Trends in live birth rates and adverse neonatal outcomes among HIV-positive women in Ontario,Canada,2002–2009: a descriptive population-based study

Abstract

To characterise trends in live birth rates, adverse neonatal outcomes and socio-demographic characteristics of pregnant women with diagnosed HIV between the ages of 18 and 49 in Ontario, Canada from 1 April 2002 to 31 March 2010, we conducted a population-based study. Utilising linked administrative healthcare databases we used generalised estimating equations to characterise secular trends and examine the association between live births and socio-demographic characteristics, including age, region of birth and neighbourhood income quintile. Between 2002/2003 and 2009/2010, there were 551 live births during 15,610 person-years of follow-up. The proportion of HIV-positive mothers originally from Africa or the Caribbean increased from 26.7% to 51.6% over the study period. The risk of pre-term (risk ratio 2.13, 95% confidence interval 1.74 to 2.61) and small for gestational age births (risk ratio 1.53, 95% confidence interval 1.20 to 1.94) was higher in women with HIV compared with provincial estimates for these outcomes. Women with HIV have rates of pre-term and small for gestational age births that exceed provincial estimates for these outcomes. Further research is required to identify factors mediating these disparities that are amenable to pre-natal risk reduction initiatives.

Keywords

HIV AIDS pregnancy complications infectious women pregnancy outcome pre-term labour small for gestational age Canada

Introduction

Globally, women account for more than half of all people living with HIV. Furthermore, the prevalence of HIV among girls and women between the ages of 15 and 24 is twice that of boys and men in the same age group, thereby rendering women of childbearing age among the fastest growing demographic of persons living with HIV.¹ However, despite expanded access to antiretroviral therapy on a global scale, only 62% of pregnant women living with HIV worldwide received such treatment in 2012.¹ Consequently, scaling up effective and comprehensive services for the prevention of mother-to-child transmission of HIV is imperative if the commitment towards eliminating HIV infection in children is to be realised. Evidence supporting the feasibility of this goal can be derived from countries with well-resourced health care systems, where comprehensive programmes for identifying and treating pregnant women living with HIV have reduced the risk of vertical transmission to 1–2%.² In Canada, where over 90% of pregnant women with HIV receive antiretroviral therapy during the antenatal period, the risk of vertical HIV transmission is less than 1%.³ However, despite this improved outlook for women with HIV and their children, there has been a paucity of population-based research examining trends in the demographic composition of pregnant women with HIV and neonatal outcomes other than rates of vertical transmission.^4,5 These data are particularly important in the Canadian province of Ontario for several reasons. First, the prevalence of HIV has increased among women of childbearing age in Ontario between 1996 and 2009, with average increases of 3.2% (95% CI 2.5% to 4.0% per year) and 11.0% (95% confidence interval [CI] 10.2% to 11.8% per year) among women aged 18 to 35 and 36 to 49, respectively, between the fiscal years 1996/1997 and 2009/2010.⁶ Overall, women comprise an increasing proportion of persons with HIV who have entered care in Ontario, representing approximately 20% of this population as of 2009/2010.⁶ These data mirror national trends, in that 23% of Canadians living with HIV are women.⁷ In addition, 82% of women with HIV in Ontario who had entered care as of 2009/2010 were of reproductive age, and a cross-sectional study of a sample of these women indicated that 57% intended to become mothers in the future.^6,8 Finally, women immigrating to Ontario from countries with a high prevalence of HIV have accounted for 50–60% of new diagnoses among women since 2002.⁹ Because these women may face several obstacles to accessing health care, including language barriers, low socio-economic status and stresses of immigration, they may be at heightened risk of adverse neonatal outcomes.^10–12

In the context of an increased number of women living with HIV who are of reproductive age and greater ethnic diversity within this demographic, population-based estimates of live birth rates and neonatal outcomes are required to optimise health service delivery and outcomes of women with HIV. Yet, these data are presently lacking for Ontario, home to over 40% of Canada’s population of persons with HIV and recipient of approximately half of all immigrants to Canada on an annual basis.¹³ Accordingly, we used administrative healthcare databases to assemble a population-based cohort of all women with diagnosed HIV who were between the ages of 18 and 49 years, and used these data to quantify trends in rates of live births, small for gestational age infants and pre-term births between 2002/2003 and 2009/2010.

Methods

Setting

We conducted a population-based study of births to women with diagnosed HIV living in Ontario aged 18 to 49 years between 1 April 2002 and 31 March 2010. Ontario has a single-payer, government administered health care system and therefore all residents of the province with an Ontario health card receive publicly funded physician and hospital care, including obstetrical care. All data for our study were analysed on a fiscal year basis (April 1 of one calendar year to March 31 of the subsequent year).

Data sources

We obtained data from Ontario’s administrative health databases, which are available at the Institute for Clinical Evaluative Sciences (ICES) through a data sharing agreement with the Ontario Ministry of Health and Long-Term Care (MOHLTC). Specifically, we identified all live births among Ontario women between the ages of 18 and 49 during the study period using the MOMBABY database, which deterministically links the Canadian Institute for Health Information Discharge Abstract Database inpatient admission records of all mothers and their newborn infants from 2002/2003 onward. Each record in the MOMBABY database contains the unique encrypted health care number of the mother and her newborn, gender of the newborn and up to 25 diagnoses based on International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10) codes. We obtained demographic information from the Registered Persons Database, a registry of all Ontario residents eligible for provincial health insurance. We used the Ontario Health Insurance Plan (OHIP) database to identify physician claims for HIV-related visits. The OHIP is a publicly funded programme which reimburses physicians for the provision of medically necessary procedural and diagnostic services to all permanent residents of the province of Ontario. Therefore, the OHIP database contains administrative data generated from all inpatient and outpatient physician billings. In order to receive payment for services rendered, physicians must submit the name, date of birth and OHIP card number of the individual patient seen, the service provided (i.e. a service code) and a single diagnosis code on each claim. For OHIP claims, the diagnosis code is a truncated three-digit version of the corresponding International Classification of Diseases, Ninth Revision (ICD-9) code. Finally, we used the Citizenship and Immigration Canada Database to identify women who had immigrated to Ontario from Africa or the Caribbean. These databases were linked in an anonymous fashion using encrypted health card numbers and are routinely used for population-based research examining maternal and neonatal outcomes.^14–16

Study population

We identified women in Ontario aged 18 to 49 years who were living with HIV between 1 April 2002 and 31 March 2010 from the Ontario HIV database, an administrative data registry of Ontario residents with diagnosed HIV infection which was generated using a previously validated case-finding algorithm.¹⁷ The definition of three physician claims to OHIP with an International Classification of Diseases, Ninth Revision code for HIV infection (042, 043, 044) within a three-year period has a sensitivity and specificity of 96.2% (95% CI 95.2% to 97.9%) and 99.6% (95% CI 99.1% to 99.8%), respectively, for identifying persons who had been diagnosed with HIV and who were receiving HIV care at primary care and specialist clinics. Individuals enter the HIV database cohort on the date that they first meet the algorithm definition for HIV infection (i.e. the date of the first of three claims for an HIV-related visit). Because HIV is incurable, individuals who meet the case-definition for HIV infection and who are therefore entered into the HIV database remain part of the cohort unless they either die or move out of the province of Ontario. We chose the end of the 2009 fiscal year for our analyses to meet the three-year ‘look forward’ criterion of the algorithm.

Outcomes

The primary outcomes of the study were annual rates of live births per 100 person-years of follow-up, and the annual proportions of live births that were pre-term or of small for gestational age, between 2002/2003 and 2009/2010. We calculated the annual live birth rate for women with and without HIV by dividing the number of live births in each fiscal year by the total number of women aged 18 to 49 years for the corresponding year. Infants considered to be small for gestational age were those newborns with a birth weight below the 10th percentile appropriate for gestational age and gender.¹⁸ We determined the annual proportion of small for gestational age newborns by dividing the number of small for gestational age live births by the number of singleton live births among HIV-infected women in a given year. We used singleton births as the denominator for this outcome because there is no consensus in the medical literature on how to determine small for gestational age status among live births that are multiples.¹⁹ We determined the annual proportion of pre-term births by dividing the number of infants born to an HIV-positive mother prior to 37 completed weeks of gestation by the number of live births among HIV-positive women in each year. To contextualise our findings, we computed annual risk ratios and 95% CI to compare risks of adverse neonatal outcomes among women living with HIV with provincial estimates of these events, available for the years 2004/2005 to 2009/2010 from the Ontario Better Outcomes Registry and Network (BORN) birth and childhood database.

Statistical analysis

We used the chi square test for linear trend to analyse secular trends in maternal characteristics, live birth rates and proportions of small for gestational infants and pre-term births in HIV-positive women between 2002/2003 and 2009/2010. We also evaluated temporal trends in rates of live birth multivariable generalised estimating equations (GEE) with a log link function and autoregressive correlation structure.²⁰ The model included fiscal year, age (<35 versus ≥35), region of origin (Africa, Caribbean, Other, Canada), recent (i.e. immigrated to Ontario within three years of entering the HIV database) immigration to Ontario and neighbourhood income quintile, which was determined by linking data from Canada’s 2001 Census with postal code information from the Registered Persons Database, using a postal code conversion file to construct community income quintiles.²¹ Because the GEE method is not a likelihood-based method, we used the quasi-likelihood under the independence model criterion both to ascertain the appropriateness of the autoregressive correlation structure relative to other working correlation matrices and to assess the fit of our regression models.²² All statistical analyses were conducted using SAS version 9.2 (SAS institute, Cary, North Carolina, USA).

Ethics approval

We obtained ethics approval for this study from the Research Ethics Board of Sunnybrook Health Sciences Centre.

Results

Trends in live birth rates and maternal characteristics

Between 2002/2003 and 2009/2010, the number of women living with HIV who were between the ages of 18 and 49 increased by 52.8% (from 1505 to 2301). Overall, there were 551 live births during 15,610 person-years of follow-up among women with HIV in Ontario, representing 0.05% of all births among Ontario women aged 18 to 49 years during this period. The live birth rate was lower in women with HIV relative to the general population of women aged 18 to 49 years (3.53 versus 4.44 live births per 100 person-years; rate ratio 0.79, 95% CI 0.73 to 0.86). The majority (n = 441; 80.0%) of these births were to women between the ages of 18 and 34 years (Table 1). In addition, most live births were to women living with HIV who lived in large urban centres (n = 536; 97.3%) and in low-income neighbourhoods (n = 397; 72.1%) (Table 1). There were no secular trends in the rate of live births among HIV-positive women during the study period or in maternal characteristics such as neighbourhood income quintile and age (Table 1). However, the proportion of live births to women living with HIV who were originally from Africa or the Caribbean increased from 26.5% (13 of 49) in 2002/2003 to 51.6% (32 of 62) in 2009/2010 (p = 0.007). The live birth rate among women with HIV originally from Africa and the Caribbean was higher relative to women with HIV who were not from these regions (4.87 versus 2.99 live births per 100 person-years; rate ratio 1.63, 95% CI 1.37 to 1.93). Following multivariable adjustment, live birth rates were higher among women living in low-income relative to high-income neighbourhoods (adjusted relative rate 1.35; 95% CI 1.11 to 1.65), women originally from Africa relative to women who were not immigrants to Ontario (adjusted relative rate 1.26; 95% CI 1.00 to 1.62) and women aged 18 to 34 years relative to women aged 35 to 49 years (adjusted relative rate 5.56; 95% CI 4.54 to 7.14) (Table 2).

Table 1.

Temporal trends in maternal characteristics.

Variable	2002/2003–2003/2004, n = 112	2004/2005–2005/2006, n = 143	2006/2007–2007/2008, n = 143	2008/2009–2009/2010, n = 153
Age, years (%)
18–34	91 (81.3%)	121 (84.6%)	113 (79.0%)	116 (75.8%)
35–49	21 (18.7%)	22 (15.4%)	30 (21.0%)	37 (24.2%)
Income quintile (%)^a
1 (lowest)	51 (45.5%)	69 (48.2%)	69 (48.2%)	79 (51.6%)
2	33 (29.5%)	35 (24.5%)	30 (21.0%)	31 (20.3%)
3	14 (12.5%)	12 (8.4%)	9 (6.3%)	13 (8.5%)
4	8 (7.1%)	13 (9.1%)	21 (14.7%)	20 (13.1%)
5	6 (5.4%)	14 (9.8%)	12 (8.4%)	8 (5.2%)
Region of origin (%)
Canada	66 (58.9%)	80 (55.9%)	74 (51.7%)	70 (45.7%)
Africa or Caribbean	36 (32.1%)	52 (36.4%)	60 (41.9%)	69 (45.1)
Other	10 (8.9%)	11 (7.7%)	9 (6.3%)	14 (9.1%)
Recent immigrant (%)	25 (22.3%)	29 (20.3%)	31 (21.7%)	39 (25.5%)

Number (%) of live births.

Calculated by linking data from Canada’s 2001 Census with postal code information from the Registered Persons Database using a postal code conversion file to construct community income quintiles.

Table 2.

Multivariable analysis of trends in live birth rates among women with HIV.

Variable	Rate ratio	95% confidence interval	p
Year
2002/2003 (reference)	1.00	–
2003/2004	1.19	0.83 to 1.70	0.35
2004/2005	1.22	0.87 to 1.72	0.25
2005/2006	1.21	0.85 to 1.72	0.28
2006/2007	1.03	0.72 to 1.47	0.86
2007/2008	1.15	0.80 to 1.65	0.44
2008/2009	1.42	1.01 to 2.00	0.04
2009/2010	0.93	0.64 to 1.35	0.69
Age (years)
35–49 (reference)	1.00	–
18–34	5.56	4.54 to7.14	<0.0001
Socio-economic status
High (reference)	1.00	–
Low^a	1.35	1.11 to 1.65	0.003
Region of origin
Canada	1.00	–
Africa	1.26	1.00 to 1.62	0.06
Caribbean	0.96	0.62–1.49	0.87
Other	0.94	0.69 to 1.29	0.72
Recent immigrant	1.19	0.93 to 1.53	0.16

Patients in the two lowest quintiles.

Pre-term births and small for gestational age infants

Between 2002/2003 and 2009/2010, 96 of the 551 live births to women with HIV were pre-term (17.42%; 95% CI 14.48 to 20.81). Among the 522 singleton births, 71 (13.60%; 95% CI 10.91 to 16.92) were small for gestational age. There were no significant secular trends in the proportions of pregnancies that were pre-term (p = 0.74) or small for gestational age (p = 0.96). For the period encompassing the fiscal years 2004/2005 to 2009/2010, women living with HIV had higher risks of both pre-term birth (17.54 versus 8.23 per 100 live births; risk ratio 2.13, 95% CI 1.74 to 2.61) and small for gestational age infants (13.60 versus 8.96 per 100 singleton live births; risk ratio 1.53, 95% CI 1.20 to 1.94) relative to provincial estimates for these outcomes.

Discussion

With the exception of an increase in the proportion of mothers with HIV originally from Africa and the Caribbean, we found no significant secular trends in the rates of live births, adverse neonatal outcomes or other maternal characteristics in our population-based study. Although we observed higher crude risks of adverse neonatal outcomes among women living with HIV when compared with provincial estimates for these outcomes, our findings require further confirmation and control for important confounders in the relationship between HIV infection and adverse neonatal outcomes before valid comparisons between women living with and without HIV infection can be made.

Our findings are similar to those described in other developed regions of the world, with proportions of pregnancies resulting in pre-term and small for gestational age births ranging from 10% to 27.1% and 13% to 23.8%, respectively.^4,5,23–34 The exact mechanisms underlying the heightened risk of adverse outcomes among women with HIV are not fully understood. Although some studies have associated protease inhibitor-based combination therapy with pre-term birth,^28,30,31 particularly when administered during the first trimester, conflicting results have been reported.^{23–25,27,29} In addition, some authors have speculated that maternal immune status, inflammatory changes accompanying immune reconstitution syndromes or antiretroviral-mediated reductions in circulating levels of interleukin-10 may contribute to an increased risk of adverse neonatal outcomes.^35,36 Also, as in HIV-negative mothers, smoking and substance use are important and modifiable risk factors for pre-term and small for gestational age births.^32,33

Our study has important implications for the management of pregnant women with HIV. Because pre-term and small for gestational age infants are at heightened risk of neonatal morbidity and mortality, elucidating risk factors for these outcomes among pregnant women with HIV that are amenable to pre-natal risk reduction initiatives is a priority.^37–39 Community-based interventions and additional research that identifies and addresses variations in utilisation of pre-natal services and the impact of structural drivers of health care utilisation such as stigma and marginalised socio-economic status are therefore required.

Strengths of our study include the use of comprehensive population-based data, thereby allowing us to examine trends in HIV-related births and outcomes in all HIV-infected women who have entered care and delivered a baby in an Ontario hospital over an eight-year observation period. Although the rates of live births and neonatal outcomes we describe represent crude estimates, surveillance of these trends among all women with HIV who are receiving routine clinical care in a setting of universal health coverage provides valuable information for needs assessment and programme planning. To our knowledge, ours is the first study examining these trends in a Canadian population of women living with HIV. However, several limitations of our work merit emphasis. First, we could not identify those births that occurred outside of a hospital. It is estimated that this accounts for approximately 1.1% of all births in Ontario.¹⁹ Furthermore, women who do not have an Ontario health card, and therefore, lack provincial health insurance (e.g. refugee claimants) could not be identified using our databases. Because the proportion of women who are immigrants to Ontario is higher among women living with HIV relative to women not living with HIV, our findings likely underestimate the number of births over the study period among women with HIV, particularly those originally from Africa and the Caribbean. In addition, we had no access to clinical information, and could therefore not generate data on the risk of perinatal HIV transmission among the women in our cohort. However, a recently published study of Canadian women with HIV found that less than 1% of pregnancies were associated with perinatal HIV transmission.³ Similarly, we had no data on potential determinants of adverse neonatal outcomes, including smoking, alcohol consumption, antiretroviral therapy and maternal height, weight and body mass index. Finally, because the absolute numbers of births that were pre-term and small for gestational age were small, we could not obtain precise estimates of the secular trend in these outcomes that were adjusted for confounding variables.

In conclusion, our population-based study indicates that the majority of Ontario mothers with HIV live in low-income neighbourhoods, are increasingly immigrants from Africa and the Caribbean, and that rates of pre-term and small for gestational age births are high relative to provincial estimates of these outcomes. Additional qualitative and quantitative research is required to identify the social, biological and structural factors mediating these disparities, so that interventions to improve the health of women with HIV and their children can be designed and evaluated.

Footnotes

Conflict of interest

During the past three years, Mona Loutfy has received unrestricted research funding from Abbott Laboratories, Merck Frosst Canada Ltd., Pfizer and ViiV Healthcare. All other authors declare (1) no support from any company for the submitted work; (2) no relationships with any companies that might have an interest in the submitted work in the previous three years; (3) their spouses, partners or children have no financial relationships that may be relevant to the submitted work and (4) no non-financial interests that may be relevant to the submitted work.

Funding

This project was supported by a research operating grant from the Ontario HIV Treatment Network (grant number ROG G768) and by the Institute for Clinical Evaluative Sciences (ICES), which is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care (MOHLTC). The sponsors had no role in the design or conduct of the study; in the collection, analysis or interpretation of the data; or in the preparation, review or approval of the manuscript. The opinions, results and conclusions reported in this paper are those of the authors and are independent from the funding source. No endorsement by ICES or the Ontario MOHLTC is intended or should be inferred. TA is supported by a post-doctoral fellowship from the Ontario HIV Treatment Network. AMB is supported by a Canadian Institutes for Health Research/Ontario Ministry of Health and Long-Term Care Applied Chair in Health Services and Policy Research. JR is supported by an Ontario HIV Treatment Network Career Scientist Award and the Skate the Dream Fund, Toronto and Western Hospital Foundation. RHG is a Clinician Scientist in the Department of Family and Community Medicine of St. Michael’s Hospital and the University of Toronto.

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