstance use (including nicotine use) rather than being an effect of methadone. Numerous studies have found an association between heroin and cocaine use and preterm delivery, as well as cocaine use and placental abruption.4,5,8,9,10 The higher rates of sepsis and jaundice may also be related to the trend towards preterm delivery in this patient population. Comparison of the obstetrical outcomes in our study with the outcomes in the MOTHER study (a double-blind, doubledummy RCT comparing methadone with buprenorphine maintenance during pregnancy11) indicates a similar trend towards a lower incidence of obstetrical complications such as premature rupture of membranes and placental abruption. Preterm premature rupture of membranes and placental abruption occurred in 3% and 2.3%, respectively, MARCH JOGC MARS 2015 l 255
Drugs in Pregnancy
Table 4. Neonatal follow-up Site Characteristic
Toronto n = 36
Vancouver n = 36
Montreal n = 22
Total cohort n = 94
P
NICU admission, n (%)
34 (94)
15 (42)
20 (91)
69 (73)
0.003
Admitted for pediatric indication, n (%)
13 (36)
14 (39)
0
27 (29)
0.003
Rooming-in, n (%)
2 (6)
33 (92)
2 (9)
37 (39)
< 0.001
Weight loss, n (%)
7.0 (4.1)
7.4 (3.0)
8.7 (3.3)
7.6 (3.5)
0.204
Mean age at weight gain, days (SD)
4.3 (2.5)
4.3 (1.9)
5.6 (2.8)
4.6 (2.4)
0.093
14 (15)
26 (16)
16 (14)
19 (16)
Length of hospital stay, days mean (SD) median range
< 0.001 6
21
12
15
1 to 66
7 to 81
3 to 72
1 to 81
25 (17)
13 (6)
30 (27)
20 (16)
24
11
26
14
Duration of NAS treatment, days mean (SD) median range
0.086
1 to 63
6 to 26
2 to 65
1 to 65
11 (31)
10 (29)
4 (18)
25 (27)
Home with mother
25 (69)
16 (41)
15 (68)
56 (61)
0.115
Family with mother
2 (6)
3 (9)
2 (9)
7 (7)
0.847
Pharmacotherapy for NAS, n (%)
0.564
Discharge planning, n (%)
Family custody Foster care Involvement of Child Protection Services, n (%)
0
3 (9)
1 (5)
4 (4)
0.205
9 (25)
14 (40)
4 (18)
27 (29)
0.167
20 (56)
32 (91)
6 (27)
58 (62)
< 0.001
of all participants in the MOTHER study. In addition, our study demonstrated a significantly lower Caesarean section rate (15%) than reported by the Canadian Perinatal Health Report in 2004 to 2005 (26%).12,13 This lower rate may be linked to maternal characteristics such as increased parity and a trend towards a higher rate of preterm delivery and lower birth weight. In addition, intrapartum care for women in this cohort was provided by family physicians with expertise in family-centred care. Birth data for this Canadian cohort of methadone-exposed neonates were also similar to the MOTHER study findings with respect to gestational age at delivery, mean birth weight and mean length of neonates.14 Although most infants in our study were born at term, the mean birth weight is below the Canadian average of approximately 3300 grams.15 This difference may be due to several factors including methadone exposure and the presence of multiple co-exposures such as smoking. Other confounding factors including poor diet, stress, and chaotic lifestyles have also been reported to contribute to lower birth weight among opioid-exposed infants.16 The main drawback of MMT during pregnancy is its association with NAS. Protocols for NAS management vary geographically; in Vancouver, rooming-in is reported 256 l MARCH JOGC MARS 2015
by the Fir Square Program, whereas in Toronto and Montreal neonates are routinely admitted to the NICU for NAS scoring. Treatment for NAS may be indicated in up to 50% of neonates.17 In our study, pharmacological treatment was required in 27% of neonates, which is much lower than the 50% rate reported in the MOTHER study and the approximately 60% rate found in a national clinical cohort study in Norway.14,18 Our lower treatment rate may be explained by the emphasis on mother–baby dyad care through non-pharmacological interventions such as skin-toskin contact and promotion of breastfeeding. In Toronto and Montreal, even while neonates remain in NICU, parents are encouraged to be present and to be involved in daily newborn care. In this study, the total length of hospital stay was significantly different among the sites because of differences in the approach to treatment of NAS. The average total length of stay was greater in Vancouver, which may be reflective of the rooming-in process for NAS management and a lack of safe housing for women at time of discharge. Furthermore, the length of NICU stay was not significantly different among the three sites; however, there was a trend towards a shorter duration of NAS treatment in the Vancouver program. This finding is consistent with evidence demonstrating that rooming-in is associated with a reduced need to treat opioid
Obstetrical and Neonatal Outcomes of Methadone-Maintained Pregnant Women: A Canadian Multisite Cohort Study
withdrawal in newborns.19 Our study indicated that roomingin was not associated with a reduced rate of NAS treatment, but resulted in a shorter duration of NAS treatment. The similar rate of NAS treatment at all sites may be related to the significantly higher prevalence of benzodiazepine use among opioid-dependent pregnant women in Vancouver.6 Use of benzodiazepines has been implicated as a confounding factor leading to longer duration of treatment for NAS.17 Clinicians should consider tapering women off benzodiazepines, if possible, especially in the third trimester of pregnancy. The median length of hospital stay of 15 days in our study is consistent with Canadian Institute for Health Information data; the average length of stay for an infant with NAS in 2009 to 2010 was reported as 15.0 days.3 It is also consistent with the findings of the MOTHER study, in which the reported mean length of hospital stay was 17.5 days.14 Our study has several limitations deriving from the fact that it was a multisite retrospective chart review. Documentation was inconsistent, and omissions were frequent in patient charts. Under-reporting of obstetrical complications may be due to women not attending for medical care or lack of communication between providers. In addition, these results may not be applicable to all pregnant women on MMT, especially those who do not attend for prenatal care, which is associated with poorer obstetrical and neonatal outcomes. CONCLUSION
In this Canadian cohort of pregnant methadone-maintained women, opioid maintenance therapy as part of an integrated care program provided satisfactory maternal, obstetrical, and neonatal outcomes. Obstetrical complications were infrequent with most infants born at term. NAS is the most significant adverse consequence of MMT during pregnancy only because of the need for prolonged hospital stay and the potential need for pharmacological treatment. Policies promoting maternal–newborn contact, roomingin, and breastfeeding may help to decrease the severity of NAS and the need for pharmacological treatment. Our findings have implications for national health policy development since access to opioid substitution is very limited in many regions of Canada, indicating a need to address this disparity for pregnant opioid-using women. ACKNOWLEDGEMENTS
Grant support was received from the Lawson Foundation to assist with data collection. The authors wish to thank Talar Boyajian and Hee Yung Lim for assistance with data entry and Dr Rahim Moineddin for advice with data analysis.
REFERENCES 1. Hayes MJ, Brown MS. Epidemic of prescription opiate abuse and neonatal abstinence. JAMA 2012;307(18):1934–40. 2. Dow K, Ordean A, Murphy-Oikonen J, Pereira J, Koren G, Roukema H, et al.; Neonatal abstinence syndrome work group. Neonatal abstinence syndrome clinical practice guidelines in Ontario. J Popul Ther Clin Pharmacol 2012;19(3):e488–e506. 3. Maternal-Newborn Advisory Committee Neonatal Abstinence Syndrome Work Group. Neonatal abstinence syndrome (NAS) clinical practice guidelines. Toronto: Provincial Council for Maternal and Child Health; 2011. Available at: http://pcmch.on.ca/initiatives/neonatal-abstinencesyndrome. Accessed December 23, 2014. 4. Wong S, Ordean A, Kahan M; Maternal Fetal Medicine Committee; Family Physicians Advisory Committee; Medico-Legal Committee; Society of Obstetricians and Gynaecologists of Canada. Substance use in pregnancy. SOGC Clinical Practice Guideline no. 256, April 2011. J Obstet Gynaecol Can 2011;33(4):367–84. 5. Winklbaur B, Kopf N, Ebner N, Jung E, Thau K, Fischer G. Treating pregnant women dependent on opioids is not the same as treating pregnancy and opioid dependence: a knowledge synthesis for better treatment for women and neonates. Addiction 2008;103(9):1429–40. 6. Ordean A, Kahan M, Graves L, Abrahams L, Boyajian T. Integrated care for pregnant women on methadone maintenance treatment. Can Fam Physician 2013;59(10):e462–e469. 7. Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation. 7th ed. Philadelphia: Lippincott Williams & Wilkins; 2005. 8. Finnegan L. Substance abuse in Canada: licit and illicit drug use during pregnancy: maternal, neonatal and early childhood consequences. Ottawa, ON: Canadian Centre on Substance Abuse; 2013. 9. Almario CV, Seligman NS, Dysart KC, Berghella V, Baxter JK. Risk factors for preterm birth among opiate-addicted gravid women in a methadone treatment program. Am J Obstet Gynecol 2009;201:326.e1–6. 10. Gouin K, Murphy K, Shah PS, Knowledge synthesis group on determinants of low birth weight and preterm births. Effects of cocaine use during pregnancy on low birthweight and preterm birth: systematic review and metaanalyses. Am J Obstet Gynecol 2011;204(4):340.e1–12. 11. Holbrook AM, Baxter JK, Jones HE, Heil SH, Coyle MG, Martin PR, et al. Infections and obstetric outcomes in opioid-dependent pregnant women maintained on methadone or buprenorphine. Addiction 2012;107(Suppl 1):83–90. 12. Public Health Agency of Canada. What mothers say: The Canadian Maternity Experiences Survey. Ottawa: PHAC; 2009. 13. Public Health Agency of Canada. Canadian Perinatal Health Report, 2008 Edition. Ottawa: PHAC; 2008. 14. Jones HE, Kaltenbach K, Heil SH, Stine SM, Coyle MG, Arria AM, et al. Neonatal abstinence syndrome after methadone or buprenorphine exposure. N Engl J Med 2010;363(24):2320–31. 15. Statistics Canada. Health Statistics Division, Births 2009, Catalogue no. 84F0210X; Ottawa: Statistics Canada; 2012. Available at: http://www.statcan.gc.ca. Accessed December 23, 2014. 16. Hepburn M. Substance abuse in pregnancy. Curr Obstet Gynaecol 2004;14:419–25. 17. Ordean A, Chisamore B. Clinical presentation and management of neonatal abstinence syndrome: an update. Res Rep Neonatol 2014;4:75–86. 18. Welle-Strand GK, Skurtveit S, Jones HE, Waal H, Bakstad B, Ravndal E. Neonatal outcomes following in utero exposure to methadone or buprenorphine: a national cohort study of opioid-agonist treatment of pregnant women in Norway from 1996 to 2009. Drug Alcohol Depend 2013;127:200–6. 19. Hodgson ZG, Abrahams R. A rooming-in program to mitigate the need to treat for opiate withdrawal in the newborn. J Obstet Gynaecol Can 2012;34(5):475–81.
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Obstetrical and Neonatal Outcomes of Methadone-Maintained Pregnant Women: A Canadian Multisite Cohort Study Alice Ordean, MD, CCFP, MHSc, FCFP,1,2 Meldon Kahan, MD, CCFP, FRCPC, FCFP,2,3 Lisa Graves, MD, CCFP, FCFP,2,4 Ron Abrahams, MD, CCFP, FCFP,5,6,7 Theresa Kim, BSc, MSc8 Toronto Centre for Substance Use in Pregnancy, St. Joseph’s Health Centre, Toronto ON
1
Department of Family and Community Medicine, University of Toronto, Toronto ON
2
Substance Use Service, Women’s College Hospital, Toronto ON
3
Department of Family and Community Medicine, St. Michael’s Hospital, Toronto ON
4
Perinatal Addictions, BC Women’s Hospital, Vancouver BC
5
Sheway Clinic, Vancouver BC
6
Department of Family Practice, University of British Columbia, Vancouver BC
7
School of Kinesiology and Health Science, York University, Toronto ON
8
Abstract Objective: To describe obstetrical and neonatal outcomes including neonatal abstinence syndrome (NAS) in a Canadian cohort of methadone-maintained pregnant women. Methods: We conducted a retrospective chart review at three integrated care programs in Vancouver, Toronto, and Montreal. Pregnant women on methadone maintenance treatment (MMT) who attended for care between 1997 and 2009 were included in this multisite study. Maternal and neonatal outcomes in each of the three contributing centres were compared. Results: A total of 94 pregnant methadone-maintained women were included in the final analysis: 36 from Toronto, 36 from Vancouver, and 22 from Montreal. Maternal demographics showed inter-site differences in ethnicity and marital status. Obstetrical complications were not frequent; the most frequent was antenatal hemorrhage, which occurred in 14% of the total cohort. The incidence of premature labour was significantly higher in Vancouver and Montreal than in Toronto. The mean gestational age at delivery for the entire cohort was 38 weeks; mean birth weight was 2856 grams. The average length of hospital stay for babies with NAS was 19 days, with 27% of neonates requiring pharmacological treatment for NAS. Approximately 60% of neonates were discharged from hospital to the care of their mother.
Key Words: Prenatal care, methadone, pregnancy complications, neonatal abstinence syndrome Competing Interests: None declared. Received on July 9, 2014 Accepted on October 8, 2014
252 l MARCH JOGC MARS 2015
Conclusion: Integrated care programs resulted in satisfactory obstetrical and neonatal outcomes for pregnant women on MMT. Policies promoting maternal–newborn contact, rooming-in, and breastfeeding may help to decrease the severity of NAS and the need for pharmacological treatment of NAS. We strongly recommend the development of similar programs across Canada to address gaps in services.
Résumé Objectif : Décrire les issues obstétricales et néonatales, y compris le syndrome d’abstinence néonatal (SAN), au sein d’une cohorte canadienne de femmes enceintes recevant un traitement de substitution à la méthadone. Méthodes : Nous avons mené une analyse de dossiers rétrospective au sein de trois programmes de soins intégrés à Vancouver, à Toronto et à Montréal. Les femmes enceintes recevant un traitement de substitution à la méthadone (TSM) qui ont sollicité les services de ces programmes entre 1997 et 2009 ont été admises à cette étude multisite. Les issues maternelles et néonatales constatées au sein de chacun des centres participants ont été comparées. Résultats : En tout, 94 femmes enceintes recevant un traitement de substitution à la méthadone ont été admises à l’analyse finale : 36 de Toronto, 36 de Vancouver et 22 de Montréal. Les caractéristiques démographiques maternelles ont révélé la présence de différences entre les programmes en matière d’ethnicité et d’état matrimonial. Les complications obstétricales n’ont pas été fréquentes : la plus fréquente a été l’hémorragie prénatale, laquelle a été constatée chez 14 % des femmes de la cohorte entière. L’incidence du travail prématuré était considérablement plus élevée à Vancouver et à Montréal qu’à Toronto. Pour l’ensemble de la cohorte, l’âge gestationnel moyen au moment de l’accouchement a été de 38 semaines; le poids de
Obstetrical and Neonatal Outcomes of Methadone-Maintained Pregnant Women: A Canadian Multisite Cohort Study
naissance moyen a été de 2 856 grammes. La durée moyenne de l’hospitalisation des nouveau-nés présentant un SAN a été de 19 jours, 27 % d’entre eux ayant nécessité une pharmacothérapie pour contrer le SAN. Environ 60 % des nouveau-nés ont été remis à leur mère à la suite de l’obtention de leur congé de l’hôpital. Conclusion : Les programmes de soins intégrés ont permis l’obtention d’issues obstétricales et néonatales satisfaisantes chez les femmes enceintes recevant un TSM. Les politiques favorisant les contacts entre la mère et le nouveau-né, le partage de la même chambre d’hôpital et l’allaitement pourraient contribuer à atténuer la gravité du SAN et la nécessité d’avoir recours à une pharmacothérapie pour contrer le SAN. Nous recommandons fortement la mise sur pied de programmes similaires partout au Canada afin de combler les écarts en matière de services. J Obstet Gynaecol Can 2015;37(3):252–257
INTRODUCTION
T
he prevalence of perinatal opioid use has been increasing over the past decade.1–3 Opioid use during pregnancy can lead to adverse obstetrical and neonatal outcomes, including an increased risk of intrauterine growth restriction, prematurity, and neonatal abstinence syndrome.4 Data from the Canadian Institute for Health Information have demonstrated that the incidence of NAS in Ontario increased from 1.3 to 3.2 cases per 1000 deliveries over the five-year period from 2004 to 2009.3 Increased perinatal opioid use is worrying, as it results in a growing number of babies being born with the effects of opioid exposure in utero. Methadone maintenance treatment has been the standard of care for the management of opioid use disorders during pregnancy since the early 1990s because of increasing evidence showing reductions in obstetrical and neonatal complications associated with methadone use in pregnancy.4,5 However, there is very little published information about the outcomes associated with MMT in Canada. The objective of this study was to document and compare obstetrical and neonatal outcomes in a Canadian cohort of methadone-maintained pregnant women receiving care in three major metropolitan areas. METHODS
We conducted a multisite retrospective review of the medical records of methadone-maintained pregnant women attending integrated care programs from 1997 to 2009 in ABBREVIATIONS MMT
methadone maintenance treatment
MOTHER Maternal Opioid Treatment: Human Experimental Research NAS
neonatal abstinence syndrome
T-CUP
Toronto Centre for Substance Use in Pregnancy
three cities (Vancouver, Toronto, and Montreal). The programs were the Sheway clinic in Vancouver, the Toronto Centre for Substance Use in Pregnancy, and the Herzl Family Practice Centre in Montreal. T-CUP and the Herzl Clinic are both hospital-based centres, whereas Sheway is a community-based clinic. These programs reduce barriers to care by providing comprehensive obstetric care and addiction treatment at a single-access site.6 For the study we included pregnant women who had a history of opioid use disorder and who were already on MMT pre-conception or who were eligible for MMT; they were excluded if they were only on MMT for chronic pain with no history of opioid dependence. A spreadsheet was developed and used to collect maternal demographics (age, marital status, gravidity, parity), obstetrical outcomes, and neonatal outcomes including NAS and management. Data entry was performed by one research assistant, who worked in both Toronto and Vancouver. The Montreal-based program used a different research assistant for data collection. Inter-rater reliability was established by having five charts from this site reviewed independently by both research assistants. Data were summarized using descriptive statistics. Means, standard deviations, and P values were reported. Differences in proportions and means among the three city groups were analyzed using chi-square tests, Fisher exact test (for less than 5 expected frequencies for each cell), and independent t tests. The assumption of normality was tested using the ShapiroWilk test. For non-normally distributed data, the KruskalWallis test was performed. All analyses were conducted using SPSS v. 21.0 (IBM Corp., Armonk, NY) and significance was set an alpha of 0.05. Further regression analysis was also performed to rule out confounding variables. Ethics approval for the study was obtained from the St. Joseph’s Health Centre Research Ethics Board (Toronto), the Jewish General Hospital Research Ethics Board (Montreal), and the University of British Columbia Research Ethics Board (Vancouver). RESULTS
A total of 94 women were included in this study: 36 from Toronto, 36 from Vancouver, and 22 from Montreal. We excluded eight women who attended the Toronto program but for whom documentation relating to delivery and neonatal outcome was not available for review because they delivered at an external hospital. Maternal demographic data are presented in Table 1. Significant inter-site differences were found in ethnicity and marital status. Women in Montreal were more likely to MARCH JOGC MARS 2015 l 253
Drugs in Pregnancy
Table 1. Maternal demographics Site Characteristic Mean age, years (SD)
Toronto n = 36
Vancouver n = 36
Montreal n = 22
Total cohort n = 94
P
29.3 (4.9)
29.2 (5.4)
29.8 (6.0)
29.4 (5.3)
0.902
19 (53)
23 (64)
3 (14)
45 (48)
Marital status, n (%) Single Married/Partnered
0.001 17 (47)
13 (36)
19 (86)
49 (52)
Mean gravidity (SD)
3.4 (2.1)
3.7 (2.0)
3.7 (1.8)
3.6 (2.0)
Mean parity (SD)
1.9 (1.0)
2.6 (1.4)
1.7 (0.8)
2.1 (1.2)
Ethnicity, n (%) White
0.700 0.006 < 0.001
23 (64)
14 (39)
22 (100)
59 (63)
Aboriginal
2 (5)
19 (53)
0
21 (23)
Asian
6 (17)
1 (3)
0
7 (7)
Other
5 (14)
2 (5)
0
7 (7)
Table 2. Obstetrical outcomes Site, n (%) Toronto n = 36
Vancouver n = 36
Montreal n = 22
Total cohort n = 94
P
Antenatal bleeding
8 (22)
0
4 (18)
12 (14)
0.026
Placental abruption
3 (8)
0
0
3 (3)
0.088
0
1 (3)
0
1 (1)
0.426
Postpartum hemorrhage
5 (14)
1 (3)
0
6 (7)
0.067
Premature rupture of membranes
2 (6)
3 (9)
1 (5)
6 (6)
0.784
Preterm delivery
5 (14)
12 (33)
9 (41)
26 (28)
0.052
Characteristic
Placenta previa
Type of delivery Spontaneous vaginal
0.743 26 (72)
25 (69)
15 (68)
66 (70)
Assisted vaginal
4 (11)
5 (14)
5 (23)
14 (15)
Caesarean section
6 (17)
6 (17)
2 (9)
14 (15)
have partners than those in other cities. In addition, there were more Caucasian women in Montreal and Toronto, whereas more women in Vancouver were Aboriginal. Polysubstance use was common throughout pregnancy.5 At delivery, heroin and benzodiazepine use was significantly different among the three sites, with both of these reported most commonly in Vancouver. Cocaine use also tended to be more common among the Vancouver population but did not reach statistical significance. Antenatal bleeding (including placental abruption and placenta previa) was the only significant pregnancy complication and was observed more commonly in Toronto and Montreal than in Vancouver (Table 2). A further regression analysis for antenatal bleeding showed no significant differences among other confounding variables such as maternal age and gestational age. 254 l MARCH JOGC MARS 2015
The majority of women had a vaginal delivery, with 15% requiring a Caesarean section. Approximately 28% of infants were delivered before 37 weeks’ gestational age, and only three births (all in Vancouver) occurred before 32 weeks’ gestational age. Prematurity rates varied among the three sites, with a non-significant trend towards higher rates of premature delivery in Vancouver and Montreal than in Toronto. The average gestational age at delivery was 38 weeks (Table 3). The mean length of neonates was significantly greater in Toronto than in Montreal and Vancouver. Resuscitation at birth consisting of either positivepressure ventilation or more extensive measures (e.g., intubation or chest compressions) was required for approximately 20% of neonates, with no inter-site differences. Acute neonatal complications occurred
Obstetrical and Neonatal Outcomes of Methadone-Maintained Pregnant Women: A Canadian Multisite Cohort Study
Table 3. Neonatal data and outcomes Site Characteristic Mean gestational age, weeks (SD) Mean birth weight, grams (SD)
Toronto n = 36
Vancouver n = 36
Montreal n = 22
Total cohort n = 94
P
38 (2)
38 (3)
38 (2)
38 (2)
0.203
2985 (607)
2775 (762)
2776 (509)
2856 (653)
0.322
Mean birth length, cm (SD)
50 (3)
47 (5)
48 (4)
48 (4)
< 0.001
Mean head circumference, cm (SD)
34 (2)
33 (4)
33 (2)
33 (3)
0.528
8
8
8
8
0.442
Mean Apgar score, 1 minute Mean Apgar score, 5 minutes
9
9
9
9
0.832
Need for resuscitation, n (%)
8 (22)
8 (23)
3 (14)
19 (20)
0.666
Neonatal jaundice, n (%)
8 (22)
27 (77)
14 (64)
49 (53)
< 0.001
Need for phototherapy, n (%)
3 (8)
8 (23)
10 (45)
21 (23)
0.005
0
11 (31)
0
11 (12)
< 0.001
6 (17)
5 (14)
4 (22)
15 (17)
0.767
Neonatal sepsis, n (%) Breastfeeding, n (%)
more frequently in Vancouver and Montreal than in Toronto. Neonatal sepsis and neonatal jaundice requiring phototherapy occurred most commonly in Vancouver. Breastfeeding was reported by only 17% of the total cohort. Breastfeeding rates and discharge status were not significantly different among the three programs. A logistic regression analysis was performed to ascertain the effects of age, marital status, birth location, length of hospital stay, breastfeeding, and gestational age on neonatal sepsis. The regression model determined that length of stay (OR 1.1; P = 0.008) and gestational age (OR 0.6; P = 0.008) were associated with the probability of neonatal sepsis. Outcomes related to assessment and management of NAS are presented in Table 4. Rates of NICU admission varied significantly between the three sites because of the different approaches to managing NAS. Babies in Toronto and Montreal were routinely admitted to the NICU for NAS scoring. In contrast, a rooming-in approach was used in Vancouver, and this led to a reduced rate of NICU admission. Overall, infants remained in hospital for an average of 19 days for management of NAS. For the entire cohort, approximately one third of neonates required pharmacotherapy for NAS. There were no significant differences between the sites in rates of use of pharmacotherapy or duration of NAS treatment. At the time of discharge, neonates in Vancouver had higher rates of involvement of child protection services; however, there were no significant differences in rates of neonates being taken into custody. Approximately two thirds of neonates were discharged in the care of their mother and/or family. These rates did not vary among the three programs.
DISCUSSION
These data provide an overview of obstetrical and neonatal outcomes for a national cohort of pregnant women on MMT. Differences in obstetrical outcomes are mostly related to maternal demographics and rates of maternal substance use. As previously reported,6 this sample of pregnant women used multiple substances including heroin, prescription opioids, nicotine, cocaine, marijuana, and benzodiazepines during pregnancy. This pattern of substance use is common among opioid-dependent women.5 The higher incidence of antenatal bleeding observed in Toronto compared with the other centres is surprising because women in the Toronto cohort reported higher rates of use of marijuana, benzodiazepines, and prescription opioids, which have not been associated with higher rates of hemorrhage.4,7,8 The reason for this inter-site difference remains unclear, since rates of cocaine and heroin use were higher in Vancouver. The trend towards preterm delivery may reflect polysubstance use (including nicotine use) rather than being an effect of methadone. Numerous studies have found an association between heroin and cocaine use and preterm delivery, as well as cocaine use and placental abruption.4,5,8,9,10 The higher rates of sepsis and jaundice may also be related to the trend towards preterm delivery in this patient population. Comparison of the obstetrical outcomes in our study with the outcomes in the MOTHER study (a double-blind, doubledummy RCT comparing methadone with buprenorphine maintenance during pregnancy11) indicates a similar trend towards a lower incidence of obstetrical complications such as premature rupture of membranes and placental abruption. Preterm premature rupture of membranes and placental abruption occurred in 3% and 2.3%, respectively, MARCH JOGC MARS 2015 l 255
Drugs in Pregnancy
Table 4. Neonatal follow-up Site Characteristic
Toronto n = 36
Vancouver n = 36
Montreal n = 22
Total cohort n = 94
P
NICU admission, n (%)
34 (94)
15 (42)
20 (91)
69 (73)
0.003
Admitted for pediatric indication, n (%)
13 (36)
14 (39)
0
27 (29)
0.003
Rooming-in, n (%)
2 (6)
33 (92)
2 (9)
37 (39)
< 0.001
Weight loss, n (%)
7.0 (4.1)
7.4 (3.0)
8.7 (3.3)
7.6 (3.5)
0.204
Mean age at weight gain, days (SD)
4.3 (2.5)
4.3 (1.9)
5.6 (2.8)
4.6 (2.4)
0.093
14 (15)
26 (16)
16 (14)
19 (16)
Length of hospital stay, days mean (SD) median range
< 0.001 6
21
12
15
1 to 66
7 to 81
3 to 72
1 to 81
25 (17)
13 (6)
30 (27)
20 (16)
24
11
26
14
Duration of NAS treatment, days mean (SD) median range
0.086
1 to 63
6 to 26
2 to 65
1 to 65
11 (31)
10 (29)
4 (18)
25 (27)
Home with mother
25 (69)
16 (41)
15 (68)
56 (61)
0.115
Family with mother
2 (6)
3 (9)
2 (9)
7 (7)
0.847
Pharmacotherapy for NAS, n (%)
0.564
Discharge planning, n (%)
Family custody Foster care Involvement of Child Protection Services, n (%)
0
3 (9)
1 (5)
4 (4)
0.205
9 (25)
14 (40)
4 (18)
27 (29)
0.167
20 (56)
32 (91)
6 (27)
58 (62)
< 0.001
of all participants in the MOTHER study. In addition, our study demonstrated a significantly lower Caesarean section rate (15%) than reported by the Canadian Perinatal Health Report in 2004 to 2005 (26%).12,13 This lower rate may be linked to maternal characteristics such as increased parity and a trend towards a higher rate of preterm delivery and lower birth weight. In addition, intrapartum care for women in this cohort was provided by family physicians with expertise in family-centred care. Birth data for this Canadian cohort of methadone-exposed neonates were also similar to the MOTHER study findings with respect to gestational age at delivery, mean birth weight and mean length of neonates.14 Although most infants in our study were born at term, the mean birth weight is below the Canadian average of approximately 3300 grams.15 This difference may be due to several factors including methadone exposure and the presence of multiple co-exposures such as smoking. Other confounding factors including poor diet, stress, and chaotic lifestyles have also been reported to contribute to lower birth weight among opioid-exposed infants.16 The main drawback of MMT during pregnancy is its association with NAS. Protocols for NAS management vary geographically; in Vancouver, rooming-in is reported 256 l MARCH JOGC MARS 2015
by the Fir Square Program, whereas in Toronto and Montreal neonates are routinely admitted to the NICU for NAS scoring. Treatment for NAS may be indicated in up to 50% of neonates.17 In our study, pharmacological treatment was required in 27% of neonates, which is much lower than the 50% rate reported in the MOTHER study and the approximately 60% rate found in a national clinical cohort study in Norway.14,18 Our lower treatment rate may be explained by the emphasis on mother–baby dyad care through non-pharmacological interventions such as skin-toskin contact and promotion of breastfeeding. In Toronto and Montreal, even while neonates remain in NICU, parents are encouraged to be present and to be involved in daily newborn care. In this study, the total length of hospital stay was significantly different among the sites because of differences in the approach to treatment of NAS. The average total length of stay was greater in Vancouver, which may be reflective of the rooming-in process for NAS management and a lack of safe housing for women at time of discharge. Furthermore, the length of NICU stay was not significantly different among the three sites; however, there was a trend towards a shorter duration of NAS treatment in the Vancouver program. This finding is consistent with evidence demonstrating that rooming-in is associated with a reduced need to treat opioid
Obstetrical and Neonatal Outcomes of Methadone-Maintained Pregnant Women: A Canadian Multisite Cohort Study
withdrawal in newborns.19 Our study indicated that roomingin was not associated with a reduced rate of NAS treatment, but resulted in a shorter duration of NAS treatment. The similar rate of NAS treatment at all sites may be related to the significantly higher prevalence of benzodiazepine use among opioid-dependent pregnant women in Vancouver.6 Use of benzodiazepines has been implicated as a confounding factor leading to longer duration of treatment for NAS.17 Clinicians should consider tapering women off benzodiazepines, if possible, especially in the third trimester of pregnancy. The median length of hospital stay of 15 days in our study is consistent with Canadian Institute for Health Information data; the average length of stay for an infant with NAS in 2009 to 2010 was reported as 15.0 days.3 It is also consistent with the findings of the MOTHER study, in which the reported mean length of hospital stay was 17.5 days.14 Our study has several limitations deriving from the fact that it was a multisite retrospective chart review. Documentation was inconsistent, and omissions were frequent in patient charts. Under-reporting of obstetrical complications may be due to women not attending for medical care or lack of communication between providers. In addition, these results may not be applicable to all pregnant women on MMT, especially those who do not attend for prenatal care, which is associated with poorer obstetrical and neonatal outcomes. CONCLUSION
In this Canadian cohort of pregnant methadone-maintained women, opioid maintenance therapy as part of an integrated care program provided satisfactory maternal, obstetrical, and neonatal outcomes. Obstetrical complications were infrequent with most infants born at term. NAS is the most significant adverse consequence of MMT during pregnancy only because of the need for prolonged hospital stay and the potential need for pharmacological treatment. Policies promoting maternal–newborn contact, roomingin, and breastfeeding may help to decrease the severity of NAS and the need for pharmacological treatment. Our findings have implications for national health policy development since access to opioid substitution is very limited in many regions of Canada, indicating a need to address this disparity for pregnant opioid-using women. ACKNOWLEDGEMENTS
Grant support was received from the Lawson Foundation to assist with data collection. The authors wish to thank Talar Boyajian and Hee Yung Lim for assistance with data entry and Dr Rahim Moineddin for advice with data analysis.
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