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Complications and adverse outcomes in pregnancy and childbirth among women who conceived by assisted reproductive technologies: a nationwide birth cohort study of Japan environment and children’s study

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BMC Pregnancy and Childbirth201919:77

https://doi.org/10.1186/s12884-019-2213-y

  • Received: 6 June 2018
  • Accepted: 4 February 2019
  • Published:
Open Peer Review reports

Abstract

Background

Although pregnancies conceived by assisted reproductive technology (ART) have a higher risk of maternal/perinatal complications, the overall risk of adverse outcomes necessitating advanced obstetric care has not been closely examined. The present study aimed to assess and compare the risk of maternal/perinatal complications and adverse outcomes in pregnancy and childbirth conceived by ART with those conceived naturally.

Methods

This study was conducted as a part of the Japan environment and children’s study (JECS), an ongoing nationwide birth cohort study in Japan. The risk of maternal/perinatal complications and adverse outcomes was assessed by mode of conception (natural conception, ovulation induction [OI] without ART, conventional in vitro fertilization and embryo transfer [IVF-ET], or intracytoplasmic sperm injection [ICSI]) using logistic regression and generalized estimating equations controlling for potential confounders.

Results

The final dataset included women who conceived naturally (N = 90,506), by OI without ART (N = 3939), by conventional IVF-ET (N = 1476), and by ICSI (N = 1671). Compared with women who conceived naturally, those who conceived by conventional IVF-ET were at higher risk of placenta previa (adjusted OR 2.90 [95% CI 1.94, 4.34]), morbidly adherent placenta (6.85 [3.88, 12.13]), and pregnancy-induced hypertension (1.40 [1.10, 1.78]) whereas those who conceived by ICSI had a higher risk of placental abruption (2.16 [1.20, 3.88]) as well as placenta previa (2.01 [1.29, 3.13]) and morbidly adherent placenta (7.81 [4.56, 13.38]). Women who conceived by ART had a higher risk of blood transfusion (conventional IVF-ET: 3.85 [2.52, 5.88]; ICSI: 3.76 [2.49, 5.66]) and ICU admission (conventional IVF-ET: 2.58 [1.11, 6.01]; ICSI: 3.45 [1.68, 7.06]) even after controlling for potential confounders. Neonates conceived by ART had a higher risk of preterm birth (conventional IVF-ET: 1.42 [1.13, 1.78]; ICSI: 1.31 [1.05, 1.64]).

Conclusions

Women who conceived by ART had a higher risk of maternal/perinatal complications necessitating advanced obstetric care. Obstetricians should be aware of the increased risk of adverse outcomes among this population.

Keywords

  • Assisted reproductive technology
  • ART
  • In vitro fertilization
  • IVF
  • Intracytoplasmic sperm injections
  • ICSI
  • Ovulation induction
  • Placental diseases
  • Blood transfusion
  • Intensive care unit

Background

In recent years, a substantial number of children have been conceived using assisted reproductive technology (ART) particularly in high-income countries [1]. Currently the proportion of children conceived by ART in Japan is roughly 5% [2] and is rising [25]. However, women who conceive by ART have a higher risk of maternal and perinatal complications, such as pregnancy-induced hypertension (PIH), placenta previa, placental abruption, morbidly adherent placenta (MAP), preterm birth, and low birth weight [610]. Numerous studies have investigated the reasons for this higher risk without reaching any definite conclusions. Potential causes include underlying maternal characteristics which necessitated the use of ART as well as the ART itself [1016].

Although complications related to ART pregnancies have been well studied using large-scale registry and cohort data worldwide, many of these studies have focused on outcomes in fetuses and neonates born after ART [79]. Less attention has been paid to adverse maternal outcomes, and only a few studies have assessed the overall risk of life-threatening conditions, such as blood transfusion, peripartum hysterectomy, intensive care unit (ICU) admission, and maternal death in this population [1520]. In Japan, there is an online registration system which covers more than 90% of ART cycles conducted nationwide and their outcomes. Although this system collects detailed information on ART, data pertaining to maternal/perinatal complications and adverse outcomes are limited [2].

To redress this omission, we conducted the present study as an adjunct to the Japan environment and children’s study (JECS), a nationwide cohort study of environmental impacts on child health. The aim of the present study was to assess and compare the risk of maternal/perinatal complications and adverse outcomes between women who conceived by ART and women who conceived naturally.

Methods

This study was conducted as an adjunct to the JECS, an ongoing nationwide birth cohort study in Japan aiming to determine the impact of environmental factors on child health (data set: jecs-ag-20,160,424). Details of the JECS protocol have been published elsewhere [21]. Briefly, JECS is being conducted in 15 regions covering a variety of regions throughout Japan. Expecting mothers were recruited either at cooperating obstetric facilities or local government offices between January 2011 and March 2014. JECS covers a total of 103,099 pregnancies and includes follow up studies of the children resulting from those pregnancies until they have reached the age of 13.

During pregnancy and at one month postpartum, various data were collected from the participants using a self-administered questionnaire. The collected information included maternal and paternal characteristics, anthropometric measurements, medical history, socio-economic status (e.g., income, occupation, and education), life-style (food consumption, exercise, and sleep), mental health, exposure to chemicals, etc. Furthermore, medical information pertaining to the pregnancy course, delivery, and postpartum condition was collected by extraction of data from the participants’ medical records either by clinicians or trained research coordinators.

JECS was approved by the institutional review board of the Ministry of the Environment and the ethics committees of all the participating institutions and is being conducted in accordance with the Declaration of Helsinki and other relevant regulations in Japan. Written informed consent was obtained from all the participants. As the present study used anonymized data, individual approval from the ethics committee was deemed unnecessary.

Target population, variables of interest, and outcomes

The target population of the present study consisted of all women who participated in JECS and conceived by one of the following methods: 1) naturally; 2) using ovulation induction (OI) without ART; 3) conventional in vitro fertilization and embryo transfer (IVF-ET); or 4) intracytoplasmic sperm injection (ICSI). For the outcomes pertaining to fetuses/neonates, we analyzed only those delivered at 22 weeks or more of gestation. The variables of interest were conventional IVF-ET and ICSI. Women who conceived naturally served as the reference group. We also included women who conceived using OI without ART in order to estimate their risk level in case this might differ from that of natural pregnancies, given the former group’s history of infertility and the effect of OI [16, 17, 22].

Maternal complications and adverse outcomes included placenta previa, placental abruption, MAP, PIH, gestational diabetes, cesarean section, maternal blood transfusion, maternal admission to the ICU, and maternal death. Stillbirth (≥ 22 weeks of gestation), pre-term birth (< 37 weeks of gestation), and low birth weight (< 2500 g) were considered to be adverse fetal/neonatal outcomes. All of the maternal/perinatal complications and adverse outcomes were diagnosed following the protocol at each participating institution, which was presumably based on the relevant Japanese guidelines. Pregnancy-induced hypertension was defined as “hypertension (systolic blood pressure ≥140mmHg or diastolic blood pressure ≥90 mmHg) observed from the 20th week of gestation to 12 weeks postpartum with or without proteinuria (≥300 mg/day), not just as a continuing pre-existing condition” [23]. Gestational diabetes was defined as a “glucose metabolism disorder occurring or recognized during pregnancy, excluding overt diabetes” [24]. An oral glucose tolerance test with 75 g sugar was used for diagnosis, and the diagnostic criteria were blood glucose values of: 1) ≥92 mg/dL in a fasted state; 2) ≥180 mg/dL after one hour; or 3) ≥153 mg/dL after two hours.

Statistical analysis

First, we described the background characteristics of the participants who were included in the analysis, their pregnancy course, maternal and perinatal complications, and adverse outcomes by group (i.e., natural conception, OI without ART, conventional IVE-ET or ICSI). Next, the effect of each mode of conception on maternal/perinatal complications and adverse outcomes was assessed using logistic regression for maternal outcomes and generalized estimating equations (GEE) for fetal/neonatal outcomes, with women who conceived naturally serving as the reference group. The crude odds ratio (OR) and adjusted odds ratio (aOR) were calculated; adjusted covariates included maternal age, maternal body mass index (BMI) before pregnancy, maternal height, maternal weight before delivery, parity, prior cesarean section, pre-existing condition (e.g., chronic hypertension, hyperthyroidism, hypothyroidism, diabetes mellitus, autoimmune disease, heart disease, kidney disease, hepatitis, cerebral infarction, intracranial hemorrhage, epilepsy, blood disease, malignancy, psychiatric disorder, neurologic disease, thrombosis, and others), multiple pregnancies, fetal presentation, folic acid supplementation, maternal smoking during pregnancy, maternal drinking during pregnancy, maternal educational level, paternal smoking, paternal educational level, and household income. The variables included in the multivariate models as potential confounders were selected based on previous studies, biological plausibility, and their availability in the JECS data set [2531]. We reported all crude ORs and aORs with the corresponding 95% confidence interval (CI). In order to improve the robustness of the analysis, we also conducted multiple imputation and compared the results with those from the model with case-wise deletion of missing data. The statistical analysis was conducted using the SAS software program (version 9.4; SAS Institute Inc., Cary, NC, USA).

Results

The final set of participants included in the main analysis consisted of women who conceived naturally (N = 90,506), by OI without ART (N = 3939), by conventional IVF-ET (N = 1476), and by ICSI (N = 1671). These pregnancies resulted in 96,860 fetuses/neonates in total delivered at 22 weeks or more of gestation, including live births and stillbirths, counting singletons and multiples, while excluding miscarriages/abortions before 22 weeks of gestation and cases with missing data on gestational age at birth. Figure 1 shows the flow chart of the participants who were either included in the main analysis or excluded for failing to meet the inclusion criteria.
Fig. 1
Fig. 1

Flow chart of participants in the analysis

Table 1 summarizes the background characteristics of the women who were included in the main analysis. Women who conceived by ART were more likely to be older, nulliparous, have a pre-existing condition, taking daily folic acid supplementation, non-smokers, have a higher education, and come from a wealthier household in contrast to women who conceived naturally. Table 2 shows the pregnancy and fetal/neonatal characteristics by mode of conception. Women who conceived by OI without ART had the highest proportion of multiple births among the four groups (4.9%). Table 3 shows the maternal/perinatal complications and adverse outcomes by mode of conception in all pregnancies, pregnancies with singletons, and pregnancies with multiples.
Table 1

Background characteristics of participants by mode of conception

 

Natural conception

OI without ART

Conventional IVF-ET

ICSI

N = 90,506

N = 3939

N = 1476

N = 1671

 

Median

IQR

Median

IQR

Median

IQR

Median

IQR

Maternal age (years)

31

8

33

6

36

6

36

6

 Missing (N)

733

31

4

17

Maternal height (cm)

158.0

8.0

158.0

7.5

158.7

8.0

158.5

7.0

 Missing (N)

477

23

3

6

Maternal BMI before pregnancy (kg/m2)

20.6

3.5

20.6

3.7

20.7

3.4

20.7

3.3

 Missing (N)

1089

41

15

17

Maternal weight before delivery (kg)

62.3

10.6

62.1

11.1

62.4

10.6

61.8

10.5

 Missing (N)

3019

158

55

79

 

N

%

N

%

N

%

N

%

Parity

 0

33,760

38.2

2290

59.9

949

66.0

1089

68.1

 1

34,934

39.5

1331

34.8

447

31.1

469

29.3

 2 or more

19,712

22.3

201

5.3

42

2.9

42

2.6

 (Missing)

2100

 

117

 

38

 

71

 

Prior cesarean section

 No

82,242

90.9

3680

93.5

1346

91.2

1530

91.6

 Yes

8200

9.1

257

6.5

130

8.8

141

8.4

 (Missing)

64

 

2

 

0

 

0

 

Marital status

 Married

85,789

95.2

3919

99.6

1474

100.0

1668

99.8

 Single

4304

4.8

16

0.4

0

0.0

3

0.2

 (Missing)

413

 

4

 

2

 

0

 

Pre-existing maternal condition

 No

74,963

85.4

3080

81.3

1087

75.3

1242

77.6

 Yes

12,858

14.6

710

18.7

357

24.7

359

22.4

 (Missing)

245

 

4

 

1

 

3

 

Folic acid supplementation

 No

47,803

53.0

1310

33.3

470

31.9

476

28.5

 A few times per month

4610

5.1

184

4.7

38

2.6

52

3.1

 A few times per week

14,127

15.7

735

18.7

251

17.0

293

17.6

 Daily

23,721

26.3

1706

43.4

716

48.5

847

50.8

 (Missing)

695

 

21

 

8

 

7

 

Maternal smoking during pregnancy

 No

85,152

94.8

3867

98.7

1453

99.0

1649

99.1

 Yes

4659

5.2

51

1.3

15

1.0

15

0.9

 (Missing)

440

 

10

 

3

 

3

 

Maternal drinking during pregnancy

 No

81,033

90.0

3579

91.1

1362

92.5

1525

91.4

 Yes

9033

10.0

350

8.9

111

7.5

143

8.6

 (Missing)

2512

 

100

 

38

 

42

 

Maternal educational level

 Junior high/high school

33,026

37.5

904

23.5

335

23.3

358

22.0

 Vocational school/junior college

36,499

41.5

1866

48.6

673

46.8

777

47.7

 University/graduate school

18,469

21.0

1069

27.8

430

29.9

494

30.3

 (Missing)

1902

 

47

 

15

 

23

 

Paternal smoking

 No

45,916

51.8

2464

63.3

977

66.9

1145

69.5

 Yes

42,688

48.2

1428

36.7

484

33.1

503

30.5

 (Missing)

3105

 

105

 

39

 

45

 

Paternal educational level

 Junior high/high school

39,601

45.3

1229

32.1

475

33.1

503

30.9

 Vocational school/junior college

19,687

22.5

902

23.5

272

18.9

351

21.6

 University/graduate school

28,113

32.2

1703

44.4

690

48.0

772

47.5

 (Missing)

8435

 

283

 

93

 

116

 

Household income (×10,000 Japanese yen)

  < 200

4956

6.0

73

2.0

17

1.2

20

1.3

  ≥ 200, < 400

29,346

35.8

949

26.0

279

20.2

258

16.6

  ≥ 400, < 600

26,979

32.9

1319

36.1

480

34.7

521

33.5

  ≥ 600, < 800

12,554

15.3

747

20.4

318

23.0

391

25.1

  ≥ 800, < 1000

5012

6.1

328

9.0

161

11.6

204

13.1

  ≥ 1000

3224

3.9

240

6.6

128

9.3

161

10.4

 (Missing)

8435

 

283

 

93

 

116

 

ART assisted reproductive technologies, BMI body mass index, ICSI intracytoplasmic sperm injection. IQR interquartile range, IVF-ET in vitro fertilization and embryo transfer, OI ovulation induction

Proportions were calculated excluding cases with missing data

Table 2

Pregnancy and fetal/neonatal characteristics by mode of conception

 

Natural conception

OI without ART

Conventional IVT-ET

ICSI

N

%

N

%

N

%

N

%

Pregnancies

N = 90,506

N = 3939

N = 1476

N = 1671

 Singleton pregnancy

88,873

99.3

3702

95.1

1407

95.7

1586

96.0

 Multiple pregnancies

625

0.7

189

4.9

63

4.3

66

4.0

 (Missing)

1008

 

48

 

6

 

19

 

Fetus/Neonate born ≥22 weeks

N = 89,576

N = 4067

N = 1518

N = 1699

Number of fetuses

 Singletons

88,337

98.6

3682

90.6

1393

91.8

1570

92.4

 Multiples

1209

1.4

383

9.4

125

8.2

129

7.6

 (Missing)

30

 

2

 

0

 

0

 

Fetal presentation

 Cephalic

85,331

96.4

3726

93.2

1345

90.7

1516

90.8

 Non-cephalic

3179

3.6

273

6.8

138

9.3

153

9.2

 (Missing)

1066

 

68

 

35

 

30

 

Sex of neonate

 Male

45,942

51.3

2062

50.7

805

53.0

850

50.0

 Female

43,608

48.7

2003

49.3

713

47.0

849

50.0

 (Missing)

26

 

2

 

0

 

0

 

ART assisted reproductive technology, ICSI intracytoplasmic sperm injection, ICU intensive care unit, IVF-ET in vitro fertilization and embryo transfer, OI ovulation induction

Proportions were calculated excluding cases with missing data

Table 3

Maternal/perinatal complications and adverse outcomes by mode of conception in all pregnancies, pregnancies with singletons, and pregnancies with multiples

 

Natural conception

OI without ART

Conventional IVT-ET

ICSI

N

%

N

%

N

%

N

%

All women and a fetus/neonate born ≥22 weeks

 Maternal outcomes

N = 90,506

N = 3939

N = 1476

N = 1671

  Placenta previa

489

0.5

22

0.6

36

2.4

30

1.8

  Placental abruption

382

0.4

19

0.5

8

0.5

19

1.2

  MAP

172

0.2

9

0.2

17

1.2

24

1.5

  Gestational diabetes

2304

2.6

138

3.5

76

5.2

80

4.8

  PIH

2632

2.9

177

4.5

101

6.9

107

6.5

  Cesarean section

16,433

18.5

933

24.2

563

38.6

617

37.8

  Blood transfusion

377

0.4

20

0.5

36

2.4

38

2.3

  ICU admission

105

0.1

8

0.2

7

0.5

15

0.9

  Maternal death

10

0

0

0

0

0

0

0

 Fetal/neonatal outcomes

N = 89,576

N = 4067

N = 1518

N = 1699

  Stillbirth

230

0.3

17

0.4

10

0.7

5

0.3

  Preterm birth < 37 w

4768

5.3

423

10.4

184

12.1

181

10.7

  Low birth weight < 2500 g

7980

8.9

651

16.0

243

16.0

245

14.4

Women with a singleton pregnancy and singleton born ≥22 weeks

 Maternal outcomes

N = 88,873

N = 3702

N = 1407

N = 1586

  Placenta previa

486

0.5

20

0.5

34

2.4

28

1.8

  Placental abruption

380

0.4

18

0.5

8

0.6

19

1.2

  MAP

172

0.2

8

0.2

17

1.2

24

1.5

  Gestational diabetes

2271

2.6

132

3.6

72

5.1

75

4.7

  PIH

2573

2.9

165

4.5

93

6.6

102

6.4

  Cesarean section

15,912

18.0

780

21.2

509

36.5

558

35.6

  Blood transfusion

368

0.4

16

0.4

33

2.4

37

2.3

  ICU admission

97

0.1

5

0.1

7

0.5

12

0.8

  Maternal death

10

0

0

0

0

0

0

0

 Fetal/neonatal outcomes

N = 88,337

N = 3682

N = 1393

N = 1570

  Stillbirth

216

0.2

8

0.2

8

0.6

4

0.3

  Preterm birth

4153

4.7

211

5.7

120

8.6

119

7.6

  Low birth weight < 2500 g

7141

8.1

373

10.1

159

11.4

159

10.1

Women with multiple pregnancies and multiples born ≥22 weeks

 Maternal outcomes

N = 625

N = 189

N = 63

N = 66

  Placenta previa

3

0.5

1

0.5

2

3.2

2

3.1

  Placental abruption

2

0.3

1

0.5

0

0

0

0

  MAP

0

0

1

0.5

0

0

0

0

  Gestational diabetes

31

5.1

6

3.2

4

6.3

5

7.8

  PIH

57

9.4

12

6.5

8

12.7

5

7.8

  Cesarean section

518

85.8

151

81.2

54

87.1

59

92.2

  Blood transfusion

9

1.5

3

1.6

3

4.8

1

1.6

  ICU admission

8

1.3

3

1.6

0

0

3

4.7

  Maternal death

0

0

0

0

0

0

0

0

 Fetal/neonatal outcomes

N = 1209

N = 383

N = 125

N = 129

  Stillbirth

13

1.1

9

2.3

2

1.6

1

0.8

  Preterm birth

613

50.7

212

55.4

64

51.2

62

48.1

  Low birth weight < 2500 g

838

69.3

278

72.8

84

67.2

86

66.7

ART assisted reproductive technologies, ICSI intracytoplasmic sperm injection, ICU intensive care unit, IVF-ET in vitro fertilization and embryo transfer, MAP morbidly adherent placenta, OI ovulation induction, PIH pregnancy-induced hypertension

Proportions were calculated excluding cases with missing data

The association between each mode of conception and maternal/perinatal complications and adverse outcomes was assessed using a logistic regression and GEE analysis, with women who conceived naturally serving as a reference (Table 4). Pregnancies resulting from OI without ART did not have an increased risk of maternal/perinatal complications or adverse outcomes. Maternal death and stillbirth were not assessed because the number of cases was insufficient to calculate the aORs.
Table 4

Effect of mode of conception on maternal/perinatal complications and adverse outcomes

 

Logistic regression with case-wise deletion of missing data

Multiple imputation

Crude OR

95% CI

aOR

95% CI

aOR

95% CI

OI without ART

 Maternal outcomesa

  Placenta previa

0.76

0.43

1.31

0.62

0.35

1.09

0.85

0.55

1.32

  Placental abruption

1.33

0.82

2.18

1.33

0.80

2.19

1.13

0.71

1.81

  MAP

1.46

0.74

2.86

1.46

0.73

2.91

1.23

0.62

2.45

  Gestational diabetes

1.40

1.16

1.69

0.97

0.80

1.19

0.98

0.81

1.18

  PIH

1.55

1.30

1.84

1.10

0.91

1.32

1.11

0.94

1.31

  Cesarean section

1.41

1.29

1.53

1.12

0.99

1.26

1.08

0.97

1.21

  Blood transfusion

1.35

0.83

2.21

1.03

0.62

1.71

0.94

0.59

1.5

  ICU admission

2.16

1.04

4.46

1.29

0.60

2.79

1.07

0.49

2.3

 Fetal/neonatal outcomesb

  Preterm birth

1.93

1.71

2.18

1.05

0.09

1.24

1.01

0.86

1.18

  Low birth weight

1.88

1.70

2.07

1.04

0.93

1.19

1.04

0.93

1.17

Conventional IVT-ET

 Maternal outcomesa

  Placenta previa

4.68

3.22

6.82

2.90

1.94

4.34

2.86

1.99

4.12

  Placental abruption

1.03

0.43

2.50

0.91

0.37

2.26

1.08

0.53

2.22

  MAP

6.88

4.09

11.58

6.85

3.88

12.13

5.74

2.93

11.2

  Gestational diabetes

1.88

1.45

2.45

0.99

0.75

1.31

1.13

0.88

1.45

  PIH

2.43

1.94

3.05

1.40

1.10

1.78

1.41

1.13

1.76

  Cesarean section

2.69

2.39

3.02

1.85

1.58

2.17

1.9

1.64

2.19

  Blood transfusion

6.18

4.20

9.09

3.85

2.52

5.88

3.57

2.45

5.21

  ICU admission

4.98

2.30

10.80

2.58

1.11

6.01

2.04

0.89

4.66

 Fetal/neonatal outcomesb

  Preterm birth

2.59

2.18

3.08

1.42

1.13

1.78

1.36

1.11

1.66

  Low birth weight

1.90

1.63

2.22

0.94

0.76

1.15

1.01

0.85

1.2

ICSI

 Maternal outcomesa

  Placenta previa

3.37

2.22

5.11

2.01

1.29

3.13

2.02

1.36

3.01

  Placental abruption

2.44

1.40

4.26

2.16

1.20

3.88

2.35

1.44

3.82

  MAP

7.41

4.57

12.00

7.81

4.56

13.38

7.86

4.56

13.5

  Gestational diabetes

1.85

1.43

2.38

0.97

0.74

1.27

1.06

0.83

1.35

  PIH

2.16

1.73

2.71

1.25

0.98

1.60

1.34

1.07

1.67

  Cesarean section

2.75

2.46

3.07

1.89

1.62

2.19

1.82

1.59

2.09

  Blood transfusion

5.98

4.11

8.69

3.76

2.49

5.66

3.43

2.37

4.96

  ICU admission

7.11

3.78

13.36

3.45

1.68

7.06

3.87

2.07

7.24

 Fetal/neonatal outcomesb

  Preterm birth

2.33

1.96

2.77

1.31

1.05

1.64

1.21

0.99

1.47

  Low birth weight

1.78

1.53

2.07

0.87

0.72

1.06

0.89

0.74

1.06

aOR adjusted odds ratio, ART assisted reproductive technologies, CI confidence intervals, ICSI intracytoplasmic sperm injection, ICU intensive care unit, IVF-ET in vitro fertilization and embryo transfer, MAP morbidly adherent placenta, OI ovulation induction, OR odds ratio, PIH pregnancy-induced hypertension

Women who conceived naturally served as the reference group

Adjusted odds ratios were calculated by controlling for maternal age, maternal body mass index (BMI) before pregnancy, maternal height, maternal weight before delivery, parity, prior cesarean section, pre-existing maternal conditions, multiple pregnancies, fetal presentation, folic acid supplementation, maternal smoking during pregnancy, maternal drinking during pregnancy, maternal educational level, paternal smoking, paternal educational level, and household income

alogistic regression; bgeneralized estimating equations (GEE)

Women who conceived by conventional IVF-ET were at higher risk of placenta previa (aOR 2.90 [95% CI 1.94, 4.34]), MAP (aOR 6.85 [95% CI 3.88, 12.13]), and PIH (aOR 1.40 [95% CI 1.10, 1.78]) than those who conceived naturally. Women who conceived by ICSI had a higher risk of placental abruption (aOR 2.16 [95% CI 1.20, 3.88]) as well as placenta previa (aOR 2.01 [95% CI 1.29, 3.13]), MAP (aOR 7.81 [95% CI 4.56, 13.38]), and marginally significant PIH (aOR 1.25 [95% CI 0.98, 1.60]). Furthermore, women who conceived by ART were more likely to have a cesarean section and had a significantly higher risk of blood transfusion (conventional IVF-ET: aOR 3.85 [95% CI 2.52, 5.88]; ICSI: aOR 3.76 [95% CI 2.49, 5.66]) and ICU admission (conventional IVF-ET: aOR 2.58 [95% CI 1.11, 6.01]; ICSI: aOR 3.45 [95% CI 1.68, 7.06]) even after controlling for potential confounders. Neonates born after ART were at higher risk of preterm birth (conventional IVF-ET: aOR 1.42 [95% CI 1.13, 1.78]; ICSI: aOR 1.31 [95% CI 1.05, 1.64]) compared to those conceived naturally.

We also performed multiple imputation and compared the results with those from the logistic regression model with case-wise deletion of missing data (Table 4). The estimated effects of the variables of interest were similar in terms of their direction and magnitude.

Discussion

Compared with women who conceived naturally, those who conceived by conventional IVF-ET were at higher risk of placenta previa, MAP, and PIH whereas those who conceived by ICSI had a higher risk of placental abruption in addition to the above. Women who conceived by ART had a significantly higher risk of blood transfusion and ICU admission even after controlling for maternal age, pre-existing condition, and other potential confounders. Neonates conceived by ART were at higher risk of preterm birth.

The increased risk of maternal and perinatal complications observed in the present study were largely consistent with the findings of previous studies [610, 1416]. Among these complications, the risk of MAP was conspicuous, with an aOR of 6.85 for conventional IVF-ET and 7.81 for ICSI. More than 1% of women who conceived by ART had MAP; however, this figure should be interpreted with caution as the diagnoses were made clinically irrespective of pathological examination in JECS. The relationship between IVF pregnancies and MAP was first reported by Esh-Broder, et al. in 2011 [10]. MAP is one of the major causes of catastrophic outcomes in obstetrics, and placenta previa and previous cesarean section are known risk factors of MAP [32, 33]. Prenatal diagnosis is crucial for appropriate management, and ultrasound examination and magnetic resonance imaging are used especially for women with risk factors [34, 35]. However, prenatal diagnosis is not always possible. Given the observed relationship between ART and MAP, obstetricians should consider women who conceived by ART as a high risk group for MAP regardless of their prenatal diagnosis. In addition to the incidence of MAP, the observed incidence of placenta previa was also high among ART pregnancies (2.4% for conventional IVF, 1.8% for ICSI).

With regard to life-threatening maternal conditions, studies such as the one by Belanoff et al. have reported a higher risk of severe maternal morbidity in women who conceived using ART [1719]. Cromi et al. reported on the risk of a peripartum hysterectomy in pregnancies resulting from ART in 2016, arguing that such pregnancies should be managed as “high risk” [20]. In our study, more than 2% of women who conceived by ART received a blood transfusion. We realize that the incidence of these complications may be overestimated (or underestimated) depending upon the participants’ characteristics, given that JECS is not completely population-based. However, according to the profile paper of JECS, characteristics of the women and children who participated in JECS appeared to be comparable to those reported in Japan’s Vital Statistics Survey [36]. Hence, the observed higher risk of blood transfusion (conventional IVF-ET: aOR 3.85, ICSI: aOR 3.76) and ICU admission (conventional IVF-ET: aOR 2.58, ICSI: aOR 3.45) in ART pregnancies is deemed to be reliable.

In the present study, we estimated the risk levels of women who conceived using OI without ART separately from those of women who conceived naturally, considering the possibility that they might differ given the former’s history of infertility and the effect of OI. Although univariate analysis demonstrated an increased risk for some of the maternal/perinatal complications and adverse outcomes, none reached statistical significance after controlling for potential confounders.

The present study has several strengths. First and foremost, JECS is the largest birth cohort in the country and collects wide-ranging, in-depth information from participants and their medical records. This enabled us to control for various potential confounders including participants’ socio-economic status. In addition, the present study included blood transfusion and ICU admission as maternal adverse outcomes, unlike previous studies.

Nonetheless, the present study has several limitations. First, JECS was not designed to cover all expecting mothers during the recruitment period or apply complete random sampling (JECS aimed to cover 50% of the births in each study area [21].) Therefore, bias may have entered into the selection of the participants, thus leading to overestimation or underestimation of the incidence of maternal/perinatal complications and adverse outcomes. As mentioned above, however, the JECS profile paper suggested that the characteristics of the study participants were comparable to those collected in the national survey [36]. Second, the data pertaining to each woman’s mode of conception were self-reported, potentially jeopardizing their reliability. Furthermore, detailed data on the drugs and techniques used for OI or ART (e.g., fresh or frozen embryo transfer, blastocyst or cleavage stage embryo transfer) were not assessed. Third, data on some of the adverse outcomes, such as hysterectomy, were not collected in JECS. The number of maternal deaths and stillbirths was limited; hence, these figures were not included in the main analysis. Last, the diagnoses of maternal and perinatal complications were made at each participating facility, and subsequent interventions (e.g., blood transfusion and ICU admission) were conducted based on institutional protocols; hence, there may have been some variation in the diagnostic criteria and/or management strategies.

Conclusions

Women who conceived by ART were at higher risk of maternal and perinatal complications necessitating advanced/emergency obstetric care, such as a blood transfusion or ICU admission. Obstetricians should be aware of the increased risk of adverse maternal outcomes among women who conceived by ART.

Abbreviations

aOR: 

Adjusted odds ratio

ART: 

Assisted reproductive technology

BMI: 

Body mass index

CI: 

Confidence interval

ICSI: 

Intracytoplasmic sperm injection

ICU: 

Intensive care unit

IQR: 

Interquartile range

IVF-ET: 

In vitro fertilization and embryo transfer

JECS: 

Japan Environment and Children’s Study

MAP: 

Morbidly adherent placenta

NA: 

Not available

OI: 

Ovulation induction

OR: 

Odds ratio

PIH: 

Pregnancy-induced hypertension

Declarations

Acknowledgements

The authors would like to express their gratitude to all the participants and collaborators who helped to make JECS a reality. The authors also would like to thank the medical editors at the National Center for Child Health and Development for their editorial assistance.

The members of the Japan Environment & Children’s Study Group includes (as of 2017): Toshihiro Kawamoto (principal investigator), Reiko Kishi (Hokkaido Regional Center for JECS, Hokkaido University, Sapporo, Japan), Nobuo Yaegashi (Miyagi Regional Center for JECS, Tohoku University, Sendai, Japan), Koichi Hashimoto (Fukushima Regional Center for JECS, Fukushima Medical University, Fukushima, Japan), Chisato Mori (Chiba Regional Center for JECS, Chiba University, Chiba, Japan), Shuichi Ito (Kanagawa Regional Center for JECS, Yokohama City University, Yokohama, Japan), Zentaro Yamagata (Koshin Regional Center for JECS, University of Yamanashi, Chuo, Japan), Hidekuni Inadera (Toyama Regional Center for JECS, University of Toyama, Toyama, Japan), Michihiro Kamijima (Aichi Regional Center for JECS, Nagoya City University, Nagoya, Japan), Takeo Nakayama (Kyoto Regional Center for JECS, Kyoto University, Kyoto, Japan), Hiroyasu Iso (Osaka Regional Center for JECS, Osaka University, Suita, Japan), Masayuki Shima (Hyogo Regional Center for JECS, Hyogo College of Medicine, Nishinomiya, Japan), Yasuaki Hirooka (Tottori Regional Center for JECS, Tottori University, Yonago, Japan), Narufumi Suganuma (Kochi Regional Center for JECS, Kochi University, Nankoku, Japan), Koichi Kusuhara (Fukuoka Regional Center for JECS, University of Occupational and Environmental Health, Kitakyushu, Japan), and Takahiko Katoh (South Kyushu/Okinawa Regional Center for JECS, Kumamoto University, Kumamoto, Japan).

Funding

JECS is funded by Japan’s Ministry of the Environment. However, the conclusions of the present study do not necessarily represent the official views of the above organization or those of other relevant bodies.

Availability of data and materials

The JECS data are not publicly available due to ethical restrictions and the legal framework of Japan. All inquiries about access to the data should be sent to the JECS Programme Office, National Institute for Environmental Studies (jecs-en@nies.go.jp).

Authors’ contributions

JECS was initiated by the Japan Environment & Children’s Study Group, and the data were collected at 15 participating regional centers. The final data set was prepared and provided by the JECS Programme Office. CN and HS conceived the present study. LY conducted the statistical analyses. CN drafted the manuscript, and all the other co-authors (KYH, HM, TA, KI, MK, YO, and HS) made substantive contribution to the conception of the study, interpretation of the results, and critically reviewed the draft. All of the authors approved the final version of the manuscript and agreed to be accountable for their own contributions and to ensure that questions regarding the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Ethics approval and consent to participate

JECS was approved by the institutional review board on epidemiological studies of the Ministry of the Environment and the ethics committees of all the participating institutions (i.e., NIES, NCCHD, Hokkaido University, Sapporo Medical University, Asahikawa Medical College, Japanese Red Cross Hokkaido College of Nursing, Tohoku University, Fukushima Medical University, Chiba University, Yokohama City University, University of Yamanashi, Shinshu University, University of Toyama, Nagoya City University, Kyoto University, Doshisha University, Osaka University, Osaka Medical Center and Research Institute for Maternal and Child Health, Hyogo College of Medicine, Tottori University, Kochi University, University of Occupational and Environmental Health, Kyushu University, Kumamoto University, University of Miyazaki, and University of the Ryukyus). JECS is being conducted in accordance with the Declaration of Helsinki and other relevant regulations in the country. Written informed consent was obtained from all participants. The present study was conducted as a part of JECS and used anonymized data; hence, additional approval from the ethics committee was not required.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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Authors’ Affiliations

(1)
Department of Education for Clinical Research, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan
(2)
Medical Support Center for Japan Environment and Children’s Study (JECS), National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan
(3)
Division of Allergy, Department of Medical Subspecialties, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan
(4)
National Research Institute for Child Health and Development, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan
(5)
Center for Maternal-Fetal, Neonatal and Reproductive Medicine, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan

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Copyright

© The Author(s). 2019

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