The rate of pregnancy-related death in the United States has been on the rise since the 1980s, increasing from 7.2 per 100,000 in 1987 to 17.8 in 2011.1 However, because mortality is so rare, surveillance efforts have also targeted severe maternal morbidity, defined as having any of 25 International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) hospitalization codes for procedures and conditions indicating a potentially life-threatening situation.2 The severe maternal morbidity rate more than doubled in the United States between 2001 and 2011, increasing from 78.6, to 162.8 per 10,000 delivery hospitalizations.2 During the same period, the proportion of neonates born as a result of assisted reproductive technology (ART), defined as “fertility treatments in which both eggs and embryos are handled in the laboratory,”3 increased from 0.9% to 1.5%.3,4
Although the profile of the ART patient population tends to reflect greater social advantage and factors protective against severe maternal morbidity than the general maternity population,5 ART has been associated with known risk factors for severe maternal morbidity including placenta accreta,6 plural births,7 and cesarean delivery.8 Furthermore, women who use ART to conceive are more likely to have underlying health and fertility problems that necessitated the use of ART.9,10 As a result, previous research has encountered difficulty in distinguishing the direct effects of ART on maternal outcomes from other contributing health issues.11 The objective of this analysis was to examine whether ART use contributed to the frequency and type of severe maternal morbidities at the time of delivery apart from maternal fertility status and other health factors.
MATERIALS AND METHODS
This is one in a series of retrospective cohort analyses evaluating the effect of maternal fertility status (subfertile women treated with ART, subfertile women not treated with ART, and fertile women) on the course and outcome of pregnancy. This analysis is part of a larger population-based study of ART in Massachusetts.9,10,12–16 The project known as the Massachusetts Outcome Study of Assisted Reproductive Technology took place under a Memorandum of Understanding for use of the Society for Assisted Reproductive Technology Clinic Outcome Reporting System data and was approved by institutional review boards of Boston University, the Massachusetts Department of Public Health, all investigator institutions, and by the Society for Assisted Reproductive Technology Research Committee.
Data for these analyses were obtained from two sources: 1) the Society for Assisted Reproductive Technology Clinic Outcome Reporting System online database; and 2) the birth certificates, fetal death records, and hospital utilization data in the Massachusetts-based Pregnancy to Early Life Longitudinal Data System.17
The Society for Assisted Reproductive Technology Clinic Outcome Reporting System is a clinic and treatment-based data system that contains cycle-based ART data from more than 90% of U.S. ART clinics and more than 97% of ART cycles.7 The Society for Assisted Reproductive Technology Clinic Outcome Reporting System data contain patient demographics (age, race, diagnosis), ART treatment data (fresh compared with frozen state, oocyte type, micromanipulation procedures, and embryos transferred), and outcome data (cancellation, pregnancy, live birth, birth outcomes) on all cycles of ART at participating clinics and data from this system are available for research from 2004 onward. All Massachusetts clinics report their data to the Society for Assisted Reproductive Technology Clinic Outcome Reporting System.
The Pregnancy to Early Life Longitudinal data system is relational and is composed of individual databases linked together by randomly generated unique identifiers for mother and child. The linked database contains information on more than 99% of all births and fetal deaths in Massachusetts from 1998 to 2010 and links these to corresponding hospital utilization data (hospital admissions, observational stays, and emergency department visits) for individual women and their children. The Massachusetts Department of Public Health and the Massachusetts Center for Health Information and Analysis are the custodians of the Pregnancy to Early Life Longitudinal data.
The construction of the Massachusetts Outcomes Study of Assisted Reproductive Technology database involved a linkage of the Society for Assisted Reproductive Technology Clinic Outcome Reporting System and Pregnancy to Early Life Longitudinal data systems for all deliveries to Massachusetts residents in Massachusetts hospitals between July 1, 2004, and December 31, 2010. To capture births plausibly attributable to ART treatment cycles beginning on January 1, 2004, we included births occurring from July 1, 2004, through December 31, 2010, the last date that birth records were available to us at the time. A detailed description of the Pregnancy to Early Life Longitudinal data system and Society for Assisted Reproductive Technology Clinic Outcome Reporting System data, their linkage, and validation have been published previously.14 Pregnancy to Early Life Longitudinal records were matched against eligible ART treatment cycle records—those occurring to Massachusetts resident women or to women who obtained treatment in a Massachusetts clinic during the same timeframe (43,214 eligible cycles for 17,547 women). Among our total sample of Pregnancy to Early Life Longitudinal deliveries, 13,981 (2.70%) linked to ART treatment cycles in Society for Assisted Reproductive Technology Clinic Outcome Reporting System, indicating that these neonates were conceived using ART. We limited our analysis to singleton or twin deliveries and excluded deliveries with incomplete data on the key predictors or outcomes of interest and those to women younger than 18 years of age.
An algorithm was developed to identify deliveries to women with indicators of subfertility who did not use ART to become pregnant.10 Briefly, subfertile deliveries were identified using three sources: 1) birth certificate items indicating the use of fertility treatment for the current or a prior pregnancy within the past 5 years; 2) hospital contact within 5 years before the current pregnancy for a condition specifically related to infertility (ICD-9-CM codes 628.0, 628.2, 628.3, 628.8, 628.9, V230); or 3) an ART treatment cycle for a prior pregnancy attempt occurring after January 1, 2004, but no ART cycle linked to the index delivery, as reported to the Society for Assisted Reproductive Technology Clinic Outcome Reporting System. From the pool of deliveries that met at least one of these criteria, we eliminated ART-assisted deliveries identified in the Society for Assisted Reproductive Technology Clinic Outcome Reporting System database in the study period and duplicate cases, which resulted in 8,984 non-ART singleton or twin deliveries between July 1, 2004, and December 31, 2010, to women with at least one indicator of subfertility.
The Centers for Disease Control and Prevention defines severe maternal morbidity using delivery hospitalization data and ICD-9-CM diagnosis and procedure codes that indicate a potentially life-threatening maternal condition or complication.18 Delivery hospitalizations with severe maternal morbidities were identified using a published algorithm that includes 25 specific ICD-9-CM diagnosis and procedure codes (Table 1) with indicators of organ system failure that likely represent specific well-defined severe events.2 Irrespective of the pregnancy outcome, women who had any ICD-9-CM codes that indicate such a potentially severe event were designated as having severe maternal morbidity.2 We applied this algorithm to all deliveries occurring at 20 weeks of gestation or greater in our study population and evaluated the differences by maternal fertility group and plurality. The primary outcome measure was severe maternal morbidity, defined as any of the 25 factors listed in Table 1.2
To estimate the association of ART with risk of any severe maternal morbidity during the delivery hospitalization, we analyzed the data using logistic generalized estimating equations. The generalized estimating equation model accounted for correlation between multiple neonates born to the same woman during the time period studied, because there were women who had more than one delivery in the Massachusetts Outcomes Study of Assisted Reproductive Technology data system. Because of the known maternal health risks associated with both plurality and cesarean delivery,17,19 and the association of these with fertility treatment, models were run separately for singleton and twin pregnancies and for vaginal and cesarean deliveries.
We tested potential confounders of the association between fertility status of the delivery and subsequent severe maternal morbidity. The final model included maternal age, education, race and ethnicity, marital status, payer for delivery, smoking during pregnancy, parity, and gestational or chronic hypertension or diabetes. To further adjust for the potentially confounding effects of certain maternal health conditions, our models also included selected obstetric or gynecologic health conditions found in the hospital discharge records and known to be associated with infertility including endometriosis; pelvic inflammatory disease; polycystic ovarian syndrome; intrauterine synechiae; peritoneal adhesions; abdominal, ovarian, or tubal pregnancy; and absence of menstruation and combined these into a single dichotomous measure as selected obstetric–gynecologic conditions.20 We tested for interaction effects between the main independent variable (fertility and treatment status of the delivery) and select demographic characteristics, (eg, maternal age and race and ethnicity) associated with each of the perinatal outcomes. We examined the type 3 analysis of effects for significance, finding no set of interaction terms meeting the criterion of P<.05.
We performed a count of the most common severe morbidities reported on maternal hospital discharge records and calculated the proportion of all deliveries affected by a given morbidity, reporting those which were most prevalent, by fertility status, plurality, and method of delivery. Finally, because blood transfusion was found to be the most common indicator of severe morbidity, we performed a post hoc analysis examining the prevalence of transfusion within the ART group across diagnoses recorded in the Society for Assisted Reproductive Technology Clinic Outcome Reporting System. Diagnoses tested included uterine factor, diminished ovarian reserve, endometriosis, male factor, ovulatory disorder, other factors, tubal factor, and unknown factors. The data were analyzed using SAS 9.2.
Of a total of 474,482 deliveries occurring between July 1, 2004, and December 31, 2010, in Massachusetts and included in the Massachusetts Outcomes Study of Assisted Reproductive Technology database, 458,918 (96.7%) were born to mothers 18 years of age or older, were liveborn singletons or twins, and had complete data on the variables of interest (Fig. 1). A description of the study population by fertility status group and plurality is shown in Table 2. Women who underwent ART, those with subfertility who did not undergo ART, and those in the fertile group differed significantly on multiple sociodemographic and health characteristics. Compared with the fertile group, the ART and subfertile groups were more likely to be older than 40 years of age (20.6% and 14.8% compared with 3.7%), white (85.2% and 84.6% compared with 67.1%), and to have private health insurance at the time of delivery (95.0% and 90.4% compared with 57.9%). Women in the ART and subfertile groups were also more likely to have delivered twins (26.0% and 8.3% compared with 1.4%), have a preterm birth (21.7% and 11.7% compared with 6.9%), and a cesarean delivery (54.2% and 45.3% compared with 31.3%). All demographic comparisons across the three groups were significant at a level of P<.001.
Among our total study population, we identified 5,318 deliveries (1.16%) that involved a severe maternal morbidity. The overall prevalences of severe maternal morbidity among fertile, subfertile, and ART deliveries were 1.09%, 1.44%, and 3.14%, respectively (data not shown). Among women with singleton pregnancies, those with cesarean delivery and ART combined had a significantly higher rate of severe maternal morbidity compared with women with cesarean delivery and subfertile (odds ratio [OR] 1.84, 95% confidence interval [CI] 1.37–2.46) or cesarean and fertile deliveries (OR 1.65, 95% CI 1.40–1.94) with crude prevalences being 3.37% compared with 1.86% and 2.07% respectively (Table 3). In the adjusted analysis, cesarean ART deliveries had 1.75 times higher odds (95% CI 1.30–2.35) compared with cesarean subfertile deliveries and 1.67 times higher odds of severe maternal morbidity (95% CI 1.40–1.98) compared with cesarean fertile deliveries. Among women with singletons who delivered vaginally, ART pregnancies had the highest proportion of any severe morbidity compared with subfertile (OR 2.21, 95% CI 1.46–3.36) and fertile deliveries (OR 2.46, 95% CI 1.96–3.09) with crude prevalences being 1.44% compared with 0.65% and 0.59%, respectively. In the adjusted analysis, women with ART who delivered vaginally had 1.97 times higher odds (95% CI 1.30–3.00) than women with subfertile deliveries and 2.27 times higher odds of severe maternal morbidity (95% CI 1.78–2.88) than those with fertile deliveries.
Twin deliveries were associated with rates of severe maternal morbidity ranging from 3.94% among fertile, vaginal deliveries to 5.76% among ART, cesarean deliveries. Among twin deliveries, the only difference in severe maternal morbidity was found between ART and fertile cesarean delivery groups (adjusted OR 1.48, 95% CI 1.14–1.93). The subfertile group did not differ significantly from a fertile group in any model.
The most common indicator of severe maternal morbidity across all deliveries, and for each subgroup, was blood transfusion (n=3,466 [0.76%]), involved in nearly two thirds of all severe maternal morbidity cases. Prevalence of transfusion varied across the groups with ART cesarean twin deliveries having the highest (4.03%) and vaginal singleton deliveries to fertile women the lowest (0.42%) transfusion rates (data not shown).
We examined hospital discharge records post hoc to see what other conditions accompanied transfusions and found that almost 90% of deliveries that involved a transfusion also had an indication of a hemorrhagic or anemic condition (data not shown). We also subcategorized ART deliveries by those involving male infertility, female infertility, both male and female infertility, and unexplained infertility to examine whether maternal, paternal, or both factors were associated with increased risk of severe maternal morbidity and found no significant differences (data not shown). When we calculated the prevalence of transfusion by specific infertility diagnoses recorded in the Society for Assisted Reproductive Technology Clinic Outcome Reporting System, only women with “uterine factor” had a significantly higher prevalence of transfusion than those without; however, only 16 (5.3%) of the 300 transfusion cases were affected by uterine factors (data not shown).
Women who conceived using ART and delivered singleton neonates were significantly more likely than women with subfertile and fertile deliveries to experience severe morbidity regardless of method of delivery and adjusting for demographic and health factors. The risk of severe maternal morbidity in women with singleton subfertile births did not differ significantly from that of the fertile group. Among twin deliveries, there were fewer significant differences, perhaps owing to smaller numbers and the higher occurrence of maternal morbidities associated with plural births in general.19 It should be noted, however, that the absolute increase in risk associated with ART was very small, under 2 percentage points, for all subgroup comparisons.
The overall prevalence of severe maternal morbidity among Massachusetts mothers (1.16%) in this study was consistent with previously reported national estimates for similar time periods. Using a national sample, Kuklina et al21 found a severe maternal morbidity prevalence of 0.81% in 2004–2005 and Callaghan et al2 found 1.29% in 2008–2009. The most common indicator of a severe maternal morbidity event in our sample, like in these previous studies, was blood transfusion, which largely accounted for greater severe maternal morbidity observed among the ART groups. However, no distinct comorbidity patterns were observed that would explain the higher transfusion rates.
Rates of blood transfusion are dependent at least in part on guidelines around acceptable maternal hemoglobin levels, and these guidelines have changed over time.22 Therefore, studies of severe maternal morbidity, particularly time trend analyses, should be mindful of changes in practice standards for management of hemorrhage and anemia in obstetric patients.
This study of the association of ART with severe maternal morbidity is important for its inclusion of a non-ART but subfertile comparison group.10 A Dutch study found 2.5 times greater risk of severe maternal morbidity among ART compared with fertile births, although the researchers did not include a subfertile comparison group.23 A study by Silberstein et al24 compared the risks of certain severe adverse outcomes among groups with ART, non-ART ovulation induction, and spontaneous conceptions, observing a significant trend of highest to lowest risk across the three groups, respectively. We observed comparable trends across our three comparison groups.
The Massachusetts Outcomes Study of Assisted Reproductive Technology database allowed us to identify pregnancies conceived with ART and distinguish them from non-ART, subfertile pregnancies. Additionally, this population-level database included nearly all births to women 18 years of age and older in Massachusetts over more than a 6-year period. Our stratification by plurality and method of delivery and comparison of ART to subfertile deliveries allowed us to account for the higher prevalence of cesarean deliveries and plural births among ART pregnancies17,19 and estimate the contribution of ART to severe morbidity apart from underlying health issues and complications more common to ART pregnancies. This approach addressed a common limitation of prior ART studies.10
One study limitation was the lack of information on non-ART fertility treatments in the subfertile group. Therefore, we could not distinguish all subtypes of subfertile pregnancies. In addition, some subfertile deliveries may have been misclassified as “fertile,” although this is unlikely to have affected the much larger fertile group. Similarly, some women who delivered in Massachusetts may have received ART out of state and thus would be misclassified as fertile or subfertile. Similarly, we could not determine whether events possibly accompanying ART such as gonadotropin medications and fetal losses contributed to the greater observed severe maternal morbidity. Lastly, our analysis of only Massachusetts births may raise concerns around generalizability; however, our findings largely corresponded to previous national data on the nature and prevalence of severe maternal morbidity by fertility groups, as noted previously, suggesting that they may well translate to other settings.
In conclusion, women who conceived through ART and delivered singleton neonates were found to be at elevated risk of severe morbidities during their delivery hospitalizations compared with women who had indicators of subfertility but did not use ART to conceive and with women who had neither indicators of subfertility nor ART. Blood transfusion was the most common indicator of a severe morbid event for all deliveries; however, further research is needed toward understanding mechanisms and accompanying conditions, which may underlie the elevated risk of severe morbidity among women who undergo ART.
2. Callaghan WM, Creanga AA, Kuklina EV. Severe maternal morbidity among delivery and postpartum hospitalizations in the United States. Obstet Gynecol 2012;120:1029–36.
3. Sunderam S, Kissin DM, Crawford SB, Folger SG, Jamieson DJ, Barfield WD; Centers for Disease Control and Prevention (CDC). Assisted reproductive technology surveillance–United States, 2011. MMWR Surveill Summ 2014;63:1–28.
4. Wright VC, Schieve LA, Reynolds MA, Jeng G, Kissin D. Assisted reproductive technology surveillance–United States, 2001. MMWR Surveill Summ 2004;53:1–20.
5. Chandra A, Copen CE, Stephen EH. Infertility service use in the United States: data from the National Survey of Family Growth, 1982–2010. National health statistics reports; no. 73. Hyattsville (MD): National Center for Health Statistics; 2014.
6. Esh-Broder E, Ariel I, Abas-Bashir N, Bdolah Y, Celnikier DH. Placenta accreta is associated with IVF pregnancies: a retrospective chart review. BJOG 2011;118:1084–9.
7. Centers for Disease Control and Prevention, American Society for Reproductive Medicine, Society for Reproductive Technology. 2012 assisted reproductive technology national summary report. Atlanta (GA): U.S. Department of Health and Human Services; 2014.
8. Sheiner E, Shoham-Vardi I, Hershkovitz R, Katz M, Mazor M. Infertility treatment is an independent risk factor for cesarean section among nulliparous women aged 40 and above. Am J Obstet Gynecol 2001;185:888–92.
9. Declercq E, Luke B, Belanoff C, Cabral H, Diop H, Gopal D, et al.. Perinatal outcomes associated with assisted reproductive technology: the Massachusetts Outcomes Study of Assisted Reproductive Technologies (MOSART). Fertil Steril 2015;103:888–95.
10. Declercq ER, Belanoff C, Diop H, Gopal D, Hornstein MD, Kotelchuck M, et al.. Identifying women with indicators of subfertility in a statewide population database: operationalizing the missing link in assisted reproductive technology research. Fertil Steril 2014;101:463–71.
11. Thomopoulos C, Tsioufis C, Michalopoulou H, Makris T, Papademetriou V, Stefanadis C. Assisted reproductive technology and pregnancy-related hypertensive complications: a systematic review. J Hum Hypertens 2013;27:148–57.
12. Luke B, Stern JE, Kotelchuck M, Declercq ER, Hornstein MD, Gopal D, et al.. Adverse pregnancy outcomes after in vitro fertilization: effect of number of embryos transferred and plurality at conception. Fertil Steril 2015;104:79–86.
13. Stern JE, Luke B, Tobias M, Gopal D, Hornstein MD, Diop H. Adverse pregnancy and birth outcomes associated with underlying diagnosis with and without assisted reproductive technology treatment. Fertil Steril 2015;103:1438–45.
14. Kotelchuck M, Hoang L, Stern JE, Diop H, Belanoff C, Declercq E. The MOSART database: linking the SART CORS clinical database to the population-based Massachusetts PELL reproductive public health data system. Matern Child Health J 2014;18:2167–78.
15. Stern JE, Kotelchuck M, Luke B, Declercq E, Cabral H, Diop H. Calculating length of gestation from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) database versus vital records may alter reported rates of prematurity. Fertil Steril 2014;101:1315–20.
16. Stern JE, Luke B, Hornstein MD, Cabral H, Gopal D, Diop H, et al.. The effect of father's age in fertile, subfertile, and assisted reproductive technology pregnancies: a population based cohort study. J Assist Reprod Genet 2014;31:1437–44.
17. Declercq E, Barger M, Cabral HJ, Evans SR, Kotelchuck M, Simon C, et al.. Maternal outcomes associated with planned primary cesarean births compared with planned vaginal births. Obstet Gynecol 2007;109:669–77.
19. Luke B, Brown MB. Contemporary risks of maternal morbidity and adverse outcomes with increasing maternal age and plurality. Fertil Steril 2007;88:283–93.
20. Adamson GD, Baker VL. Subfertility: causes, treatment and outcome. Best Pract Res Clin Obstet Gynaecol 2003;17:169–85.
21. Kuklina EV, Meikle SF, Jamieson DJ, Whiteman MK, Barfield WD, Hillis SD, et al.. Severe obstetric morbidity in the United States: 1998–2005. Obstet Gynecol 2009;113:293–9.
22. Jansen AJ, van Rhenen DJ, Steegers EA, Duvekot JJ. Postpartum hemorrhage and transfusion of blood and blood components. Obstet Gynecol Surv 2005;60:663–71.
23. van Roosmalen J, Zwart J. Severe acute maternal morbidity in high-income countries. Best Pract Res Clin Obstet Gynaecol 2009;23:297–304.
© 2016 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.
24. Silberstein T, Levy A, Harlev A, Saphier O, Sheiner E. Perinatal outcome of pregnancies following in vitro fertilization and ovulation induction. J Matern Fetal Neonatal Med 2014;27:1316–9.