Potential Impact on Using Aspirin as the Primary Prevention of Adverse Pregnancy Outcomes in Twins conceived using ART: A Retrospective Case-Control Study in A Tertiary Hospital

doi:10.21203/rs.3.rs-3405175/v1

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Potential Impact on Using Aspirin as the Primary Prevention of Adverse Pregnancy Outcomes in Twins conceived using ART: A Retrospective Case-Control Study in A Tertiary Hospital

https://doi.org/10.21203/rs.3.rs-3405175/v1

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published 26 Jan, 2024

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With the development of assisted reproductive technology, the number of twin pregnancies is increasing year by year. Given the increased risk of pregnancy complications associated with twin pregnancies, and the fact that these babies are rare and difficult to obtain through assisted reproductive technology, clinicians urgently need to find effective and safe drugs to improve pregnancy outcomes. Aspirin can not only promote placental blood supply, but also effectively anti-inflammatory. Whether aspirin can effectively reduce the risk of pregnancy complications in this special group needs to be clarified. We therefore retrospectively analyzed 665 twin pregnancies from assisted reproduction technology, grouped according to aspirin use, and followed pregnancy outcomes to assess bleeding risk. Aspirin was found to be effective in preventing hypertensive disorders of pregnancy without a significant risk of bleeding. However, aspirin does not prevent specific complication in twins and may increase the incidence of uterine artery embolization, which should alarm clinicians should not blindly using aspirin in this particular group.

Health sciences/Risk factors

Biological sciences/Drug discovery/Drug safety

Aspirin

Twin pregnancies

Assisted Reproductive Technology

Prevention

Advanced Maternal Age

Hypertensive Disorders of Pregnancy

Selective Intrauterine Growth Restriction

Assisted reproductive technology (ART) has become an integral part of modern medicine since 1978 [1]. However, pregnancies from ART might not have a better perinatal outcome than non-assisted pregnancies [2]. On the other hand, growing utilization of assisted reproductive technology (ART) and advanced maternal age births have resulted in an overall increase in the incidence of twin pregnancies [3]. However, comparing singletons, the complication of twin pregnancies with their increased morbidity and mortality has created significant problems. including preterm labor (PTL), hypertensive disorders of pregnancy, intrauterine growth restriction and scarred uterus [4]. The rate of preterm labor in twins is > 50%, approximately two to three times greater as compared to singleton pregnancies [5]. The relative risk of preeclampsia also has dramatically increase among twins compared to singletons, 3.50 for dichorionic twins and 2.61 for monochorionic twins, respectively [6]. Rates of caesarean section were significantly higher in twin pregnancies than that in singletons [7]. Moreover, clinicians also should be aware of the likelihood of psychological problems in mothers of multiples and women undergoing assisted reproductive treatment because of the higher expectation of their pregnancy outcomes [8].

Among singletons, preeclampsia and fetal growth restriction often coexist, with related placental pathologies [9]. Strong evidence suggests that initiation of low-dose aspirin prophylaxis prior to 16 weeks gestation reduces the relative risk of developing preeclampsia (PE) or delivering a small for gestational age (SGA) neonate [10]. Thus, aspirin has been suggested to prevent preeclampsia, fetal growth restriction or birth of a small-for-gestational-age (SGA) neonate [11]. There was a randomised, double-blind, placebo-controlled trial rolled 11976 women suggested that the incidence of preterm labor in women took aspirin was 11.6%, lower than that in women took aspirin (13.1, RR 0·89 [95% CI 0·81 to 0·98], p = 0·012) [12]. In addition to these potential benefits, clinicians also need to weigh risks, that is using aspirin during pregnancy might increase the risk of postpartum bleeding [13]. However, few studies have reported the effectiveness of LDA in twin pregnancies, especially in twin pregnancies from ART [14]. Accordingly, it was our aim to assess whether there is a beneficial improvement of pregnancy outcomes after LDA use in twin pregnancies from ART.

In total, 665 twin pregnancies from ART were recruited in this study. Among them, 155 lost to follow-up were excluded for final analysis. Finally, we obtained complete information from 510 pregnancies (253 in LDA and 257 in control group). The study population included 476 DC and 34 MC twin pregnancies,. The baseline characteristics of the twin pregnancies included in the study are shown in Table 1.

Table 1

Maternal baseline clinical characteristics
Characteristics	Total cases (510)
Year, n (%)
2016		43 (8.43%)
2017		63 (12.4%)
2018		73 (14.3%)
2019		92 (18.0%)
2020		108 (21.2%)
2021		131 (25.7%)
Age (y), n (%)		31.4 ± 3.83
≤35		437 (85.7%)
>35		73 (14.3%)
BMI(kg/m²), mean ± SD		21.9 (21.9 ± 2.94)
Parity, n (%)
Nulliparous		450 (88.23%)
1–3		59 (11.57)
≥ 4		1 (0.20%)
Previous cesarean delivery, n (%)
Yes		25 (4.90%)
Occupation, n (%)
Employed		481(94.31%)
Unemployed		29 (5.69%)
Type of twin pregnancy
DCDA		476 (93.3%)
MCDA		34 (6.67%)
Gestational age at delivery (wk), n (%)
<32		9 (1.76%)
32–34		9 (1.76%)
34–37		52 (10.2%)
>=37		440 (86.3%)
Mode of delivery, n (%)
Vaginal delivery		494 (96.86%)
Cesarean delivery		16(3.14%)
Birth weight (g), mean ± SD		2540 (2540 ± 932)
Apgar score in 5 mins, mean ± SD		9.89 (9.89 ± 0.41)
Aspirin use, n (%)
Yes		253 (49.6%)

Comparison of prevalence of aspirin use in .

In this nearly six-year study, we found that twin pregnancies from ART are increasing. Aspirin use is also increasingly prevalent in this particular group of pregnant women (χ2 = 75.513, p < 0.05) (Table 2). However, the benefits and risks of aspirin are not clear.

Table 2

Prevalence of aspirin use
		Aspirin use		X²	P value
		No	Yes	X²	P value
Years	2016	7	2	75.513	< 0.001
	2017	6	3
	2018	27	25
	2019	217	223
	2020	239	221
	2021	18	32

Comparison of Complications in Twin Pregnancies from ART with Different Aspirin use or not.

Complications were compared between the two groups. The incidence of women overall hypertensive disorders of pregnancy was lower in women taking aspirin than in women taking nothing (χ2 = 4.593, p < 0.05). Out of we expected, aspirin use did not contribute much to gestational age at delivery. In addition, the incidence of gestational diabetes (χ2 = 0.001, p = 0.978), placenta accrete (χ2 = 0.098, p = 0.754) and placental abruption (χ2 = 1.866, p = 0.172) were not different between women who received aspirin or not. However, The rate of cesarean section neonatal was lower in aspirin use group than that of the no use group, and the difference was statistically significant ( χ2 = 4.001, p = 0.045). Other maternal outcomes were similar between the groups (Table 3). The protective role of LDA on specific complication in twins, however, was uncertain (χ2 = 1.623, p = 0.203) (Table 4).

Table 3

Gestational disorders by aspirin use during pregnancy
		Aspirin use		X²	P value
		No	Yes	X²	P value
Gestational age at delivery (wk)	< 32	7	2	3.905	0.272
	32–34	6	3
	34–37	27	25
	>=37	217	223
Hypertensive disorders of pregnancy—all forms	No	239	221	4.593	0.032
Hypertensive disorders of pregnancy—all forms	Yes	18	32	4.593	0.032
Gestational diabetes	No	174	83	0.001	0.978
Gestational diabetes	Yes	171	82	0.001	0.978
Premature rupture of membranes	No	205	215	2.385	0.123
Premature rupture of membranes	Yes	52	38	2.385	0.123
Placenta accrete	No	212	206	0.098	0.754
Placenta accrete	Yes	45	47
Placenta previa	No	248	246	0.227	0.634
Placenta previa	Yes	9	7
Placental abruption	No	256	249	1.866	0.172
Placental abruption	Yes	1	4
ICP	No	223	225	0.558	0.455
ICP	Yes	34	28
Abnormal amniotic fluid volume	No	246	240	0.209	0.647
Abnormal amniotic fluid volume	Yes	11	13
Thyroid dysfunction	No	227	220	0.221	0.638
Thyroid dysfunction	Yes	30	33
Mode of delivery	Cesarean delivery	245	249	4.001	0.045
Mode of delivery	Vaginal delivery	12	4

Table 4

Specific complication in twins by aspirin use during pregnancy
		Aspirin use		X²	P value
		No	Yes
Gestational typical disorders in twins^*	No	243	232	1.623	0.203
	Yes	14	21
^* The number of mothers who experienced at least one of the 7 outcomes including SGA, SIUGR, TRAP, TTTS, Stillbirth in one of the twins; Stillbirth of twins, Abortion;

Comparison of bleeding risk in Twin Pregnancies from ART with Different Aspirin use or not

Notably, Aspirin use did not increase the risk of bleeding during delivery or postpartum. No difference in Postpartum hemorrhage (χ2 = 0.063, p = 0.801) between the two groups. Also, there was no observed increase in the transfer to Intensive Care Unit (ICU) (χ2 = 0.32, p = 0.572) and postpartum blood transfusion (χ2 = 0.186, p = 0.666). Aspirin's antithrombotic properties may lead to more uterine embolism (χ2 = 4.095, p = 0.043) (Table 5).

Table 5

Labor and postpartum bleeding-related complications by aspirin use during pregnancy
		Aspirin use		X²	P value
		No	Yes	X²	P value
Postpartum hemorrhage	No	223	225	0.063	0.801
Postpartum hemorrhage	Yes	34	28
Transfusion Therapy	No	246	240	0.186	0.666
	Yes	11	13
Uterine artery embolization	No	227	220	4.095	0.043
	Yes	30	33
Transfer to ICU	No	223	225	0.32	0.572
	Yes	34	28
^* Weight medium (large-small)/large *100% ≥ 20%

Comparison of neonatal outcomes in Twin Pregnancies from ART with Different Aspirin use or not

There was no statistical significance of the outcome of neonates between the groups except neonatal gender (P = 0.006). Aspirin may affect uterine artery blood flow, however, neither affect neonatal weight gain (P = 0.491) nor cause their weight differences (0.966). Unfortunately, aspirin use did not reduce their admission to the NICU (P = 0.768) (Table 6).

Table 6

Birth and birth-related characteristics by aspirin use during pregnancy
	Aspirin use		P value
	No	Yes	P value
Neonatal gender:
Like-sex male	60 (23.3%)	79 (31.2%)	0.006
Unlike-sex	144 (56.0%)	106 (41.9%)
Like-sex female	53 (20.6%)	68 (26.9%)
Percent difference in birth weight > 20%, n (%)
No	229 (89.1%)	216 (85.4%)	0.258
Yes	28 (10.9%)	37 (14.6%)	0.258
Mean birth weight (g), mean ± SD	2528 (2528 ± 967)	2552 (2552 ± 898)	0.775
Smaller birth weight (g), mean ± SD	2334 (2334 ± 477)	2361 (2361 ± 398)	0.491
Difference in birth weight^* (g), mean ± SD	388 (388 ± 1712)	382 (382 ± 1643)	0.966
Transfer to NICU
No	187 (72.8%)	188 (74.3%)	0.768
Yes	70 (27.2%)	65 (25.7%)	0.768

Twin pregnancies are occurring more frequently with the development of ART, and these women are more likely to develop complications such as gestational hypertension, gestational diabetes, and premature birth [15–17]. There is general consensus on the potential effect of aspirin in early pregnancy for singleton pregnancies to prevent preeclampsia [18–20], selective fetal restriction [21], or preterm labor [12]. However, the effect and safety of aspirin prophylaxis during pregnancy for twin pregnancies from ART have not been discussed. Aspirin also seems to have a good preventive effect in Twin pregnancies [22]. Coincidentally, A large proportion of IVF pregnant women will take aspirin in the first trimester because they need to increase uterine artery blood flow [23, 24], which leads us to believe empirically that aspirin will bring good prevention effect in this special group of IVF twins. As it turns out, the tepid performance of aspirin surprised us. Our study found that aspirin does reduce the risk of hypertensive disorders of pregnancy. However, there was no significant protective effect on other outcomes such as premature delivery and fetal weight. In addition, although aspirin use in the first trimester did not appear to carry a significant risk of bleeding, it was associated with uterine artery embolization. This indicates that aspirin as a double-edged sword, can effectively prevent the occurrence of pregnancy hypertension disease, but also brings more risks of interventional operation.

Unlike common anticoagulants such as heparin, low-dose aspirin the most widely used antipyretic analgesic and anti-inflammatory drug in the world. After hydrolysis in vivo, aspirin is distributed throughout the body as salicylate and can pass through the placenta [25]. As a popular and affordable drug in obstetrics and gynecology, low-dose aspirin can effectively prevent preeclampsia and fetal growth restriction in singleton pregnancy due to its effect on improving placentation [26]. Aspirin's role in preventing preterm labor require further investigation, with some studies showing that low-dose aspirin can prevent iatrogenic preterm labor caused by preeclampsia [27] and others showing that aspirin can reduce the risk of recurrent preterm births [28]. But there is little strong evidence that low-dose aspirin as an anti-inflammatory prolongs gestational weeks and prevents spontaneous preterm labor. Onset of preterm labor remains multifactorial with infammation and immunological disorders. Aspirin could downregulate many infammatory factors [29], could theoretically lower the incidence of PTL as an immunomodulatory agent. We were fortunate to find that aspirin was still effective in preventing hypertensive disorders of pregnancy in twin pregnancies from ART, however aspirin was not found to prevent selective fetal restriction or other Specific complication in twins. Nor did it prolong pregnancy and prevent spontaneous preterm labor. Pregnancy complications in twin pregnancies have more complex mechanisms than in singleton pregnancies, so aspirin may not solve all of these problems. Selective fetal restriction does have a similar pathogenesis to hypertensive disorders of pregnancy [14, 30], aspirin may prevent preeclampsia by altering placental blood supply, however, in twin idiopathic disorders, such as TRAP and TTTS, most are caused by abnormal placental angiogenesis during early embryogenesis or abnormal development of the heart in one of the fetuses[31, 32]. Aspirin alone may not be able to reverse this problem. Even if ART does not increase major obstetric complications and perinatal risk in twin pregnancies[33], women who need ART may have underlying problems themselves that increase the risk of adverse pregnancy outcomes. This may also be why aspirin does not have the desired overall effect.

Besides, a number of studies have also questioned aspirin, which may connect to increased bleeding such as placental abruption and postpartum hemorrhage, leading to concerns that this harmful side effect may outweigh its benefits [34–37]. However, low-dose aspirin in our study did not increase the risk of bleeding, which may be due to our dose selection of 100mg/d and timely discontinuation in the third trimester. The increased incidence of uterine artery embolization in aspirin use group may be due to prophylactic embolization performed by clinicians considering the potential bleeding risk associated with aspirin use. It cannot be completely ruled out that this procedure corrects the effect of aspirin on postpartum hemorrhage. And the price of uterine artery embolization can become an economic burden on pregnant women, contrary to the economic benefits advocated by aspirin.

Highlights

To our knowledge, this is a novel study in the obstetrics field, which revealed the effectiveness and risk of aspirin in IVF twin pregnancy. To enable clinical workers to correctly face the advantages and disadvantages of drug use, and effectively improve the pregnancy outcome of specific pregnant women on the premise of ensuring the safety of drug use.

As aspirin became more widely available, we found that aspirin did not have the totally same therapeutic effect in twin pregnancies from ART. Low-dose aspirin (100mg/d) initiated at early gestational age in twin pregnancies from ART could significantly reduce the risk of hypertensive disorders of pregnancy without increasing the risk of serious bleeding-related complications. This study focuses on the advantages and disadvantages of aspirin application and provides a multi-dimensional reference for clinical work.

Study population

This study was a tertiary hospital-based retrospective cohort study that included women with twin pregnancies from ART between January 2016 to December 2021 were included in the study (n = 665), and their data from electronic standardized prenatal, delivery, and neonatal records. Informed consent was obtained from all participants. Inclusion criteria were: Twins conceived using ART diagnosed by ultrasound in the first visit (gestational age less than 16 weeks); 18–55 years old. Those who did not start their first antenatal care in our hospital were excluded because of their missing maternal prenatal health records. We also excluded women who had reported use of low-molecular-weight heparin or selective serotonin reuptake inhibitors, since we aim to explore the potential benefits of aspirin on twin pregnancies from ART. We finally followed up 510 women (253 in the LDA group and 257 in the control group). The ethics approval was obtained from the Ethics Committee of the First Affiliated Hospital of Chongqing Medical University. All experiments were performed in accordance with relevant guidelines and regulations.Research involving human research participants have been performed in accordance with the Declaration of Helsinki. Enrollment characteristics are presented in Table 1.

Exposure

Owing the fact that there were few evidences suggest the safety of aspirin given in twin pregnancy from ART, the obstetricians in this study carried out different policies on aspirin use for twin pregnancies from ART randomly and thus made this observational study feasible. 100mg/d given in first prenatal visit (10–16 gestational weeks) was set as aspirin group. All data on aspirin use were obtained from prenatal care records.

Outcome measures

The primary outcomes were the incidence of pregnancy complications which was categorized into (1) common complications during pregnancy, such as gestational age at delivery, hypertensive disorders of pregnancy, gestational diabetes (GDM), premature rupture of membranes (PROM), placenta accreta placenta, previa placental abruption, intrahepatic cholestasis of pregnancy (ICP), abnormal amniotic fluid, abnormal thyroid function, mode of delivery. and secondary outcomes were specific complication in twins included small for gestational age (SGA), selective intrauterine growth restriction (SIUGR), twin reverse arterial perfusion sequence sign (TRAP), twin-to-twin transfusion syndrome (TTTS), stillbirth and abortion. Clinical safety of aspirin was evaluated by the occurrence of postpartum hemorrhage, transfusion. uterine artery embolization and transfer to ICU. The assessment of birth and birth-related characteristics included sex ratio, birth weight and transfer to NICU.

Definition

Hypertensive disorders of pregnancy including gestational hypertension, Preeclampsia, Eclampsia or HELLP syndrome were defined by blood pressure ≥ 140/90mmHg associated with proteinuria (> 300mg/day) or not) after 20 weeks of gestational age. Blood pressure was measured by a mercury sphygmomanometer and urine samples were collected and tested by the clinical laboratory in hospital. When calculating the amount of bleeding, intraoperative blood loss was recorded by the container of suction apparatus, while postoperative bleeding volume was counted by weighting. Cesarean postpartum hemorrhage was defined as postoperative bleeding volume > 1000ml in 24h, as for vaginal postpartum hemorrhage, was > 500ml in 24h. All other complications and adverse pregnancy outcomes were defined following international obstetrical practice.

Statistical analysis

SPSS version 22.0 software (SPSS Inc., Chicago, USA) was used for all statistical analyses. We described as mean ± standard deviation if continuous variables were in accordance with a normal distribution and examined them by the T test. The correlation coefficient is calculated by chi-square test and Fisher exact test to illustrate the correlation between classified variables those were presented by percentage. P < 0.05 were considered statistically significant.

ART Assisted reproductive technology

PE preeclampsia

PTL preterm labor

SGA small for gestational age

LDA low-dose aspirin

GDM gestational diabetes

PROM premature rupture of membranes

ICP intrahepatic cholestasis of pregnancy

SIUGR selective intrauterine growth restriction

TRAP twin reverse arterial perfusion sequence sign

TTTS twin-to-twin transfusion syndrome

Acknowledgments

We thank participants in this retrospective cohort study and the study physicians and nurses for their contributions to this study.

Authors' contributions

Conception of the study: DH, XL and HQ. Data collection: YX, PD, JW and JX. Statistical analysis: DH. All authors made substantial contributions to the paper and read and approved the final manuscript.

Data availability statement

All data generated for this study are included in the article, and further inquiries can be directed to the corresponding author.

Additional Information

Competing interests: The author(s) declare no competing interests.

Correspondence and requests for materials should be addressed to X.L. or H.Q.

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No competing interests reported.

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Potential Impact on Using Aspirin as the Primary Prevention of Adverse Pregnancy Outcomes in Twins conceived using ART: A Retrospective Case-Control Study in A Tertiary Hospital

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Journal Publication

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Abstract

Introduction

Results

Comparison of bleeding risk in Twin Pregnancies from ART with Different Aspirin use or not

Comparison of neonatal outcomes in Twin Pregnancies from ART with Different Aspirin use or not

Discussion

Conclusion

Material and Methods

Study population

Exposure

Outcome measures

Definition

Statistical analysis

Abbreviations

Declarations

References

Additional Declarations

Status:

Journal Publication

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