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Severe Maternal Morbidity and Maternal Mortality Associated with Assisted Reproductive Technology

Open AccessPublished:June 20, 2022DOI:https://doi.org/10.1016/j.jogc.2022.05.012

      Abstract

      Objective

      To assess the association between use of assisted reproductive technologies (ART) and severe maternal morbidity and maternal mortality (SMM).

      Methods

      We carried out a cohort study that included all hospital deliveries at ≥20 weeks gestation in Canada (excluding Québec) between April 2009 and March 2018. Outcomes of interest included composite SMM and SMM types (e.g., severe preeclampsia, HELLP syndrome, and eclampsia; severe hemorrhage; acute renal failure). Multivariable regression was used to estimate crude and adjusted rate ratios (RR and aRR) and 95% confidence intervals (CI).

      Results

      The study included 2 535 056 women, of whom 72 023 (2.8%) delivered following the use of ART. The composite SMM rate for women who used ART was 34.7 per 1000 deliveries (95% CI 33.0–36.0) versus 11.5 per 1000 deliveries (95% CI 11.4–11.6) for women who did not use ART (RR 3.01; 95% CI 2.89–3.14). ART use was associated with SMM types such as severe preeclampsia, HELLP syndrome, and eclampsia (RR 3.50; 95% CI 3.27–3.73), severe hemorrhage (RR 3.58, 95% CI 3.27–3.92), and acute renal failure (RR 6.79; 95% CI 5.78–7.98). Associations between ART and composite SMM were attenuated but remained elevated after adjusting for maternal characteristics (aRR 2.34; 95% CI 2.24–2.45). Women who used ART and had a multi-fetal pregnancy had a 4.7 times higher rate of composite SMM compared with women who did not use ART and delivered singletons.

      Conclusion

      Women who deliver following the use of ART have increased risks of SMM and require counselling that includes mention of the lower risks of SMM associated with ART-conceived singleton pregnancy.

      Résumé

      Objectif

      Évaluer l’incidence du recours aux technologies de procréation assistée (TPA) sur la mortalité et la morbidité maternelle grave (MMMG).

      Méthodologie

      Nous avons mené une étude de cohorte comprenant tous les accouchements en milieu hospitalier à ≥ 20 semaines d’aménorrhée survenus entre avril 2009 et mars 2018 au Canada (sauf au Québec). Les critères de jugement étaient le taux composite de MMMG et les types de MMMG (p. ex., pré-éclampsie sévère, syndrome HELLP et éclampsie; hémorragie sévère; insuffisance rénale aiguë). Nous avons effectué une analyse de régression multivariée pour estimer les rapports de taux d’incidence non corrigé et ajusté (RTI et RTIa) et l’intervalle de confiance (IC).

      Résultats

      L’étude portait sur 2 535 056 femmes, dont 72 023 (2,8 %) qui ont donné naissance après avoir eu recours aux TPA. Le taux composite de MMMG était de 34,7 par 1 000 accouchements (IC à 95 % : 33,0–36,0) chez les femmes ayant eu recours aux TPA, comparativement à 11,5 par 1 000 accouchements (IC à 95 % : 11,4–11,6) chez les femmes n’y ayant pas eu recours (RTI : 3,01; IC à 95 % : 2,89–3,14). Le recours aux TPA était associé à des types de MMMG comme la pré-éclampsie sévère, le syndrome HELLP et l’éclampsie (RTI : 3,50; IC à 95 % : 3,27–3,73), l’hémorragie sévère (RTI : 3,58; IC à 95 % : 3,27–3,92) et l’insuffisance rénale aiguë (RTI : 6,79; IC à 95 % : 5,78–7,98). L’association entre le recours aux TPA et le taux composite de MMMG a été atténuée, mais est demeurée élevée après ajustement en fonction des caractéristiques maternelles (RTIa : 2,34; IC à 95 % : 2,24–2,45). Chez les femmes ayant eu une grossesse multifœtale après un recours aux TPA, le taux composite de MMMG était 4,7 fois supérieur à celui en cas de grossesse monofœtale sans recours aux TPA.

      Conclusion

      Les femmes qui donnent naissance après avoir eu recours aux TPA ont un risque accru de MMMG et doivent être informées du moindre risque de MMMG associées à la grossesse monofœtale découlant des TPA.

      Keywords

      Introduction

      Pregnancies after an infertility treatment, such as in vitro fertilization (IVF), are known to be at an increased risk of pregnancy complications. These complications appear to arise in part due to the factors associated with underlying infertility and include placental abruption, placenta previa, premature rupture of the membranes, excessive bleeding after vaginal delivery, and thromboembolism.
      • Kallen B.
      • Finnstrom O.
      • Nygren K.G.
      • et al.
      In vitro fertilization in Sweden: obstetric characteristics, maternal morbidity and mortality.
      • Tan S.L.
      • Doyle P.
      • Campbell S.
      • et al.
      Obstetric outcome of in vitro fertilization pregnancies compared with normally conceived pregnancies.
      • Ochsenkuhn R.
      • Strowitzki T.
      • Gurtner M.
      • et al.
      Pregnancy complications, obstetric risks, and neonatal outcome in singleton and twin pregnancies after GIFT and IVF.
      • Thomson F.
      • Shanbhag S.
      • Templeton A.
      • et al.
      Obstetric outcome in women with subfertility.
      • Mara M.
      • Koryntova D.
      • Rezabek K.
      • et al.
      Thromboembolic complications in patients undergoing in vitro fertilization: retrospective clinical study.
      Higher rates of pregnancy complications, including placenta praevia and placenta abruption, have also been described among subfertile women who conceived spontaneously,
      • Chan W.S.
      • Dixon M.E.
      The “ART” of thromboembolism: a review of assisted reproductive technology and thromboembolic complications.
       and this supports the notion that underlying infertility issues could be responsible for higher rates of pregnancy complications after assisted reproductive technology (ART). However, among women who have had both spontaneous and ART-initiated pregnancy, the rate of placenta previa is 3-fold higher after ART, suggesting additional risks conferred by the ART procedures.
      • Chan W.S.
      • Dixon M.E.
      The “ART” of thromboembolism: a review of assisted reproductive technology and thromboembolic complications.
      Finally, the disproportionate rate of multifetal pregnancy after ART contributes to elevated risks of pregnancy complications.
      • Allen V.M.
      • Wilson R.D.
      • Cheung A.
      • et al.
      Pregnancy outcomes after assisted reproductive technology.
      • Gunby J.
      • Daya S.
      IVF Directors Group of the Canadian Fertility and Andrology Society
      Assisted reproductive technologies (ART) in Canada: 2003 results from the Canadian ART Register.
      • Kushnir V.A.
      • Barad D.H.
      • Albertini D.F.
      • et al.
      Systematic review of worldwide trends in assisted reproductive technology 2004-2013.
      Most of the literature dealing with treated infertility and child-bearing to date has focussed on fetal, infant, and obstetric outcomes, and less is known about rates of severe maternal morbidity and maternal mortality (SMM) among women who conceive after ART. A few recent studies have quantified the rates of SMM among women who conceived after ART and they have showed that ART confers an increased risk of some specific SMM types.
      • Martin A.S.
      • Monsour M.
      • Kissin D.M.
      • et al.
      Trends in severe maternal morbidity after assisted reproductive technology in the United States, 2008–2012.
      • Wang E.T.
      • Ozimek J.
      • Greene N.
      • et al.
      Impact of fertility treatment on severe maternal morbidity.
      • Belanoff C.
      • Declercq E.R.
      • Diop H.
      • et al.
      Severe maternal morbidity and the use of assisted reproductive technology in Massachusetts.
      • Dayan N.
      • Joseph K.S.
      • Fell D.
      • et al.
      Infertility treatment and risk of severe maternal morbidity: a propensity score–matched cohort study.
      • Gui J.
      • Ling Z.
      • Hou X.
      • et al.
      In vitro fertilization is associated with the onset and progression of preeclampsia.
      However, no study has comprehensively assessed the associations between ART and composite SMM and SMM types and subtypes. For instance, the relationship between ART and obstetric acute renal failure and the relationship between ART and myocardial infarction have not been examined to date. Such information is important for counselling women prior to ART, for selecting the appropriate ART method (with respect to its potential for resulting in multifetal gestation), and for the obstetric management of ART pregnancies.
      We therefore carried out a population-based study that examined the association between ART and SMM. We also attempted to quantify the association between ART and SMM in singleton versus multifetal pregnancy. Such information is important for women at high risk for complications, as ART procedures can increasingly assure success while limiting the chance of a multifetal pregnancy.

      Methods

      Study Population and Data Source

      This study was approved by the research ethics board of the University of British Columbia-Children’s and Women’s Hospital and Health Centre of British Columbia (H13–02896). The study included all hospital deliveries at ≥20 weeks gestation in Canada (excluding Québec) between April 1, 2009, and March 31, 2018. Data on these deliveries were obtained from the discharge abstract database (DAD), which is maintained by the Canadian Institute for Health Information and contains information on about 98% of all deliveries in Canada (excluding Québec).
      • Wen S.W.
      • Liu S.
      • Marcoux S.
      • et al.
      Uses and limitations of routine hospital admission/separation records for perinatal surveillance.
      Maternal and perinatal information in this database includes information on maternal age, gestational age at delivery (in completed weeks), parity, and up to 25 diagnostic codes and 20 procedure codes related to delivery hospitalization. Diagnoses were coded using the International Statistical Classification of Diseases and Related Health Problems, 10th edition, Canadian version (ICD-10CA), and procedures were coded using the Canadian Classification of Health Interventions. The DAD data have been validated against medical charts and other data sources and have been routinely used for surveillance and population research.
      • Joseph K.S.
      • Fahey J.
      Validation of perinatal data in the Discharge Abstract Database of the Canadian Institute for Health Information.
      ,
      The data on parity were systematically collected only in some provinces (approximately 79% of the study population).

      Deliveries After ART

      The ICD-10CA codes in the DAD were used to identify pregnancies resulting from ART and included assisted reproduction, ovulation induction, intracytoplasmic sperm injection, embryo transfer, and IVF. These codes included the appropriate six-digit variations of ICD-10CA codes Z37 and Z38 (e.g., Z37001, which codes for a single live birth, pregnancy resulting from ART).

      Deliveries With SMM

      Composite SMM included all of the types and subtypes of SMM as described by the Canadian Perinatal Surveillance System in 2019 and 2020.
      • Dzakpasu S.
      • Deb-Rinker P.
      • Arbour L.
      • et al.
      for the Canadian Perinatal Surveillance System (Public Health Agency of Canada). Severe maternal morbidity surveillance: monitoring pregnant women at high risk for prolonged hospitalisation and death.
      ,
      • Dzakpasu S.
      • Deb-Rinker P.
      • Arbour L.
      • et al.
      for the Canadian Perinatal Surveillance System (Public Health Agency of Canada). Severe maternal morbidity in Canada: temporal trends and regional variations, 2003-2016.
      This list of conditions was created based on a priori clinical expertise and empirical evidence showing a high case fatality rate or prolonged hospitalization. The list included 44 SMM subtypes that were grouped into the following types: (1) severe preeclampsia, eclampsia, and hemolysis, elevated liver enzymes, and low platelets (HELLP); (2) severe hemorrhage (requiring transfusion or surgical procedures to control bleeding); (3) maternal intensive care unit (ICU) admission; (4) surgical complications; (5) hysterectomy; (6) sepsis; (7) embolism, shock, or disseminated intravascular coagulation (DIC); (8) assisted ventilation; (9) cardiac conditions; (10) acute renal failure; (11) severe uterine rupture; (12) cerebrovascular accidents; and (13) miscellaneous conditions (e.g., status epilepticus). The information on severe preeclampsia and HELLP syndrome was coded in the DAD from 2012 onwards and the database also had not included information on maternal ICU admissions from 2009 to 2012.

      Statistical Analysis

      The frequency of ART was expressed per 100 deliveries at ≥20 weeks gestation, composite SMM rates were expressed per 1000 deliveries, and the rates of the less frequent SMM types and subtypes were calculated per 100 000 deliveries. Crude associations between maternal and obstetric characteristics and ART deliveries were assessed using rate ratios (RR) and 95% CI. The RRs and 95% CIs were also used to compare the rates of SMM between women with and without ART.
      Logistic regression was used to assess the independent association between ART and composite SMM after adjusting for maternal characteristics that are known determinants of SMM. These included maternal age (<20, 20–24, 25–29, 30–34, 35–39, and ≥40 years), parity (nulliparity, parity 1–4, grand multiparity, and missing parity), chronic hypertension (yes vs. no), diabetes (yes vs. no), and previous cesarean delivery (yes vs. no). Maternal age was also modeled as a continuous variable with an additional quadratic term to assess if such representation improved model fit. The models with maternal age represented using indicator variables are presented, as the continuous variable and quadratic term did not improve model fit, and the adjusted associations between ART and SMM were unchanged. The associations between ART and SMM obtained from logistic models were expressed as crude RRs and adjusted rate ratios (aRR) with 95% CIs (because the frequency of SMM was low, odds ratios obtained from the logistic models approximated rate ratios). A second set of adjusted logistic regression models included an additional adjustment for plurality (singleton vs. multifetal pregnancy)—these models quantified the independent association between ART and SMM among singletons and also the same association among multifetal pregnancies. All analyses were carried out using SAS 9.4 (SAS Institute Inc., Cary, NC).

      Results

      Study Population and ART Rates

      The study population included 2 535 056 women who delivered at ≥20 weeks gestation between April 2009 and March 2018. Overall, 72 023 women delivered after ART (2.8%). The proportion of deliveries resulting from ART was significantly higher among women who were of advanced age, nulliparous, and had chronic hypertension or diabetes. The ART rates were also higher among women who delivered preterm, after labour induction or by cesarean delivery (Table 1). On the other hand, the women who had a previous cesarean delivery, who were <25 years of age, grand multiparous, and those who delivered post-term were less likely to have had ART (Table 1). Among the women who delivered twins or higher-order multiple births, 27% had ART.
      Table 1Numbers, rates, and rate ratios showing the frequency of deliveries following ART use, by maternal and clinical characteristics, Canada (excluding Québec), April 2009 to March 2018
      CharacteristicAll, no. of deliveries; n = 2 535 056Deliveries following ARTRate ratio
      Calculated by dividing the rate of assisted reproductive technology in the index group (e.g., chronic hypertension) by the rate of assisted reproductive technology in the reference group (no chronic hypertension).
      (95% CI)
      No. of; n = 72 023Rate/100
      Age group, y
       <2067 149460.070.06 (0.04–0.08)
       20–24310 6558220.260.23 (0.22–0.25)
       25–29681 35178991.161.00
       30–34881 19424 2282.752.37 (2.31–2.43)
       35–39478 91525 4875.324.59 (4.48–4.71)
       ≥40115 79213 54111.710.1 (9.82–10.4)
      Parity
       0915 25337 9614.152.63 (2.58–2.68)
       1–41 084 16117 1041.581.00
       ≥567 5225270.780.49 (0.45–0.54)
       Missing540 14316 4313.041.93 (1.89–1.97)
      Plurality
       Singleton2 460 11851 8032.111.00
       Twins or higher74 93820 22027.012.8 (12.6–13.0)
      Previous cesarean
       Yes285 05666912.350.81 (0.79–0.83)
       No2 250 00065 3322.901.00
      Diabetes
       Yes193 69610 2165.272.00 (1.96–2.04)
       No2 341 36061 8072.641.00
      Chronic hypertension
       Yes16 58811056.662.37 (2.23–2.51)
       No2 518 46870 9182.821.00
      Labour induction
       Yes656 19323 1103.521.35 (1.33–1.37)
       No1 878 86348 9132.601.00
      Cesarean delivery
       Yes738 81937 2995.052.61 (2.57–2.65)
       No1 796 23734 7241.931.00
      Gestation, wk
       20–3350 305626512.55.41 (5.28–5.54)
       34–36149 92212 0818.063.50 (3.43–3.57)
       37–412 323 43653 5152.301.00
       ≥4290541401.550.67 (0.57–0.79)
      Region
       Atlantic188 96535841.900.65 (0.63–0.68)
       Ontario1 209 72435 0912.901.00
       Prairies744 84419 2962.590.89 (0.88–0.91)
       British Columbia377 95313 9323.691.27 (1.25–1.30)
       Northern13 5701200.880.30 (0.26–0.36)
      ART: assisted reproductive technology.
      a Calculated by dividing the rate of assisted reproductive technology in the index group (e.g., chronic hypertension) by the rate of assisted reproductive technology in the reference group (no chronic hypertension).

      ART and SMM Rates

      The incidence of composite SMM was 34.7 per 1000 deliveries among women with ART, whereas the incidence in the comparison group was 11.5 per 1000 deliveries (as mentioned, information on severe preeclampsia, etc., was not available for the early years of the study period; Table 2). The median length of hospital stay for women in the ART group was 3 days (compared with 2 days for women who did not receive ART), and the proportion of women who had a prolonged hospital stay (≥7 days) was substantially higher among women with ART (5.5% vs. 1.1% in the ART vs. no ART group, respectively; RR 4.96; 95% CI 4.80–5.12). There were few (<5) maternal deaths among women who delivered after ART.
      Table 2Frequency of severe maternal morbidity and maternal mortality (SMM), case fatality, and length of stay among deliveries to women following use of assisted reproductive technology (ART), Canada (excluding Québec), April 2009 to March 2018
      ART: assisted reproductive technology; SMM: severe maternal morbidity and maternal mortality.
      IndexUsed ARTDid not use ARTRate ratio (95% CI)
      No. of deliveries72 0232 463 033
      SMM
       No.249728 340
       Rate/1000 (95% CI)34.7 (33.3–36.0)11.5 (11.4–11.6)3.01 (2.89–3.14)
      Deaths
       No.<5
      Cell counts <5 suppressed for confidentiality (rate and rate ratio calculated with an assumed numerator value of 3).
      59
       Rate/100 000 deliveries6.942.41.74 (0.55–5.55)
      Length of stay, d, median (IQR)3 (2–4)2 (1–3)
      Percentage with length of stay ≥7 d (95% CI)5.5 (5.4–5.7)1.1 (1.1–1.1)4.96 (4.80–5.12)
      NOTE. Information on some severe maternal morbidity and maternal mortality types, namely severe preeclampsia, hemolysis, elevated liver enzymes, and low platelets syndrome, and intensive care unit admission, was not available for the early part of the study period (see Methods section).
      a Cell counts <5 suppressed for confidentiality (rate and rate ratio calculated with an assumed numerator value of 3).
      Rates of severe preeclampsia, HELLP syndrome, eclampsia, severe hemorrhage, maternal ICU admission, surgical complications, hysterectomy, sepsis, embolism, shock, DIC, assisted ventilation, cardiac conditions, acute renal failure, and miscellaneous SMM were significantly higher among women who conceived following ART (Table 3). There were also strong associations between ART and specific SMM subtypes, including intrapartum hemorrhage with blood transfusion (RR 8.55; 95% CI 4.66–15.7), cesarean hysterectomy (RR 3.36; 95% CI 2.67–4.24), cardiac complications of anesthesia (RR 4.60; 95% CI 2.64–8.04), cardiac arrest and resuscitation (RR 5.65; 95% CI 3.52–9.07), and pulmonary edema and heart failure (RR 6.27; 95% CI 5.19–7.58; Table 4).
      Table 3Numbers, rates, and rate ratios showing the frequency of severe maternal morbidity and maternal mortality types and maternal death among deliveries with and without use of ART, Canada (excluding Québec), April 2009 to March 2018
      Severe maternal morbidity typeDeliveries not following ARTDeliveries following ARTRate ratio (95% CI)
      No. ofRate/100 000No. ofRate/100 000
      SPE, HELLP syndrome, eclampsia
      Severe preeclampsia, hemolysis, elevated liver enzymes, and low platelets syndrome, and eclampsia numbers and rates based on data for the period April 2012 to March 2018, that is, these rates were based on 1 638 796 and 50 937 deliveries in the non-assisted reproductive technology (ART) and ART groups, respectively; maternal intensive care unit admission rates based on 1 366 006 and 42 848 deliveries in non-ART and ART groups (April 2013 to March 2018), respectively; and all other rates based on 2 463 033 and 72 023 deliveries in non-ART and ART groups (April 2009 to March 2018), respectively. Cell counts <5 suppressed for confidentiality (rate ratios calculated with an assumed numerator value of 3).
      8799536.99561876.83.50 (3.27–3.73)
      Severe hemorrhage4986202.4522724.83.58 (3.27–3.92)
      Maternal ICU admission
      Severe preeclampsia, hemolysis, elevated liver enzymes, and low platelets syndrome, and eclampsia numbers and rates based on data for the period April 2012 to March 2018, that is, these rates were based on 1 638 796 and 50 937 deliveries in the non-assisted reproductive technology (ART) and ART groups, respectively; maternal intensive care unit admission rates based on 1 366 006 and 42 848 deliveries in non-ART and ART groups (April 2013 to March 2018), respectively; and all other rates based on 2 463 033 and 72 023 deliveries in non-ART and ART groups (April 2009 to March 2018), respectively. Cell counts <5 suppressed for confidentiality (rate ratios calculated with an assumed numerator value of 3).
      2490182.3177413.12.27 (1.95–2.65)
      Surgical complications4445180.5317440.12.44 (2.18–2.73)
      Hysterectomy3454140.2378524.83.74 (3.37–4.16)
      Sepsis210685.5154213.82.50 (2.12–2.94)
      Embolism, shock, DIC158364.3125173.62.70 (2.25–3.24)
      Assisted ventilation138656.3114158.32.81 (2.32–3.40)
      Cardiac conditions136855.5176244.44.40 (3.76–5.15)
      Acute renal failure88636.0176244.46.79 (5.78–7.98)
      Severe uterine rupture1566.3<56.940.66 (0.21–2.06)
      Cerebrovascular accidents2188.968.30.94 (0.42–2.12)
      Miscellaneous severe morbidity185075.1105145.81.94 (1.59–2.36)
      Maternal death592.40<56.941.74 (0.55–5.55)
      Any severe maternal morbidity or death28 3401150.624973467.03.01 (2.89–3.14)
      ART: assisted reproductive technology; DIC: disseminated intravascular coagulation; HELLP: hemolysis, elevated liver enzymes, and low platelets; ICU: intensive care unit; SPE: severe preeclampsia.
      a Severe preeclampsia, hemolysis, elevated liver enzymes, and low platelets syndrome, and eclampsia numbers and rates based on data for the period April 2012 to March 2018, that is, these rates were based on 1 638 796 and 50 937 deliveries in the non-assisted reproductive technology (ART) and ART groups, respectively; maternal intensive care unit admission rates based on 1 366 006 and 42 848 deliveries in non-ART and ART groups (April 2013 to March 2018), respectively; and all other rates based on 2 463 033 and 72 023 deliveries in non-ART and ART groups (April 2009 to March 2018), respectively. Cell counts <5 suppressed for confidentiality (rate ratios calculated with an assumed numerator value of 3).
      Table 4Numbers, rates, and rate ratios showing the frequency of severe maternal morbidity and maternal mortality subtypes among deliveries with and without use of ART, Canada (excluding Québec), April 2009 to March 2018
      Severe maternal morbidity subtype or deathDeliveries not following ARTDeliveries following ARTRate ratio (95% CI)
      No.Rate/100 000No.Rate/100 000
      Severe preeclampsia
      Severe preeclampsia; hemolysis, elevated liver enzymes, and low platelets syndrome; and eclampsia numbers and rates based on data for the period April 2012 to March 2018 (i.e., these rates were based on 1 638 796 and 50 937 deliveries in the non-assisted reproductive technology [ART] and ART groups, respectively). All other rates based on 2 463 033 and 72 023 deliveries in non-ART and ART groups (April 2009 to March 2018), respectively.
      3983243.0429842.23.47 (3.14–3.83)
      HELLP syndrome
      Severe preeclampsia; hemolysis, elevated liver enzymes, and low platelets syndrome; and eclampsia numbers and rates based on data for the period April 2012 to March 2018 (i.e., these rates were based on 1 638 796 and 50 937 deliveries in the non-assisted reproductive technology [ART] and ART groups, respectively). All other rates based on 2 463 033 and 72 023 deliveries in non-ART and ART groups (April 2009 to March 2018), respectively.
      4406268.95151011.13.76 (3.43–4.11)
      Eclampsia
      Severe preeclampsia; hemolysis, elevated liver enzymes, and low platelets syndrome; and eclampsia numbers and rates based on data for the period April 2012 to March 2018 (i.e., these rates were based on 1 638 796 and 50 937 deliveries in the non-assisted reproductive technology [ART] and ART groups, respectively). All other rates based on 2 463 033 and 72 023 deliveries in non-ART and ART groups (April 2009 to March 2018), respectively.
      75045.83670.71.54 (1.11–2.16)
      Placenta previa with hemorrhage and red cell transfusion89936.5141195.85.36 (4.49–6.40)
      Placental abruption with coagulation defect32913.41419.41.46 (0.85–2.48)
      Antepartum hemorrhage with coagulation defect1315.3268.331.57 (0.69–3.55)
      Intrapartum hemorrhage with coagulation defect1686.821926.43.87 (2.41–6.22)
      Intrapartum hemorrhage with red cell transfusion522.111318.08.55 (4.66–15.7)
      Severe postpartum hemorrhage
      Severe postpartum hemorrhage refers to postpartum hemorrhage with red cell transfusion, procedures to the uterus, or hysterectomy.
      2537103.0334463.74.50 (4.02–5.05)
      Curettage with red cell transfusion165467.2101140.22.09 (1.71–2.55)
      Complications of obstetric surgery and procedures236996.2192266.62.77 (2.39–3.21)
      Evacuation incisional hematoma and red cell transfusion1134.59811.12.42 (1.18–4.96)
      Repair of bladder, urethra, or intestine169468.8107148.62.16 (1.78–2.63)
      Reclosure of cesarean wound34514.01419.41.39 (0.81–2.37)
      Cesarean hysterectomy79332.278108.33.36 (2.67–4.24)
      Hysterectomy (open approach)
      Hysterectomy (open approach) excludes cases with bladder neck suspension, suspension of vaginal vault, or pelvic floor repair. Cell counts <5 suppressed for confidentiality (rate ratio calculated with an assumed numerator value of 3).
      2668108.3300416.53.85 (3.41–4.33)
      Puerperal sepsis164166.6129179.12.69 (2.25–3.22)
      Septicemia during labour46618.92534.71.83 (1.23–2.74)
      Obstetric shock72129.36691.63.13 (2.43–4.03)
      Obstetric embolism73830.05677.82.59 (1.98–3.40)
      Disseminated intravascular coagulation1867.551115.32.02 (1.10–3.72)
      Assisted ventilation through endotracheal tube137455.8114158.32.84 (2.34–3.43)
      Assisted ventilation through tracheostomy251.0200.0
      Cardiac complications of anesthesia1044.221419.44.60 (2.64–8.04)
      Cardiomyopathy54522.13852.82.38 (1.72–3.31)
      Cardiac arrest and resuscitation1214.912027.85.65 (3.52–9.07)
      Myocardial infarction271.10<56.943.80 (1.15–12.5)
      Pulmonary edema and heart failure68727.9126174.96.27 (5.19–7.58)
      Acute renal failure84334.2175243.07.10 (6.03–8.35)
      Dialysis933.7879.722.57 (1.19–5.55)
      Cerebral venous thrombosis in pregnancy632.56<56.941.63 (0.51–5.19)
      Cerebral venous thrombosis in the puerperium80.3200.00
      Subarachnoid/intracranial hemorrhage/cerebral infarction1506.09<56.940.68 (0.22–2.14)
      Acute fatty liver with red cell/plasma transfusion2229.013852.765.85 (4.15–8.26)
      Hepatic failure602.44<56.941.71 (0.54–5.45)
      Cerebral edema or coma281.1400.00
      Complications of anaesthesia29712.11824.992.07 (1.29–3.33)
      Status asthmaticus562.27<56.941.83 (0.57–5.85)
      Adult respiratory distress syndrome813.29811.113.38 (1.63–6.98)
      Acute abdomen1797.2779.721.34 (0.63–2.85)
      Sickle cell anemia with crisis943.8200.00
      Acute psychosis933.78<56.941.10 (0.35–3.48)
      Status epilepticus843.41<56.941.22 (0.39–3.86)
      HIV disease44117.91520.831.16 (0.70–1.95)
      Maternal death592.40<56.941.74 (0.55–5.55)
      Any severe maternal morbidity/death28 3401150.618893467.03.01 (2.89–3.14)
      ART: assisted reproductive technology; HELLP: hemolysis, elevated liver enzymes, and low platelets; HIV: human immunodeficiency virus.
      a Severe preeclampsia; hemolysis, elevated liver enzymes, and low platelets syndrome; and eclampsia numbers and rates based on data for the period April 2012 to March 2018 (i.e., these rates were based on 1 638 796 and 50 937 deliveries in the non-assisted reproductive technology [ART] and ART groups, respectively). All other rates based on 2 463 033 and 72 023 deliveries in non-ART and ART groups (April 2009 to March 2018), respectively.
      b Severe postpartum hemorrhage refers to postpartum hemorrhage with red cell transfusion, procedures to the uterus, or hysterectomy.
      c Hysterectomy (open approach) excludes cases with bladder neck suspension, suspension of vaginal vault, or pelvic floor repair. Cell counts <5 suppressed for confidentiality (rate ratio calculated with an assumed numerator value of 3).
      Table 5Logistic regression analysis showing unadjusted and adjusted rate ratios expressing the association between assisted reproductive technology and specific severe maternal morbidity types, Canada (excluding Québec) April 2009 to March 2018
      Severe maternal morbidity typeCrude rate ratio (95% CI)Adjusted rate ratio (95% CI)
      Adjusted for maternal age, parity, hypertension, diabetes, and previous cesarean delivery.
      Adjusted rate ratio (95% CI)
      Additionally adjusted for plurality.
      SPE, HELLP syndrome, eclampsia
      Severe preeclampsia and hemolysis, elevated liver enzymes, and low platelets syndrome numbers and rates based on data for the period April 2012 to March 2018.
      3.55 (3.31–3.79)2.58 (2.40–2.77)1.48 (1.37–1.60)
      Severe hemorrhage3.60 (3.29–3.94)2.90 (2.64–3.19)2.14 (1.93–2.37)
      Maternal ICU admission
      Maternal intensive care unit admission numbers and rates based on data for the period April 2013 to March 2018.
      2.27 (1.95–2.65)1.71 (1.46–2.01)1.23 (1.04–1.46)
      Surgical complications2.45 (2.18–2.74)2.07 (1.84–2.33)1.59 (1.40–1.81)
      Hysterectomy3.76 (3.38–4.18)2.00 (1.79–2.24)1.79 (1.59–2.02)
      Sepsis2.50 (2.13–2.95)2.23 (1.88–2.65)1.63 (1.35–1.96)
      Embolism, shock, DIC2.70 (2.25–3.24)2.22 (1.83–2.68)1.58 (1.29–1.95)
      Assisted ventilation2.82 (2.33–3.41)2.00 (1.64–2.45)1.38 (1.11–1.72)
      Cardiac conditions4.41 (3.77–5.16)2.81 (2.37–3.32)1.58 (1.31–1.90)
      Acute renal failure6.81 (5.79–8.00)3.81 (3.19–4.55)1.92 (1.57–2.35)
      Severe uterine rupture0.65 (0.21–2.05)0.58 (0.18–1.83)0.48 (0.15–1.57)
      Cerebrovascular accidents0.93 (0.42–2.12)0.69 (0.30–1.57)0.52 (0.22–1.23)
      Miscellaneous SMM1.94 (1.60–2.37)1.69 (1.38–2.07)1.32 (1.06–1.64)
      Maternal death1.14 (0.28–4.66)0.81 (0.19–3.40)0.81 (0.18–3.56)
      Any SMM3.15 (3.02–3.29)2.34 (2.24–2.45)1.60 (1.52–1.67)
      Note: Crude rate ratios in this table differ slightly from those in Table 3 because the crude rate ratios in this table are approximated from the crude adjusted odds ratios obtained from the logistic model.
      DIC: disseminated intravascular coagulation; HELLP: hemolysis, elevated liver enzymes, and low platelets; ICU: intensive care unit; SMM: severe maternal morbidity and maternal mortality types; SPE: severe preeclampsia.
      a Adjusted for maternal age, parity, hypertension, diabetes, and previous cesarean delivery.
      b Additionally adjusted for plurality.
      c Severe preeclampsia and hemolysis, elevated liver enzymes, and low platelets syndrome numbers and rates based on data for the period April 2012 to March 2018.
      d Maternal intensive care unit admission numbers and rates based on data for the period April 2013 to March 2018.
      Logistic regression showed a three-fold higher rate of composite SMM among women who had used ART (RR 3.15; 95% CI 3.02–3.29). This association was attenuated by adjustment for maternal age, parity, hypertension, diabetes, and previous cesarean delivery (aRR 2.34; 95% CI 2.24–2.45). The aRR expressing the association between ART and SMM was 1.60 (95% CI 1.52–1.67) among singletons, whereas the aRR for the association between multifetal pregnancy and SMM was 2.96 (95% CI 2.83–3.08). Thus, women who used ART and had multifetal pregnancies had 4.7-fold higher rates of SMM compared with women who did not have ART and delivered singletons (aRR 1.60 × aRR 2.96). The associations between severe preeclampsia, HELLP syndrome, eclampsia, severe hemorrhage, ICU admission, surgical complications, hysterectomy, sepsis, embolism, shock, DIC, assisted ventilation, cardiac conditions, acute renal failure, and miscellaneous SMM were significant and remained significant despite the adjustment for maternal characteristics (Table 5). ART was not significantly associated with maternal death, severe uterine rupture, or cerebrovascular accidents.
      Additional analyses showed significant crude associations between ART and maternal morbidity types such as postpartum hemorrhage (RR 1.87; 95% CI 1.83–1.92), preeclampsia (RR 3.43; 95% CI 3.32–3.56), and also blood transfusion (RR 2.69; 95% CI 2.54–2.84). These associations remained significant after adjustment for maternal factors, namely, age, parity, chronic hypertension, diabetes, previous cesarean delivery, and plurality.

      Discussion

      Our large population-based study showed that 2.8% of deliveries between April 2009 and March 2018 followed the use of ART, and ART rates were higher among older, nulliparous women and those with chronic hypertension or diabetes. ART was also highly associated with multifetal gestation, preterm birth, labour induction, and cesarean delivery. ART deliveries were at a three-fold higher risk of composite SMM (crude RR 3.01; 95% CI 2.89–3.14), and this association was partially attenuated by adjustment for maternal characteristics (aRR 2.34; 95% CI 2.24–2.45). The association between ART and SMM was significant among singletons deliveries (aRR 1.60; 95% CI 1.52–1.67) and 4.7-fold higher among multifetal pregnancies after ART (compared with singleton pregnancies not using ART). ART was associated with higher rates of several specific types of SMM, including severe preeclampsia, HELLP, eclampsia, severe hemorrhage, maternal ICU admission, surgical complications, hysterectomy, sepsis, embolism, shock, DIC, assisted ventilation, cardiac conditions, acute renal failure, and miscellaneous SMM.
      Our study corroborated previous studies that showed an approximately two- to three-fold higher risk of composite SMM associated with ART.
      • Martin A.S.
      • Monsour M.
      • Kissin D.M.
      • et al.
      Trends in severe maternal morbidity after assisted reproductive technology in the United States, 2008–2012.
      • Wang E.T.
      • Ozimek J.
      • Greene N.
      • et al.
      Impact of fertility treatment on severe maternal morbidity.
      • Belanoff C.
      • Declercq E.R.
      • Diop H.
      • et al.
      Severe maternal morbidity and the use of assisted reproductive technology in Massachusetts.
      • Dayan N.
      • Joseph K.S.
      • Fell D.
      • et al.
      Infertility treatment and risk of severe maternal morbidity: a propensity score–matched cohort study.
      One hospital-based study from Nanjing et al.
      • Gui J.
      • Ling Z.
      • Hou X.
      • et al.
      In vitro fertilization is associated with the onset and progression of preeclampsia.
      showed that women who conceived after IVF had a 2.6-fold higher rate of preeclampsia (95% CI 2.0–3.4) compared with women who conceived spontaneously. This was similar to the 3.43-fold difference in the crude rates of preeclampsia and the 2.58-fold difference in the adjusted rates of severe preeclampsia, HELLP, and eclampsia in our study, although the factors included in the multivariable adjustment differed between the 2 studies. The Chinese study
      • Gui J.
      • Ling Z.
      • Hou X.
      • et al.
      In vitro fertilization is associated with the onset and progression of preeclampsia.
      included maternal age, parity, weight at delivery, gestational age, and mode of delivery in their multivariable model, whereas our models included maternal age, parity, hypertension, diabetes, and previous cesarean delivery. Another population-based study from Ontario in 2006 to 2012 used propensity score matching to examine the association between infertility treatments and SMM, and showed a 1.4-fold increase in SMM and 1.7-, 1.5-, and 1.5-fold higher rates of severe postpartum hemorrhage, ICU admission, and puerperal sepsis, respectively.
      • Dayan N.
      • Joseph K.S.
      • Fell D.
      • et al.
      Infertility treatment and risk of severe maternal morbidity: a propensity score–matched cohort study.
      Our study provided a comprehensive quantification of the risks of specific types and subtypes of SMM that were increased after ART. This elevation in risk was evident even after adjustment for various maternal characteristics, including maternal age, parity, chronic hypertension, diabetes mellitus, and previous cesarean delivery. It is noteworthy that many of the factors adjusted in our models were more prevalent in women who required ART, and although discounted as confounders in the analysis, serve as markers that signify an added burden of SMM among individual women who undergo ART. The absolute risks of severe maternal complications among women having ART were not insignificant: the absolute risk of severe hypertensive complications, including severe preeclampsia, HELLP syndrome, or eclampsia in women with ART was 1.9%, whereas the risk of composite SMM was 3.5%.
      Our study showed that SMM rates were almost five-fold higher among women who conceived after ART and had a multifetal pregnancy (compared with women who conceived without ART and had singletons). The increased risk of SMM in multifetal pregnancy is well-recognized,
      • Wen S.W.
      • Demissie K.
      • Yang Q.
      • et al.
      Maternal morbidity and obstetric complications in triplet pregnancies and quadruplet and higher-order multiple pregnancies.
      • Luke B.
      • Brown M.B.
      Contemporary risks of maternal morbidity and adverse outcomes with increasing maternal age and plurality.
      • Young B.C.
      • Wylie B.J.
      Effects of twin gestation on maternal morbidity.
      • Witteveen T.
      • Van Den Akker T.
      • Zwart J.J.
      • et al.
      Severe acute maternal morbidity in multiple pregnancies: a nationwide cohort study.
      and added caution is required to ensure that ART practices do not favour multifetal pregnancy.
      • Velez M.P.
      • Connolly M.P.
      • Kadoch I.J.
      • et al.
      Universal coverage of IVF pays off.
      The high rate of SMM among women using ART also highlights the need for specific counselling for women with pre-existing medical conditions and chronic disease. Advances in medicine and surgery have improved the survival and quality of life of many women with chronic conditions, and ART increasingly helps such women to become pregnant. Nevertheless, it is important to place health risks in perspective and acknowledge the risk that pregnancy confers on women with specific chronic conditions. The high SMM risk associated with such conditions, coupled with the higher SMM risks associated with ART and multifetal pregnancy, could result in a highly morbid state among such women, and women should be informed about these risks in pre-pregnancy counselling.
      • Velez M.P.
      • Hamel C.
      • Hutton B.
      • et al.
      Care plans for women pregnant using assisted reproductive technologies: a systematic review.
      The strengths of our study include its large study size and population-based nature. Another key aspect of the study was the comprehensive examination of SMM types and subtypes, and our results quantified the adjusted relationship between ART and composite SMM and also several different SMM types. The limitations of our study included the lack of diagnostic codes for severe preeclampsia and HELLP syndrome in the early study years, as these codes were introduced into the Canadian version of ICD-10 in 2012. Similarly, the information on maternal ICU admission in this study was restricted to the years 2013 to 2017. These limitations affected the absolute rates of composite SMM in the study but did not affect the relative assessment of risk. Our data source did not include specific details regarding the type of ART used, and therefore we could not separate the association between SMM and IVF versus other ART modalities. We also lacked information on some maternal clinical and behavioural characteristics that are associated with SMM, such as pre-pregnancy body mass index, race/ethnicity, education, income, and smoking. The lack of adjustment for these factors would have likely resulted in residual confounding.

      Conclusion

      SMM rates are significantly elevated among women who deliver after ART. This association is partly attenuated but remains significant after adjusting for maternal characteristics such as age, parity, chronic hypertension, diabetes, and previous cesarean delivery. The ART association with SMM rates also differs substantially among singleton and multifetal pregnancies. Women contemplating ART require specific counselling and should be informed about the elevated risks of SMM, and that these risks are lowered if ART results in singleton pregnancy. This study also provides information relevant to the obstetric management of delivery in ART-initiated pregnancies.

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