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Adverse obstetric and perinatal outcomes of singleton pregnancies may be related to maternal factors associated with infertility rather than the type of assisted reproductive technology procedure used

      Objective

      To compare obstetric and perinatal outcomes of singleton pregnancies conceived with different types of assisted reproductive technology (ART) procedures with those of naturally conceived pregnancies.

      Design

      Retrospective cohort study.

      Setting

      The perinatal database of the Japanese Society of Obstetrics and Gynecology.

      Patient(s)

      A total of 242,715 women with singleton pregnancies were examined as a base cohort. Three study groups were created according to the type of ART procedure used, namely ovulation stimulation medications (n = 4,111), IUI (n = 2,351), and IVF-ET (n = 4,570). Controls adjusted for multiple maternal characteristics were selected randomly for each study group.

      Intervention(s)

      None.

      Main Outcome Measure(s)

      Obstetric and perinatal outcomes.

      Result(s)

      Patients who conceived through the ART procedures were associated with an increased incidence of placenta previa, preterm delivery, and low birth weight infant and a decreased incidence of spontaneous cephalic delivery, regardless of the type of ART procedure.

      Conclusion(s)

      Among singleton pregnancies, patients conceived with ART procedures were at increased risk for several adverse obstetric and perinatal outcomes, regardless of the type of ART procedure used. These results suggest that maternal factors associated with infertility may contribute to the adverse outcomes rather than the ART procedures themselves.

      Key Words

      Discuss: You can discuss this article with its authors and with other ASRM members at http://fertstertforum.com/hayashim-adverse-obstetric-perinatal-outcomes-infertility-assisted-reproductive-technology/
      Assisted reproductive technology (ART) has been a highly successful and widely used modality for treating infertility for the past 30 years. Although many studies have attempted to evaluate obstetric and perinatal outcomes in women conceiving with the aid of ART, it is unclear whether ART procedures or maternal factors associated with infertility contribute to these adverse outcomes (
      • Bower C.
      • Hansen M.
      Assisted reproductive technologies and birth outcomes: overview of recent systematic reviews.
      ,
      • Helmerhorst F.M.
      • Perquin D.A.
      • Donker D.
      • Keirse M.J.
      Perinatal outcome of singletons and twins after assisted conception: a systematic review of controlled studies.
      ,
      • Jackson R.A.
      • Gibson K.A.
      • Wu Y.W.
      • Croughan M.S.
      Perinatal outcomes in singletons following in vitro fertilization: a meta-analysis.
      ,
      • Lambert R.D.
      Safety issues in assisted reproductive technology: aetiology of health problems in singleton ART babies.
      ,
      • Romundstad L.B.
      • Romundstad P.R.
      • Sunde A.
      • von During V.
      • Skjaerven R.
      • Gunnell D.
      • et al.
      Effects of technology or maternal factors on perinatal outcome after assisted fertilisation: a population-based cohort study.
      ,
      • Jaques A.M.
      • Amor D.J.
      • Baker H.W.
      • Healy D.L.
      • Ukoumunne O.C.
      • Breheny S.
      • et al.
      Adverse obstetric and perinatal outcomes in subfertile women conceiving without assisted reproductive technologies.
      ).
      It is well recognized that an increased ART-related risk of adverse obstetric and perinatal outcomes is mainly due to the high frequency of multiple pregnancies (
      Practice Committee of Society for Assisted Reproductive Technology; Practice Committee of American Society for Reproductive Medicine
      Guidelines on number of embryos transferred.
      ). Several studies have also suggested an increased risk of perinatal complications, such as chromosomal abnormalities, low birth weight, and preterm delivery (
      • Perri T.
      • Chen R.
      • Yoeli R.
      • Merlob P.
      • Orvieto R.
      • Shalev Y.
      • et al.
      Are singleton assisted reproductive technology pregnancies at risk of prematurity?.
      ,
      • Schieve L.A.
      • Meikle S.F.
      • Ferre C.
      • Peterson H.B.
      • Jeng G.
      • Wilcox L.S.
      Low and very low birth weight in infants conceived with use of assisted reproductive technology.
      ,
      • Retzloff M.G.
      • Hornstein M.D.
      Is intracytoplasmic sperm injection safe?.
      ,
      • Zadori J.
      • Kozinszky Z.
      • Orvos H.
      • Katona M.
      • Kaali S.G.
      • Pal A.
      The incidence of major birth defects following in vitro fertilization.
      ), as well as maternal complications, such as preeclampsia, gestational diabetes, placental abruption, and placenta previa. These factors were also associated with an increased incidence of cesarean deliveries (
      • Jackson R.A.
      • Gibson K.A.
      • Wu Y.W.
      • Croughan M.S.
      Perinatal outcomes in singletons following in vitro fertilization: a meta-analysis.
      ,
      • Reddy U.M.
      • Wapner R.J.
      • Rebar R.W.
      • Tasca R.J.
      Infertility, assisted reproductive technology, and adverse pregnancy outcomes: executive summary of a National Institute of Child Health and Human Development workshop.
      ) in women with singleton pregnancies. In contrast, other studies have concluded that the ART procedures associated with IVF are not responsible for these adverse outcomes. These latter results are supported by studies of subfertile women who conceived without the aid of ART and yet exhibited an increased risk for preterm delivery (
      • Jaques A.M.
      • Amor D.J.
      • Baker H.W.
      • Healy D.L.
      • Ukoumunne O.C.
      • Breheny S.
      • et al.
      Adverse obstetric and perinatal outcomes in subfertile women conceiving without assisted reproductive technologies.
      ,
      • Joffe M.
      • Li Z.
      Association of time to pregnancy and the outcome of pregnancy.
      ,
      • Henriksen T.B.
      • Baird D.D.
      • Olsen J.
      • Hedegaard M.
      • Secher N.J.
      • Wilcox A.J.
      Time to pregnancy and preterm delivery.
      ,
      • Basso O.
      • Baird D.D.
      Infertility and preterm delivery, birthweight, and Caesarean section: a study within the Danish National Birth Cohort.
      ,
      • Axmon A.
      • Hagmar L.
      Time to pregnancy and pregnancy outcome.
      ,
      • Thomson F.
      • Shanbhag S.
      • Templeton A.
      • Bhattacharya S.
      Obstetric outcome in women with subfertility.
      ), low birth weight (
      • Jaques A.M.
      • Amor D.J.
      • Baker H.W.
      • Healy D.L.
      • Ukoumunne O.C.
      • Breheny S.
      • et al.
      Adverse obstetric and perinatal outcomes in subfertile women conceiving without assisted reproductive technologies.
      ,
      • Basso O.
      • Baird D.D.
      Infertility and preterm delivery, birthweight, and Caesarean section: a study within the Danish National Birth Cohort.
      ,
      • Thomson F.
      • Shanbhag S.
      • Templeton A.
      • Bhattacharya S.
      Obstetric outcome in women with subfertility.
      ), perinatal death (
      • Zhu J.L.
      • Obel C.
      • Hammer Bech B.
      • Olsen J.
      • Basso O.
      Infertility, infertility treatment, and fetal growth restriction.
      ), birth defects (
      • Jaques A.M.
      • Amor D.J.
      • Baker H.W.
      • Healy D.L.
      • Ukoumunne O.C.
      • Breheny S.
      • et al.
      Adverse obstetric and perinatal outcomes in subfertile women conceiving without assisted reproductive technologies.
      ,
      • Zhu J.L.
      • Basso O.
      • Obel C.
      • Bille C.
      • Olsen J.
      Infertility, infertility treatment, and congenital malformations: Danish national birth cohort.
      ), pregnancy-induced hypertension or preeclampsia (
      • Jaques A.M.
      • Amor D.J.
      • Baker H.W.
      • Healy D.L.
      • Ukoumunne O.C.
      • Breheny S.
      • et al.
      Adverse obstetric and perinatal outcomes in subfertile women conceiving without assisted reproductive technologies.
      ,
      • Basso O.
      • Baird D.D.
      Infertility and preterm delivery, birthweight, and Caesarean section: a study within the Danish National Birth Cohort.
      ,
      • Thomson F.
      • Shanbhag S.
      • Templeton A.
      • Bhattacharya S.
      Obstetric outcome in women with subfertility.
      ), gestational diabetes (
      • Jaques A.M.
      • Amor D.J.
      • Baker H.W.
      • Healy D.L.
      • Ukoumunne O.C.
      • Breheny S.
      • et al.
      Adverse obstetric and perinatal outcomes in subfertile women conceiving without assisted reproductive technologies.
      ), and cesarean delivery (
      • Jaques A.M.
      • Amor D.J.
      • Baker H.W.
      • Healy D.L.
      • Ukoumunne O.C.
      • Breheny S.
      • et al.
      Adverse obstetric and perinatal outcomes in subfertile women conceiving without assisted reproductive technologies.
      ,
      • Basso O.
      • Baird D.D.
      Infertility and preterm delivery, birthweight, and Caesarean section: a study within the Danish National Birth Cohort.
      ,
      • Thomson F.
      • Shanbhag S.
      • Templeton A.
      • Bhattacharya S.
      Obstetric outcome in women with subfertility.
      ). One possible explanation for these conflicting results is that several maternal factors associated with infertility may contribute to adverse obstetric and perinatal outcomes. Although these studies included subjects who were controlled for maternal age and parity, other known maternal factors, such as smoking, alcohol consumption, and pre-existing maternal disease, were not controlled.
      The present study aimed to evaluate and compare obstetric and perinatal outcomes in singleton pregnancies conceived with the aid of different types of ART procedures, namely ovulation stimulation medications, IUI, and IVF-ET, using a relatively large sample. We used the perinatal database of the Japanese Society of Obstetrics and Gynecology, which allowed us to investigate and control for multiple maternal characteristics, behaviors, and lifestyle factors, as well as differentiate IVF-ET, IUI, and ovulation stimulation outcomes.

      Materials and methods

      This study protocol was reviewed and approved by the Institutional Review Board of Tokyo Women's Medical University and Nippon Medical School. A case-control design was applied to clarify the relationship between specific types of ART procedures and obstetric and perinatal complications.
      Data in this retrospective cohort study were derived from the perinatal database of the Japanese Society of Obstetrics and Gynecology. This nationwide registry was established in 1974. Detailed descriptions of the database have been published previously (
      • Matsuda Y.
      • Kawamichi Y.
      • Hayashi K.
      • Shiozaki A.
      • Satoh S.
      • Saito S.
      Impact of maternal age on the incidence of obstetrical complications in Japan.
      ). Briefly, the attending physicians at 125 tertiary centers of the Perinatal Research Network in Japan collected yearly data for each pregnant woman in an off-line clinical database with a common format. The data were sent to the perinatal committee of the Japan Society of Obstetrics and Gynecology, where quality control for the database was assessed.
      We used the data of 281,157 pregnancies reported during the period 2001 through 2005. Gestational age was determined on the basis of menstrual history, a prenatal examination, and ultrasound findings, such as gestational sac diameter, crown rump length, and biparietal diameter. The linked data included information on maternal characteristics, such as maternal age, parity, prepregnancy height and weight, cigarette smoking and alcohol consumption during pregnancy, history of treatment for infertility (ovulation stimulation, IUI, or IVF-ET), medical complications, and complications of pregnancy. Fetal and infant outcomes were also routinely recorded by attendants at the time of delivery. These data conform to uniform coding specifications, have passed a rigorous quality check, and have been edited and reviewed. The current study limited the analysis to women who delivered a singleton live birth or stillbirth at ≥22 weeks of gestation. After excluding missing data, 242,715 singleton births were included in the analysis.
      The study group included women with singleton pregnancies conceived through different types of ART procedures. Three study groups were set up on the basis of the types of treatment available in the database, namely ovulation stimulation medications, IUI, and IVF-ET. Ovulation stimulation involves the use of medication without any additional ART procedures to stimulate one or more mature follicles. Intrauterine insemination involves a fertilization procedure in which sperms are washed, concentrated, and injected directly into the uterus without ovulation stimulation medications. We excluded the stimulated IUI with the purpose of elucidation of the relationship between IUI and perinatal outcomes without the influence of the ovulation stimulation. In addition, the source of the sperms (i.e., husbands or donors) was not available in our database. In vitro fertilization-embryo transfer involves spontaneous fertilization of an egg by a sperm in vitro or by intracytoplasmic sperm injection (ICSI), followed by transfer of the embryo back into the uterine cavity. However, the use of ICSI was not available in our database. The control group comprised women with naturally conceived singleton pregnancies. Controls matched for maternal age, parity, prepregnancy height and weight, smoking, alcohol consumption, and pre-existing maternal diseases, such as respiratory disease, cardiovascular complications, diabetes, hypertension, thyroid disease, renal disease, and gynecologic disease were selected randomly for each study group.
      Data were analyzed using SPSS 17.0 (IBM Corp.) and an Excel spreadsheet (Microsoft). Statistical analysis was performed using Student's t-test for continuous variables, such as maternal age, body mass index (BMI), and birth weight, and the χ2 test for categorical variables. A P value of <.05 was considered statistically significant. The logistic regression method was used to compare adjusted odds ratios (OR) and 95% confidence intervals (CI) for adverse obstetric and perinatal outcomes between the groups that underwent the various ART procedures and the corresponding matched control groups.

      Results

      In total, 11,032 (4.5%) patients conceived through the different types of ART procedures during the study period. These patients were divided into three groups according to the treatment: a group that used ovulation stimulation medications (n = 4,111; 1.7%), a group that underwent IUI without ovulation stimulation medications (n = 2,351; 1%), and a group that underwent IVF-ET (n = 4,570; 1.9%). Three corresponding matched control groups were created for each study group: one for the ovulation stimulation group (n = 4,468), one for the IUI group (n = 5,305), and one for the IVF-ET group (n = 4,264).
      The maternal characteristics of the three study groups are summarized in Table 1. Among the three study groups, maternal age and BMI tended to be higher in the IVF-ET and ovulation stimulation groups, respectively. No significant differences were observed in maternal age, parity, BMI, smoking, alcohol consumption, or pre-existing medical complications between the study groups and corresponding control groups.
      Table 1Maternal characteristics of the study population.
      Ovulation stimulationIUIIVF-ET
      Study group (n = 4,111)Control group (n = 4,468)P valueStudy group (n = 2,351)Control group (n = 5,305)P valueStudy group (n = 4,570)Control group (n = 4,264)P value
      Maternal age (y)32.2 ± 4.232.1 ± 5.6.83334.1 ± 3.934.0 ± 5.1.25435.3 ± 4.235.4 ± 4.4.383
      Parity
       Nulliparous72.571.4.24879.179.5.69781.882.0.862
       Multiparous27.528.620.920.518.218.0
      Body mass index22.0 ± 4.621.7 ± 3.6.20721.3 ± 3.421.4 ± 3.5.45621.2 ± 3.221.3 ± 3.4.702
      Smoking in pregnancy
       No97.497.0.34798.197.7.36597.597.5.978
       Yes2.63.01.92.32.52.5
      Alcohol consumption in pregnancy
       No96.296.3.88196.396.3.95497.597.5.926
       Yes3.83.73.73.72.52.5
      Pre-existing medical complications
       No68.669.7.29265.565.7.83566.767.0.793
       Yes31.430.334.534.333.333.0
      Note: Values are percentage or mean ± SD.
      The overall incidence of obstetric and perinatal complications in the study population is shown in Table 2. The obstetric and perinatal outcomes in the three study groups are compared with those in the corresponding matched control groups in Table 3. Patients who conceived through ART procedures exhibited an increased incidence of placenta previa and preterm delivery (at <37 and <34 weeks of gestation). This was independent of the type of ART procedure. The strength of the association between these complications and the type of ART procedure was relatively weak, except for the increased incidence of placenta previa in patients who underwent IVF-ET (OR, 2.20; 95% CI 1.68–2.87). A marked increase in the incidence of placenta accreta (OR, 2.67; 95% CI 1.42–5.03) and a significant decrease in the incidence of pregnancy-induced hypertension (OR, 0.74; 95% CI 0.62–0.89) were also noted in patients who underwent IVF-ET, but not in patients who used ovulation stimulation medication or underwent IUI. The percentage of patients with spontaneous cephalic deliveries among those who underwent ART procedures was lower than that among patients in each corresponding control group. This result was also independent of the type of infertility treatment. Only IVF-ET was associated with an increased incidence of elective (OR, 1.38; 95% CI 1.23–1.55) and emergency (OR, 1.19; 95% CI 1.07–1.32) cesarean deliveries. A slightly increased incidence of postpartum hemorrhage was observed in patients who underwent IVF-ET. No association was observed between the different types of ART procedures and adverse maternal outcomes, such as intensive care unit (ICU) admission or maternal death.
      Table 2Incidence of pregnancy-related complications in the groups that underwent specific types of ART procedures and the corresponding matched controls.
      OutcomeOvulation stimulationIUIIVF-ET
      Study group (n = 4,111)Control group (n = 4,468)P valueStudy group (n = 2,351)Control group (n = 5,305)P valueStudy group (n = 4,570)Control group (n = 4,264)P value
      Pregnancies
       PIH5.35.5815.05.6.2404.96.5.001
       Eclampsia0.10.1.7280.10.2.3670.10.2.083
       Placenta abruption1.10.9.1690.91.0.9341.10.9.378
       Placenta previa1.91.1.0022.21.5.03341.9<.001
       Placenta accreta0.20.4.1950.70.5.2010.80.3.002
       PTD <37 wk of gestation16.913.6<.00116.114.2.03218.114.6<.001
       PTD <34 wk of gestation8.26.4.0017.86.5.0357.96.1.001
       Type of delivery
      Spontaneous cephalic60.362.6.02155.859.2.10349.957.1<.001
      Instrumental7.98.39.89.29.19
      Elective cesarean13.212.614.113.118.814.3
      Emergency cesarean17.215.819.617.921.819
      Others1.40.80.70.60.50.6
       Postpartum hemorrhage3.93.2.0643.93.2.1164.83.3.001
       ICU admission0.020.06.6260.10.1.9610.020.12.113
       Maternal death0.020.04.6130.040.0410.020.05.612
      Infants
       Birth weight (g)
      Mean ± SD.
      2,772 ± 6662,849 ± 605<.0012,798 ± 6502,838 ± 612.0102,770 ± 6492,834 ± 610<.001
      <2,50023.418.4<.00122.119.4.0092420<.001
      <1,5006.24.7.0015.84.8.0635.84.5.007
      <1,0003.31.9<.0012.82.1.0402.82.01
       SGA7.45.2<.0017.05.6.0186.96.2.194
       UmA pH
      Mean ± SD.
      7.29 ± 0.087.29 ± 0.090.9927.28 ± 0.097.28 ± 0.15.1817.29 ± 0.097.28 ± 0.09.261
      <7.0000.50.8.2671.10.9.5430.80.8.850
       Apgar score (5 min) <73.43.1.4173.83.1.1083.73.1.167
       Neonatal resuscitation25.821.2<.00123.422.4.34326.923.1<.001
       NICU admission15.214.1181414.5.5821614.5.05
       Infant death1.71.4.2361.71.4.3071.61.3.203
      Note: Values are percentages. ICU = intensive care unit; NICU = neonatal intensive care unit; PIH = pregnancy-induced hypertension; PTD = pre-term delivery; SGA = small for gestational age; UmA = umbilical artery.
      a Mean ± SD.
      Table 3Comparison of adverse obstetric outcomes between the groups that underwent specific types of ART procedures and the corresponding matched controls.
      OutcomeOvulation stimulationIUIIVF-ET
      OR95% CIOR95% CIOR95% CI
      Pregnancies
       PIH1.060.87–1.280.880.70–1.090.740.62–0.89
       Eclampsia0.650.16–2.730.410.09–1.850.310.08–1.15
       Placenta abruption1.350.88–2.080.980.59–1.621.210.79–1.87
       Placenta previa1.771.24–2.541.461.03–2.082.21.68–2.87
       Placenta accrete0.60.28–1.311.510.80–2.842.671.42–5.03
       PTD <37 wk of gestation1.291.15–1.451.161.01–1.331.291.16–1.45
       PTD <34 wk of gestation1.311.11–1.541.221.01–1.471.331.13–1.57
       Type of delivery
      Spontaneous cephalic0.910.83–0.990.870.79–0.960.750.69–0.81
      Instrumental0.950.82–1.111.070.91–1.261.010.87–1.66
      Elective cesarean1.060.93–1.201.090.95–1.261.381.23–1.55
      Emergency cesarean1.110.99–1.251.110.98–1.261.191.07–1.32
      Others1.681.11–2.551.20.66–2.160.820.47–1.44
       Postpartum hemorrhage1.240.99–1.561.230.95–1.601.461.18–1.81
       ICU admission0.360.04–3.480.770.20–2.980.190.02–1.60
       Maternal death0.540.05–5.991.130.10–12.450.470.04–5.14
      Infants
       Birth weight, g
      <2,5001.351.21–1.501.171.04–1.321.271.15–1.40
      <1,5001.361.13–1.641.230.99–1.521.31.08–1.57
      <1,0001.771.34–2.321.381.01–1.881.441.09–1.90
       SGA1.451.21–1.731.271.04–1.551.120.94–1.33
       UmA pH <7.000.60.25–1.491.260.59–2.700.930.45–1.92
       Apgar score (5 min) <71.110.87–1.411.240.95–1.621.180.93–1.49
       Neonatal resuscitation1.291.17–1.431.060.94–1.191.231.12–1.35
       NICU admission1.10.98–1.240.960.84–1.111.121.00–1.26
       Infant death1.230.87–1.751.220.83–1.801.250.89–1.78
      Note: 95% CI = 95% confidence interval; ICU = intensive care unit; NICU = neonatal intensive care unit; OR = odds ratio; PIH = pregnancy-induced hypertension; PTD = pre-term delivery; SGA = small for gestational age; UmA = umbilical artery.
      The delivery of low birth weight (<2,500 g) and extremely low birth weight (<1,000 g) infants was common among patients in all study groups, regardless of the type of infertility treatment. Ovulation stimulation medications and IUI were associated with an increased incidence of delivery of small for gestational age (SGA) infants. Although the requirement of neonatal resuscitation was slightly higher in patients who used ovulation stimulation medications or underwent IVF-ET, no association was observed between the different types of ART procedures and adverse neonatal outcomes such as neonatal ICU admission and infant death.

      Discussion

      This study compared obstetric and perinatal outcomes between women with singleton pregnancies conceived through ART procedures and corresponding controls who conceived naturally and matched by multiple maternal characteristics, behaviors, and lifestyle factors. The results indicated that singleton pregnancies conceived through ART procedures pose an increased risk of several adverse obstetric and perinatal outcomes. This is independent of the type of treatment, suggesting that maternal factors associated with infertility may contribute to such adverse outcomes rather than the type of ART procedure used.
      Several studies have suggested an increased risk of preterm delivery and low birth weight in women with singleton pregnancies conceived through ART procedures (
      • Perri T.
      • Chen R.
      • Yoeli R.
      • Merlob P.
      • Orvieto R.
      • Shalev Y.
      • et al.
      Are singleton assisted reproductive technology pregnancies at risk of prematurity?.
      ,
      • Schieve L.A.
      • Meikle S.F.
      • Ferre C.
      • Peterson H.B.
      • Jeng G.
      • Wilcox L.S.
      Low and very low birth weight in infants conceived with use of assisted reproductive technology.
      ,
      • Retzloff M.G.
      • Hornstein M.D.
      Is intracytoplasmic sperm injection safe?.
      ,
      • Zadori J.
      • Kozinszky Z.
      • Orvos H.
      • Katona M.
      • Kaali S.G.
      • Pal A.
      The incidence of major birth defects following in vitro fertilization.
      ). Some possible explanations for these adverse outcomes have been discussed. The use of hMG, as part of procedures involving ART, has been associated with an increase in insulin-like growth factor binding protein-1 (IGFBP-1), which has been linked to fetal growth restriction (
      • Johnson M.R.
      • Irvine R.
      • Hills F.
      • Bolton V.N.
      • Abbas A.A.
      • Brooks A.A.
      • et al.
      Superovulation, IGFBP-1 and birth weight.
      ). Altered levels of other endometrial proteins and increased rates of placental structural abnormalities have also been reported in women who conceived through ART procedures (
      • Jauniaux E.
      • Englert Y.
      • Vanesse M.
      • Hiden M.
      • Wilkin P.
      Pathologic features of placentas from singleton pregnancies obtained by in vitro fertilization and embryo transfer.
      ,
      • Johnson M.R.
      • Abbas A.
      • Norman-Taylor J.Q.
      • Riddle A.F.
      • Grudzinskas J.G.
      • Chard T.
      • et al.
      Circulating placental protein 14: in the first trimester of spontaneous and IVF pregnancies.
      ). These factors may also contribute to fetal growth restriction. However, these possibilities seem less likely in view of reports showing an increased risk of preterm delivery and delivery of low birth weight infants in infertile (
      • Joffe M.
      • Li Z.
      Association of time to pregnancy and the outcome of pregnancy.
      ,
      • Henriksen T.B.
      • Baird D.D.
      • Olsen J.
      • Hedegaard M.
      • Secher N.J.
      • Wilcox A.J.
      Time to pregnancy and preterm delivery.
      ,
      • Basso O.
      • Baird D.D.
      Infertility and preterm delivery, birthweight, and Caesarean section: a study within the Danish National Birth Cohort.
      ,
      • Axmon A.
      • Hagmar L.
      Time to pregnancy and pregnancy outcome.
      ,
      • Thomson F.
      • Shanbhag S.
      • Templeton A.
      • Bhattacharya S.
      Obstetric outcome in women with subfertility.
      ) and subfertile women without treatment (
      • Jaques A.M.
      • Amor D.J.
      • Baker H.W.
      • Healy D.L.
      • Ukoumunne O.C.
      • Breheny S.
      • et al.
      Adverse obstetric and perinatal outcomes in subfertile women conceiving without assisted reproductive technologies.
      ). Our results, which demonstrate a slight increase in the incidence of preterm delivery and delivery of low birth weight infants regardless of the type of procedure, confirm and extend these findings. Because these adverse outcomes were obtained in all patients who underwent different types of ART procedures, it seems likely that the risk of preterm delivery and low birth weight may be related to maternal factors associated with infertility rather than the type of ART procedure used.
      Previous studies have suggested that patients who undergo ART procedures are managed differently, and these patients are subject to iatrogenic causes of preterm delivery and delivery of low birth weight infants (
      • Verlaenen H.
      • Cammu H.
      • Derde M.P.
      • Amy J.J.
      Singleton pregnancy after in vitro fertilization: expectations and outcome.
      ,
      • Koivurova S.
      • Hartikainen A.L.
      • Gissler M.
      • Hemminki E.
      • Sovio U.
      • Jarvelin M.R.
      Neonatal outcome and congenital malformations in children born after in-vitro fertilization.
      ,
      • Allen C.
      • Bowdin S.
      • Harrison R.F.
      • Sutcliffe A.G.
      • Brueton L.
      • Kirby G.
      • et al.
      Pregnancy and perinatal outcomes after assisted reproduction: a comparative study.
      ). In fact, the results of many studies (
      • Verlaenen H.
      • Cammu H.
      • Derde M.P.
      • Amy J.J.
      Singleton pregnancy after in vitro fertilization: expectations and outcome.
      ,
      • Koivurova S.
      • Hartikainen A.L.
      • Gissler M.
      • Hemminki E.
      • Sovio U.
      • Jarvelin M.R.
      Neonatal outcome and congenital malformations in children born after in-vitro fertilization.
      ,
      • Allen C.
      • Bowdin S.
      • Harrison R.F.
      • Sutcliffe A.G.
      • Brueton L.
      • Kirby G.
      • et al.
      Pregnancy and perinatal outcomes after assisted reproduction: a comparative study.
      ), in addition to our results on patients who underwent IVF-ET, have reported higher rates of cesarean section deliveries in patients who undergo ART procedures. Such patients are also more anxious about the outcome of their pregnancies compared with those who conceive naturally (
      • McMahon C.A.
      • Ungerer J.A.
      • Beaurepaire J.
      • Tennant C.
      • Saunders D.
      Anxiety during pregnancy and fetal attachment after in-vitro fertilization conception.
      ). Therefore, the increased rates of cesarean section deliveries may reflect patient and physician choice rather than an inherent biological abnormality in the concerned patient.
      Several studies have shown a more than sixfold risk of placenta previa in patients who undergo ART procedures (
      • Allen C.
      • Bowdin S.
      • Harrison R.F.
      • Sutcliffe A.G.
      • Brueton L.
      • Kirby G.
      • et al.
      Pregnancy and perinatal outcomes after assisted reproduction: a comparative study.
      ,
      • Shevell T.
      • Malone F.D.
      • Vidaver J.
      • Porter T.F.
      • Luthy D.A.
      • Comstock C.H.
      • et al.
      Assisted reproductive technology and pregnancy outcome.
      ,
      • Romundstad L.B.
      • Romundstad P.R.
      • Sunde A.
      • von During V.
      • Skjaerven 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.
      ). A meta-analysis also indicated a threefold risk of placenta previa in women who underwent ART procedures to conceive than in those who did not (
      • Jackson R.A.
      • Gibson K.A.
      • Wu Y.W.
      • Croughan M.S.
      Perinatal outcomes in singletons following in vitro fertilization: a meta-analysis.
      ). However, that analysis included only 39 cases of placenta previa among 1,610 pregnancies conceived with the aid of ART. In addition, these studies did not control for risk factors like parity, uterine surgery, number of previous cesarean sections, or maternal complications. Therefore, we used a relatively large nationwide database and selected adequate controls matched by multiple maternal characteristics, behaviors, and lifestyle factors. Our results indicated that patients who underwent ART had a twofold increased risk of placenta previa compared with those who did not. The IVF-ET and embryo culture can change key metabolic pathways in the embryo (
      • Leese H.J.
      • Donnay I.
      • Thompson J.G.
      Human assisted conception: a cautionary tale. Lessons from domestic animals.
      ), and these effects may interfere with implantation and early embryo development. In IVF-ET, embryos are placed in the uterine cavity by the transcervical route using a catheter. This procedure may induce uterine contraction, possibly because of the release of prostaglandins after mechanical stimulation of the internal cervical os (
      • Romundstad L.B.
      • Romundstad P.R.
      • Sunde A.
      • von During V.
      • Skjaerven 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.
      ,
      • Fanchin R.
      • Righini C.
      • Olivennes F.
      • Taylor S.
      • de Ziegler D.
      • Frydman R.
      Uterine contractions at the time of embryo transfer alter pregnancy rates after in-vitro fertilization.
      ,
      • Mansour R.
      Minimizing embryo expulsion after embryo transfer: a randomized controlled study.
      ). These investigators speculated that mechanically induced uterine contractions can lead to higher frequencies of implantation in the lower uterine segment, thereby increasing the risk of placenta previa. However, our results indicated a significant increase in the risk of placenta previa in both patients who used ovulation stimulation medications and those who underwent IUI, suggesting that mechanisms not associated with the type of ART procedure used contributed to the increased risk of placenta previa.
      These mechanical procedures may interfere with the development of the maternal–fetal interface during the early stages of implantation (
      • Jauniaux E.
      • Englert Y.
      • Vanesse M.
      • Hiden M.
      • Wilkin P.
      Pathologic features of placentas from singleton pregnancies obtained by in vitro fertilization and embryo transfer.
      ,
      • Daniel Y.
      • Schreiber L.
      • Geva E.
      • Amit A.
      • Pausner D.
      • Kupferminc M.J.
      • et al.
      Do placentae of term singleton pregnancies obtained by assisted reproductive technologies differ from those of spontaneously conceived pregnancies?.
      ). Some studies (
      • Jauniaux E.
      • Englert Y.
      • Vanesse M.
      • Hiden M.
      • Wilkin P.
      Pathologic features of placentas from singleton pregnancies obtained by in vitro fertilization and embryo transfer.
      ,
      • Daniel Y.
      • Schreiber L.
      • Geva E.
      • Amit A.
      • Pausner D.
      • Kupferminc M.J.
      • et al.
      Do placentae of term singleton pregnancies obtained by assisted reproductive technologies differ from those of spontaneously conceived pregnancies?.
      ) have investigated the pathologic features of singleton pregnancies conceived through ART procedures, and they found that the placentas in these patients had significantly higher weights, appeared thicker, and had a higher incidence of abnormal shapes and cord insertion compared with placentas in patients with naturally conceived pregnancies. These observations suggest that ART may be associated with placenta-mediated pregnancy complications, such as preeclampsia, placenta abruption, delivery of small for gestational age infants, and pregnancy loss. However, a recent study indicated that ART procedures are not associated with an increased risk of placenta-mediated pregnancy complications (
      • Sun L.M.
      • Walker M.C.
      • Cao H.L.
      • Yang Q.
      • Duan T.
      • Kingdom J.C.
      Assisted reproductive technology and placenta-mediated adverse pregnancy outcomes.
      ), which was in agreement with our results, which indicated no association between our study groups and placenta abruption. However, patients who used ovulation stimulation medications or underwent IUI showed a slightly increased risk of delivery of small for gestational age infants. Furthermore, patients who underwent ART procedures had a 2.7-fold increased risk for placenta accreta compared with the corresponding controls, whereas they had a significantly decreased risk of pregnancy-induced hypertension. These confusing results rule out the possibility that the type of ART procedure used contributes to adverse obstetric and perinatal outcomes.
      Several maternal complications, behaviors, and lifestyle factors are related not only to infertility but also to adverse perinatal outcomes. From the results of the present study, wherein maternal effects were excluded by using matched controls, we conclude that infertility factors in women requiring ART procedures to conceive contribute to adverse obstetric and perinatal outcomes independent of the type of ART procedure used. Our results in part complement a recent publication (
      • Davies M.J.
      • Moore V.M.
      • Willson K.J.
      • Van Essen P.
      • Priest K.
      • Scott H.
      • et al.
      Reproductive technologies and the risk of birth defects.
      ), which demonstrated that although the increased risk of birth defects associated with IVF was no longer significant after adjustment for parental factors, the risk of birth defects associated with ICSI remained increased after multivariate adjustment. We acknowledge that the inability to identify ICSI cycles is a limitation in this study, because a large proportion of women undergoing ICSI may have no maternal factors. In addition, the inability to identify cycles when donor sperm is used may be a limitation. Although these results should be interpreted with caution because the specificities of the subjects and database vary among studies, it seems likely that maternal factors associated with infertility may contribute to the adverse outcomes rather than the ART procedures themselves. However, the mechanisms leading to these adverse outcomes in infertile women remain unclear and require further study for elucidation.

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