Table 4 Open in new tab Adjusted hazard...

Joint categories of PL and metabolic disorders	Events, no.	Crude incidence per 1000 person-years	HR (95% CI)
Type 2 diabetes
No PL and type 2 diabetes	1376	0.86	1.00 (reference)	1.00 (reference)	1.00 (reference)
PL only	561	1.05	1.24 (1.12–1.37)	1.25 (1.13–1.38)	1.23 (1.11–1.36)
Type 2 diabetes only	207	3.84	3.28 (2.82–3.81)	2.45 (2.10–2.85)	2.02 (1.73–2.36)
Both PL and type 2 diabetes	81	4.09	3.60 (2.87–4.52)	2.61 (2.07–3.29)	2.18 (1.73–2.76)
Proportion mediated by type 2 diabetes^a			4.20% (2.40–7.20%)	2.10% (1.00–4.30%)	<1.00%
Hypertension
No PL and hypertension	824	0.63	1.00 (reference)	1.00 (reference)	1.00 (reference)
PL only	312	0.72	1.16 (1.02–1.32)	1.17 (1.03–1.34)	1.15 (1.01–1.31)
Hypertension only	759	2.24	2.78 (2.50–3.08)	2.20 (1.98–2.45)	1.97 (1.76–2.19)
Both PL and hypertension	330	2.78	3.52 (3.09–4.02)	2.79 (2.44–3.20)	2.49 (2.17–2.86)
Proportion mediated by hypertension^a			8.30% (5.10–13.20%)	3.50% (1.90–6.30%)	1.30% (0.40–4.30%)
Hypercholesterolaemia
No PL and hypercholesterolaemia	661	0.60	1.00 (reference)	1.00 (reference)	1.00 (reference)
PL only	249	0.68	1.16 (1.01–1.35)	1.18 (1.02–1.37)	1.16 (1.00–1.35)
Hypercholesterolaemia only	922	1.68	2.16 (1.95–2.40)	1.84 (1.66–2.05)	1.66 (1.49–1.85)
Both PL and hypercholesterolaemia	393	2.08	2.71 (2.38–3.08)	2.30 (2.02–2.63)	2.06 (1.80–2.35)
Proportion mediated by hypercholesterolaemia^a			8.20% (5.10–13.00%)	2.90% (1.60–5.20%)	1.70% (0.70–3.80%)

Joint categories of PL and metabolic disorders

Events, no.

Crude incidence per 1000 person-years

HR (95% CI)

Age-adjusted model^a

Multivariable model 1^b

Multivariable model 2^c

Type 2 diabetes

No PL and type 2 diabetes

1376

0.86

1.00 (reference)

PL only

561

1.05

1.24 (1.12–1.37)

1.25 (1.13–1.38)

1.23 (1.11–1.36)

Type 2 diabetes only

207

3.84

3.28 (2.82–3.81)

2.45 (2.10–2.85)

2.02 (1.73–2.36)

Both PL and type 2 diabetes

4.09

3.60 (2.87–4.52)

2.61 (2.07–3.29)

2.18 (1.73–2.76)

Proportion mediated by type 2 diabetes^a

4.20% (2.40–7.20%)

2.10% (1.00–4.30%)

<1.00%

Hypertension

No PL and hypertension

824

0.63

1.00 (reference)

PL only

312

0.72

1.16 (1.02–1.32)

1.17 (1.03–1.34)

1.15 (1.01–1.31)

Hypertension only

759

2.24

2.78 (2.50–3.08)

2.20 (1.98–2.45)

1.97 (1.76–2.19)

Both PL and hypertension

330

2.78

3.52 (3.09–4.02)

2.79 (2.44–3.20)

2.49 (2.17–2.86)

Proportion mediated by hypertension^a

8.30% (5.10–13.20%)

3.50% (1.90–6.30%)

1.30% (0.40–4.30%)

Hypercholesterolaemia

No PL and hypercholesterolaemia

661

0.60

1.00 (reference)

PL only

249

0.68

1.16 (1.01–1.35)

1.18 (1.02–1.37)

1.16 (1.00–1.35)

Hypercholesterolaemia only

922

1.68

2.16 (1.95–2.40)

1.84 (1.66–2.05)

1.66 (1.49–1.85)

Both PL and hypercholesterolaemia

393

2.08

2.71 (2.38–3.08)

2.30 (2.02–2.63)

2.06 (1.80–2.35)

Proportion mediated by hypercholesterolaemia^a

8.20% (5.10–13.00%)

2.90% (1.60–5.20%)

1.70% (0.70–3.80%)

Joint categories of PL and metabolic disorders	Events, no.	Crude incidence per 1000 person-years	HR (95% CI)
Type 2 diabetes
No PL and type 2 diabetes	1376	0.86	1.00 (reference)	1.00 (reference)	1.00 (reference)
PL only	561	1.05	1.24 (1.12–1.37)	1.25 (1.13–1.38)	1.23 (1.11–1.36)
Type 2 diabetes only	207	3.84	3.28 (2.82–3.81)	2.45 (2.10–2.85)	2.02 (1.73–2.36)
Both PL and type 2 diabetes	81	4.09	3.60 (2.87–4.52)	2.61 (2.07–3.29)	2.18 (1.73–2.76)
Proportion mediated by type 2 diabetes^a			4.20% (2.40–7.20%)	2.10% (1.00–4.30%)	<1.00%
Hypertension
No PL and hypertension	824	0.63	1.00 (reference)	1.00 (reference)	1.00 (reference)
PL only	312	0.72	1.16 (1.02–1.32)	1.17 (1.03–1.34)	1.15 (1.01–1.31)
Hypertension only	759	2.24	2.78 (2.50–3.08)	2.20 (1.98–2.45)	1.97 (1.76–2.19)
Both PL and hypertension	330	2.78	3.52 (3.09–4.02)	2.79 (2.44–3.20)	2.49 (2.17–2.86)
Proportion mediated by hypertension^a			8.30% (5.10–13.20%)	3.50% (1.90–6.30%)	1.30% (0.40–4.30%)
Hypercholesterolaemia
No PL and hypercholesterolaemia	661	0.60	1.00 (reference)	1.00 (reference)	1.00 (reference)
PL only	249	0.68	1.16 (1.01–1.35)	1.18 (1.02–1.37)	1.16 (1.00–1.35)
Hypercholesterolaemia only	922	1.68	2.16 (1.95–2.40)	1.84 (1.66–2.05)	1.66 (1.49–1.85)
Both PL and hypercholesterolaemia	393	2.08	2.71 (2.38–3.08)	2.30 (2.02–2.63)	2.06 (1.80–2.35)
Proportion mediated by hypercholesterolaemia^a			8.20% (5.10–13.00%)	2.90% (1.60–5.20%)	1.70% (0.70–3.80%)

Table 4

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Adjusted hazard ratios (95%) of cardiovascular disease according to the joint categories of pregnancy loss and subsequent metabolic disorders among 95 465 ever-gravid women (Nurses’ Health Study II, 1993–2017)

Joint categories of PL and metabolic disorders	Events, no.	Crude incidence per 1000 person-years	HR (95% CI)
Joint categories of PL and metabolic disorders	Events, no.	Crude incidence per 1000 person-years	Age-adjusted model^a	Multivariable model 1^b	Multivariable model 2^c
Type 2 diabetes
No PL and type 2 diabetes	1376	0.86	1.00 (reference)	1.00 (reference)	1.00 (reference)
PL only	561	1.05	1.24 (1.12–1.37)	1.25 (1.13–1.38)	1.23 (1.11–1.36)
Type 2 diabetes only	207	3.84	3.28 (2.82–3.81)	2.45 (2.10–2.85)	2.02 (1.73–2.36)
Both PL and type 2 diabetes	81	4.09	3.60 (2.87–4.52)	2.61 (2.07–3.29)	2.18 (1.73–2.76)
Proportion mediated by type 2 diabetes^a			4.20% (2.40–7.20%)	2.10% (1.00–4.30%)	<1.00%
Hypertension
No PL and hypertension	824	0.63	1.00 (reference)	1.00 (reference)	1.00 (reference)
PL only	312	0.72	1.16 (1.02–1.32)	1.17 (1.03–1.34)	1.15 (1.01–1.31)
Hypertension only	759	2.24	2.78 (2.50–3.08)	2.20 (1.98–2.45)	1.97 (1.76–2.19)
Both PL and hypertension	330	2.78	3.52 (3.09–4.02)	2.79 (2.44–3.20)	2.49 (2.17–2.86)
Proportion mediated by hypertension^a			8.30% (5.10–13.20%)	3.50% (1.90–6.30%)	1.30% (0.40–4.30%)
Hypercholesterolaemia
No PL and hypercholesterolaemia	661	0.60	1.00 (reference)	1.00 (reference)	1.00 (reference)
PL only	249	0.68	1.16 (1.01–1.35)	1.18 (1.02–1.37)	1.16 (1.00–1.35)
Hypercholesterolaemia only	922	1.68	2.16 (1.95–2.40)	1.84 (1.66–2.05)	1.66 (1.49–1.85)
Both PL and hypercholesterolaemia	393	2.08	2.71 (2.38–3.08)	2.30 (2.02–2.63)	2.06 (1.80–2.35)
Proportion mediated by hypercholesterolaemia^a			8.20% (5.10–13.00%)	2.90% (1.60–5.20%)	1.70% (0.70–3.80%)

Joint categories of PL and metabolic disorders	Events, no.	Crude incidence per 1000 person-years	HR (95% CI)
Joint categories of PL and metabolic disorders	Events, no.	Crude incidence per 1000 person-years	Age-adjusted model^a	Multivariable model 1^b	Multivariable model 2^c
Type 2 diabetes
No PL and type 2 diabetes	1376	0.86	1.00 (reference)	1.00 (reference)	1.00 (reference)
PL only	561	1.05	1.24 (1.12–1.37)	1.25 (1.13–1.38)	1.23 (1.11–1.36)
Type 2 diabetes only	207	3.84	3.28 (2.82–3.81)	2.45 (2.10–2.85)	2.02 (1.73–2.36)
Both PL and type 2 diabetes	81	4.09	3.60 (2.87–4.52)	2.61 (2.07–3.29)	2.18 (1.73–2.76)
Proportion mediated by type 2 diabetes^a			4.20% (2.40–7.20%)	2.10% (1.00–4.30%)	<1.00%
Hypertension
No PL and hypertension	824	0.63	1.00 (reference)	1.00 (reference)	1.00 (reference)
PL only	312	0.72	1.16 (1.02–1.32)	1.17 (1.03–1.34)	1.15 (1.01–1.31)
Hypertension only	759	2.24	2.78 (2.50–3.08)	2.20 (1.98–2.45)	1.97 (1.76–2.19)
Both PL and hypertension	330	2.78	3.52 (3.09–4.02)	2.79 (2.44–3.20)	2.49 (2.17–2.86)
Proportion mediated by hypertension^a			8.30% (5.10–13.20%)	3.50% (1.90–6.30%)	1.30% (0.40–4.30%)
Hypercholesterolaemia
No PL and hypercholesterolaemia	661	0.60	1.00 (reference)	1.00 (reference)	1.00 (reference)
PL only	249	0.68	1.16 (1.01–1.35)	1.18 (1.02–1.37)	1.16 (1.00–1.35)
Hypercholesterolaemia only	922	1.68	2.16 (1.95–2.40)	1.84 (1.66–2.05)	1.66 (1.49–1.85)
Both PL and hypercholesterolaemia	393	2.08	2.71 (2.38–3.08)	2.30 (2.02–2.63)	2.06 (1.80–2.35)
Proportion mediated by hypercholesterolaemia^a			8.20% (5.10–13.00%)	2.90% (1.60–5.20%)	1.70% (0.70–3.80%)

CI, confidence interval; CVD, cardiovascular disease; HR, hazard ratios; PL, pregnancy loss.

Estimated proportion of association between PL and CVD explained by tested metabolic disorders.

Age in months (continuous) at the start of follow-up and calendar year of the current questionnaire cycle were included as stratified variables.

Based on the age-adjusted model, multivariable model 1 was further adjusted for White race/ethnicity (yes vs. no), parental history of myocardial infarction or stroke (yes/no), body mass index at age 18 years (<19, 20.5–21.9, 22–24.9, 25–29.9, or ≥30 kg/m²), and time-varying history of gestational diabetes (yes vs. no), hypertensive disorders of pregnancy (yes vs. no), menopausal status (premenopausal, postmenopausal, or unsure/biologically uncertain), current hormone therapy use (never, past, or current), breastfeeding duration (<3, 3–12, or >12 months), daily aspirin use (yes vs. no), infertility (never vs. ever), and marital status (ever/currently married vs. never).

Based on multivariable model 1, multivariable model 2 was further adjusted for time-varying smoking status (never, former, or current), physical activity (0, 0.1–1.0, 1.1–2.4, 2.5–5.9, or ≥6 h/week), Alternative Healthy Eating Index 2010 diet quality score (quintiles), and body mass index (<23, 23–24.9, 25–29.9, and ≥30 kg/m²).

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