Aspirin use during pregnancy and placental pathology in obese women in a large prospective cohort study

doi:10.21203/rs.3.rs-1591777/v1

Background:

The placenta plays a critical role in the development of preeclampsia. Low-dose aspirin can prevent preeclampsia in high-risk women, but the mechanisms are unclear. We examined the association between aspirin use during pregnancy and the placental pathology in obese women to better understand how aspirin may work.

Methods:

Data were taken from the U.S. Collaborative Perinatal Project (CPP), a large prospective cohort study conducted at 12 centers from 1959 to 1976. Live singleton pregnancies (n=42,308) with information on placental pathology and aspirin exposure during pregnancy were included. Pre-pregnancy BMI >= 30.0 kg/m² and 25.0 kg/m² <= BMI < 30.0 kg/m² were defined as obese (n=2,286) and overweight (n=5,673), respectively. Placental pathology examinations were performed by a team of trained pathologists according to a standard protocol. We further divided the placental pathology into three clusters: hypoxia-related, inflammation-related, and hemorrhage-related placental indicators. Generalized estimating equation was used to examine the association between aspirin use during pregnancy and placental pathological changes adjusting for potential confounders.

Results:

Among obese women, aspirin use in one, two and three trimesters during pregnancy tended to have lower risks of hypoxia-related placental pathologic changes (OR=0.99, 95% CI: 0.70-1.39; OR=0.77, 95% CI: 0.48-1.24; OR=0.43, 95% CI: 0.20-0.91, respectively) and hemorrhage-related placental pathologic changes (OR=0.89, 95% CI: 0.60-1.32; OR=0.50, 95% CI: 0.28-0.89; OR=0.49, 95%CI: 0.21-1.19, respectively) compared to women who did not use aspirin during pregnancy. In addition, aspirin use in all three trimesters may have a protective effect on inflammation-related placental pathologic changes (OR=0.43, 95% CI: 0.15-1.25). The positive association was not as prominent in overweight women. Aspirin use was associated with lower risks of thrombus, calcification, cysts, fibrin deposition, syncytium-nuclear clumping, necrosis, macrophage, and neutrophilic infiltration in the placentae.

Conclusions:

Our study suggests that aspirin use during pregnancy was associated with a decreased risk of placental pathological changes in obese women. The positive association increase with the duration of use.

Aspirin

Placenta

pathology

Obese

Epidemiology

CPP

It was estimated that more than 650 million adults in the world are obese and over 15% of women are affected [1, 2]. In some high-income countries, approximately 30% women of childbearing age are obese [3, 4]. Obesity is a strong risk factor for preeclampsia and other pregnancy complications [5, 6].

The placenta plays a pivotal role in pregnancy, and its abnormalities cause many pregnancy complications, including preeclampsia, preterm birth, placental abruption, fetal growth restriction and late pregnancy loss [7, 8]. Compared to normal weight women, obese women are more likely to suffer from placental abnormalities, including placental vascular infarct, villous infarct, thrombosis, and vessels atheroma [9]. The infarction and endothelial dysfunction may further develop into profound hypoxia in some areas of the placenta, leading to deficient placental implantation and microvascular fibrin deposition, and finally evolving into severe complications such as preeclampsia [10].

Aspirin can prevent or delay the onset of preeclampsia in high-risk women [11–13], but the exact underlying mechanisms remain unclear. We hypothesize that use of aspirin during pregnancy reduces the placental abnormalities in obese women and, in turn, decreases the risk of preeclampsia. To test our hypothesis, we examined the association between aspirin use during pregnancy and the placental pathology in obese women in a large prospective cohort study.

2.1 Study population

The Collaborative Perinatal Project (CPP) was a prospective cohort study that recruited 46,021 women who sought prenatal care and gave 51,983 singleton births at 12 centers in the United States from 1959 to 1965. The offspring were followed up to 7 years of age. The detailed description of the CPP was provided elsewhere [14].

Of the 51,983 live singleton pregnancies, women without detailed information on placental pathology (n = 6,192) were excluded (Fig. 1). Live births with a gestational age of less than 28 weeks or more than 43 weeks were also excluded (n = 3,483). Women were further stratified by their pre-pregnancy body mass index (BMI) into normal weight, overweight, and obesity. Self-reported pre-pregnancy weight and measured height were used to calculate the pre-pregnancy BMI [15]. According to the WHO classification, BMI ≥ 30.0 kg/m² was considered as obese, and 25.0 kg/m² ≤ BMI < 30.0 kg/m² as overweight [16]. Women with BMI less than 25 or unknown BMI were excluded (n = 18,992). Finally, 5,673 overweight and 2,286 obese subjects remained in our analyses.

2.2 Placental pathology and the composite pathologic placental index

Placental pathology assessment in the CPP was performed by a team of trained pathologists according to a standard protocol written by Dr. Benirschke [17]. Of the 103 placental pathological measures, 81 gross and microscopic lesions were selected by five invited placental pathologists. These lesions on the cord, membranes, decidua, fetal surface, maternal surfaces, cut surfaces, terminal villi, and intervillous space were considered as having significant clinical values [18]. The selected placental lesions were further divided into three clusters: hemorrhage-related (16 lesions), inflammation-related (26 lesions), and hypoxia-related (47 lesions) placental indicators, among which 6 lesions were overlapped. The detailed description of the index selection and categorization has been provided previously [18–20]. Furthermore, all the selected placental lesions were transformed into categorical variables and a composite pathologic placental index was generated as a sum of the placental lesions score. Thus, the hemorrhage-related, inflammation-related, and hypoxia-related placental indicators were calculated as a cumulative score of the classified placental pathologic lesions, respectively. Detailed methods have been published elsewhere [18]. For the current analyses, the placental pathologic indices were further transformed into a dichotomous variable with the cutoff point at the 75th percentile of the score in the total population (n = 42,308). If an index of the obese/overweight women had a score above the 75th percentile of the score in the total population, this index was coded as 1 (which means abnormal placenta); otherwise, it was 0 (which means healthy placenta).

2.3 Aspirin exposure during pregnancy

In the CPP, aspirin intake was for therapeutic purposes, which was recorded as aspirin compound, acetylsalicylic acid, and alka seltzer. The duration of aspirin use was recorded as: not taken, taken only 1 day, taken 1–7 days, and taken more than 7 days in one month during pregnancy. The dose of aspirin was not recorded. In the current study, we defined the exposure of aspirin as using aspirin for more than 7 days in one month. Women who did not use aspirin in any month during the whole pregnancy were served as the non-exposed group. An exposed trimester was defined as women having used aspirin for more than 7 days in at least one month during the trimester. Accordingly, the cumulative duration of aspirin use during pregnancy were categorized into not used, used in one, two or three trimesters.

2.4 Confounders

Perinatal factors that may affect the association between aspirin use and placental pathologic lesions were chosen as potential confounders according to the previous literature [21, 22], including: maternal age (< 20, 20–29, 30–39, and ≥40 years old), maternal race (White, Black, and Others), socioeconomic status (SES), smoking status (nonsmoker, < 1, 1–5, 6–10, 11–20, and ≥20 cigarettes/day), parity (0, 1, and ≥2) and gestational age at birth. SES was a combined score of maternal education, occupation, and family income, which was further coded in quantile [23].

2.5 Statistical analysis

We first described the maternal baseline characteristics by aspirin exposure in overweight and obese groups, respectively. Wilcoxon rank sum test was used to compare the differences in the placental lesion scores between the exposed and non-exposed groups due to the skew distribution of the scores. Generalized estimating equation (GEE) was conducted to test the association between aspirin use during pregnancy and placental pathological index. All the GEE models were adjusted for maternal age, maternal race, SES, smoking status, parity, and gestational age regardless of statistical significance. We used PROC GENMOD in SAS 9.2 (SAS Institute, Cary, North Carolina, USA) to perform the analyses.

Table 1 shows that Black women were more likely to have taken aspirin in both obese and overweight populations (P < 0.001, respectively). Also, a higher percentage of multiparous women took aspirin in pregnancy.

Table 1

Maternal characteristics by aspirin use during pregnancy in overweight and obese women, respectively
	Obese (n = 2286)			Overweight (n = 5673)
	Not use (n = 1687)	Use of aspirin (n = 416)	P	Not use (n = 4266)	Use of aspirin (n = 941)	P
Race, n (%)			< 0.001			< 0.001
Non-Hispanic white	609 (36.1)	126 (30.3)		1659 (38.9)	344 (36.6)
Non-Hispanic black	979 (58.0)	283 (68.0)		2248 (52.7)	569 (60.5)
Others	99 (5.9)	7 (1.7)		359 (8.4)	28 (3.0)
Maternal age (years), n (%)			0.109			0.031
<20	121 (7.2)	19 (4.6)		629 (14.7)	104 (11.1)
20–29	869 (51.5)	232 (55.8)		2365 (55.4)	538 (57.2)
30–39	602 (35.9)	148 (35.6)		1144 (26.8)	270 (28.7)
≥40	95 (5.6)	17 (4.1)		128 (3.0)	29 (3.1)
Maternal educational levels (year), n (%)			0.647			0.010
Less than high school (≤9)	642 (38.6)	149 (36.1)		1397 (33.2)	280 (30.0)
High school (10–12)	947 (56.9)	244 (59.1)		2474 (58.9)	598 (64.0)
College and above (> 12)	76 (4.6)	20 (4.8)		332 (7.9)	57 (6.1)
Socioeconomic status, n (%)			0.409			0.595
1	142 (8.6)	30 (7.3)		341 (8.1)	73 (7.8)
2	651 (39.2)	165 (39.9)		1439 (34.2)	319 (34.2)
3	577 (34.7)	145 (35.0)		1426 (33.9)	307 (32.9)
4	236 (14.2)	57 (13.8)		739 (17.6)	183 (19.6)
5	36 (2.2)	15 (3.6)		224 (5.3)	47 (5.0)
Smoking status, n (%)			0.472			0.531
Nonsmoker	999 (59.6)	237 (57.0)		2443 (57.6)	526 (56.1)
<1 cigarette/day	37 (2.2)	16 (3.9)		76 (1.8)	22 (2.4)
1–5 cigarettes/day	218 (13.0)	54 (13.0)		511 (12.1)	104 (11.1)
6–10 cigarettes/day	165 (9.9)	39 (9.4)		444 (10.5)	100 (10.7)
11–20 cigarettes/day	179 (10.7)	48 (11.5)		593 (14.0)	138 (14.7)
≥21 cigarettes/day	77 (4.6)	22 (5.3)		172 (4.1)	47 (5.0)
Parity, n (%)			0.002			< 0.001
0	219 (13.0)	32 (7.7)		783 (18.4)	120 (12.8)
1	284 (16.9)	55 (13.2)		899 (21.1)	166 (17.6)
≥2	1181 (70.1)	329 (79.1)		2581 (60.5)	655 (69.6)
Gestational age (weeks, %)			0.563			0.266
28–36	231 (13.7)	65 (15.6)		591 (13.9)	129 (13.7)
37–41	1259 (74.6)	301 (72.4)		3214 (75.3)	693 (73.7)
42–44	197 (11.7)	50 (12.0)		461 (10.8)	119 (12.7)
Preeclampsia/eclampsia	467 (27.8)	114 (27.5)	0.899	731 (17.2)	172 (18.4)	0.391

The composite placental lesion scores were similar between the exposed and non-exposed groups in both obese and overweight groups (Supplementary Table 1). In obese women, there was no significant difference in the incidence of preeclampsia/eclampsia between women used aspirin or not during pregnancy.

Obese women having used aspirin in the 1st trimester appeared to have had decreased risks of hypoxia (odds ratio [OR] = 0.84, 95% confidence interval [CI]: 0.57–1.24), hemorrhage (OR = 0.72, 95% CI: 0.46–1.12) and inflammation (OR = 0.75, 95% CI: 0.47–1.21) lesions, though none of them reached statistical significance. The association were found in the overweight population as well, but not as strong as those in the obese population (Table 2). In contrast, aspirin had little effect in normal weight women (Supplementary Tables 2–3)

Table 2

Association between aspirin use during pregnancy and placental pathologic lesions with cutoff point at the 75th percentile of the composite placenta index score
	Obese (n = 2286)				Overweight (n = 5673)
	N	Placental lesion (n, %)	Crude OR (95%CI)	Adjusted OR a (95%CI)	N	Placental lesion (n, %)	Crude OR (95%CI)	Adjusted OR a (95%CI)
General pathologic changes in placenta
Not use	1286	371 (28.9)	Ref·	Ref·	3211	860 (26.8)	Ref·	Ref·
1st trimester	144	45 (31.3)	1.12 (0·77, 1·62)	1·11 (0·77, 1·60)	339	83 (24.5)	0·89 (0·68, 1·15)	0·92 (0·71, 1·19)
2nd trimester	222	70 (31.5)	1·14 (0·84, 1·54)	1·13 (0·83, 1·53)	511	120 (23.5)	0·84 (0·67, 1·04)	0·85 (0·68, 1·06)
3rd trimester	157	38 (24.2)	0·79 (0·54, 1·15)	0·76 (0·52, 1·12)	347	91 (26.2)	0·97 (0·76, 1·25)	0·97 (0·76, 1·26)
Inflammation-related placental change
Not use	1481	257 (17·4)	Ref·	Ref·	3792	565 (14.9)	Ref·	Ref·
1st trimester	157	22 (14·0)	0·78 (0·48, 1·25)	0·75 (0·47, 1·21)	378	54 (14·3)	0·95 (0·71, 1·28)	0·95 (0·70, 1·28)
2nd trimester	243	43 (17·7)	1·02 (0·72, 1·46)	1·02 (0·71, 1·46)	570	79 (13·9)	0·92 (0·71, 1·18)	0·91 (0·71, 1·18)
3rd trimester	175	23 (13·1)	0·72 (0·46, 1·14)	0·73 (0·46, 1·15)	389	66 (17·0)	1·17 (0·88, 1·55)	1·16 (0·87, 1·54)
Hemorrhage-related placental change
Not use	1491	288 (19·3)	Ref·	Ref·	3703	618 (16.7)	Ref·	Ref·
1st trimester	170	25 (14·7)	0·72 (0·46, 1·13)	0·72 (0·46, 1·12)	382	50 (13·1)	0·75 (0·55, 1·02)	0·74 (0·54, 1·02)
2nd trimester	256	35 (13·7)	0·66 (0·45, 0·97)	0·65 (0·44, 0·96)	580	76 (13·1)	0·75 (0·58, 0.98)	0·75 (0·58, 0.97)
3rd trimester	193	28 (14·5)	0·71 (0·47, 1·08)	0·67 (0·44, 1·02)	401	66 (16·5)	0.98 (0·74, 1·30)	0.99 (0·75, 1·31)
Hypoxia-related placental change
Not use	1638	383 (23·4)	Ref·	Ref·	4127	865 (21·0)	Ref·	Ref·
1st trimester	179	36 (20·1)	0·82 (0·56, 1·21)	0·84 (0·57, 1·24)	406	79 (19·5)	0·91 (0·71, 1·18)	0·98 (0·76, 1·28)
2nd trimester	275	59 (21·5)	0·90 (0·66, 1·22)	0·91 (0·66, 1·24)	625	117 (18·7)	0·87 (0·70, 1·08)	0·90 (0·73, 1·12)
3rd trimester	205	41 (20·0)	0·82 (0·57, 1·18)	0·80 (0·55, 1·15)	430	81 (18·8)	0·88 (0·68, 1·13)	0.80 (0·69, 1·16)
a. GEE model, adjusted for mother age, race, social economic status, smoking, gestational age at birth, and parity.

Duration of aspirin use appears to have had more pronounced effects. In obese women, use aspirin in at least one month group had a decreased risk of hypoxia-related placental pathologic lesions compared to not use aspirin group during pregnancy, (OR = 0.91, 95% CI: 0.85–0.98). The longer women had used aspirin during pregnancy, the lower the risk of hypoxia-related placental pathologic lesions (OR = 0.99, 95% CI: 0.70–1.39; OR = 0.77, 95% CI: 0.48–1.24; and OR = 0.43, 95% CI: 0.20–0.91 in women having used aspirin for one, two, and three trimesters, respectively). The duration of aspirin uses during pregnancy tended to reduce the risk of hemorrhage-related placental pathologic lesions (P-value for trend analysis is 0.03, OR = 0.89, 95% CI: 0.60–1.32; OR = 0.50, 95% CI: 0.28–0.89; and OR = 0.49, 95% CI: 0.21–1.19 for women who took aspirin for one, two, and three trimesters, respectively). Obese women who used aspirin in three trimesters were associated with a decreased risk of inflammation-related placental pathologic lesions (OR = 0.43, 95% CI: 0.15–1.25) (Table 3).

Table 3

Associations between the duration of aspirin use during pregnancy and placental pathologic lesions with cutoff point at the 75th percentile of the composite placenta index score
Aspirin exposure	Obese (n = 2286)					Overweight (n = 5673)
Aspirin exposure	N	Placental lesion (n, %)	Crude OR (95% CI)	Adjusted OR ^a (95% CI)	P-value for trend test	N	Placental lesion (n, %)	Crude OR (95% CI)	Adjusted OR ^a (95% CI)	P-value for trend test
General pathologic changes in placenta					0.998					0.268
Not use	1286	371 (28.9)	Ref.	Ref.		3211	860 (26.8)	Ref.	Ref.
Use aspirin ^b	321	99 (30.8)	0.99 (0.93, 1.05)	0.97 (0.91, 1.04)		751	184 (24.5)	0.97 (0.93, 1.02)	0.97 (0.92, 1.02)
Use in one trimester	166	55 (33.1)	1.22 (0.87, 1.72)	1.26 (0.88, 1.80)		404	101 (25.0)	0.91 (0.72, 1.16)	0.90 (0.70, 1.15)
Use in two trimesters	108	34 (31.5)	1.13 (0.74, 1.72)	1.03 (0.65, 1.63)		248	56 (22.6)	0.80 (0.59, 1.08)	0.83 (0.61, 1.15)
Use in three trimesters	47	10 (21.3)	0.67 (0.33, 1.34)	0.58 (0.28, 1.19)		99	27 (27.3)	1.03 (0.65, 1.61)	0.95 (0.58, 1.56)
Inflammation-related placental change					0.362					0.956
Not use	1481	257 (17.4)	Ref.	Ref.		3792	565 (14.9)	Ref.	Ref.
Use aspirin ^b	358	58 (16.2)	0.95 (0.88, 1.02)	0.95 (0.87, 1.03)		838	121 (14.4)	1.01 (0.96, 1.06)	0.99 (0.94, 1.05)
Use in one trimester	192	32 (16.7)	0.95 (0.64, 1.42)	1.04 (0.69, 1.56)		450	63 (14.0)	0.93 (0.70, 1.24)	0.92 (0.69, 1.24)
Use in two trimesters	115	22 (19.1)	1.13 (0.69, 1.83)	1.17 (0.70, 1.95)		277	38 (13.7)	0.91 (0.64, 1.29)	0.92 (0.64, 1.33)
Use in three trimesters	51	4 (7.8)	0.41 (0.14, 1.14)	0.43 (0.15, 1.25)		111	20 (18.0)	1.26 (0.77, 2.06)	1.08 (0.63, 1.86)
Hemorrhage-related placental change					0.03					0.107
Not use	1491	288 (19.3)	Ref.	Ref.		3703	618 (16.7)	Ref.	Ref.
Use aspirin ^b	383	59 (15.4)	0.94 (0.87, 1.01)	0.91 (0.83, 1.00)		854	117 (13.7)	0.97 (0.92, 1.02)	0.97 (0.92, 1.03)
Use in one trimester	202	37 (18.3)	0.94 (0.64, 1.37)	0.89 (0.60, 1.32)		458	64 (14.0)	0.81 (0.61, 1.07)	0.81 (0.61, 1.08)
Use in two trimesters	126	15 (11.9)	0.56 (0.32, 0.98)	0.50 (0.28, 0.89)		283	31 (11.0)	0.61 (0.42, 0.90)	0.65 (0.43, 0.97)
Use in three trimesters	55	7 (12.7)	0.61 (0.27, 1.36)	0.49 (0.21, 1.19)		113	22 (19.5)	1.21 (0.75, 1.94)	1.21 (0.74, 2.00)
Hypoxia-related placental change					0.244					0.253
Not use	1638	383 (23.4)	Ref.	Ref.		4127	865 (21.0)	Ref.	Ref.
Use aspirin ^b	408	89 (21.8)	0.95 (0.90, 1.02)	0.91 (0.85, 0.98)		912	168 (18.4)	0.98 (0.94, 1.02)	0.98 (0.93, 1.03)
Use in one trimester	216	51 (23.6)	1.01 (0.73, 1.41)	0.99 (0.70, 1.39)		485	89 (18.4)	0.85 (0.66, 1.08)	0.85 (0.66, 1.09)
Use in two trimesters	133	29 (21.8)	0.91 (0.60, 1.40)	0.77 (0.48, 1.24)		305	49 (16.1)	0.72 (0.53, 0.99)	0.74 (0.53, 1.04)
Use in three trimesters	59	9 (15.3)	0.59 (0.29, 1.21)	0.43 (0.20, 0.91)		122	30 (24.6)	1.23 (0.81, 1.87)	1.20 (0.75, 1.92)
a. GEE model, adjusted for mother age, race, social economic status, smoking, gestational age at birth, and parity.
b. Considered the number of months of aspirin use during pregnancy as a continuous variable into GEE model.

The association between aspirin use during pregnancy and specific placental lesions were further explored in both obese and overweight populations. Aspirin exposure was significantly associated with a lower risk of hypoxia-related placental pathology, such as thrombus, calcification, cysts, fibrin deposition and syncytium-nuclear clumping (Table 4).

Table 4

Separate hypoxia-related placenta measures associated with the duration of aspirin use in pregnancy ^a
		Obese (n = 2286)			Overweight (n = 5673)
		One trimester	Two trimesters	Three trimesters	One trimester	Two trimesters	Three trimesters
Gross
Membranes and fetal surface
Color	0.72 (0.38, 1.39)		0.34 (0.11, 1.06)	0.35 (0.11, 1.09)	0.63 (0.38, 1.06)	0.66 (0.35, 1.27)	1.39 (0.60, 3.14)
Opacity of membranes	1.06 (0.66, 1.71)		0.41 (0.18, 0.95)	0.47 (0.14, 1.62)	0.92 (0.65, 1.32)	0.55 (0.31, 0.99)	1.43 (0.78, 2.60)
Sub-chorionic fibrin	1.57 (0.97, 2.53)		0.91 (0.54, 1.53)	1.36 (0.54, 3.42)	1.01 (0.75, 1.36)	0.70 (0.50, 0.98)	0.88 (0.48, 1.60)
Description of sub-chorionic fibrin	1.63 (1.00, 2.67)		0.90 (0.54, 1.52)	1.35 (0.54, 3.40)	0.99 (0.73, 1.33)	0.69 (0.49, 0.96)	0.86 (0.47, 1.56)
Thrombosed fetal vessels	1.82 (0.25, 13.08)		-	-	0.54 (0.07, 4.02)	1.11 (0.15, 8.42)	-
Cysts	1.23 (0.65, 2.33)		1.01 (0.41, 2.47)	1.25 (0.41, 3.85)	0.87 (0.54, 1.42)	0.88 (0.46, 1.68)	0.73 (0.28, 1.92)
Maternal surface
Total number of infarcts	1.23 (0.88, 1.73)		0.98 (0.61, 1.57)	0.96 (0.52, 1.79)	0.90 (0.70, 1.14)	0.72 (0.51, 1.00)	1.14 (0.73, 1.77)
Infarcts pink-red, marginal	1.04 (0.41, 2.65)		0.78 (0.16, 3.84)	1.76 (0.44, 7.04)	1.23 (0.69, 2.18)	0.79 (0.34, 1.81)	2.34 (0.92, 5.93)
Infarcts pink-red, not marginal	1.77 (0.82, 3.83)		0.46 (0.11, 2.03)	0.52 (0.09, 2.98)	1.90 (1.00, 3.58)	1.80 (0.80, 4.05)	2.72 (0.90, 8.21)
Infarcts yellow-white, marginal	0.88 (0.55, 1.42)		0.97 (0.52, 1.82)	1.08 (0.49, 2.39)	0.77 (0.57, 1.05)	0.58 (0.36, 0.93)	0.96 (0.56, 1.66)
Infarcts yellow-white, not marginal	1.27 (0.81, 2.01)		0.94 (0.48, 1.83)	0.35 (0.09, 1.32)	0.95 (0.68, 1.32)	0.72 (0.45, 1.17)	0.85 (0.42, 1.70)
Infarcts yellow-white, unknown location	1.66 (0.37, 7.52)		-	-	1.66 (0.37, 7.45)	2.89 (0.63, 13.24)	-
Infarcts unknown color, marginal	-		-	-	1.49 (0.19, 11.80)	-	-
Cut surface
Infarcts unknown color, unknown location	0.15 (0.04, 0.54)		-	-	1.07 (0.25, 4.53)	-	-
Size of infarcts	1.27 (0.91, 1.77)		0.96 (0.59, 1.55)	0.86 (0.46, 1.62)	0.91 (0.72, 1.16)	0.70 (0.50, 0.98)	1.18 (0.76, 1.83)
Maternal floor infarcts	0.73 (0.09, 5.84)		1.36 (0.17, 10.50)	-	1.13 (0.26, 4.91)	1.01 (0.13, 7.62)	-
Color	0.25 (0.03, 1.90)		0.97 (0.24, 3.82)	-	2.20 (1.29, 3.78)	0.90 (0.35, 2.31)	2.57 (1.00, 6.58)
Consistency	1.14 (0.67, 1.95)		1.06 (0.50, 2.25)	0.61 (0.19, 1.97)	1.11 (0.78, 1.57)	0.94 (0.60, 1.49)	0.96 (0.45, 2.04)
Calcification	0.91 (0.70, 1.20)		0.52 (0.35, 0.77)	0.54 (0.32, 0.91)	0.81 (0.68, 0.98)	0.94 (0.74, 1.19)	0.99 (0.68, 1.45)
Total of intervillous thrombosis	0.95 (0.60, 1.49)		0.55 (0.26, 1.16)	0.39 (0.12, 1.29)	0.65 (0.47, 0.92)	0.48 (0.28, 0.80)	0.56 (0.26, 1.21)
Total number of laminated thrombus	0.99 (0.62, 1.59)		0.65 (0.31, 1.37)	0.44 (0.13, 1.50)	0.69 (0.48, 0.99)	0.61 (0.37, 1.03)	0.63 (0.27, 1.44)
Number of laminated thrombus in marginal sinus	0.72 (0.09, 5.50)		-	-	0.74 (0.17, 3.14)	-	-
Total number of not laminated thrombus	0.60 (0.16, 2.17)		0.20 (0.05, 0.77)	-	0.58 (0.25, 1.32)	0.18 (0.02, 1.27)	-
Number of not laminated thrombus in marginal sinus	-		-	-	0.47 (0.05, 4.23)	-	0.46 (0.10, 2.16)
True cysts	1.12 (0.50, 2.51)		0.50 (0.10, 2.53)	0.56 (0.12, 2.50)	0.56 (0.30, 1.08)	0.82 (0.38, 1.74)	1.14 (0.43, 3.04)
Microscopic
Cord
Thrombosis of vessels	0.59 (0.08, 4.48)		1.32 (0.17, 10.12)	-	-	1.52 (0.36, 6.50)	-
Membrane
Macrophage in amnion or chorion	0.62 (0.19, 2.06)		0.64 (0.14, 2.85)	-	0.19 (0.05, 0.77)	0.57 (0.18, 1.76)	-
Macrophage in decidua	0.36 (0.05, 2.77)		1.53 (0.40, 5.85)	-	0.26 (0.06, 1.05)	1.01 (0.35, 2.89)	0.76 (0.24, 2.42)
Decidua
Vessels thrombosis	1.36 (0.46, 4.03)		1.21 (0.28, 5.21)	-	1.28 (0.54, 3.06)	1.15 (0.35, 3.75)	-
Vessels fibrinoid	2.28 (0.96, 5.44)		1.19 (0.28, 5.07)	1.51 (0.20, 11.38)	0.71 (0.30, 1.65)	0.28 (0.11, 0.75)	0.62 (0.06, 5.93)
Vessels atheroma	-		3.36 (0.71, 15.87)	-	2.09 (0.58, 7.48)	-	4.46 (0.58, 34.18)
Cytotrophoblast of columns fibrin deposition	0.77 (0.36, 1.63)		0.35 (0.13, 0.91)	0.17 (0.02, 1.15)	0.66 (0.38, 1.16)	0.66 (0.32, 1.35)	0.38 (0.10, 1.47)
Cytotrophoblast of columns cystic change	1.55 (1.13, 2.14)		2.31 (1.56, 3.41)	1.20 (0.64, 2.28)	1.48 (1.20, 1.83)	1.42 (1.09, 1.87)	1.23 (0.78, 1.95)
Syncytium -Nuclear clumping	1.22 (0.79, 1.90)		0.56 (0.28, 1.10)	0.58 (0.19, 1.84)	0.98 (0.72, 1.34)	0.72 (0.48, 1.10)	1.08 (0.59, 1.96)
Terminal villi
Langhens layer	-		2.67 (0.59, 12.06)	-	0.31 (0.03, 3.15)	0.12 (0.02, 0.68)	0.18 (0.02, 1.51)
Hofbauer cells	1.26 (0.44, 3.67)		2.19 (0.87, 5.56)	1.96 (0.37, 10.46)	0.43 (0.16, 1.18)	1.35 (0.64, 2.86)	1.80 (0.64, 5.03)
Stromal fibrosis	0.69 (0.29, 1.64)		1.03 (0.38, 2.76)	0.33 (0.05, 2.05)	0.84 (0.47, 1.51)	1.19 (0.60, 2.34)	1.53 (0.59, 3.96)
Pathological edema	0.89 (0.37, 2.17)		0.49 (0.16, 1.57)	0.69 (0.14, 3.49)	0.62 (0.32, 1.20)	1.79 (1.05, 3.07)	2.31 (1.01, 5.28)
Micro infarcts	0.95 (0.61, 1.47)		1.14 (0.66, 1.95)	0.70 (0.27, 1.83)	0.93 (0.68, 1.28)	1.08 (0.73, 1.60)	1.06 (0.57, 1.97)
Nucleated RBC in fetal circulation	-		1.65 (0.38, 7.27)	-	1.12 (0.52, 2.38)	0.85 (0.29, 2.53)	0.95 (0.22, 4.15)
Intervillous space
Intervillous thrombi and adjacent villous	0.85 (0.53, 1.38)		0.63 (0.31, 1.28)	0.82 (0.33, 2.08)	0.78 (0.55, 1.12)	0.62 (0.37, 1.04)	0.81 (0.37, 1.76)
Marginal sinus thrombi	0.21 (0.03, 1.56)		0.93 (0.22, 4.03)	0.67 (0.14, 3.15)	0.83 (0.33, 2.10)	0.86 (0.29, 2.57)	-
Sickling-Maternal blood	0.31 (0.04, 2.40)		0.57 (0.08, 4.31)	-	1.23 (0.55, 2.72)	1.14 (0.40, 3.21)	-
Apparent maturity of placenta	0.75 (0.44, 1.26)		1.10 (0.53, 2.30)	4.61 (0.56, 37.88)	1.13 (0.77, 1.66)	1.49 (0.88, 2.54)	0.67 (0.36, 1.25)
Women who did not use aspirin during pregnancy were considered as a reference group.
a. GEE model, adjusted for mother age, race, social economic status, smoking, gestational age at birth, and parity. Adjusted OR (95% CI) were showed in the table.

Our prospective cohort study found that aspirin use during pregnancy was associated with a lower risk of hypoxia-related and hemorrhage-related placental pathologic lesions in obese population and may also have a protective effect on inflammation-related placental pathology. The effect in overweight population was not as prominent as that showed in obese women. The longer women used aspirin during pregnancy, the lower the risk of hypoxia-related, hemorrhage-related, and inflammation-related placental pathology. Furthermore, aspirin use during pregnancy was associated with lower risks of placental pathology, such as thrombus, calcification, cysts, fibrin deposition, syncytium-nuclear clumping, necrosis, infiltration of macrophage and neutrophil.

Placenta delivers oxygen and nutrients from maternal to the growing fetus. Placental pathology plays an essential role in placenta-mediated pregnancy complications, such as preeclampsia, preterm birth, and fetal growth restriction [8]. In our previous analysis with CPP data, we demonstrated that compared to normal weight women, obese women were more likely to suffer from abnormal placental pathology, including placental vascular infarct, villous infarct, thrombosis, and vessels atheroma [9]. These infarction and endothelial dysfunction further may develop into profound hypoxia in some area. Our current findings suggest that aspirin was associated with a lower risk of hypoxia-related placental pathologies during pregnancy in obese population. The role of aspirin was mainly reflected in the reduced thrombosis, calcification, and fibrin deposition, which may be associated with the duration of aspirin use during pregnancy. Hypoxia-related placental pathologies may lead to deficient implantation and circulation of the placenta, and finally evolve into the pathogenesis of preeclampsia [10]. The similar effects of aspirin on placental pathologies were also found in women with chronic hypertension [18], which was mainly due to aspirin’s antithrombotic effect.

Obesity is a chronic inflammatory condition which is triggered by inflammatory cytokines secreted by adipocytes, leading to the recruitment of macrophages to adipose tissue [24]. The inflamed adipose microenvironment promotes the polarization of anti-inflammatory M2 macrophages to pro-inflammatory M1 macrophages [25]. Thus, obesity drives a shift in the number and phenotype of immune cells, including decreased numbers of eosinophils and Tregs, and increased numbers of neutrophils, B cells and mast cells, finally leading to systematic inflammation [26]. The activation of prothrombotic signaling pathways in vascular cells and impairment of fibrinolysis are the major consequences of the chronic inflammatory state of obesity [26]. In our study, there was no significant difference in the inflammatory-related cell infiltration in placentae between two groups (aspirin use or not). However, a tendency that aspirin reduced inflammatory-related cell infiltration was observed. Studies with low-dose aspirin from 10–12 weeks till term are needed to verify this finding.

In addition to the known antithrombotic and anti-inflammatory effects of aspirin, other potential effects of aspirin have recently prompted interests from researchers. Recent studies demonstrated that aspirin could enhance cell invasiveness of trophoblasts [27–29], which contributes to the conversion of the maternal spiral artery and increase the blood perfusion of the placenta. Evidence showed the defects in spiral artery remodeling in obese women manifested by a greater degree of muscularity in the uteroplacental vasculature than non-obese controls [30]. In addition, an animal experiment observed that the placental spiral arteries of high fat diet mice were surrounded by a higher level of smooth muscle cells, suggesting impaired spiral artery remodeling [31]. Unfortunately, CPP did not have direct measures on placental pathology of vascularization. We, thus, cannot be certain of aspirin’s effect in that aspect. Nonetheless, healthy vascularization may decrease the risks of hypoxia- and hemorrhage-related pathologies. As such, our finding that aspirin use in early pregnancy was associated with lower risks of such placental pathologies supports the overall concept.

The current study showed that aspirin use during pregnancy was associated with a lower risk of hemorrhage-related placental pathologic changed in obese women, which are similar to previous findings. Our previous research demonstrated that aspirin does not increase the risk of placental hemorrhage [18]. A meta-analysis found that taking aspirin at a daily dose greater than 100mg before the 16th week of gestation may decrease the risk of prenatal hemorrhage and placental abruption (OR = 0.62, 95%CI: 0.31–1.26) [32]. Recently, Hasan et al. also reported that aspirin had a protective effect on preventing aneurysmal subarachnoid hemorrhage (OR = 0.27, 95%CI: 0.11–0.67) [33]. It was speculated that matrix metalloproteinase secreted by macrophages were involved in the formation and rupture of diseased blood vessels [34]. Aspirin was showed to inhibit the expression of matrix metalloproteinase and recruitment of monocytes and macrophages by tissue [35, 36].

The CPP is a unique prospective birth cohort study that collected reliable maternal characteristics and medical information including placental measures in a large population [14]. More than 40,000 placenta pathological examinations were performed blindly to clinical diagnoses by a team of specially trained pathologists according to a standardized protocol and strict quality control procedures. CPP is still the most comprehensive and largest placenta database in the world, providing an excellent opportunity to explore the association between placental pathological changes and aspirin exposure during pregnancy in different populations with a large sample size.

However, several limitations of our study are worth mentioning. First, in the CPP era, aspirin was widely used as an antipyretic, analgesic, and anti-inflammatory drug. Its administration dosage was over 300mg, higher than the current recommended low dose (60-150mg daily) for the prevention of preeclampsia [12, 37, 38]. The difference in duration and dosage of aspirin use during pregnancy made it difficult to evaluate the protective effect on preeclampsia accurately. Nonetheless, our findings are consistent with the possible mechanisms of aspirin preventing preeclampsia in obese women. Second, the duration of aspirin was recorded semi-quantitatively. Thus, we were unable to estimate a precise duration of aspirin use. Inaccurate classification may have reduced the validity of our results. However, we found that the duration of aspirin use were positively associated with favorable placental pathology, which is consistent with a possible cause-effect. Future studies on low-dose aspirin are needed to confirm our findings.

We found that aspirin use during pregnancy may decrease the risk of placental pathological lesions in obese women. There was a positive relationship between the duration of use and favorable placental pathology. This study provided some evidence on the biological mechanisms of aspirin in the prevention of placenta-mediated pregnancy complications in obese women.

Ethics approval and consent to participant

Waiver of ethics approval was given by the Ethics Review Board of the Xinhua Hospital Affiliated to the Shanghai Jiao Tong University School of Medicine. All methods were performed in accordance with the relevant guidelines and regulations. The CPP data used in this study was anonymized before its use. Since the data are publicly available, no administrative permission was required to access the raw data.

Consent for publication

Not applicable.

Availability of data and materials

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests

All the authors did not have conflict of interest.

Funding

JZ acknowledges financial support from the Shanghai Municipal Health Commission (GWV-10.1-XK07; 2020CXJQ01)

Authors’ contributors

JZ conceived and designed the study. SJ and YJ analyzed the data and drafted the manuscript. DL verified the underlying data. ZX, LF and HX commented and revised drafts of the manuscript. All authors contributed to the review and revision, approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

Acknowledgements

Not applicable.

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No competing interests reported.

Supplementary.docx

Aspirin use during pregnancy and placental pathology in obese women in a large prospective cohort study

Status:

Version 1

Abstract

Figures

1 Background

2 Methods

2.1 Study population

2.2 Placental pathology and the composite pathologic placental index

2.3 Aspirin exposure during pregnancy

2.4 Confounders

2.5 Statistical analysis

3 Results

4 Discussion

5 Conclusions

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1