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Contributions to prematurity of maternal health conditions, subfertility, and assisted reproductive technology

      Objective

      To determine the maternal demographic, health, and fertility variables underlying prematurity.

      Design

      Retrospective: Society for Assisted Reproductive Technology Clinic Outcome Reporting System data linked to Massachusetts birth certificates and hospital stays.

      Setting

      Not applicable.

      Patients

      We included 166,963 privately insured, singleton, first births to women ≥18 years of age between 2004 and 2013. Deliveries were as follows: assisted reproductive technology (ART) when linked to Society for Assisted Reproductive Technology Clinic Outcome Reporting System, medically assisted reproduction (MAR) when fertility treatment was indicated on the birth certificate, unassisted subfertile (USF) when there were indications of subfertility but no treatment, and fertile if none of the above.

      Intervention

      None.

      Main Outcome Measures

      Late preterm birth (LPTB; 34–36 weeks) and early preterm birth (EPTB; <34 weeks) were compared with term deliveries (≥37 weeks). Covariates that statistically significantly influenced prematurity in binary analysis were modeled by using multinomial logistic regression. Backward elimination and mediation analysis were used to determine the influence of single parameters on outcomes of others.

      Results

      LPTB was increased in the USF (adjusted odds ratio [AOR] 1.32, 95% confidence interval [CI] 1.06–1.65) and ART (AOR 1.42, 95% CI 1.30–1.56) but not MAR (AOR 1.16, 95% CI 0.98–1.37). ETPB was increased in all (USF: AOR 1.67, 95% CI 1.21–2.31; MAR: AOR 1.67, 95% CI 1.31–2.12; ART: AOR 1.40, 95% CI 1.21–1.61). The strongest effectors of prematurity were placental problems (LPTB: AOR 4.02; EPTB: AOR 10.28), pregnancy hypertension (LPTB: AOR 2.14; EPTB: AOR 2.88), and chronic hypertension (LPTB: AOR 1.85; EPTB: AOR 2.79). Mediation analysis demonstrated a statistically significant indirect effect of placental problems for ART and subfertility.

      Conclusion

      The greatest effectors of prematurity were placental problems and hypertensive disorders. ART and, to a lesser extent, subfertility were both associated with preterm birth directly and indirectly mediated by placenta problems.
      Contribuciones a la prematurez de las condiciones de salud materna, subfertilidad, y técnicas de reproducción asistida.

      Objetivo

      Determinar las variables demográficas, de salud, y de fertilidad maternas que subyacen a la prematurez.

      Diseño

      Retrospectivo: datos del Sistema de Notificación de Resultados Clínicos de la Sociedad de Técnicas de Reproducción Asistida vinculados a los certificados de nacimiento y estadía hospitalaria de Massachusetts.

      Escenario

      No aplica.

      Paciente(s)

      Incluimos 166,963 primeros partos, únicos, asegurados en forma privada de mujeres ≥ 18 años entre 2004 y 2013. Los partos fueron como sigue: técnicas de reproducción asistida (ART) cuando estaba vinculado al Sistema de Notificación de Resultados Clínicos de la Sociedad de Técnicas de Reproducción Asistida, reproducción asistida médicamente (MAR) cuando el tratamiento de fertilidad estaba indicado en el certificado de nacimiento, subfertilidad no asistida (USF) cuando había indicaciones de subfertilidad pero sin tratamiento, y fértil si ninguna de las anteriores.

      Intervención

      Ninguna.

      Medida(s) de Resultado Principal

      Parto prematuro tardío (LPTB; 34-36 semanas) y parto prematuro temprano (EPTB; < 34 semanas) fueron comparados con partos de término (≥ 37 semanas). Las covariables que influenciaron de forma estadísticamente significativa la prematurez en análisis binario fueron modeladas usando regresión logística multinomial. Análisis de mediación y eliminación hacia atrás fueron utilizados para determinar la influencia de parámetros individuales sobre los resultados de otros.

      Resultado(s)

      LPTB estuvo aumentado en el USF (razón de probabilidad ajustada [AOR] 1.32, intervalo de confianza del 95% [CI] 1.06-1.65) y ART (AOR 1.42, 95% CI 1.30-1.56) pero no MAR (AOR 1.16, 95% CI 0.98-1.37). EPTB estuvo aumentado en todos (USF: AOR 1.67, 95% CI1.21-2.31; MAR: AOR 1.67, 95% CI 1.31-2.12; ART: AOR 1.40, 95% CI 1.21-1.61). Los efectores más fuertes de prematurez fueron problemas placentarios (LPTB: AOR 4.02; EPTB: AOR 10.28), hipertensión gestacional (LPTB: AOR 2.14; EPTB: AOR 2.88), e hipertensión crónica (LPTB: AOR 1.85; EPTB: AOR 2.79). El análisis de mediación demostró un efecto indirecto estadísticamente significativo de los problemas placentarios para ART y subfertilidad.

      Conclusión(es)

      Los efectores más grandes de prematurez fueron problemas placentarios y desórdenes hipertensivos. ART y, en un menor grado, subfertilidad estuvieron ambos asociados con parto pretérmino directa o indirectamente mediado por problemas placentarios.

      Key Words

      Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/users/16110-fertility-and-sterility/posts/64161-29328
      It is now well known that singleton deliveries to assisted reproductive technology (ART)-treated women are at greater risk for adverse birth outcomes than the general population. There is an increased risk for prematurity and low birthweight (
      • Schieve L.A.
      • Ferre C.
      • Peterson H.B.
      • Macaluso M.
      • Reynolds M.A.
      • Wright V.C.
      Perinatal outcome among singleton infants conceived through assisted reproductive technology in the United States.
      ,
      • Dunietz G.L.
      • Holzman C.
      • McKane P.
      • Li C.
      • Boulet S.L.
      • Todem D.
      • et al.
      Assisted reproductive technology and the risk of preterm birth among primiparas.
      ,
      • 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).
      ,
      • Luke B.
      • Gopal D.
      • Cabral H.
      • Stern J.E.
      • Diop H.
      Pregnancy, birth, and infant outcomes by maternal fertility status: the Massachusetts Outcomes Study of Assisted Reproductive Technology.
      ). Pregnancies to ART-treated women are themselves at greater risk and include increased rates of gestational diabetes, pregnancy hypertensive disorders (pregnancy hypertension, preeclampsia, and eclampsia), and placental abnormalities (
      • Luke B.
      • Gopal D.
      • Cabral H.
      • Stern J.E.
      • Diop H.
      Pregnancy, birth, and infant outcomes by maternal fertility status: the Massachusetts Outcomes Study of Assisted Reproductive Technology.
      ,
      • Romundstad L.B.
      • Romundstad P.R.
      • Sunde A.
      • von Düring V.
      • Skjærven R.
      • Vatten L.J.
      Increased risk of placenta previa in pregnancies following IVF/ICSI: a comparison of ART and non-ART pregnancies in the same mother.
      ,
      • Schachter M.
      • Tovbin Y.
      • Arieli S.
      • Friedler S.
      • Ron-El R.
      • Sherman D.
      In vitro fertilization is a risk factor for vasa previa.
      ,
      • Luke B.
      • Brown M.B.
      • Wantman E.
      • Seifer D.B.
      • Sparks A.T.
      • Lin P.C.
      • et al.
      Risk of prematurity and infant morbidity and mortality by maternal fertility status and plurality.
      ).
      Pregnancies and deliveries in women dealing with infertility who are not treated with ART have also been shown to be at increased risk for these same factors. Declercq et al. (
      • 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).
      ) found that a subfertile population had an increased risk of gestational diabetes and pregnancy hypertension, preterm birth, and low birthweight. Similarly, Luke et al. (
      • Luke B.
      • Gopal D.
      • Cabral H.
      • Stern J.E.
      • Diop H.
      Pregnancy, birth, and infant outcomes by maternal fertility status: the Massachusetts Outcomes Study of Assisted Reproductive Technology.
      ) found an increase in placental problems, pregnancy hypertension, gestational diabetes, pregnancy-associated bleeding, preterm birth, and low birthweight among subfertile women. The reasons for these increases are not known but could involve both ART treatment parameters and underlying infertility (
      • Luke B.
      • Brown M.B.
      • Wantman E.
      • Seifer D.B.
      • Sparks A.T.
      • Lin P.C.
      • et al.
      Risk of prematurity and infant morbidity and mortality by maternal fertility status and plurality.
      ,
      • Stern J.E.
      • Luke B.
      • Tobias M.
      • Gopal D.
      • Hornstein M.D.
      • Diop H.
      Adverse pregnancy and birth outcomes by infertility diagnoses with and without ART treatment.
      ).
      Prior studies have looked at the risk of prematurity by evaluating cohorts of ART-treated and subfertile women as compared with fertile individuals to see whether prematurity increased. However, given the increase in pregnancy-associated risk factors in ART and subfertile deliveries, it is possible that some of these factors contribute directly to shortened gestation. In this study, our goal was to look more directly at the risk for prematurity, to evaluate several maternal health and pregnancy factors that could potentially influence this endpoint, and to assess whether subfertility and/or ART influence or are influenced by these maternal health and pregnancy conditions.

      Materials and methods

       Data Sources

      This was a retrospective cohort study that used Massachusetts ART data linked to state vital records and hospital discharges.
      We used data from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) and the Massachusetts-based Pregnancy to Early Life Longitudinal (PELL) data system. SART CORS is a national registry containing cycle-based ART data from most ART clinics in the United States. PELL is an ongoing population-based data system that compiles information from birth certificates, fetal death certificates, and corresponding delivery hospital discharge records and ongoing hospital utilization records for mothers and infants over time. A memorandum of understanding among SART, the Massachusetts Department of Public Health (MDPH), and the project’s principal investigators was executed before initiation of the project. Approval for this study was obtained from MDPH and the Dartmouth-Hitchcock Health Institutional Review Board.
      The SART CORS database is used to collect ART cycle-specific demographics, infertility diagnoses, ART treatment, pregnancy, and outcome data under the auspices of SART. Data are collected from more than 90% of ART clinics in the United States and from all Massachusetts clinics. Data are entered by the clinics and reported to the Centers for Disease Control and Prevention in compliance with the Fertility Clinic Success Rate and Certification Act of 1992 (Public Law 102–493). The data in the SART CORS are validated annually, with random clinics having on-site visits for chart review based on an algorithm for clinic selection. During these visits, data reported by the clinic are compared with information recorded in patients’ charts. In 2014, the data fields selected for validation were found to have discrepancy rates of ≤6% (
      Centers for Disease Control and Prevention
      Assisted Reproductive Technology Clinic Success Rate Report 2014: Appendix A technical notes.
      ).
      The PELL data system has linked>98% of Massachusetts births and fetal deaths to corresponding hospital utilization data (hospital admissions, observational stays, and emergency room visits) for individual women and their children since 1998. PELL is a relational data system composed of individual databases linked by randomly generated unique identification numbers for mothers and infants. The MDPH and the Massachusetts Center for Health Information and Analysis are custodians of the PELL data, which are housed at MDPH.

       Linkage of SART CORS to PELL

      The Massachusetts Outcome Study of Assisted Reproductive Technology (MOSART) database was constructed by linking the SART CORS and PELL data systems for all Massachusetts resident women delivering in Massachusetts hospitals. The starting date represents the earliest SART CORS data available for research. A deterministic 5-phase linkage algorithm methodology was used to link data for deliveries between July 1, 2004 (January 1, 2004, cycle starts with first deliveries in July), and December 31, 2013. Linkage was based on mother’s date of birth, her first name, and last name; father/partner’s last name; baby’s date of birth, plurality, and infant’s sex (
      • Kotelchuck M.
      • Hoang L.
      • Stern J.E.
      • Diop H.
      • Belanoff C.
      • Declercq E.R.
      The MOSART database: linking the SART CORS clinical database to the population-based Massachusetts PELL reproductive public health data system.
      ). The linkage rate for 2004–2013 data was 90.2% overall and 94.5% for deliveries in which both mother’s zip code and clinic were in Massachusetts. Consistency of the demographic data in the SART CORS in comparison with birth certificates has been previously reported by us and shown to be high (
      • Stern J.E.
      • Gopal D.
      • Anderka M.
      • Liberman R.
      • Kotelchuck M.
      • Luke B.
      Validation of birth outcomes in the SART CORS: population-based analysis from the Massachusetts Outcome Study of Assisted Reproductive Technology (MOSART).
      ). Whereas only 43.1% of deliveries identified through linkage as ART deliveries were identified as having used ART treatment according to the checkbox on the birth certificate, those that did have the checkbox checked accurately reported ART treatment 75% of the time. Although we have no external validation for it, we assume that other medically assisted treatments also had the same ratios and thus that medically assisted reproduction (MAR) treatment when indicated is accurate, although not all MAR treatments would have been captured.

       Patients

      The study sample included first deliveries to women from the MOSART database who were ≥18 years of age and who had a singleton live birth. The deliveries were to women with private health insurance for whom we had complete data (Supplemental Fig. 1, available online). We excluded gestational carriers, multiparous women, and women who had stillbirths. Multiparous women were excluded for 2 reasons: that including them would require the addition of covariates for results of the prior delivery, such as prior prematurity; and that including them would have required adjustment for multiple deliveries to the same woman.

       Outcome Measures

      Gestational age was obtained from birth certificates and modified, when needed, by reported dates of last menstrual period. Gestational ages outside of the range of 17–44 weeks were considered as missing. Outcome groups included term deliveries (≥37 weeks gestation), late preterm deliveries (34–36 weeks gestation), and early preterm deliveries (<34 weeks gestation).

       Fertility Groups

      Women were classified as ART-treated if the delivery was linked to an ART cycle in the SART CORS database. The definition of the MOSART subfertile group has been previously described (
      • Declercq E.R.
      • Belanoff C.
      • Diop H.
      • Gopal D.
      • Hornstein M.D.
      • Kotelchuck M.
      • et al.
      Identifying women with indicators of subfertility in a statewide population database: operationalizing the missing link in assisted reproductive technology research.
      ). In this study we divided this group into 2 groups. Women were classified as having MAR treatment if the birth certificate for the delivery indicated receipt of fertility treatment but the delivery was not linked to an ART cycle in SART CORS. They were classified as “unassisted subfertile” if they had a diagnosis of infertility (International Classification of Diseases-9 628.9) in a hospital discharge, observational visit, or emergency room visit before the index delivery or if they had an unsuccessful ART cycle before the index delivery. Finally, women were classified as fertile if they did not fall into the ART-treated, MAR-treatment, or unassisted subfertile groups.

       Covariates

      We evaluated many maternal conditions with the potential to influence prematurity. Only those demonstrating statistically significant differences (at P<.05) were included in the final model. Covariates for analysis were obtained from birth certificates, hospital discharges, or a combination of both. The following covariates were obtained from birth certificates: maternal and paternal demographics including age, race/ethnicity, and education; country of origin; prior gravidity; year of delivery; and infant sex. From hospital discharges we obtained these maternal disease conditions: uterine surgery before conception (Current Procedural Terminology codes 57460, 57461, 57800, 58140, 58145, 58558, 58560, 58561, 59136, 59140, International Classification of Disease [ICD9] codes 752.2, 761.4, 68.22, 68.29, 69.49), and conditions 5 years before conception, including ectopic pregnancy/miscarriage (ICD9 633, 634), leiomyoma (ICD9 218), bleeding diseases of the reproductive tract (ICD9 626, 256), thyroid disease (ICD9 240–246), electrolyte imbalance (ICD9 276), psychological disorders (ICD9 E50, V62, 296, 300, 301, 309, 311), overweight or obese status (ICD9 278), any hospitalization, endometriosis (ICD9 617), asthma (ICD9 493), and drug abuse/addiction (ICD9 292, 303–305). For those conditions, 5 years was chosen to provide a consistent timeframe for all years of study, given that PELL data are available from 1998 and SART CORS data from 2004. A combination of birth certificates and hospital discharge records was used to define chronic hypertension and diabetes, gestational diabetes, pregnancy hypertension/preeclampsia/eclampsia, pregnancy-associated bleeding, and placental problems (abrupto placenta, placenta previa, vasa previa, and placenta accreta), other delivery complications including cephalopelvic disproportion, breech/malpresentation, prolonged labor, dysfunctional labor, febrile, fetal distress, cord prolapse, rupture membrane premature, rupture member prolonged, caesarian hysterectomy, and method of delivery.

       Statistical Analyses

      Bivariate and multivariate multinomial logistic regressions were used to estimate the crude and adjusted associations between outcome (full-term, late preterm birth [LPTB], early preterm birth [EPTB]), and variables of interest (fertility status and covariates). Both crude and adjusted odds ratios (AOR) and 95% confidence intervals (95% CI) for each outcome comparing the LPTB and EPTB deliveries were reported. A full multivariable model included all 24 covariates shown in Tables 1 and 2. Backward eliminations were used to explore how the presence or absence of a particular variable (i.e., fertility group and covariates) influenced the associations between preterm births and other variables. Using CAUSALMED procedures in the statistical software SAS 9.4 (SAS, version 9.4; 2016; SAS Institute, Cary, NC), mediation analyses were performed to quantify the direct and indirect effects of fertility status on LPTBs and EPTBs. All other analyses were performed in SAS software 9.3 (SAS Institute, Cary, NC).
      Table 1Associations of demographic characteristics with prematurity.
      CharacteristicTotal (n)Term, ≥37 wk (%)Late preterm birth, 34–36 wk (%)Early Preterm birth, <34 wk (%)Crude association (ref: ≥37 wk)Adjusted association
      Adjusted odds ratios and 95% confidence intervals adjusted for mother’s age, race/ethnicity, and education; chronic diabetes and hypertension; prior uterine surgery; thyroid disease; ectopic pregnancy; leiomyoma; reproductive; bleeding and menstrual disorders; electrolyte imbalance; psychological disorders; overweight/obesity; prior hospitalizations; gravidity; gestational diabetes; pregnancy hypertension; placental problems; pregnancy-associated bleeding; father’s age, race, and education; and infant sex.
      (ref: ≥37 wk)
      %Late preterm birthEarly preterm birthLate preterm birthEarly preterm birth
      Total166,96393.44.91.7OR95% CIOR95% CIAOR95% CIAOR95% CI
      Maternal age, y
       18–3067,99293.84.71.5refrefrefref
       30–3466,30393.84.71.51.000.96–1.061.010.92–1.101.020.96–1.081.111.00–1.23
       35–3719,63192.45.52.11.201.11–1.28
      P<.0001.
      1.451.29–1.62
      P<.0001.
      1.131.03–1.23
      P<.01.
      1.431.24–1.65
      P<.0001.
       38–409,14591.26.32.61.371.25–1.50
      P<.0001.
      1.791.55–2.07
      P<.0001.
      1.191.06–1.33
      P<.01.
      1.561.30–1.86
      P<.0001.
       41–553,89291.16.22.71.371.19–1.56
      P<.0001.
      1.871.53–2.30
      P<.0001.
      1.010.87–1.191.351.05–1.72
      P<.05.
      Maternal race/ethnicity
       Hispanic7,96792.55.42.11.121.01–1.23
      P<.05.
      1.391.18–1.62
      P<.0001.
      1.070.95–1.211.321.09–1.59
      P<.01.
       NH-white132,57593.54.91.5refrefrefref
       NH-black6,82090.95.43.81.121.01–1.25
      P<.05.
      2.522.21–2.88
      P<.0001.
      0.950.82–1.111.761.43–2.17
      P<.0001.
       NH-Asian17,75294.24.51.30.910.85–0.98
      P<.05.
      0.840.73–0.96
      P<.05.
      1.110.98–1.251.050.85–1.30
       NH-other1,84993.14.72.20.960.77–1.191.441.05–1.97
      P<.05.
      0.950.75–1.211.431.00–2.04
      Maternal education
       ≤High school graduate32,56292.75.22.11.131.07–1.19
      P<.0001.
      1.431.31–1.56
      P<.0001.
      1.040.97–1.111.241.11–1.39
      P<.0001.
       Some college19,22092.45.62.01.211.13–1.30
      P<.0001.
      1.361.22–1.52
      P<.0001.
      1.131.06–1.22
      P<.0001.
      1.211.07–1.37
      P<.01.
       College graduate115,18193.84.71.5refrefrefref
      Father’s age, y
       <3043,28893.74.81.5refrefrefref
       30–3465,61293.94.71.50.970.92–1.030.950.86–1.050.980.92–1.050.970.87–1.09
       35–3725,03393.35.01.71.060.98–1.131.100.97–1.240.980.90–1.070.950.82–1.10
       38–4014,39792.85.22.01.101.01–1.20
      P<.05.
      1.331.16–1.53
      P<.0001.
      0.950.86–1.050.990.84–1.17
       >4014,77792.35.72.11.201.10–1.30
      P<.0001.
      1.371.20–1.57
      P<.0001.
      0.980.89–1.090.900.75–1.06
       Unknown3,85691.55.72.71.221.06–1.41
      P<.01.
      1.811.47–2.23
      P<.0001.
      1.130.85–1.511.000.64–1.55
      Father’s race/ethnicity
       Hispanic7,76992.95.31.81.080.98–1.201.180.99–1.401.030.91–1.160.950.78–1.17
       NH-white130,22293.54.91.6refrefrefref
       NH-black7,72191.05.63.41.161.05–1.29
      P<.01.
      2.241.97–2.56
      P<.0001.
      1.120.97–1.291.361.10–1.67
      P<.01.
       NH-Asian15,28294.64.21.20.850.78–0.92
      P<.0001.
      0.790.68–0.91
      P<.01.
      0.850.75–0.97
      P<.05.
      0.920.73–1.17
       NH-other1,95793.35.01.81.010.82–1.241.150.82–1.621.040.83–1.310.980.67–1.44
       Unknown4,01291.95.52.61.140.99–1.311.701.39–2.07
      P<.0001.
      0.990.72–1.370.760.45–1.29
      Father’s education
       ≤High school graduate33,53292.45.52.11.201.13–1.27
      P<.0001.
      1.461.33–1.60
      P<.0001.
      1.131.05–1.20
      P<.0001.
      1.281.15–1.43
      P<.0001.
       Some college29,46793.45.01.51.081.02–1.15
      P<.05.
      1.040.94–1.161.030.96–1.090.940.83–1.05
       ≥College graduate100,08093.94.71.5refrefrefref
       Unknown3,88491.75.52.81.211.06–1.40
      P<.01.
      1.941.59–2.36
      P<.0001.
      1.020.71–1.471.881.11–3.20
      P<.05.
      Note: AOR = adjusted odds ratio; CI = confidence interval; NH = non-Hispanic; OR = odds ratio; ref = reference.
      a Adjusted odds ratios and 95% confidence intervals adjusted for mother’s age, race/ethnicity, and education; chronic diabetes and hypertension; prior uterine surgery; thyroid disease; ectopic pregnancy; leiomyoma; reproductive; bleeding and menstrual disorders; electrolyte imbalance; psychological disorders; overweight/obesity; prior hospitalizations; gravidity; gestational diabetes; pregnancy hypertension; placental problems; pregnancy-associated bleeding; father’s age, race, and education; and infant sex.
      b P<.05.
      c P<.01.
      d P<.0001.
      Table 2Associations of maternal health, pregnancy conditions, and infant sex with prematurity.
      CharacteristicTotal (n)Term, ≥37 wk (%)Late preterm birth, 34–36 wk (%)Early preterm birth, <34 wk (%)Crude association (ref: ≥37 wk)Adjusted association
      Adjusted odd ratios and 95% confidence intervals adjusted for mother’s age, race/ethnicity, and education; chronic diabetes and hypertension; prior uterine surgery; thyroid disease; ectopic pregnancy; leiomyoma; reproductive, bleeding, and menstrual disorders; electrolyte imbalance; psychological disorders; overweight/obesity, prior hospitalizations; gravidity; gestational diabetes; pregnancy hypertension; placental problems; pregnancy-associated bleeding; father’s age, race, and education; and infant sex.
      (ref: ≥37 wk)
      %Late preterm birthEarly preterm birthLate preterm birthEarly preterm birth
      OR95% CIOR95% CIAOR95% CIAOR95% CI
      Fertility group
       Fertile154,11593.74.71.5refrefrefref
       Unassisted subfertile1,31789.86.93.31.521.23–1.89
      P<.0001.
      2.211.63–3.01
      P<.0001.
      1.321.06–1.65
      P<.05.
      1.671.21–2.31
      P<.01.
       MAR2,73691.45.82.81.261.07–1.48
      P<.01.
      1.881.49–2.36
      P<.0001.
      1.160.98–1.371.671.31–2.12
      P<.0001.
       ART8,79589.387.632.991.691.56–1.84
      P<.0001.
      2.041.79–2.32
      P<.0001.
      1.421.30–1.56
      P<.0001.
      1.401.21–1.61
      P<.0001.
      Chronic diabetes (ref=no)1,74184.810.54.72.392.04–2.79
      P<.0001.
      3.172.53–3.98
      P<.0001.
      1.721.46–2.02
      P<.0001.
      2.021.58–2.58
      P<.0001.
      Chronic hypertension (ref=no)3,11083.110.76.22.522.24–2.83
      P<.0001.
      4.453.82–5.18
      P<.0001.
      1.851.64–2.09
      P<.0001.
      2.792.37–3.28
      P<.0001.
      Uterine surgery before conception75789.87.13.01.511.15–2.00
      P<.01.
      1.921.27–2.92
      P<.01.
      1.691.00–2.860.640.26–1.59
      Conditions 5 y before conception
       Thyroid conditions51290.46.62.91.400.99–1.981.841.10–3.08
      P<.05.
      1.100.76–1.581.180.68–2.04
       Leiomyoma69190.36.23.51.310.96–1.792.191.46–3.30
      P<.0001.
      0.610.34–1.101.370.55–3.37
       Ectopic pregnancy/miscarriage67990.76.32.91.330.97–1.811.841.18–2.88
      P<.01.
      1.090.78–1.511.210.74–1.97
       Any other reproductive/bleeding/menstrual disorder43188.47.04.61.501.03–2.17
      P<.05.
      2.991.90–4.69
      P<.0001.
      1.120.75–1.671.671.00–2.78
       Fluid electrolyte imbalance1,08490.77.32.01.531.22–1.93
      P<.0001.
      1.270.83–1.941.281.00–1.640.810.52–1.28
       Psychological disorders1,88190.57.12.31.501.26–1.80
      P<.0001.
      1.471.09–1.99
      P<.05.
      1.341.10–1.64
      P<.01.
      1.100.79–1.55
       Overweight/obesity80391.45.43.21.110.82–1.522.021.36–2.99
      P<.0001.
      0.800.58–1.111.090.70–1.68
       Any prior hospitalization12,09392.05.72.31.191.10–1.30
      P<.0001.
      1.501.32–1.70
      P<.0001.
      0.970.88–1.081.120.95–1.31
      Gravidity
       1135,30093.54.81.7refrefrefref
       216,43393.05.51.51.151.07–1.23
      P<.0001.
      0.900.79–1.031.121.04–1.20
      P<.01.
      0.840.73–0.96
      P<.05.
       ≥36,66691.36.42.31.361.23–1.51
      P<.0001.
      1.411.20–1.67
      P<.0001.
      1.231.11–1.36
      P<.0001.
      1.090.92–1.30
       Unknown8,56494.64.11.20.840.76–0.94
      P<.01.
      0.740.61–0.90
      P<.01.
      0.840.75–0.94
      P<.01.
      0.750.61–0.91
      P<.01.
      Pregnancy conditions
       Gestational diabetes9,72090.67.42.11.601.48–1.73
      P<.0001.
      1.311.13–1.51
      P<.0001.
      1.371.26–1.49
      P<.0001.
      0.980.84–1.14
       Pregnancy hypertension/preeclampsia/eclampsia17,03886.69.34.12.292.16–2.43
      P<.0001.
      3.232.96–3.52
      P<.0001.
      2.142.01–2.27
      P<.0001.
      2.882.63–3.16
      P<.0001.
       Placenta problems4,02172.515.312.24.253.88–4.65
      P<.0001.
      11.4110.28–12.67
      P<.0001.
      4.023.67–4.41
      P<.0001.
      10.289.22–11.47
      P<.0001.
       Bleeding problems during pregnancy and delivery4,21286.87.95.31.761.57–1.98
      P<.0001.
      3.673.19–4.23
      P<.0001.
      1.491.32–1.67
      P<.0001.
      2.502.15–2.90
      P<.0001.
      Infant sex
       Female81,33594.04.51.5refrefrefref
       Male85,62892.95.31.81.191.14–1.25
      P<.0001.
      1.281.18–1.38
      P<.0001.
      1.201.14–1.25
      P<.0001.
      1.291.19–1.39
      P<.0001.
      Note: AOR = adjusted odds ratio; ART = assisted reproductive technology; CI = confidence interval; MAR = medically assisted reproduction; OR = odds ratio; ref = reference.
      a Adjusted odd ratios and 95% confidence intervals adjusted for mother’s age, race/ethnicity, and education; chronic diabetes and hypertension; prior uterine surgery; thyroid disease; ectopic pregnancy; leiomyoma; reproductive, bleeding, and menstrual disorders; electrolyte imbalance; psychological disorders; overweight/obesity, prior hospitalizations; gravidity; gestational diabetes; pregnancy hypertension; placental problems; pregnancy-associated bleeding; father’s age, race, and education; and infant sex.
      b P<.05.
      c P<.01.
      d P<.0001.

      Results

      The study sample included 166,963 deliveries, of which 155,997 were term, 8,210 were LPTB, and 2,756 were EPTB. The fertility groups included 8,795 ART, 2,736 MAR, 1,317 unassisted subfertile, and 154,115 fertile deliveries. Table 1 shows the demographic characteristics that were statistically significant in the crude analysis, and Table 2 shows the statistically significant maternal health, pregnancy, and infant sex characteristics that were statistically significant. Others that were not statistically significant or that were related to delivery and not considered directly relevant to the fertility group pathway to prematurity were omitted. Furthermore, year of delivery was not a statistically significant predictor, and including it resulted in only minor changes to AORs; it was thus omitted from the final models.
      Adjusted odds ratios are shown in Tables 1 and 2. The covariates with greatest AORs were placental problems (4.02 LPTB and 10.28 EPTB) followed by pregnancy hypertensive disorders (2.14 LTPB, 2.88 EPTB), chronic hypertension (1.85 LPTB, 2.79 EPTB), and bleeding problems during pregnancy (1.49 LPTB, 2.50 EPTB). Compared with the fertile group, all other fertility groups had increased risk for prematurity: AORs for ART (1.42 LPTB, 1.40 EPTB), MAR (1.16 LPTB and 1.67 EPTB), and unassisted subfertility (1.32 LPTB, 1.67 EPTB).
      We then asked the question whether any of the covariates influenced the effect of other covariates on prematurity. To evaluate this, we used backwards elimination of individual covariates from the model. Eliminating fertility groups did not affect any value. As examples, chronic diabetes with AOR of 1.72 and 2.02 for LPTB and EPTB, respectively, had AOR of 1.73 and 2.04 for LPTB and EPTB, respectively, after the removal of fertility groups: chronic hypertension with AORs of 1.85 for LPTB and 2.79 for EPTB with all covariates had AORs of 1.85 and 2.79 for LPTB and EPTB, respectively, with fertility groups removed. By contrast, removing placental problems resulted in apparent changes in AORs for placental bleeding (1.49 for LPTB and 2.50 for EPTB with all covariates and 1.66 for LPTB and 3.27 for EPTB with placental problems removed) and the 3 fertility groups (AOR ART 1.42 for LPTB and 1.40 EPTB with all covariates and 1.53 and 1.66 for LPTB and EPTB, respectively, with placental problems removed; AOR unassisted subfertile 1.32 for LPTB and 1.67 EPTB with all covariates and 1.35 and 1.79 for LPTB and EPTB, respectively, with placental problems removed; AOR MAR 1.16 for LPTB and 1.67 for EPTB with all covariates and 1.17 and 1.71 for LPTB and EPTB, respectively, with placental problems removed). Removing pregnancy hypertensive disorders did not change the risk for prematurity in the fertility groups.
      To further explore whether placental problems influenced the effect of subfertility and ART on prematurity, we performed a mediation analysis. This analysis distinguishes between the direct effect of an exposure on an outcome and the indirect effect mediated through a third variable (Fig. 1). In this case we were seeking to determine whether the influence of fertility group on prematurity, was mediated through placental problems. Table 3 shows the results of this analysis: the total, direct and indirect effects. Although there is direct effect in all cases, the indirect effect was also statistically significant for ART, MAR and unassisted subfertile groups. Calculation of percent mediation, which corresponds to the percentage of the total effect mediated through placental problems, demonstrated that for LPTB and EPTB ART deliveries, 15% and 32% respectively were mediated through placental problems. A smaller proportion of MAR (12%) and unassisted subfertile (14%) groups’ effects on EPTB were accounted for by an indirect effect however, the indirect effect on LPTB in the unassisted subfertile and MAR groups was not statistically significant.
      Figure thumbnail gr1
      Figure 1Mediation analysis showing results for mediation by using placental problems as the mediator. ART = assisted reproductive technology.
      Table 3Mediation analysis.
      FactorTotal effectDirect effectIndirect effect
      Indirect effect and % mediation are mediated through placental problems, with odds ratios and 95% confidence intervals.
      % Mediation
      Indirect effect and % mediation are mediated through placental problems, with odds ratios and 95% confidence intervals.
      LPTBEPTBLPTBEPTBLPTBEPTBLPTBEPTB
      OR95% CIOR95% CIOR95% CIOR95% CIOR95% CIOR95% CI95% CI95% CI
      Fertility group
       Fertilerefrefrefrefrefref
       Unassisted subfertile1.351.05–1.65
      P<.0001.
      1.781.19–2.36
      P<.0001.
      1.331.03–1.62
      P<.0001.
      1.671.12–2.21
      P<.0001.
      1.021.00–1.04
      P<.0001.
      1.071.02–1.12
      P<.0001.
      7 (0–15)14 (3–25)
      P<.05.
       MAR1.170.98–1.371.731.31–2.15
      P<.0001.
      1.160.97–1.351.641.25–2.04
      P<.0001.
      1.011.00–1.02
      P<.0001.
      1.051.01–1.09
      P<.0001.
      7 (−3 to 18)12 (3–20)
      P<.01.
       ART1.491.36–1.62
      P<.0001.
      1.601.37–1.84
      P<.0001.
      1.411.29–1.54
      P<.0001.
      1.411.20–1.61
      P<.0001.
      1.051.04–1.06
      P<.0001.
      1.141.11–1.16
      P<.0001.
      15 (12–19)
      P<.0001.
      32 (24–41)
      P<.0001.
      Note: ART = assisted reproductive technology; CI = confidence interval; EPTB = early preterm birth; LPTB = late preterm birth; MAR = medically assisted reproduction; OR = odds ratio; ref = reference.
      a Indirect effect and % mediation are mediated through placental problems, with odds ratios and 95% confidence intervals.
      b P<.05.
      c P<.01.
      d P<.0001.

      Discussion

      The results of this study demonstrate that although ART and subfertility statistically significantly increase the risk of prematurity, their effect is less than that of other factors such as placental problems and chronic and pregnancy-associated hypertensive disorders. The results further demonstrate that a portion of the effect of ART and, to a lesser extent, subfertility is mediated through placental problems.
      As Schieve et al. (
      • Schieve L.A.
      • Ferre C.
      • Peterson H.B.
      • Macaluso M.
      • Reynolds M.A.
      • Wright V.C.
      Perinatal outcome among singleton infants conceived through assisted reproductive technology in the United States.
      ) first reported in 2004, ART singletons have an increased risk of preterm delivery when compared with the general population. Dunietz et al. (
      • Dunietz G.L.
      • Holzman C.
      • McKane P.
      • Li C.
      • Boulet S.L.
      • Todem D.
      • et al.
      Assisted reproductive technology and the risk of preterm birth among primiparas.
      ) further demonstrated that the risk of prematurity differs according to the infertility diagnosis with AORs of 1.24 for male infertility, 1.60 for female infertility, 1.49 for combined male and female infertility, and 1.26 for unexplained infertility. Deliveries by women with subfertility who have not been treated with ART have also been reported to have an increased risk of prematurity. Declercq et al. (
      • 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).
      ) demonstrated an increased risk of prematurity in singleton deliveries of 1.53 for ART and 1.24 for subfertile women without ART treatment. The increases in prematurity in singleton deliveries by ART-treated and subfertile women, as shown in this study, are consistent with those previous results.
      Previous studies have also demonstrated an increase in a variety of pregnancy-related abnormalities in both ART-treated and subfertile women carrying singleton pregnancies. Placental problems including placenta previa and vasa previa have been shown to be increased in ART pregnancies (
      • Romundstad L.B.
      • Romundstad P.R.
      • Sunde A.
      • von Düring V.
      • Skjærven R.
      • Vatten L.J.
      Increased risk of placenta previa in pregnancies following IVF/ICSI: a comparison of ART and non-ART pregnancies in the same mother.
      ,
      • Schachter M.
      • Tovbin Y.
      • Arieli S.
      • Friedler S.
      • Ron-El R.
      • Sherman D.
      In vitro fertilization is a risk factor for vasa previa.
      ). A growing body of information also suggests that there may be changes in DNA methylation patterns in the placenta and cord blood after ART treatment (
      • Nelissen E.C.
      • Dumoulin J.C.
      • Daunay A.
      • Evers J.L.
      • Tost J.
      • van Montfoort A.P.
      Placentas from pregnancies conceived by IVF/ICSI have a reduced DNA methylation level at the H19 and MEST differentially methylated regions.
      ,
      • Litzky J.F.
      • Deyssenroth M.A.
      • Everson T.M.
      • Armstrong D.A.
      • Lamertini L.
      • Chen J.
      • et al.
      Placental imprinting variation associated with assisted reproductive technologies and subfertility.
      ,
      • Castillo-Fernandez J.E.
      • Loke Y.J.
      • Bass-Stringer S.
      • Gao F.
      • Xia Y.
      • Wu H.
      • et al.
      DNA methylation changes at infertility genes in newborn twins conceived by in vitro fertilisation.
      ). Luke et al. (
      • Luke B.
      • Gopal D.
      • Cabral H.
      • Stern J.E.
      • Diop H.
      Pregnancy, birth, and infant outcomes by maternal fertility status: the Massachusetts Outcomes Study of Assisted Reproductive Technology.
      ) demonstrated that placental problems are increased in ART-treated (AOR 2.81) and subfertile (AOR 1.44) pregnancies when compared with pregnancies in fertile women. These ART-treated and subfertile women, when compared with fertile women, also had increased pregnancy hypertension (AOR 1.22 ART; AOR 1.12 subfertile), gestational diabetes (AOR 1.41 ART; AOR 1.60 subfertile) and pregnancy-associated bleeding (AOR 3.80 ART; AOR 1.67 subfertile). Infertility diagnosis and treatment may influence these risks. Stern et al. (
      • Stern J.E.
      • Luke B.
      • Tobias M.
      • Gopal D.
      • Hornstein M.D.
      • Diop H.
      Adverse pregnancy and birth outcomes by infertility diagnoses with and without ART treatment.
      ) found gestational diabetes to be increased for women with ovulation disorders both with (AOR 2.17) and without (1.94) ART treatment. To our knowledge, the reasons for these increased risks have never been clearly determined, nor has it been determined what ART treatments or aspects of subfertility most contribute to these problems.
      Our mediation analysis clearly demonstrated that although most of the effect of ART on prematurity is through a direct effect, a considerable portion of the effect of ART on prematurity is mediated through placental problems. This is consistent with the knowledge that placental abnormality can lead to prematurity (
      • Faye-Petersen O.M.
      The placenta in preterm birth.
      ,
      • Morgan T.K.
      Role of the placenta in preterm birth: a review.
      ). This is also consistent with the known increase in placental problems with ART. Luke et al. (
      • Luke B.
      • Brown M.B.
      • Wantman E.
      • Seifer D.B.
      • Sparks A.T.
      • Lin P.C.
      • et al.
      Risk of prematurity and infant morbidity and mortality by maternal fertility status and plurality.
      ) suggest that certain ART parameters increased the risk for both placental problems and prematurity. Both fresh and frozen donor egg cycles increased prematurity compared with fresh autologous cycles. Fresh and frozen donor egg groups also manifested a greater risk of gestational diabetes, pregnancy hypertension, and placental problems. Determining which ART characteristics are most strongly associated with prematurity through mediation by placental problems will be the subject of future evaluation.
      The unassisted subfertile group manifested greater odds of prematurity than did the MAR group. Given that this group was identified by hospitalizations and prior unsuccessful ART, this is not surprising. Most infertility is diagnosed and treated as outpatient problems. Only a small proportion of infertility treatment involves hospitalization, and that occurs largely when the condition is more serious. The data from the unassisted subfertile group strongly suggest that more severe infertility is more strongly associated with prematurity than non-ART treatment. We assume that ART patients, by virtue of the fact that they have reached the most advanced treatment option for infertility, also have more severe infertility than do women in the MAR group. Nevertheless, the fact that considerably more prematurity is mediated through placental problems in the ART group than in the unassisted subfertile group suggests that additional factors related to the ART treatment itself are instrumental in increasing the risk for prematurity through abnormal placentation.
      This study has strengths and limitations. The strengths lie in the fact that MOSART is a large population-based database with maternal and infant hospital discharge records linked to birth certificate data, allowing for dyadic longitudinal analysis of maternal and infant health outcomes. The limitations include that this was a retrospective study and some important covariates such as smoking, diet, and Body Mass Index were not available, were not available for all years, or had statistically significant inaccuracies. Further, the fertile group may have contained some unidentified subfertile deliveries, although those would have served only to decrease the magnitude of the observed differences. Covariates were identified by hospitalization for each condition; thus, we were unable to identify women with any conditions diagnosed and treated solely on an outpatient basis. Because the unassisted subfertile group was defined by prior hospitalization with a recorded diagnosis of infertility and prior unsuccessful ART, this group may have had more severe subfertility than a random population of infertile women. Finally, the study was performed in a single state, Massachusetts, and the results may not be generalizable to all states and countries.
      In summary, the data show that among our cohort, the greatest effectors of prematurity were placental problems and chronic and gestational hypertensive disorders. Subfertility and ART both increased LPTB and EPTB but to a lesser extent than those 2 conditions. In addition, we saw no indication that subfertility/ART directly altered the effect of other parameters. By contrast, removing placental problems appeared to affect the influence of subfertility and ART. Mediation analysis demonstrated that placental problems are on the pathway to LPTB and EPTB for a portion of ART and, to a lesser extent, subfertile deliveries. The ART and subfertility parameters responsible for the effect on placental problems remains to be determined.

      Acknowledgments

      SART thanks its members for providing clinical information to the SART CORS database for use by patients and researchers. Without the efforts of our members, this research would not have been possible.

      Supplementary data

      Figure thumbnail figs1

      References

        • Schieve L.A.
        • Ferre C.
        • Peterson H.B.
        • Macaluso M.
        • Reynolds M.A.
        • Wright V.C.
        Perinatal outcome among singleton infants conceived through assisted reproductive technology in the United States.
        Obstet Gynecol. 2004; 103: 1144-1153
        • Dunietz G.L.
        • Holzman C.
        • McKane P.
        • Li C.
        • Boulet S.L.
        • Todem D.
        • et al.
        Assisted reproductive technology and the risk of preterm birth among primiparas.
        Fertil Steril. 2015; 103: 974-979
        • 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: 888-895
        • Luke B.
        • Gopal D.
        • Cabral H.
        • Stern J.E.
        • Diop H.
        Pregnancy, birth, and infant outcomes by maternal fertility status: the Massachusetts Outcomes Study of Assisted Reproductive Technology.
        Am J Obstet Gynecol. 2017; 217: 327.e1-327.e14
        • Romundstad L.B.
        • Romundstad P.R.
        • Sunde A.
        • von Düring V.
        • Skjærven R.
        • Vatten L.J.
        Increased risk of placenta previa in pregnancies following IVF/ICSI: a comparison of ART and non-ART pregnancies in the same mother.
        Hum Reprod. 2006; 21: 2353-2358
        • Schachter M.
        • Tovbin Y.
        • Arieli S.
        • Friedler S.
        • Ron-El R.
        • Sherman D.
        In vitro fertilization is a risk factor for vasa previa.
        Fertil Steril. 2002; 78: 642-643
        • Luke B.
        • Brown M.B.
        • Wantman E.
        • Seifer D.B.
        • Sparks A.T.
        • Lin P.C.
        • et al.
        Risk of prematurity and infant morbidity and mortality by maternal fertility status and plurality.
        J Assist Repro Genet. 2019; 36: 121-138
        • Stern J.E.
        • Luke B.
        • Tobias M.
        • Gopal D.
        • Hornstein M.D.
        • Diop H.
        Adverse pregnancy and birth outcomes by infertility diagnoses with and without ART treatment.
        Fertil Steril. 2015; 103: 1438-1445
        • Centers for Disease Control and Prevention
        Assisted Reproductive Technology Clinic Success Rate Report 2014: Appendix A technical notes.
        (Available at:)
        • Kotelchuck M.
        • Hoang L.
        • Stern J.E.
        • Diop H.
        • Belanoff C.
        • Declercq E.R.
        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: 2167-2178
        • Stern J.E.
        • Gopal D.
        • Anderka M.
        • Liberman R.
        • Kotelchuck M.
        • Luke B.
        Validation of birth outcomes in the SART CORS: population-based analysis from the Massachusetts Outcome Study of Assisted Reproductive Technology (MOSART).
        Fertil Steril. 2016; 106: 717-722.e2
        • Declercq E.R.
        • Belanoff C.
        • Diop H.
        • Gopal D.
        • Hornstein M.D.
        • 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: 463-471
        • Nelissen E.C.
        • Dumoulin J.C.
        • Daunay A.
        • Evers J.L.
        • Tost J.
        • van Montfoort A.P.
        Placentas from pregnancies conceived by IVF/ICSI have a reduced DNA methylation level at the H19 and MEST differentially methylated regions.
        Hum Reprod. 2013; 28: 1117-1126
        • Litzky J.F.
        • Deyssenroth M.A.
        • Everson T.M.
        • Armstrong D.A.
        • Lamertini L.
        • Chen J.
        • et al.
        Placental imprinting variation associated with assisted reproductive technologies and subfertility.
        Epigenetics. 2017; 12: 653-661
        • Castillo-Fernandez J.E.
        • Loke Y.J.
        • Bass-Stringer S.
        • Gao F.
        • Xia Y.
        • Wu H.
        • et al.
        DNA methylation changes at infertility genes in newborn twins conceived by in vitro fertilisation.
        Genome Med. 2017; 9: 28
        • Faye-Petersen O.M.
        The placenta in preterm birth.
        J Clin Pathol. 2008; 61: 1261-1275
        • Morgan T.K.
        Role of the placenta in preterm birth: a review.
        Am J Perinatol. 2016; 33: 258-266