Phenotypic Classification of Preterm Birth Among Nulliparous Women: A Population-Based Cohort Study

MATERNAL FETAL MEDICINE

Phenotypic Classification of Preterm Birth Among Nulliparous Women: A Population-Based Cohort Study Siavash Maghsoudlou, PhD;1,2 Zhijie Michael Yu, PhD;1 Joseph Beyene, PhD;3 Sarah D. McDonald, MD1,3,4 1

Department of Obstetrics and Gynecology, McMaster University, Hamilton, ON

2

Clinical Epidemiology Unit, Department of Medicine, Solna, Karolinska Institute, Stockholm, Sweden

3

Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON

4

Department of Radiology, McMaster University, Hamilton, ON

S. Maghsoudlou

Abstract Objective: A classification model based on preterm birth clinical presentations (phenotypes) was proposed at the International Conference on Prematurity and Stillbirth, with calls for validation. This study sought to determine the distribution of clinical phenotypes of preterm birth among nulliparous women, their corresponding associations with maternal characteristics, and the odds ratios (ORs) of preterm Caesarean section and other adverse outcomes. Methods: A population-based cohort study was performed of all nulliparous women with singleton pregnancies (>20 weeks) who gave birth in a hospital in Ontario between 2012 and 2014. Logistic regression models were used to estimate adjusted ORs (Canadian Task Force Classification II-2). Results: Among 113 942 nulliparous women, 6.1% delivered at <37 weeks, at a mean gestational age of 33.9 weeks. Of those women, 34.1% did not meet the criteria for the presence of any clinical phenotype; 42.3% had one maternal, fetal, or placental condition; 22.3% had two clinical conditions; and 1.3% had three clinical conditions. The most common preterm birth phenotypes were worsening of maternal diseases (24.0%), intrauterine growth restriction (23.5%), and fetal distress (23.0%). Compared with preterm births without any significant clinical phenotype, those with maternal, fetal, or placental phenotypes were associated with Key Words: Preterm birth, prematurity, phenotyping, clinical presentations, risk factors, population-based, cohort study Corresponding author: Dr. Sarah McDonald, Departments of Obstetrics and Gynecology, Radiology, and Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON. [email protected] Competing interests: See Acknowledgements. Each author has indicated that they meet the journal’s requirements for authorship. Received on December 4, 2018 Accepted on February 6, 2019 Available online on April 30, 2019

increased odds of Caesarean section (adjusted ORs 2.70 [95% confidence interval [CI] 2.30−3.17], 1.66 [95% CI 1.36−2.03], and 6.49 [95% CI 4.29−9.80], respectively). Conclusion: Approximately two thirds of nulliparous preterm births were grouped into distinct clinical phenotypes. This study demonstrated that outcomes varied across phenotypes, thus providing evidence of benefit for the phenotypic classification model.

Résumé
le de classification base  sur le tableau clinique Objectif : Un mode  notype) des accouchements pre mature s a e  te  soumis pour (phe
la confe rence internationale sur la pre  maturite  et la validation a  . Cette e tude visait a
de terminer la distribution des mortinatalite notypes cliniques lie s aux accouchements pre  mature  s chez les phe ristiques maternelles, et nullipares, leur association avec les caracte  sariennes avant terme et les rapports de cotes (RC) pour les ce sirables. d’autres issues inde  une e tude de cohorte base  e sur Méthodologie : Nous avons effectue  du la population regroupant toutes les nullipares qui ont accouche ^pital de l’Ontario (>20 seul enfant qu’elles portaient dans un ho
les de re gression semaines) entre 2012 et 2014. Des mode te  utilise s pour estimer les RC ajuste  s (classification logistique ont e tude canadien). II-2 du Groupe d’e Résultats : Parmi les 113 942 nullipares incluses, 6,1 % avaient  avant 37 semaines, en moyenne a
33,9 semaines. De ce accouche pondaient aux crite
res d’aucun phe notype groupe, 34,1 % ne re sentaient une pathologie maternelle, fœtale ou clinique; 42,3 % pre placentaire; 22,3 % avaient deux pathologies cliniques; et 1,3 % en notypes les plus commune ment lie s a
la avaient trois. Les phe maturite e taient l’aggravation des maladies maternelles pre  rin (23,5 %) et la de  tresse (24,0 %), le retard de croissance intra-ute mature es fœtale (23,0 %). Comparativement aux naissances pre notype clinique notable, les cas de pathologie maternelle, sans phe taient associe s a
une augmentation du fœtale ou placentaire e sarienne (RC ajuste s respectifs : 2,70 [intervalle de risque de ce
95 % : 2,30-3,17]; 1,66 [IC a
95 % : 1,36-2,03]; confiance [IC] a
95 % : 4,29-9,80]). et 6,49 [IC a mature s Conclusion : Environ les deux tiers des accouchements pre
re nullipare ont e te  regroupe s avec deux phe  notypes par une me tude de montre que les issues varient cliniques distincts. Cette e

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notypes, prouvant ainsi qu’utiliser un mode
le de selon les phe notypes a des avantages. classification par phe © 2019 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.

J Obstet Gynaecol Can 2019;41(10):1423−1432 https://doi.org/10.1016/j.jogc.2019.02.005

INTRODUCTION

reterm birth (before 37 completed weeks of gestation) is the leading cause of neonatal and infant death.1,2 Moreover, it is a major determinant of childhood mortality and short- and long-term morbidity.3,4 The World Health Organization notes that 15 million babies worldwide are born preterm every year.2 Although the rates of other adverse pregnancy outcomes have substantially improved, the frequency of preterm birth has remained stable in many developed countries, including Canada.4,5 The frequency of preterm birth varies from approximately 5% of live births in northern Europe, 7.8% in Canada, and 9.6% in the United States to up to 18% in some low- and middle-income countries.6−8

P

Rather than the traditional approach of examining preterm birth by risk factors, a newer approach classifies it instead by distinct clinical characteristics.9,10 This comprehensive and uniform classification of preterm birth that is based on clinical presentations was developed at the International Conference on Prematurity and Stillbirth convened by the Global Alliance to Prevent Prematurity and Stillbirth11 to “phenotype” preterm birth in terms of one or more maternal, fetal, and placental conditions, combined with two other components: signs of initiation of parturition and pathways to delivery. The goals of phenotyping are to apply a standard clinical classification of preterm birth to all cases, to improve birth surveillance across populations, to enhance understanding of variation by time and region, and consequently to develop effective interventions.12−15 Our study investigated the prevalence of clinical phenotypes of preterm birth in a large, population-based cohort and their corresponding associations with maternal characteristics and key perinatal indicators such as Caesarean section delivery, low Apgar score, and neonatal death. As a secondary aim, we also investigated the differences in clinical presentations between spontaneous and caregiver-initiated preterm births.

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MATERIALS AND METHODS

A population-based cohort study was performed using information on all in-hospital births of nulliparous women with singleton pregnancy (after 20 weeks gestation) between April 1, 2012 and March 31, 2014, using Ontario’s Better Outcomes Registry and Network.16 Gestational age of birth was estimated by ultrasound examination or calculated from the first day of the last menstrual period. On the basis of gestational age, preterm births were stratified into four groups: <28 weeks, 280 to 316 weeks, 320 to 336 weeks, and 340 to 366 weeks. According to the phenotypic classification model, each preterm birth was categorized into one or more maternal, fetal, or placental condition, with each condition including various phenotypes defined by explicit clinical characteristics.13 Maternal conditions were categorized into extrauterine infection, clinical chorioamnionitis (clinically suspected intrauterine infection), worsening maternal diseases, preeclampsia, eclampsia, and uterine rupture. Fetal conditions included antepartum and intrauterine fetal death, intrauterine growth restriction, intrauterine distress, anomalies, anemia, polyhydramnios, and oligohydramnios. Finally, placental conditions included abruption, placenta previa, and other placental abnormalities. Preterm births could be categorized into one or more phenotypes within a clinical condition or across different conditions. The second component of the phenotyping model involved classification by the presence of “evidence of initiation of parturition” (cervical signs, preterm premature rupture of membranes, bleeding, and unknown initiation) or the absence of any sign of parturition. Bishop score ≥3 and isoimmunization or alloimmunization were used as surrogates for cervical signs of initiation of parturition and fetal anemia, respectively. The third and final component involved characterization on the basis of “the pathway of delivery”: spontaneous preterm births (regular or augmented contractions) or caregiver-initiated preterm births (clinically mandated, discretionary, no clinical indication, or pregnancy termination). Comprehensive definitions and a detailed list of variables are provided in online Table A. Maternal characteristics included age (≤19, 20−29, 30−34, and ≥35), history of abortion, gestational hypertensive disorders (none; gestational hypertension; preeclampsia; superimposed preeclampsia; severe preeclampsia complicated by hemolysis, elevated liver enzymes, and low platelets [HELLP]; and eclampsia), mental health concerns (one or more of anxiety, depression, bipolar disorder, addiction, and others), maternal smoking (none, ex-smoker, and smoker), drug abuse (one or more of marijuana, opioids,

Phenotypic Classification of Preterm Birth Among Nulliparous Women: A Population-Based Cohort Study

cocaine, and others), and alcohol consumption during pregnancy (exposed and unexposed). Maternal body mass index (BMI) (<18.5 kg/m2, 18.5−24.9 kg/m2, 25−29.9 kg/m2, 30−34.9 kg/m2 and ≥35 kg/m2) and height (<150 cm, 150−159 cm, 160−169 cm, and ≥170 cm) were also applied as categorical and continuous variables. Gestational weight gain was classified according to the Institute of Medicine’s recommendations, adopted by Health Canada, which take into account gestational age at birth.17,18 Plausible values of gestational weight gain (¡30 to 50 kg), maternal BMI (15−70 kg/m2), pre-pregnancy weight (40−150 kg), and maternal height (140−200 cm) were included in the analysis when available. Information on socioeconomic status was based on the neighbourhoods’ median household income. Statistical Analysis

We used chi-square tests to compare proportions and t tests to compare means of variables. We calculated the odds of preterm Caesarean section and key adverse infant outcomes such as 5-minute Apgar score <4 and neonatal death for each phenotype of preterm birth by using logistic regression models. We also calculated the associations between preterm birth phenotypes and maternal characteristics, including anthropometric indexes, drug abuse history, and socioeconomic status, by using logistic regression

models. Implausible values, such as maternal BMI (<15 or >70 kg/m2), pre-pregnancy weight (<40 or >150 kg), and height (<140 or >200 cm), were considered outliers. Because exclusion of missing data may result in selection bias, multiple imputation with five imputations was used for the logistic regression analyses in the event of missing recorded values or outliers, including maternal age (3.0%), pre-pregnancy maternal BMI (15.4%), and mother’s height (13.4%).19 A sensitivity analysis was also performed restricting the analysis to women without any missing data or outliers. In addition, we conducted sensitivity analyses excluding fetal distress and placenta previa from the outcome of Caesarean section. Statistical significance was defined as P values <0.05 (two-tailed). The study was approved by the Hamilton Integrated Research Ethics Board before commencement. SAS software version 9.4 was used for analysis (SAS Institute, Cary, NC). RESULTS

The incidence of preterm birth (n = 6983) in nulliparous women (N = 113 919) was 6.13% (Figure 1). Online Table B presents the association between preterm birth and maternal characteristics. Maternal age between 30 and 34 and older than 35 was associated with higher odds of preterm birth compared with maternal age between 18.5 and 30. Obesity

Figure 1. Flow diagram of all hospital births in nulliparous women with singleton pregnancies (>20 weeks) in Ontario between 2012 and 2014.

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Table 1. Preterm birth phenotypes by gestational ages among nulliparous women Preterm birth Gestational age, weeks Phenotyping of preterm birth

All N (%)a

Continuous mean (SD)

<28 n (%)b

28−31 n (%)b

32−33 n (%)b

34−36 n (%)b

All preterm

6983 (100)

33.9 (3.22)

423 (6.1)

500 (7.2)

766 (11.0)

5294 (75.8)

Significant maternal conditions

2860 (41.0)

34.0 (2.99)

162 (5.7)

242 (8.5)

322 (11.3)

2134 (74.6)

1134 (16.2)

34.2 (3.03)

64 (5.6)

72 (6.3)

104 (9.2)

894 (78.8)

22 (0.3)

31.4 (4.58)

6 (27.3)

3 (13.6)

2 (9.1)

11 (50.0)

Worsening maternal diseases

1673 (24.0)

33.9 (3.06)

100 (6.0)

158 (9.4)

200 (12.0)

1215 (72.6)

Preeclampsia

730 (10.4)

34.0 (2.67)

27 (3.7)

71 (9.7)

107 (14.7)

525 (71.9)

Extrauterine infection Clinical chorioamnionitis

Eclampsia Significant fetal conditions Fetal death

185 (2.6)

33.8 (2.93)

13 (7.0)

28 (15.1)

29 (15.7)

115 (62.2)

3025 (43.3)

33.6 (3.39)

247 (8.2)

293 (9.7)

400 (13.2)

2085 (68.9)

158 (2.3)

27.7 (5.72)

79 (50.0)

23 (14.6)

19 (12.0)

37 (23.4)

Intrauterine growth restriction

1641 (23.5)

33.5 (3.16)

120 (7.3)

193 (11.8)

239 (14.6)

1089 (66.4)

Intrauterine fetal distress

1604 (23.0)

34.0 (2.75)

83 (5.2)

143 (8.9)

206 (12.8)

1172 (73.1)

480 (6.9)

33.1 (3.69)

53 (11.0)

52 (10.8)

79 (16.5)

296 (61.7)

Fetal anomaly Fetal anemia

4 (0.1)

34.5 (2.38)

0 (0.0)

1 (25.0)

0 (0.0)

3 (75.0)

Polyhydramnios

49 (0.7)

33.9 (2.57)

3 (6.1)

4 (8.2)

9 (18.4)

33 (67.3)

Oligohydramnios

179 (2.6)

34.3 (2.93)

8 (4.5)

13 (7.3)

21 (11.7)

137 (76.5)

455 (6.5)

33.2 (3.45)

41 (9.0)

68 (14.9)

70 (15.4)

276 (60.7)

Placental abruption

205 (2.9)

32.0 (3.84)

32 (15.6)

39 (19.0)

42 (20.5)

92 (44.9)

Placenta previa

180 (2.6)

34.2 (2.48)

6 (3.3)

19 (10.6)

22 (12.2)

133 (73.9)

Other placental abnormalities

90 (1.3)

34.4 (2.70)

6 (6.7)

13 (14.4)

10 (11.1)

61 (67.8)

No significant clinical conditions

2381 (34.1)

34.4 (2.70)

105 (4.4)

104 (4.4)

203 (8.5)

1969 (82.7)

Maternal conditions only

1333 (19.1)

34.5 (2.55)

53 (4.0)

78 (5.9)

130 (9.8)

1072 (80.4)

Fetal conditions only

1438 (20.6)

33.6 (3.48)

127 (8.8)

111 (7.7)

198 (13.8)

1002 (69.7)

182 (2.6)

33.5 (3.37)

14 (7.7)

21 (11.5)

26 (14.3)

121 (66.5)

1376 (19.7)

33.7 (3.26)

97 (7.0)

139 (10.1)

165 (12.0)

975 (70.9)

Maternal and placental conditions

62 (0.9)

34.2 (3.16)

4 (6.5)

4 (6.5)

7 (11.3)

47 (75.8)

Fetal and placental conditions

122 (1.7)

32.6 (3.56)

15 (12.3)

22 (18.0)

17 (13.9)

68 (55.7)

Three conditions

89 (1.3)

32.4 (3.44)

8 (9.0)

21 (23.6)

20 (22.5)

40 (44.9)

No evidence of initiation

1552 (22.2)

34.0 (3.09)

75 (4.8)

152 (9.8)

227 (14.6)

1098 (70.7)

Evidence of initiation parturition

5421 (77.6)

34.0 (2.9)

347 (6.4)

348 (6.4)

536 (9.9)

4190 (77.3)

Cervical signs only

292 (5.4)

34.6 (3.02)

15 (5.1)

8 (2.7)

14 (4.8)

255 (87.3)

PPROM only

1395 (25.7)

33.7 (3.11)

90 (6.5)

123 (8.8)

190 (13.6)

992 (71.1)

112 (2.1)

31.6 (4.15)

25 (22.3)

16 (14.3)

20 (17.9)

51 (45.5)

566 (10.4)

35.2 (1.70)

9 (1.6)

1 (0.2)

13 (2.3)

543 (95.9)

Significant placental conditions

Overall

Placental conditions only Maternal and fetal conditions

Signs of initiation of parturition

Bleeding only Cervical signs and PPROM PPROM and bleeding

1 (0.0)

33 (NA)

8 (33.3)

10 (41.7)

3 (12.5)

3 (12.5)

Cervical sign and bleeding

24 (0.4)

28.8 (4.15)

0 (0.0)

0 (0.0)

1 (100)

0 (0.0)

All conditions Unknown initiated Missing

2 (0.0)

35 (NA)

0 (0.0)

0 (0.0)

0 (0.0)

2 (100)

3029 (55.9)

34.1 (3.11)

200 (6.6)

190 (6.3)

295 (9.7)

2344 (77.4)

10 (0.1) (continued)

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Phenotypic Classification of Preterm Birth Among Nulliparous Women: A Population-Based Cohort Study

Table 1. (Continued) Preterm birth Gestational age, weeks Phenotyping of preterm birth

All N (%)a

Continuous mean (SD)

<28 n (%)b

28−31 n (%)b

32−33 n (%)b

34−36 n (%)b

3494 (50.0)

34.2 (2.79)

171 (4.9)

256 (7.3)

393 (11.2)

2674 (76.5)

Pathway to delivery Caregiver initiated Clinically mandated

3358 (48.1)

34.3 (2.61)

142 (4.2)

245 (7.3)

377 (11.2)

2594 (77.2)

Clinically discretionary

3 (0.0)

34.0 (1.73)

0 (0.0)

0 (0.0)

2 (66.7)

1 (33.3)

No clinical indication

40 (0.6)

35.0 (2.56)

2 (5.0)

0 (0.0)

0 (0.0)

38 (95.0)

Pregnancy termination

93 (1.3)

30.7 (5.52)

27 (29.0)

11 (11.8)

14 (15.1)

41 (44.1)

3489 (50.0)

33.3 (3.71)

252 (7.2)

244 (7.0)

373 (10.7)

2620 (75.1)

Regular contractions

1604 (23.0)

34.3 (2.62)

165 (10.3)

139 (8.7)

213 (13.3)

1087 (67.8)

Augmented

1885 (27.0)

34.3 (2.76)

87 (4.6)

105 (5.6)

160 (8.5)

1533 (81.3)

Spontaneous

NA: standard deviations are not applicable due to the data availability. PPROM: preterm premature rupture of membranes. a

The proportion of preterm birth phenotypes among all preterm births in nulliparous women (column percent).

b

Distribution of preterm birth phenotypes categorized by gestational age (row percent).

Figure 2. Gestational age at birth and phenotypic classification of preterm birth. The cumulative proportion (%) of the gestational age at birth in weeks of the preterm birth phenotypes (no significant clinical condition, maternal fetal, placental condition, two, and three clinical conditions).

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was more common among women with a preterm birth compared with women with a term birth (14.6% vs. 13.2%, respectively). Compared with mothers who gave birth at term, those in the preterm group were shorter and had higher rates of mental health concerns, smoking, and drug abuse during pregnancy. Approximately 34% of preterm births were classified as idiopathic entities (spontaneous preterm delivery without any significant clinical condition). Most preterm births (65.9%) met phenotypic criteria for at least one maternal, fetal, or placental condition: 42.3% met the criteria for

one, 22.3% for two, and 1.3% for all three types of conditions. Following the one-third of preterm births without any significant clinical condition (34.1%), the most common significant clinical conditions were worsening of maternal diseases, intrauterine growth restriction, and fetal distress. Three-quarters (75.8%) of preterm births occurred between 34 and 37 weeks gestation (Table 1). Compared with pregnancies without any significant clinical conditions or those with only the presence of a maternal condition, women with pregnancies with fetal, placental, or more than one clinical condition tended to deliver at an earlier gestational age (Figure 2).

Table 2. Preterm birth phenotypes based on signs of initiation of parturition and pathway to delivery among nulliparous women Preterm birth Phenotyping of preterm birth All preterm

Initiation of parturition n (%)b

Spontaneous delivery n (%)c

6983 (100)

5421 (77.6)

3489 (50.0)

No significant clinical conditions

2381 (34.1)

2285 (96.0)

1748 (73.4)

Maternal conditions only

1333 (19.1)

1020 (76.5)

624 (46.8)

Fetal conditions only

1438 (20.6)

1093 (76.0)

656 (45.6)

182 (2.6)

104 (57.1)

44 (24.2)

Placental conditions only Maternal and fetal conditions

1376 (19.7)

773 (56.2)

367 (26.7)

Maternal and placental conditions

62 (0.9)

36 (58.1)

15 (24.2)

Fetal and placental conditions

122 (1.7)

69 (56.6)

20 (16.4)

Three conditions

89 (1.3)

41 (46.1)

15 (16.9)

2860 (41.0)

1870 (65.4)

1021 (35.7)

1134 (16.2)

899 (79.3)

536 (47.3)

Significant maternal conditions Extrauterine infection Clinical chorioamnionitis

22 (0.3)

20 (90.9)

0 (0.0)

Worsening maternal diseases

1673 (24.0)

1115 (66.6)

611 (36.5)

Preeclampsia

730 (10.4)

201 (27.5)

22 (3.0)

Eclampsia Significant fetal conditions Fetal death

185 (2.6)

29 (15.7)

5 (2.7)

3025 (43.3)

1976 (65.3)

1058 (35.0)

158 (2.3)

81 (51.3)

41 (25.9)

Intrauterine growth restriction

1641 (23.5)

942 (57.4)

537 (32.7)

Intrauterine fetal distress

1604 (23.0)

1047 (65.3)

450 (28.1)

480 (6.9)

329 (68.5)

175 (36.5)

Fetal anomaly Fetal anemia

4 (0.1)

4 (100.0)

1 (25.0)

Polyhydramnios

49 (0.7)

25 (51.0)

11 (22.4)

Oligohydramnios

179 (2.6)

65 (36.3)

19 (10.6)

455 (6.5)

250 (54.9)

94 (20.7)

Placental abruption

205 (2.9)

140 (68.3)

52 (25.4)

Placenta previa

180 (2.6)

69 (38.3)

9 (5.0)

Other placental abnormalities

90 (1.3)

58 (64.4)

35 (38.9)

Significant placental conditions

a

All n (%)a

The proportion of different phenotypes among all preterm births in nulliparous women (column percent).

b

Distributions of preterm birth phenotypes categorized according to having signs of initiation of parturition (row percent).

c

Distributions of preterm birth phenotypes categorized according to pathway to delivery (row percent).

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Table 3. Distribution of preterm birth categories based on evidence of initiation of parturition among different pathways to delivery among nulliparous women Evidence of the initiation of parturition Pathway to delivery

All n (%)a

No n (%)a

Yes n (%)a

Caregiver initiated

3494 (50.0)

1550 (99.9)

1936 (35.7)

3358 (48.1)

1469 (94.7)

1881 (34.7)

Clinically discretionary

3 (0.0)

2 (0.1)

1 (0.0)

No clinical indication

40 (0.6)

18 (1.2)

22 (0.4)

Pregnancy termination

93 (1.3)

61 (3.9)

32 (0.6)

Clinically mandated

Spontaneous

3489 (50.0)

2 (0.1)

3485 (64.2)

Regular contraction

1604 (23.0)

0 (0.0)

1604 (29.6)

Augmented

1885 (27.0)

2 (0.1)

1881 (34.7)

a

Distributions of pathways to delivery categorized by initiation of parturition (column percent).

Evidence of initiation of parturition was present in 77.6% of preterm births. Half of preterm births were caregiver initiated, and half were spontaneous. Preterm births without any significant maternal, fetal, or placental clinical conditions had high frequencies of signs of initiation of parturition (96.0%) and spontaneous delivery (73.4%) (Table 2). In contrast, pregnancies that met the criteria for one or more clinical conditions often resulted in caregiverinitiated preterm birth. Almost all pregnancies with no evidence of initiation of parturition ended with a caregiver-initiated preterm delivery. In contrast, 64.2% of pregnancies with evidence of parturition ended with a spontaneous delivery (Table 3). The presence of fetal conditions was associated with at least two-fold increased odds of low Apgar score and neonatal death, compared with pregnancies without any significant clinical condition (Table 4). Compared with preterm births with no significant clinical conditions, preterm births that met the criteria for one, two, or three (maternal, fetal, or placental) conditions were all significantly associated with increased odds of Caesarean section. This association was stronger among phenotypes with placental conditions. The associations among clinical conditions with Caesarean section were attenuated but remained significant when fetal distress and placenta previa were excluded from fetal and placental conditions, respectively (Table 4). A sensitivity analysis of non-imputed data was performed, with virtually unchanged results (data available on request). The frequencies and adjusted odds ratios of maternal characteristics associated with phenotypes of preterm birth are presented in online Tables C and D. Preterm births without

any significant maternal, fetal, or placental clinical conditions were significantly associated with short maternal stature, inadequate gestational weight gain, and drug abuse during pregnancy (online Table D). DISCUSSION

The phenotypic classification system13−15 was applied in this study to describe a large, population-based cohort of nulliparous preterm births. Nearly two-thirds of all preterm births had one or more of the three main distinct maternal, fetal, or placental clinical conditions. Approximately 23% of all preterm births had two or more clinical conditions. This study demonstrated that risk factors varied across the phenotypes of preterm birth. Among preterm births, those without a significant maternal, fetal, or placental clinical condition tended to deliver later and spontaneously. The risks of low Apgar score and Caesarean section also varied with the clinical phenotype of preterm birth. The associations did not change notably when fetal distress and placenta previa were excluded from the analysis to account for bias by indication. The findings of previous studies using the preterm birth phenotype classification system were consistent with and expanded on by our results.20−22 We explored the associations among preterm birth phenotypes with maternal characteristics, preterm Caesarean section, and low Apgar score. The odds of Caesarean section and low Apgar score were related to the number of the clinical phenotypes of preterm birth. Barros et al. found significant associations between preterm birth phenotype and risk of neonatal death, neonatal intensive care unit admission ≥7 days, and infant size at birth in a multiethnic cross-sectional study of 5828 preterm births.20 Manuck et al. found differences in the prevalence of preterm birth phenotypes between African American and White women in a multicenter study of 1025 singleton spontaneous preterm births.21 In addition to our exploration of new outcomes, a strength of our study is the population-based cohort design using information from a large provincial database, which allowed us to stratify our sample and examine nulliparous women with adequate statistical power. Limitations of our study include a lack of data on maternal trauma, intrauterine invasive procedures during pregnancy, fetal-maternal hemorrhage, and histopathological examination of the placenta. Socioeconomic status was represented by neighbourhood median household incomes because patientlevel data were not available. Bishop score ≥3 and isoimmunization or alloimmunization were used as surrogates of “cervical signs of initiation of parturition” and “fetal

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Table 4. Preterm birth phenotypes and risks of preterm Caesarean section and adverse pregnancy outcomes among nulliparous women Alla

Subjects

n (%)

n (%)

Crude odds ratiob OR

(95% CI)

Adjusted odds ratiob OR

(95% CI)

5-minute Apgar score <4 (among live preterm births) Preterm birth phenotypes No significant clinical conditions

2376 (35.1)

44 (28.9)

Maternal conditions

1332 (19.7)

20 (13.2)

0.77

(0.49−1.22)

0.90

(0.51−1.56)

Fetal conditions

1322 (19.5)

33 (21.7)

1.80

(1.24−2.61)

2.03

(1.29−3.20)

Placental conditions

Reference

180 (2.7)

5 (3.3)

1.22

(0.52−2.87)

0.84

(0.31−2.30)

1310 (19.3)

40 (26.3)

1.61

(1.12−2.32)

1.87

(1.21−2.89)

Maternal and placental conditions

62 (0.9)

2 (1.3)

1.16

(0.28−4.84)

0.78

(0.14−4.29)

Fetal and placental conditions

111 (1.6)

5 (3.3)

3.37

(1.70−6.71)

2.64

(1.20−5.84)

Three conditions

81 (1.2)

3 (2.0)

2.08

(0.78−5.59)

1.74

(0.59−5.11)

0.77

(0.49−1.22)

0.92

(0.51−1.67)

Maternal and fetal conditions

Preterm birth phenotypes (fetal distress and placental previa were excluded) No significant clinical conditions

2376 (47.2)

44 (38.6)

Maternal conditions

1332 (26.5)

20 (17.5)

590 (11.7)

19 (16.7)

2.34

(1.52−3.62)

2.45

(1.39−4.31)

91 (1.8)

4 (3.5)

2.03

(0.80−5.18)

0.73

(0.23−2.37)

Fetal conditions Placental conditions Maternal and fetal conditions

Reference

567 (11.3)

23 (20.2)

1.98

(1.27−3.08)

2.50

(1.41−4.41)

Maternal and placental conditions

33 (0.7)

2 (1.8)

2.20

(0.52−9.38)

0.97

(0.15−6.47)

Fetal and placental conditions

26 (0.5)

1 (0.9)

7.52

(2.89−19.6)

4.02

(1.20−13.4)

Three conditions

20 (0.4)

1 (0.9)

1.66

(0.22−12.5)

1.80

(0.20−16.0)

0.48

(0.27−0.86)

0.50

(0.24−1.03)

Neonatal death (among live preterm births) Preterm birth phenotypes No significant clinical conditions

2376 (35.1)

40 (44.4)

Maternal conditions

1332 (19.7)

9 (10.0)

Fetal conditions

1322 (19.5)

19 (21.1)

2.00

(1.34−2.99)

3.00

(1.74−5.16)

180 (2.7)

4 (4.4)

0.96

(0.34−2.68)

0.58

(0.16−2.05)

Placental conditions Maternal and fetal conditions

Reference

1310 (19.3)

14 (15.6)

1.17

(0.76−1.81)

1.50

(0.87−2.60)

Maternal and placental conditions

62 (0.9)

2 (2.2)

1.37

(0.33−5.76)

0.93

(0.15−5.84)

Fetal and placental conditions

111 (1.6)

1 (1.1)

2.84

(1.31−6.16)

2.63

(1.04−6.64)

Three conditions

81 (1.2)

1 (1.1)

2.37

(0.88−6.37)

2.73

(0.89−8.39)

Preterm birth phenotypes (fetal distress and placental previa were excluded) No significant clinical conditions

2376 (47.2)

40 (50.6)

Maternal conditions

1332 (26.5)

9 (11.4)

590 (11.7)

15 (19.0)

91 (1.8)

4 (5.1)

Fetal conditions Placental conditions Maternal and fetal conditions

Reference 0.48

(0.27−0.86)

0.49

(0.23−1.05)

2.73

(1.72−4.33)

4.00

(2.05−7.81)

1.91

(0.67−5.40)

0.62

(0.16−2.39)

567 (11.3)

8 (10.1)

1.11

(0.62−2.00)

1.25

(0.57−2.74)

Maternal and placental conditions

33 (0.7)

2 (2.5)

2.61

(0.61−11.2)

1.19

(0.16−8.99)

Fetal and placental conditions

26 (0.5)

1 (1.3)

9.31

(3.69−23.5)

7.22

(2.01−25.9)

Three conditions

20 (0.4)

0 (0.0)

0.00

(0.00−0.00)

0.00

(0.00−0.00) (continued)

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Phenotypic Classification of Preterm Birth Among Nulliparous Women: A Population-Based Cohort Study

Table 4. (Continued) Alla

Subjects

n (%)

n (%)

Crude odds ratiob OR

(95% CI)

2.64

(2.24−3.11)

Adjusted odds ratiob OR

(95% CI)

Caesarean section Phenotyping of preterm birth No significant clinical conditions

2381 (34.1)

334 (14.5)

Maternal conditions

1333 (19.1)

401 (17.4)

Fetal conditions

1438 (20.6)

523 (22.7)

3.50

182 (2.6)

134 (5.8)

17.10

Placental conditions Maternal and fetal conditions

Reference 2.70

(2.29−3.17)

(2.99−4.10)

3.25

(2.79−3.80)

(12.1−24.3)

16.30

(11.6−22.8)

1376 (19.7)

712 (30.9)

6.57

(5.62−7.69)

6.46

(5.53−7.53)

Maternal and placental conditions

62 (0.9)

43 (1.9)

13.90

(7.98−24.1)

12.30

(7.27−21.0)

Fetal and placental conditions

122 (1.7)

93 (4.0)

19.70

(12.8−30.3)

16.40

(11.2−23.9)

Three conditions

89 (1.3)

62 (2.7)

14.10

(8.83−22.4)

14.80

(9.57−22.8)

Phenotyping of preterm birth (fetal distress and placental previa were excluded) No significant clinical conditions

2381 (45.6)

334 (26.9)

Maternal conditions

1333 (25.5)

401 (32.3)

2.64

(2.24−3.11)

2.70

(2.30−3.17)

Fetal conditions

697 (13.3)

166 (13.4)

1.92

(1.55−2.36)

1.66

(1.36−2.03)

Placental conditions

Reference

93 (1.8)

48 (3.9)

6.54

(4.28−9.98)

6.49

(4.29−9.80)

628 (12.0)

255 (20.5)

4.19

(3.44−5.10)

4.01

(3.31−4.86)

Maternal and placental conditions

33 (0.6)

15 (1.2)

5.11

(2.55−10.2)

4.62

(2.32−9.19)

Fetal and placental conditions

32 (0.6)

15 (1.2)

5.41

(2.67−10.9)

5.54

(3.03−10.1)

Three conditions

26 (0.5)

8 (0.6)

2.72

(1.17−6.31)

3.22

(1.42−7.30)

Maternal and fetal conditions

Bold font indicates significant associations. a

For neonatal death and 5-minute Apgar score <4, the study was restricted to live births.

Odds ratios were calculated based on imputed data with five imputations. Adjusted odds ratios were calculated with adjustment for gestational age at birth (as a continuous variable). b

anemia,” respectively, which Villar et al. defined in the phenotypic classification model.13 Finally, information on maternal smoking, alcohol consumption, and drug abuse during pregnancy were obtained by self-report and hence are likely underestimates, as may be the case for clinical chorioamnionitis as well. CONCLUSION

In this population-based cohort study implementing the preterm birth phenotypic system, approximately two-thirds of preterm births presented with the most common phenotypes: worsening of maternal diseases, intrauterine growth restriction, and fetal distress. The mean gestational age at birth, risks of maternal and fetal morbidities, and associations of risk factors varied across different preterm birth clinical conditions. We found that preterm birth conditions were independently associated with maternal and neonatal outcomes. This finding contributes to the literature on the utility of the phenotypic model in surveillance across populations.

Acknowledgements

This study was supported by a Ministry of Health and Long-term Care Academic Funding Plan Innovation Fund Grant to the Hamilton Academic Health Sciences Organization Innovation Fund. Dr. Beyene holds the John D. Cameron Endowed Chair in Determinants of Chronic Diseases, McMaster University. Dr. McDonald is supported by a Canadian Institutes of Health Research Canada Research Chair (950-229920). None of the funding agencies had any role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The authors would like to thank Kristen Viaje and Sugee Korale Liyanage for their administrative contributions to this manuscript. SUPPLEMENTARY DATA

Supplementary data related to this article can be found at https://doi.org/10.1016/j.jogc.2019.02.005.

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REFERENCES

12. Esplin M. The importance of clinical phenotype in understanding and preventing spontaneous preterm birth. Am J Perinatol 2016;33:236–44.

1. Liu L, Johnson HL, Cousens S, et al. Global, regional, and national causes of child mortality: an updated systematic analysis for 2010 with time trends since 2000. Lancet 2012;379:2151–61.

13. Villar J, Papageorghiou AT, Knight HE, et al. The preterm birth syndrome: a prototype phenotypic classification. Am J Obstet Gynecol 2012;206:119–23.

2. Kramer MS. The contribution of mild and moderate preterm birth to infant mortality. JAMA 2000;284:843.

14. Goldenberg RL, Gravett MG, Iams J, et al. The preterm birth syndrome: issues to consider in creating a classification system. Am J Obstet Gynecol 2012;206:113–8.

3. Crump C, Sundquist K, Sundquist J, et al. Gestational age at birth and mortality in young adulthood. JAMA 2011;306:1233–40. 4. Goldenberg RL, Culhane JF, Iams JD, et al. Epidemiology and causes of preterm birth. Lancet 2008;371:75–84. 5. Statistics Canada. Preterm Live Births in Canada, 2000 to 2013. Health Fact Sheets. Ottawa: Statistics Canada; 2016. Available at: http://www.statcan.gc. ca/pub/82-625-x/2016001/article/14675-eng.htm. Accessed December 1, 2017. 6. Blencowe H, Cousens S, Oestergaard MZ, et al. National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications. Lancet 2012;379:2162–72. 7. Chang HH, Larson J, Blencowe H, et al. Preventing preterm births: analysis of trends and potential reductions with interventions in 39 countries with very high human development index. Lancet 2013;381:223–34. 8. Martin JA, Hamilton BE, Osterman MJK, et al. Births: final data for 2015. Natl Vital Stat Rep 2017;66:1. 9. Villar J, Abalos E, Carroli G, et al. Heterogeneity of perinatal outcomes in the preterm delivery syndrome. Obstet Gynecol 2004;104:78–87.

15. Kramer MS, Papageorghiou A, Culhane J, et al. Challenges in defining and classifying the preterm birth syndrome. Am J Obstet Gynecol 2012;206:108–12. 16. BORN Ontario. Data Quality Framework. Ottawa: BORN Ontario; 2013. Available at: http://datadictionary.bornontario.ca/assets/documents/ Data%20Quality/BORN%20Ontario%20Data%20Quality%20Framework. pdf. Accessed March 27, 2019. 17. Health, Canada. Prenatal Nutrition. Ottawa: Health Canada; 2019. Available at: http://www.hc-sc.gc.ca/fn-an/nutrition/prenatal/index-eng.php. Accessed September 13, 2017. 18. Dzakpasu S, Fahey J, Kirby RS, et al. Contribution of prepregnancy body mass index and gestational weight gain to adverse neonatal outcomes: population attributable fractions for Canada. BMC Pregnancy Childbirth 2015;15:21. 19. Sterne JAC, White IR, Carlin JB, et al. Multiple imputation for missing data in epidemiological and clinical research: potential and pitfalls. BMJ 2009;338:b2393. 20. Barros FC, Papageorghiou AT, Victora CG, et al. The distribution of clinical phenotypes of preterm birth syndrome implications for prevention. JAMA Pediatr 2015;169:220–9.

10. Esplin MS, Manuck TA, Varner MW, et al. Cluster analysis of spontaneous preterm birth phenotypes identifies potential associations among preterm birth mechanisms. Am J Obstet Gynecol 2015;213. 429e1−9.

21. Manuck TA, Esplin MS, Biggio J, et al. The phenotype of spontaneous preterm birth: application of a clinical phenotyping tool. Am J Obstet Gynecol 2015;212:487.. e1−11.

11. Gravett MG, Rubens CE, Nunes TM. Global report on preterm birth and stillbirth (2 of 7): discovery science. BMC Pregnancy Childbirth 2010;10 (Suppl 1):S2.

22. Brown HK, Speechley KN, MacNab J, et al. Maternal, fetal, and placental conditions associated with medically indicated late preterm and early term delivery: a retrospective study. BJOG 2016;123:763–70.

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Supplemental Table A. Documentation on phenotyping of preterm birth method using BORN dataset Phenotypes

Villar’s definition

Our definition based on available data

Significant maternal conditions 1. Extra uterine infection

Significant maternal infective illness that is If the variable called "Infection and Pregnancy” does not associated with pyrexia and the correinclude “None” or “chorioamnionitis” and/ or if “labor and birth sponding clinical manifestations (e.g., baccomplications” included fever or “All indications for cesarean teremia, malaria, and pyelonephritis). section” were equal to herpes simplex or HIV infection or if “Pre-existing maternal health conditions” include “infection”, then extra uterine infection was equal to “YES”.

2. Clinical chorioamnionitis

Clinically suspected intrauterine infection, manifest by maternal fever and rupture of the membranes, plus 2 features from maternal tachycardia, uterine tenderness, purulent amniotic fluid, fetal tachycardia, and maternal leukocytosis.

3. Maternal trauma

A serious or critical bodily injury, wound, or We do not have any information on maternal trauma during shock (in turn defined as a failure of the cirpregnancy. culatory system to maintain adequate blood flow).

4. Worsening maternal diseases

Examples include worsening maternal carIf “Pre-existing maternal health conditions” includes “infection” diac, respiratory, or renal disease or hemoor “None” then “Worsening maternal diseases” was equal to “NO”. Otherwise, it was assumed “Yes”. If “All indications for dynamic instability that poses an cesarean section” was equal to “Maternal/Health Conditions” immediate, significant, or life-threatening or “All indications for induction of labor” was equal to “Materrisk to the mother/fetus. nal / Pre-existing maternal medical conditions” then “Worsening maternal diseases” was assumed “YES”.

5. Uterine rupture

A defect that occurs in the uterus and that involves the entire uterine wall; this is symptomatic and requires surgical intervention.

If “Labor and birth complications”, “Primary indication for induction”, or “All indications for cesarean section” were equal to “Uterine rupture”, then uterine rupture was assumed “Yes”.

6. Preeclampsia

Gestational hypertension with proteinuria of ≥300 mg in a 24-hour period or 2 readings of at least “++” on dipstick analysis of midstream or catheter urine specimens, if no 24- hour collection is available.

If “All indications for cesarean section”, “All indications for induction of labor”, or “Hypertension disorder in pregnancy” included Preeclampsia then Preeclampsia was assumed “Yes”.

7. Eclampsia

Convulsions (seizures) that occur in the presence of preeclampsia and have no other cause.

If “All indications for cesarean section”, “All indications for induction of labor”, or “Hypertension disorder in pregnancy” included Eclampsia, then Eclampsia was assumed “Yes”.

If either the variable "Infection and Pregnancy" includes “chorioamnionitis”, or the primary or all indications for cesarean section were equal to “suspected chorioamnionitis”, then extra chorioamnionitis was equal to “YES”.

Significant fetal conditions 1. Fetal death

Intrauterine fetal death before the onset of If the primary or all indications for induction of labor included labor (we recognize that, in some cases, it “fetal demise” or pregnancy outcome was equal to “stillbirth” will be difficult to distinguish between then fetal death was assumed “Yes”. recent antepartum and intrapartum deaths; however, in the consideration of the etiologic differences, efforts must be made to establish the timing of the death).

2. Intrauterine growth restriction

If complications of pregnancy or all indications for induction of Growth restriction (estimated fetal weight labor or all indications for cesarean section included “IUGR” ≤10th percentile) with abnormal umbilical artery blood flow, abnormal fetal heart rate, then intrauterine growth restriction was assumed “Yes”. or abnormal biophysical profile.

3. Intrauterine fetal distress

Abnormal fetal heart rate. Antepartum persistently reduced short-term variability or decelerations. Abnormal biophysical profile. Biophysical profile of ≤6/10.

If either labor and birth complications, primary or all indications for induction of labor, or cesarean section included “Atypical Surveillance” then Intrauterine fetal distress was assumed “Yes”.

We do not have any information on Infection/ inflammatory 4. Infection/inflammatory response Infection. Usually the presence of clinical chorioamnionitis with fetal tachycardia or response during pregnancy. neonatal sepsis. Fetal inflammatory response syndrome. Systemic fetal inflammation and elevated fetal plasma interleukin-6 levels. (continued)

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Supplemental Table A. (Continued) Phenotypes

Villar’s definition

Our definition based on available data

5. Invasive intrauterine procedures Invasive procedures that include prenatal We do not have any information on Invasive intrauterine prodiagnosis (e.g., amniocentesis, chorionic cedures during pregnancy. villus sampling), fetal blood sampling, and endoscopic procedures (e.g., laser ablation of placental vessels, fetoscopy). 6. Multiple fetuses

Multiple pregnancies subdivided into the number of fetuses and by chorionicity.

Our study was limited to singleton pregnancies.

7. Fetal anomaly

Fetal structural abnormality by ultrasound scanning or during the neonatal examination.

If the complication of pregnancy, primary indication or all indications for labor or cesarean sections included “Anomaly” then Fetal anomaly was assumed “Yes”.

8. Fetal anemia

Fetal anemia that is caused by immune fac- If primary or all indications for induction of labor or complicators that are suggested by (1) hematocrit or tions of pregnancy included “Isoimmunization/ Alloimmunihemoglobin concentration >2 SD below zation” then Fetal anemia was assumed “Yes”. the mean for gestational age or (2) middle cerebral artery Doppler peak systolic velocity of >1.5 multiples of the median.

9. Polyhydramnios

Excess amniotic fluid subjectively or objectively that is measured as amniotic fluid index above the 95th percentile for gestational age or a maximum vertical pool of at least 8 cm.

10. Oligohydramnios

Reduced amniotic fluid subjectively or objec- If primary or all indications for induction of labor or complicatively measured as amniotic fluid index tions of pregnancy included “Oligohydramnios” then Oligobelow the 5th percentile for gestational age hydramnios was assumed “Yes”. or a maximum vertical pool of <2 cm.

If primary or all indications for induction of labor or complications of pregnancy included “Polyhydramnios” then Polyhydramnios was assumed “Yes”.

Significant placental conditions 1. Histologic chorioamnionitis

We do not have any information on histologic chorioamnionitis The presence of inflammatory infiltrate of during pregnancy. neutrophils in the chorionic plate and extra placental membranes. Or any histologic evidence of vasculitis/infarction/ necrosis. Or other histologic/microscopic findings (e.g., villitis, thrombosis).

2. Placental abruption

Premature separation of the placenta from If primary or all indications of cesarean section or complicathe uterine wall that is diagnosed by a comtions of pregnancy included “Placental/Abruption”, then Plabination of vaginal bleeding, maternal cental abruption was assumed “Yes”,. abdominal pain, and a retro-placental blood clot at delivery.

3. Placenta previa

Implantation of the placenta over the internal If primary or all indications of cesarean section or complicaos of the cervix. tions of pregnancy included “Placenta previa”, then Placenta previa was assumed “Yes”.

4. Fetal-Maternal Hemorrhage

Evidence of fetal-maternal hemorrhage on the Kleihauer Betke and Neirhaus test.

We do not have any information on Fetal-Maternal Hemorrhage during pregnancy.

5. Other placental abnormalities

Placental abnormalities that may lead to or necessitate delivery (e.g., placental giant chorioangioma, circumvallate placenta).

If complications of pregnancy included “Placental Percreta”, “Placental Accreta” or “Placental Increta” or “Placental Other”, then other placental conditions was assumed “Yes”.

Signs of the initiation of parturition Evidence of initiation parturition 1). Cervical signs

Either: (Shortening of the uterine cervix on clinical and/or ultrasound examination OR Dilation of the uterine cervix on clinical examination) AND regular uterine contractions that lead to cervical effacement or dilation.

If cervical ripening prior to induction was equal to “None” and birth type was “Spontaneous Vaginal” or Bishop score was ≥ 3 then “Cervical signs” was assumed “Positive”. Only a total Bishop score, not the individual components are available.

(continued)

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Supplemental Table A. (Continued) Phenotypes

Villar’s definition

2). PPROM

Rupture of the amniotic membranes before the onset of labor at <39 weeks’ gestation.

If primary or all indications of induction for labor or complications of pregnancy included “PPROM” or “PROM”, then PPROM was assumed “Yes”.

3). Bleeding

Any evidence of bleeding from the uterus or cervix.

If pregnancy complications included “Bleeding” then Bleeding was assumed to be “Positive”.

4). Unknown

Cases in which it is not possible to establish the initial step in the parturition process.

If the type of labor was equal to "Spontaneous", then initiation of parturition was assumed to be “Unknown”.

No evidence of initiation

Our definition based on available data

Otherwise, we assumed there was no evidence of initiation. Pathway to delivery

Caregiver initiated 1. Clinically mandated

Cases in which the caregiver initiates delivIf the type of labor included “induced” or “cesarean section” ery because there is an immediate and sigand primary and all indications for induction of labor and for nificant or life threatening risk to the cesarean section were not equal to “Maternal Request”, mother/fetus (e.g., preterm delivery for “Accommodates Care Provider” or “Distance from birth hossevere maternal preeclampsia). pital/Safety”, then “Caregiver initiated” was assumed to be “Clinically mandated”.

2. Clinically discretionary

Cases in which the caregiver initiates delivIf the type of labor included “induced” or “cesarean section” and primary and all indications for induction of labor and for ery although there is no immediate or sigcesarean section were equal to “Distance from birth hospital/ nificant risk to the mother/fetus (there may Safety” then “Caregiver initiated” was assumed to be “Clinibe some evidence that delivery associated cally discretionary”. with a better outcome).

3. No clinical indications

Cases in which the caregiver initiates delivery for reasons (such as errors in gestational age estimation, the convenience of timing, precious fetus, maternal request) that were stated on or inferred from the medical records.

4. Pregnancy termination

Cases in which termination is caused for rea- If the type of labor included “induced” or “cesarean section” sons such as fetal abnormality, medical and primary and all indications for induction of labor and for contraindication to pregnancy, or maternal cesarean section were equal to “anomaly/ies”, “Fetal\Termirequest. nation Pregnancy” or “Fetal demise” then “Caregiver initiated” was assumed to be “Pregnancy termination”.

5. Unknown

Cases in which the caregiver initiates delivIf the type of labor included “induced” or “cesarean section” ery, but there is no documentation of any and primary and all indications for induction of labor or indication or supporting information of any cesarean section were “Not available ” then “Caregiver initiated” was assumed “Unknown\initiated”. indication, including a range of several less well understood social and personal factors that are seldom documented that could motivate a preterm birth.

If the type of labor included “induced” or “cesarean section” and primary and all indications for induction of labor and for cesarean section were equal to “Accommodates Care Provider” or “Maternal Request” then Caregiver initiated was assumed to be “No clinical indications”.

Spontaneous 6. Regular contractions

Regular contractions. Regular uterine conIf the type of labor did not include “induced” or “cesarean sectractions that lead to cervical effacement or tion” and augmentation was “None”, then Spontaneous was dilation. assumed to be “Regular contractions”

7. Augmented

Augmentation or stimulation; of uterine con- If the type of labor did not include “induced” or “cesarean sectractions by oxytocin; without spontaneous tion” and augmentation was not “None” then Spontaneous contraction. was assumed to be “Augmented”. Otherwise, Pathway of delivery was assumed to be “Missing”.

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Supplemental Table B. Maternal characteristics and risk of preterm birth among nulliparous women Term birth Maternal characteristics All subjects (113924)

N

(%)

Crude Odds RatiosA

Preterm birth N

106397 (93.39) 6983

(%)

Adjusted Odds Ratios A,B

A

P value

ORs

(95% CI)

ORs

(95% CI)

<0.0001

0.86

(0.77-0.97)

0.85

(0.73-0.98)

(6.13)

Maternal Age (years) ≤19

5551

(5.2)

239

(3.4)

20-29

51645 (48.5)

2774

(39.7)

30-34

33004 (31.0)

1967

(28.2)

1.08

(1.02-1.15)

1.13

(1.04-1.22)

≥35

14007 (13.2)

904

(12.9)

1.19

(1.11-1.27)

1.21

(1.101.33)

1.14

(1.04-1.26)

1.16

(1.02-1.31)

Reference

Body mass index (kg/m2) <18.5

5703

(5.4)

353

(5.1)

18.5-24.9

51184 (48.1)

2963

(42.4)

25-29.9

19466 (18. 3)

1297

(18.6)

1.17

(1.10-1.24)

1.13

(1.05-1.23)

30-34.9

7934

558

(8.0)

1.26

(1.17-1.37)

1.34

(1.22-1.47)

≥35

6018

(5.7)

464

(6.6)

1.33

(1.21-1.47)

1.34

(1.20-1.49)

Mean (SD)

24.9

(6.2)

25.5

(6.6)

90305 (85.0)

5635

(80.7)

1.14

(1.10-1.18)

1.11

(1.07-1.16)

Continuous (10 kg/m2)

(7.5)

<0.0001

Reference

<0.0001

Height (cm) <150

78

(1.1)

150-159

21527 (20.2)

895

(0.8)

1640

(23.5)

160-169

56815 (53.4)

3399

(48.7)

≥170

13154 (12.4)

657

(9.4)

Mean (SD)

163.9

(7.03)

162.9

(7.1)

Continuous (Decimeter)

92391 (86.8)

5774

<0.0001

1.62

(1.35-1.95)

1.43

(1.14-1.80)

1.30

(1.21-1.39)

1.27

(1.18-1.35)

Reference 0.84

(0.77-0.92)

0.80

(0.72-0.89)

(82.7)

0.83

(0.80-0.85)

0.84

(0.81-0.86)

1.68

(1.54-1.84)

1.65

(1.51-1.81)

<0.0001

Gestational weight gain C < recommended

12079 (11.4)

871

(12.5)

Recommended

18856 (17.7)

963

(13.8)

> recommended

39548 (37.2)

2291

(32.8)

No

75891 (71.3)

4791

(68.6) <0.0001

Yes

25063 (23.6)

1784

(25.5)

None

93702 (88.1)

5981

(85.7) <0.0001

Ex-smoker (were smoker at the first visit)

2867

(2.7)

183

(2.6)

1.02

(0.88-1.18)

1.03

(0.86-1.22)

Smoker

7713

(7.2)

591

(8.5)

1.24

(1.14-1.34)

1.15

(1.01-1.28)

None

93913 (88.3)

5479

(78.5) <0.0001

Gestational Hypertension

4754

(4.5)

516

(7.4)

2.01

(1.84-2.18)

1.89

(1.67-2.14)

Preeclampsia and superimposed preeclampsia

907

(0.9)

342

(4.9)

6.60

(5.84-7.46)

6.14

(5.29-7.12)

Eclampsia and HELLP D

120

(0.1)

122

(1.7)

18.00

(14.1-23.0)

18.80

(14.3-24.9)

None

91484 (86.0)

5670

(81.2)

Gestational diabetes

4784

(4.5)

463

(6.6)

1.59

(1.45-1.73)

1.44

(1.28-1.61)

Pre-gestational diabetes

638

(0.6)

205

(2.9)

5.13

(4.39-6.01)

4.64

(3.80-5.66)

Reference 1.20

(1.11-1.30)

1.16

(1.10-1.22)

1.13

(1.04-1.22)

History of abortion/miscarriage Reference 1.07

(1.00-1.14)

Smoking at time of birth Reference

Reference

Hypertensive disorders Reference

Diabetes Reference

(continued)

1432.e4



OCTOBER JOGC OCTOBRE 2019

Phenotypic Classification of Preterm Birth Among Nulliparous Women: A Population-Based Cohort Study

Supplemental Table B. (Continued) Term birth Maternal characteristics

N

(%)

Crude Odds RatiosA

Preterm birth N

(%)

P valueA

ORs

(95% CI)

Adjusted Odds Ratios A,B ORs

(95% CI)

Mental health concerns 5435

(77.8) <0.0001

(9.5)

750

(10.7)

1.22

(1.13-1.31)

1.17

(1.06-1.28)

(3.3)

292

(4.2)

1.37

(1.22-1.54)

1.27

(1.10-1.48)

6158

(88.2) <0.0001

None

86608 (81.4)

One

10148

Two or more

3496

96642 (90.8)

Reference

Maternal drug abuse None

Reference

One

2115

(2.0)

195

(2.8)

1.49

(1.30-1.72)

1.43

(1.19-1.71)

Two or more

206

(0.2)

39

(0.6)

3.08

(2.22-4.27)

2.24

(1.45-3.45)

Maternal alcohol use No

95879 (90.1)

6136

(87.9) <0.0001

Yes

2039

(1.9)

149

(2.1)

First quartile (lowest)

28149 (26.5)

1855

(26.6)

Second quartile

23653 (22.2)

1552

(22.2)

Reference 1.14

(0.97-1.34)

1.06

(0.87-1.29)

1.06

(1.00-1.14)

0.96

(0.88-1.05)

1.06

(0.99-1.14)

1.01

(0.92-1.10)

1.04

(0.97-1.11)

0.99

(0.90-1.08)

Neighborhood income quartile E

Third quartile

24605 (23.1)

1605

(23.0)

Fourth quartile (highest)

25948 (24.4)

1638

(23.5)

0.0005

Reference

A. P-values are calculated by Pearson Chi-Square for categorical variables and for the continuous values was calculated by T-test; odds ratios were calculated based on imputed data with five imputations. B. Adjusted for all variables in the table except for hypertensive disorders and diabetes. C. Recommended gestational weight gain according to IOM guidelines adjusted for gestational age at birth. D. Severe preeclampsia complicated by hemolysis, elevated liver enzymes and low platelets E. Neighborhood median household income values distributed by dissemination area were categorized by quartiles which represent approximately a quarter of the total population for Ontario.

OCTOBER JOGC OCTOBRE 2019



1432.e5



Preterm birth

OCTOBER JOGC OCTOBRE 2019

One condition All Maternal characteristics

(%)

Maternal conditions

Fetal conditions

Placental conditions

Two conditions

Three conditions

N

(%)

N

(%)

N

(%)

N

(%)

N

(%)

N

(%)

6983 (100)

2381

(100)

1333

(100)

1438

(100)

182

(100)

1560

(100)

89

(100)

≤19

239 (3.4)

65

(2.7)

31

(2.3)

72

(5.0)

0

(0.0)

67

(4.3)

4

(4.5)

20-29

2774 (39.7)

1002

(42.1)

500

(37.5)

594

(41.3)

56

(30.8)

590

(37.8)

32

(36.0)

30-34

1967 (28.2)

740

(31.1)

388

(29.1)

359

(25.0)

67

(36.8)

385

(24.7)

28

(31.5)

≥35

904 (12.9)

231

(9.7)

183

(13.7)

186

(12.9)

31

(17.0)

260

(16.7)

13

(14.6)

ALL

N

No significant clinical conditions

Maternal Age (year)

Body mass index (kg/m2) <18.5

348 (5.0)

118

(5.0)

67

(5.0)

87

(6.1)

14

(7.7)

60

(3.8)

2

(2.2)

18.5-24.9

2959 (42.4)

1081

(45.4)

542

(40.7)

624

(43.4)

76

(41.8)

599

(38.4)

37

(41.6)

25-29.9

1303 (18.7)

434

(18.2)

266

(20.0)

255

(17.7)

27

(14.8)

305

(19.6)

16

(18.0)

30-34.9

559 (8.0)

157

(6.6)

119

(8.9)

104

(7.2)

9

(4.9)

160

(10.3)

10

(11.2)

≥35

466 (6.7)

114

(4.8)

114

(8.6)

73

(5.1)

12

(6.6)

147

(9.4)

6

(6.7)

Height (cm) <150

(1.1)

26

(1.1)

15

(1.1)

21

(1.5)

1

(0.5)

13

(0.8)

2

(2.2)

150-159

1640 (23.5)

78

556

(23.4)

320

(24.0)

339

(23.6)

36

(19.8)

371

(23.8)

18

(20.2)

160-169

3399 (48.7)

1154

(48.5)

659

(49.4)

700

(48.7)

90

(49.5)

761

(48.8)

35

(39.3)

≥170

657 (9.4)

224

(9.4)

136

(10.2)

110

(7.6)

21

(11.5)

152

(9.7)

14

(15.7)

Gestational weight gain (kg) < recommended

817 (11.7)

262

(11.0)

145

(10.9)

206

(14.3)

23

(12.6)

168

(10.8)

13

(14.6)

Recommended

908 (13.0)

344

(14.4)

178

(13.4)

188

(13.1)

25

(13.7)

168

(10.8)

5

(5.6)

> recommended

2400 (34.4)

794

(33.3)

529

(39.7)

444

(30.9)

44

(24.2)

560

(35.9)

29

(32.6)

No

4791 (68.6)

1680

(70.6)

902

(67.7)

1000

(69.5)

120

(65.9)

1039

(66.6)

50

(56.2)

Yes

1784 (25.5)

571

(24.0)

352

(26.4)

354

(24.6)

50

(27.5)

425

(27.2)

32

(36.0)

None

5981 (85.7)

2067

(86.8)

1152

(86.4)

1226

(85.3)

148

(81.3)

1317

(84.4)

71

(79.8)

Ex-smoker (at first visit)

183 (2.6)

50

(2.1)

34

(2.6)

37

(2.6)

4

(2.2)

56

(3.6)

2

(2.2)

Smoker

591 (8.5)

116

(4.9)

58

(4.4)

67

(4.7)

10

(5.5)

61

(3.9)

5

(5.6)

History of abortion/ miscarriage

Smoking at time of birth

(continued on next page)

MATERNAL FETAL MEDICINE

1432.e6

Supplemental Table C. Maternal characteristics and preterm birth phenotype among nulliparous women

Supplemental Table C. (Continued) Preterm birth One condition All Maternal characteristics

N

No significant clinical conditions (%)

Maternal conditions

Fetal conditions

Placental conditions

Two conditions

Three conditions

(%)

N

(%)

N

(%)

N

(%)

N

(%)

N

(%)

5479 (78.5)

2155

(90.5)

907

(68.0)

1258

(87.5)

162

(89.0)

944

(60.5)

53

(59.6)

Gestational Hypertension

516 (7.4)

54

(2.3)

157

(11.8)

66

(4.6)

5

(2.7)

222

(14.2)

12

(13.5)

Preeclampsia and superimposed preeclampsia

342 (4.9)

0

(0.0)

119

(8.9)

0

(0.0)

0

(0.0)

213

(13.7)

10

(11.2)

Eclampsia and HELLP

122 (1.7)

0

(0.0)

55

(4.1)

0

(0.0)

0

(0.0)

61

(3.9)

6

(6.7)

5670 (81.2)

1962

(82.4)

1034

(77.6)

1225

(85.2)

158

(86.8)

1219

(78.1)

72

(80.9)

Hypertensive disorders None

Diabetes None Gestational diabetes

463 (6.6)

83

(3.5)

76

(5.7)

43

(3.0)

3

(1.6)

47

(3.0)

2

(2.2)

Pre-gestational diabetes

205 (2.9)

63

(2.6)

40

(3.0)

39

(2.7)

1

(0.5)

65

(4.2)

1

(1.1)

5416 (77.6)

1941

(81.5)

987

(74.0)

1143

(79.5)

141

(77.5)

1138

(72.9)

66

(74.2)

Anxiety

366 (5.2)

100

(4.2)

87

(6.5)

61

(4.2)

8

(4.4)

107

(6.9)

3

(3.4)

Mood disorders

614 (8.8)

0

(0.0)

1

(0.1)

0

(0.0)

0

(0.0)

2

(0.1)

0

(0.0)

Other

58

(0.8)

15

(0.6)

13

(1.0)

10

(0.7)

0

(0.0)

15

(1.0)

1

(1.1)

Addiction

23

(0.3)

7

(0.3)

5

(0.4)

3

(0.2)

3

(1.6)

5

(0.3)

0

(0.0)

Mental health concerns None

Maternal drug abuse

OCTOBER JOGC OCTOBRE 2019

None

6158 (88.2)

2116

(88.9)

1175

(88.1)

1270

(88.3)

156

(85.7)

1364

(87.4)

77

(86.5)

Marijuana

148 (2.1)

48

(2.0)

29

(2.2)

31

(2.2)

4

(2.2)

34

(2.2)

2

(2.2)

Opioids

26

6

(0.3)

10

(0.8)

3

(0.2)

2

(1.1)

4

(0.3)

1

(1.1)

(0.4)

Other

21

(0.3)

3

(0.1)

1

(0.1)

3

(0.2)

0

(0.0)

6

(0.4)

0

(0.0)

Multiple drugs

39

(0.6)

6

(0.3)

9

(0.7)

6

(0.4)

2

(1.1)

15

(1.0)

1

(1.1)

Maternal alcohol use No

6136 (87.9)

2099

(88.2)

1180

(88.5)

1263

(87.8)

160

(87.9)

1357

(87.0)

77

(86.5)

Yes

149 (2.1)

43

(1.8)

26

(2.0)

29

(2.0)

2

(1.1)

47

(3.0)

2

(2.2)

1855 (26.6)

604

(25.4)

338

(25.4)

412

(28.7)

48

(26.4)

422

(27.1)

31

(34.8)

Neighborhood income quartile First quartile (lowest)

1552 (22.2)

550

(23.1)

277

(20.8)

307

(21.3)

42

(23.1)

358

(22.9)

18

(20.2)

Third quartile

1605 (23.0)

542

(22.8)

306

(23.0)

348

(24.2)

42

(23.1)

345

(22.1)

22

(24.7)

Fourth quartile (highest)

1638 (23.5)

572

(24.0)

336

(25.2)

311

(21.6)

42

(23.1)

360

(23.1)

17

(19.1)



Second quartile

1432.e7

Phenotypic Classification of Preterm Birth Among Nulliparous Women: A Population-Based Cohort Study

N



OCTOBER JOGC OCTOBRE 2019

Preterm birth (outcome) One condition No significant clinical conditions Maternal characteristics (exposures)

OR

A

(95% CI)

Maternal conditions OR

A

(95% CI)

Fetal conditions OR

A

(95% CI)

Placental conditions OR

A

Two conditions

(95% CI)

OR

A

Three conditions

(95% CI)

OR A

(95% CI)

Maternal Age (years) ≤19

0.70

20-29

(0.53-0.93) Reference

30-34 ≥35

0.64

(0.43-0.96)

1.08

(0.83-1.41)

0.00

(0.00-NA)

1.10

(0.83-1.47)

0.97

(0.25-3.74)

B

1.08

(0.94-1.23)

1.19

(1.02-1.38)

1.11

(0.94-1.30)

1.85

(1.09-3.14)

1.10

(0.94-1.29)

1.63

(0.83-3.19)

0.79

(0.65-0.97)

1.30

(1.06-1.61)

1.23

(0.98-1.55)

2.37

(1.33-4.20)

1.57

(1.31-1.87)

2.64

(1.37-5.07)

1.10

(0.89-1.36)

1.17

(0.88-1.55)

1.36

(1.07-1.73)

1.74

(0.89-3.40)

1.00

(0.74-1.35)

0.28

(0.04-2.06)

1.20

(1.01-1.43)

1.21

(1.02-1.42)

0.59

(0.32-1.10)

1.34

(1.14-1.58)

1.12

(0.54-2.34)

2

Body mass index (kg/m ) <18.5 18.5-24.9

Reference

B

25-29.9

0.98

(0.85-1.12)

30-34.9

1.06

(0.88-1.27)

1.38

(1.12-1.69)

1.26

(1.03-1.55)

0.83

(0.37-1.88)

1.90

(1.59-2.27)

1.81

(0.87-3.79)

≥35

0.90

(0.73-1.11)

1.57

(1.27-1.95)

1.08

(0.84-1.37)

0.93

(0.41-2.10)

2.15

(1.76-2.63)

1.93

(0.92-4.07)

<150

1.41

(0.93-2.14)

1.03

(0.59-1.81)

1.86

(1.20-2.89)

0.79

(0.11-5.69)

1.49

(0.96-2.29)

1.10

(0.14-8.33)

150-159

1.30

(1.15-1.46)

1.26

(1.09-1.46)

1.25

(1.07-1.45)

0.89

(0.54-1.46)

1.28

(1.12-1.48)

1.22

(0.66-2.27)

(0.71-1.00)

0.87

(0.70-1.08)

0.70

(0.55-0.88)

0.93

(0.50-1.73)

0.73

(0.59-0.90)

1.24

(0.59-2.58)

(1.09-1.48)

1.26

(1.02-1.56)

2.32

(1.94-2.77)

1.88

(1.05-3.35)

1.96

(1.62-2.38)

4.21

(1.85-9.56)

1.18

(1.00-1.40)

1.04

(0.88-1.23)

1.13

(0.67-1.92)

1.28

(1.08-1.52)

1.59

(0.72-3.49)

1.08

(0.93-1.25)

1.02

(0.88-1.19)

0.98

(0.63-1.52)

1.18

(1.04-1.35)

1.64

(0.96-2.79)

Height (cm)

Reference B

160-169 ≥170

0.85

Gestational weight gain (kg) < recommended

1.27

Reference B

Recommended > recommended

1.06

(0.93-1.20)

History of abortion/ miscarriage Reference B

No Yes

1.00

(0.88-1.13)

Smoking at time of birth Reference B

None Ex-smoker (at the first visit)

0.79

(0.56-1.12)

0.95

(0.64-1.42)

1.19

(0.84-1.69)

0.65

(0.12-3.46)

1.28

(0.93-1.77)

0.79

(0.15-4.25)

Smoker

1.10

(0.90-1.34)

1.03

(0.79-1.34)

1.40

(1.12-1.75)

1.63

(0.78-3.43)

1.04

(0.80-1.33)

1.20

(0.51-2.85)

(continued on next page)

MATERNAL FETAL MEDICINE

1432.e8

Supplemental Table D. The adjusted odds ratios of the association between maternal characteristics and risk of preterm birth phenotypes among nulliparous women

Supplemental Table D. (Continued) Preterm birth (outcome) One condition No significant clinical conditions Maternal characteristics (exposures)

OR

A

(95% CI)

Maternal conditions OR

A

(95% CI)

Fetal conditions OR

A

(95% CI)

Placental conditions OR

A

(95% CI)

Two conditions OR

A

Three conditions

(95% CI)

OR A

(95% CI)

Reference B

None One

0.88

(0.73-1.07)

1.39

(1.14-1.69)

1.04

(0.85-1.27)

1.17

(0.62-2.22)

1.48

(1.24-1.76)

1.41

(0.67-2.98)

Two or more

1.01

(0.76-1.34)

1.83

(1.40-2.40)

0.94

(0.66-1.32)

1.26

(0.49-3.27)

1.50

(1.14-1.98)

1.61

(0.54-4.79)

Maternal drug abuse Reference B

None One

1.52

(1.10-2.09)

1.51

(1.03-2.22)

1.25

(0.85-1.85)

1.58

(0.46-5.45)

1.39

(0.96-2.00)

2.19

(0.63-7.66)

Two or more

1.27

(0.46-3.51)

3.11

(1.39-6.98)

1.70

(0.62-4.69)

4.62

(0.56-38.2)

2.86

(1.40-5.85)

0.01

(0.00-NA)

0.96

(0.62-1.48)

0.89

(0.57-1.39)

0.76

(0.18-3.22)

1.52

(1.10-2.10)

0.97

(0.17-5.65)

Maternal alcohol use Reference B

No Yes

0.91

(0.63-1.32)

Neighborhood income quartile First quartile (lowest)

0.90

(0.78-1.04)

0.94

(0.77-1.15)

1.19

(0.99-1.45)

1.14

(0.66-1.96)

0.84

(0.70-1.01)

1.36

(0.67-2.75)

Second quartile

0.98

(0.84-1.14)

0.94

(0.78-1.13)

1.14

(0.94-1.38)

0.93

(0.50-1.71)

1.01

(0.85-1.20)

0.98

(0.47-2.04)

Third quartile

0.98

(0.85-1.13)

0.97

(0.80-1.18)

1.14

(0.94-1.39)

1.03

(0.59-1.79)

0.89

(0.75-1.05)

1.03

(0.50-2.12)

Fourth quartile

Reference B

A. Adjusted for all variables in the table. All analyses were done with the imputed data with five imputations. B. For each exposure term births and unexposed pregnancies were chosen as the reference group. NA = not available.

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Phenotypic Classification of Preterm Birth Among Nulliparous Women: A Population-Based Cohort Study

Mental health concerns