Medically assisted reproduction and the risk of preterm birth: a case–control study using data from the Quebec Pregnancy Cohort

Jessica Gorgui; Odile Sheehy; Jacquetta Trasler; William Fraser; Anick Bérard

doi:10.9778/cmajo.20190082

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Figure 1:
Flow chart of the selection process for the study population. ART = assisted reproductive technologies, OS = ovarian stimulators.

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Table 1:

Characteristics of the study population

Characteristic	No. (%) of pregnancies^*		Standardized mean difference^†	p value^‡
Characteristic	Term delivery (≥ 37 wk) n = 53 947	Preterm delivery (< 37 wk) n = 3677	Standardized mean difference^†	p value^‡
Pregnancy characteristics
Pregnancies conceived spontaneously	52 074 (96.5)	3495 (95.1)	−0.07
Pregnancies conceived through use of OS and ART	1873 (3.5)	182 (5.0)	0.07	< 0.001
OS alone	381 (0.7)	38 (1.0)	0.03
ART alone	135 (0.2)	15 (0.4)	0.03
OS and ART combined	1357 (2.5)	129 (3.5)	0.06	< 0.001
Maternal and child sociodemographic characteristics^§
Maternal
Maternal age, yr, mean ± SD	29.14 ± 5.6	29.23 ± 6.0	−0.02	< 0.001
Maternal age, yr
< 25	12 096 (22.4)	865 (23.5)	0.03
25–35	32 077 (59.5)	2047 (55.7)	−0.08
35–40	7931 (14.7)	586 (15.9)	0.03
≥ 40	1843 (3.4)	179 (4.9)	0.07	< 0.001
Recipient of social assistance	9848 (18.2)	997 (27.1)	0.21	< 0.001
Urban dweller	44 667 (82.8)	3008 (81.8)	−0.03	0.12
Child
Sex, male	27 581 (51.1)	2038 (55.4)	0.09	< 0.001
Birth weight, g, mean ± SD	3401.90 ± 455.56	2412.44 ± 648.78	2.10	< 0.001
Pregnancies conceived spontaneously	3402.15 ± 455.33	2418.47 ± 643.11
Pregnancies conceived through use of OS or ART or both	3394.13 ± 462.45	2296.56 ± 741.81
Maternal comorbidities^¶
Diabetes	1536 (2.8)	124 (3.4)	0.03	0.07
Hypertension	1118 (2.1)	88 (2.4)	0.02	0.19
Obesity	1270 (2.4)	104 (2.8)	0.03	0.07
Asthma	4771 (8.8)	358 (9.7)	0.03	0.07
Epilepsy	619 (1.2)	53 (1.4)	0.03	0.11
Smoking	1054 (2.0)	81 (2.2)	0.02	0.29
Infection	15 847 (29.4)	1076 (29.3)	0.00	0.89
Thyroid disease	3123 (5.8)	236 (6.4)	0.03	0.12
Depression or anxiety	6912 (12.8)	513 (14.0)	0.03	0.05
Coagulopathy	221 (0.4)	22 (0.6)	0.03	0.09
Previous pregnancy	6382 (11.8)	477 (13.0)	0.03	0.04
Delivery	2175 (4.0)	140 (3.8)
Abortion	2609 (4.8)	199 (5.4)
Miscarriage	1598 (3.0)	138 (3.8)
No. of any other medications used^**
0	19 735 (36.6)	1292 (35.1)	−0.09
1	10 529 (19.5)	753 (20.5)	0.02
2 or 3	12 980 (24.1)	889 (24.2)	0.00
≥ 4	10 703 (19.8)	743 (20.2)	0.01	0.28
Pregnancy complications
Premature rupture of membranes	2994 (5.6)	222 (6.0)	0.02	0.21
Placental dysfunction	280 (0.5)	26 (0.7)	0.02	0.13
Preterm labour	526 (1.0)	46 (1.2)	0.03	0.10
Bleeding	1291 (2.49)	105 (2.9)	0.03	0.08
Utilization of health care services
Follow-up by obstetrician^‡‡	31 066 (57.6)	2121 (57.7)	0.002	0.91
Follow-up by general practitioner or family physician^‡‡	13 354 (24.8)	891 (24.2)	−0.01	0.48
Hospital admission and/or visit to emergency department^§§	20 725 (38.4)	1399 (38.0)	−0.01	0.66

Note: ART = assisted reproductive technologies, OS = ovarian stimulators, SD = standard deviation.
↵* Unless indicated otherwise.
↵† Standardized mean differences ≥ 0.10 represent a clinically significant difference between groups.
↵‡ p values were calculated to compare term births with preterm births using Pearson χ² tests for categorical variable and t tests for continuous variables.
↵§ Measured at the first day of gestation.
↵¶ Measured in the 12 mo before the first day of gestation. Diagnoses are based on International Classification of Diseases and Related Health Problems, 10th Revision, codes or a filled prescription or both in relation to the comorbidity.
↵** Excludes all prescriptions filled for comorbidities listed above.
†† Defined as ≥ 5 visits over the course of the pregnancy.
↵‡‡ In the 12 mo before the first day of gestation.

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Table 2:

Risk of preterm birth, by category of assisted reproduction

Category	No. (%) of pregnancies		Crude OR (95% CI)	Adjusted OR^* (95%CI)
Category	Term birth n = 53 947	Preterm birth n = 3677	Crude OR (95% CI)	Adjusted OR^* (95%CI)
Spontaneous	52 074 (96.5)	3495 (95.0)	1.00	1.00
Use of OS or ART or both	1873 (3.5)	182 (5.0)	1.44 (1.23–1.69)	1.46 (1.25–1.72)
Use of OS alone	381 (0.7)	38 (1.0)	1.47 (1.04–2.07)	1.47 (1.04–2.07)
Use of ART alone	135 (0.2)	15 (0.4)	1.66 (0.96–2.87)	1.76 (1.01–3.06)
Use of both OS and ART	1357 (2.5)	129 (3.5)	1.41 (1.17–1.70)	1.43 (1.19–1.73)

Note: ART = assisted reproductive technologies, CI = confidence interval, OR = odds ratio, OS = ovarian stimulators.
↵* Adjusted for sociodemographic variables (maternal age, urban dwelling, recipient of social assistance, sex of the child) as well as maternal comorbidities measured within 12 mo before the first day of gestation (hypertension, diabetes, asthma, epilepsy, depression or anxiety, coagulopathy, other medication use, infection, prior pregnancy and other medication use) and during pregnancy (smoking, obesity).

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Table 3:

Risk of preterm birth, by category of prematurity

Timing of birth	No. (%) of pregnancies that involved use of OS or ART or both n = 2055	Crude OR (95% CI)	Adjusted OR^* (95% CI)
Term birth	1873 (91.1)	1.00	1.00
Preterm birth
Late preterm (34–37 weeks’ gestation)	134 (6.5)	1.34 (1.12–1.59)	1.36 (1.13–1.63)
Moderate preterm (32–34 weeks’ gestation)	20 (1.0)	1.57 (1.01–2.42)	1.61 (1.03–2.51)
Very preterm (28–32 weeks’ gestation)	16 (0.8)	1.65 (1.01–2.72)	1.59 (0.94–2.68)
Extremely preterm (< 28 weeks’ gestation)	12 (0.6)	2.47 (1.35–4.51)	2.39 (1.30–4.39)

Note: ART = assisted reproductive technologies, CI = confidence interval, OR = odds ratio, OS = ovarian stimulators.
↵* Adjusted for sociodemographic variables (maternal age, urban dwelling, recipient of social assistance, sex of the child) as well as maternal comorbidities measured within 12 mo before the first day of gestation (hypertension, diabetes, asthma, epilepsy, depression or anxiety, coagulopathy, infection, prior pregnancy and other medication use) and during pregnancy (smoking, obesity).

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Table 4:

Risk of preterm birth by category of assisted reproduction among 2055 pregnancies that involved the use of ovarian stimulators or assisted reproductive technologies or both

Category of assisted reproduction	No. (%) of preterm births n = 182	Crude OR (95%CI)	Adjusted OR^* (95%CI)
Use of OS alone	38 (20.9)	1.00	1.00
Use of ART alone	15 (1.0)	1.13 (0.60–2.13)	1.08 (0.58–2.08)
Use of both OS and ART	103 (2.8)	0.96 (0.65–1.41)	0.91 (0.61–1.36)

Note: ART = artificial reproductive technologies, CI = confidence interval, OR = odds ratio, OS = ovarian stimulators.
↵* Adjusted for sociodemographic variables (maternal age, urban dwelling, recipient of social assistance, sex of the child) as well as maternal comorbidities measured within 12 mo before the first day of gestation (hypertension, diabetes, asthma, epilepsy, depression or anxiety, coagulopathy, infection, prior pregnancy and other medication use) and during pregnancy (smoking and obesity).