In vitro fertilization and embryo transfer is an independent risk factor of the placenta accreta spectrum in the termination of pregnancy during the mid-trimester：a retrospective cohort study on perinatal management

doi:10.21203/rs.3.rs-3987938/v1

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In vitro fertilization and embryo transfer is an independent risk factor of the placenta accreta spectrum in the termination of pregnancy during the mid-trimester：a retrospective cohort study on perinatal management

https://doi.org/10.21203/rs.3.rs-3987938/v1

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BACKGROUND

The most common aetiology of placenta accreta spectrum (PAS) is a defect in the endometrial-myometrial interface. The incidence and characteristics of the PAS among women with termination of pregnancy after the second trimester are unknown. This study aimed to determine the effect of in vitro fertilization and embryo transfer (IVF-ET) on patients with termination of pregnancy during the mid-trimester and the risk factors of placenta accreta spectrum among this population.

METHOD

This was a retrospective observational study of women who underwent induced abortion or termination of pregnancy in the second trimester from January 2013 to October 2023 in the Sixth Affiliated Hospital of Sun Yat-sen University. A total of 230 patients were age-matched and divided into a spontaneous conception group and an in vitro fertilization and embryo transfer group to compare the difference in incidence of placenta accreta spectrum and their outcomes during follow-up. The primary outcome was the morbidity of the placenta accreta spectrum.

RESULTS

Our results indicated that women with IVF-ET had a significantly higher risk of suffering PAS (29.6% vs. 13.0%, P = 0.002) as well as morbid placenta accreta spectrum (13.9% vs.5.2%, P = 0.039) during abortion. The amount of postpartum bleeding [200(100.0-520.0) ml vs. 140.0(80.0-240.0)ml, P = 0.004], the rate of postpartum haemorrhage (24.3% vs.11.3%, P = 0.010), and the time of retained products of conception > 4 weeks (40.4%vs.24.8%, P = 0.030) were significantly higher in the IVF-ET group than in the spontaneous conception group. IVF-ET (odds ratio = 2.42, P = 0.027), a hysteroscopy history(odds ratio = 2.67, P = 0.028), and cryopreserved embryo transfer (odds ratio = 4.26, P < 0.001) were independent risk factors for PAS during abortion.

CONCLUSION

Patients with IVF-ET, especially cryopreserved embryo transfer, had a significantly high risk of PAS and postpartum haemorrhage during the abortion of mid-trimester, suggesting that these patients need more attention to avoid severe complications and preserve fertility during labour.

in vitro fertilization and embryo transfer

cryopreserved embryo transfer

termination of pregnancy

placenta accreta spectrum

placenta adherent

second trimester

postpartum haemorrhage

fertility preserve

The placenta accreta spectrum (PAS) is one of the most morbid aetiologies of postpartum haemorrhage. The current rapid increase in caesarean delivery rates worldwide has changed the epidemiology of the placenta accreta spectrum (PAS) from a rare, serious, pathological condition to an increasingly common major obstetric complication[1]. In China, with the increase in the caesarean section rate and the adoption of a two-child policy, the incidence of placenta accreta increased significantly from 0.18–2.2%[2, 3]. Since the International Federation of Gynaecology and Obstetrics (FIGO) guidelines had published the terminology PAS in 2019, placenta adherenta or creta, placenta increta, placenta percreta were encompassed in these terms. Morbidly adherent placenta and invasive placentation were defined by the abnormal placental attachment to the uterus or other structures. The prevalence of the PAS from 1982 to 2018 varied in different studies from 1/100 ~ 1/1000 births[1]. However, the occurrence of PAS in the termination of pregnancy during the mid-trimester was unknown. Placental development starts 6–10 days after conception when trophoblast cells invade the decidua[4]. The maternal decidua is supplied with blood from the spiral arteries, which extensively remodel from the first trimester onwards after the invasion of the extravillous trophoblast[5]. Deficiencies in remodelling have been associated with severe pregnancy complications, such as miscarriage, foetal growth restriction, and preeclampsia[6]. The most common hypothesis for the aetiology of the PAS is a defect in the endometrial-myometrial interface, which is caused by disruptions within the uterine cavity, leading to a failure of normal decidualization in the area of a uterine scar. The defect in the endometrial-myometrial interface allows abnormally deep placental anchoring villi and trophoblast infiltration, increasing the likelihood of placenta accreta[7].

The second trimester is crucial for placenta development and may be greatly associated with myometrium invasion. Thus, the characteristics of the PAS in the second trimester may be different from full-term delivery. The occurrence of placental remnants after first- and second-trimester termination of pregnancy depends primarily on gestational age, treatment of choice, and follow-up protocol. In medical termination of pregnancy after 12 weeks of gestation, late (> 24 hours) retention of pregnancy tissue is observed in approximately 1.5% of patients[8]. According to current research, in vitro fertilization and embryo transfer (IVF-ET) is a risk factor for PAS among women with full-term live births[9], but whether it affects the adherence of the placenta in mid-trimester is not reported. To further understand the PAS characteristics and risk factors in patients with the termination of pregnancy, we conducted a retrospective observational study in our centre.

Study population

The study was conducted in the Sixth Affiliated Hospital of Sun Yat-sen University. Women who underwent induced abortion or termination of pregnancy in the second trimester from January 2013 to October 2023 were included in our retrospective study. The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Ethics Committee of the Sixth Affiliated Hospital of Sun Yat-sen University (protocol code 2022ZSLYEC-5558 and date of approval 24/11/2022) for studies involving humans. The reasons for abortion included miscarriage, intrauterine demise, and fatal foetal malformation. We divided the women into two groups according to their fertilization methods (spontaneous conception or IVF-ET). In the IVF-ET group, patients who utilized IVF-ET and/or intracytoplasmic sperm injection delivered after 12 weeks of gestation. In the spontaneous conception group, the patients got pregnant without in vitro fertilization-embryo transfer, including those who got pregnant with artificial insemination and ovulation induction. There were 370 pregnant women recruited in our study. As maternal age is also a risk factor for placenta accreta[10], we used propensity score matching to match maternal age with a 1:1 ratio in the spontaneous conception group and IVF-ET group. A total of 230 patients were finally selected.

Data collection

In this cohort, PAS was identified by electronic medical record review, and the grades of PAS were also recorded. Further demographic characteristics, such as uterine surgical history, placenta previa history, presence of placenta previa, and history of hysteroscopic surgery, were collected by retrospective review of our medical records.

Definition and treatment policy

The definition of placenta previa was defined as the internal os is covered partially or completely by the placenta according to ultrasound. The uterine condition included uterine myoma with a diameter > 5 cm, adenomyosis and septate uterus. The uterine surgical history included myomectomy, caesarean section, adenomyomectomy, myohysterectomy, and laparoscopic wedge resection due to cornual pregnancy. The hysteroscopic surgery included hysteroscopic endometrial polypectomy, hysteroscopic adhesiolysis, uterus septum resection, and diagnostic curettage. The methods of termination of pregnancy depended on the clinical situation and the uterine surgery history. The majority of methods of abortions included drug-induced abortion (oxytocin, mifepristone combined with misoprostol or ethacridine) and balloon-induced abortion. The majority of patients underwent at least one uterine ultrasound scan to confirm the retention of pregnancy tissue. The remaining volume, the blood flow of the retention tissue, and the time of uterine recovery were also collected from their medical records. For the patients with suspected morbid PAS, magnetic resonance imaging (MRI) was conducted during follow-up. Intrauterine adhesion was identified by hysteroscopy when patients had symptoms of spanomenorrhea or ultrasound finding. The treatment for the PAS included observation, oral administration of mifepristone, uterine artery embolization with or without methotrexate, hysteroscopic resection of retained products of conception, placement of an intrauterine tamponade balloon, percutaneous uterine artery embolization and/or methotrexate intramuscular injection. Retention of the placenta in situ was also used in some extreme cases.

Primary and secondary outcome

The primary outcome was the occurrence of the PAS, which was defined clinically description of an abnormal adherent or invasive full range or partial of the placenta by the attending obstetrician at the time of the abortion or by the histological confirmation of chorionic villi directly attached to invading the myometrium. Patients diagnosed with accreta based solely on radiographic or ultrasound findings with no clinical suspicion at delivery or pathological confirmation cannot be diagnosed with the PAS. The condition of the placenta was divided into the following categories: without accreta, placenta adherenta, placenta increta and placenta percreta, according to the guideline of FIGO in 2019[1]. The secondary outcome was the occurrence of morbid PAS. Morbid placenta accreta is defined by any of the following, in addition to accreta: nonroutine procedures to stop excess blood loss (placement of an intrauterine tamponade balloon, oversewing of the placental bed, ligation of the uterine, utero-ovarian arteries, percutaneous transcatheter embolization or gravid hysterectomy), methotrexate intramuscular injection, and hysteroscopic resection of retained products of conception.

Statistics analysis

Statistical analysis was performed with SPSS, version 27.0. Quantitative variables with normal distribution are expressed as the means with their standard deviation, while the variables with nonnormal distribution are expressed as medians with 25th and 75th percentile. Chi-square tests or Fisher’s exact tests were used for distribution-based comparisons between groups. T-tests or Wilcoxon rank sum tests were conducted to compare the differences between groups. Logistic regression analysis was used to identify the association between IVF and placenta accreta. The 95% confidence intervals (CIs) and 2-sided Wald P values were also calculated. The results are presented as P values, and a two-tailed P value < 0.05 was regarded as statistically significant.

There were 370 pregnant women recruited in our study. The total incidence of the PAS in our study population was 20.3% (75/370). After matching for maternal age, which is a risk factor for placenta accreta, at a ratio of 1:1, 230 women were included to analysis in the spontaneous conception and IVF-ET groups, respectively. Only one patient had a history of PAS, but none of them was diagnosed the PAS prenatally. Regarding the reasons for termination, there were 48 cases of intrauterine demise, 109 cases of inevitable abortion, and 73 cases of fatal anomaly.

Demographics and Characteristics

Table 1 shows the characteristics of the two groups of the study population. The average maternal age (32.4 ± 4.8 vs. 32.5 ± 4.7, P = 0.900), prenatal placenta previa [7.0 (8/115) vs. 7.8 (9/115), P = 0.801] according to radiology or ultrasound in the spontaneous conception (SC) group were not significantly different from those in the IVF-ET group. Gravidity [2(2–3) vs. 2(1–3), P < 0.001], parity [1(0–1) vs. 0(0–0), P < 0.001], and terminal gestation weeks [21.4 (18.6–24.3) vs. 20.3 (17.3–22.6), P = 0.004], were significantly higher than those in the IVF-ET group. Caesarean history was significantly more common in the spontaneous conception group(P = 0.005), while the hysteroscope history was significantly more common in the IVF-ET group(P < 0.001). The reasons for termination between the two groups were not significantly different (P = 0.283).

Table 1

Demographics and baseline uterine characteristics between spontaneous conception group and in vitro fertilization and embryo transfer group
	SC n = 115	IVF-ET n = 115	P
Age(years), mean ± SD	32.4 ± 4.8	32.5 ± 4.7	0.900
Gravidity(times), median(25th -75th quartiles)	2.0(2.0–3.0)	2.0(1.0–3.0)	<0.001
Parity(times), median(25th -75th quartiles)	1.0(0–1.0)	0(0–0)	<0.001
PAS history, n(%)	1(0.87)	0(0.0)	>0.999
Uterine condition, n(%)	8(6.96)	11(9.6)	0.472
Uterine Surgery, n(%)	27(23.5)	11(9.6)	0.004
Caesarean section history, n(%)	25(21.7)	7(6.1)	<0.001
Times of caesarean section, n(%)
1	21(18.3)	7(6.1)	-
≥ 2	4(3.5)	0	-
Hysteroscope history, n(%)	3(2.60)	33(28.7)	<0.001
Placenta Previa, n(%)	8(7.0)	9(7.8)	0.801
Terminal Gestation(weeks), median(25th -75th quartiles)	21.43(18.57–24.29)	20.286(17.29–22.59)	0.004
Missed abortion or stillborn, n(%)	24(20.9)	24(20.9)	-
Inevitable abortion, n(%)	49(42.6)	60(52.2)	-
Fatal deformities, n(%)	42(36.5)	31(27.0)	-
Number of foetuses(n), median(25th -75th quartiles)	1.0(1.0–1.0)	1.0(1.0–2.0)	<0.001
PAS: placenta accreta spectrum; SC: spontaneous conception; SD: standard deviation.

The outcomes of the termination pregnancy between the spontaneous conception group and the IVF-ET group

The incidence of the PAS (P = 0.002) and the morbid PAS (P = 0.039) were significantly higher in the IVF-ET group than in the spontaneous conception group. Among the patients with the PAS, the PAS grades in the IVF-ET group seemed severer than those in the spontaneous conception group (P = 0.058). The postpartum haemorrhage volume [140.0(80.0-240.0) ml vs. 200.0(100.0-520.0) ml, P = 0.004] and the rate of postpartum haemorrhage (11.3% vs.24.3%, P = 0.010) were significantly higher in the IVF-ET group than in the spontaneous conception group. The sharp curettage times were significantly higher in the IVF-ET group than in the spontaneous conception group [0(0–1.0) times vs. 1.0(0–1.0) times, P = 0.008], and the incidence of intrauterine adhesion after abortion was relatively higher in the IVF-ET group than in the spontaneous conception group (7.8% vs. 2.6%, P = 0.109). The results are shown in Table 2.

Table 2

The outcome between spontaneous conception group and IVF-ET group.
	SC n = 115	IVF-ET n = 115	P
PAS, n(%)	15(13.0)	34(29.6)	0.002
Degree of PAS			0.058
Placenta adherenta, n(%)	8(7.0)	12(10.4)	-
Placenta increta, n(%)	7(6.1)	22(19.1)	-
Placenta percreta, n(%)	0	0	-
Morbid PAS, n(%)	6(5.2)	15(13.9)	0.039
Intrauterine tamponade balloon,n	1	7	-
Percutaneous transcatheter embolization, n	1	4	-
Hysteroscopic resection,n	2	1	-
Methotrexate intramuscular injection, n	2	3	-
Volume of Blood loss(ml), median(25th -75th quartiles)	140.0(80.0,240.0)	200(100,520)	0.004
Postpartum haemorrhage, n(%)	13(11.3)	28(24.3)	0.010
Postpartum haemorrhage >1000ml, n(%)	4(3.5)	9(7.8)	0.153
Curettage times(n), median(25th -75th quartiles)	0(0–1.0)	1.0(0–1.0)	0.008
Time of RPOC
<2 weeks, n(%)	67 (58.3)	38(33.0)	-
2–4 weeks, n(%)	12(10.4)	18(15.7)	-
>4 weeks, n(%)	26(22.6)	36(31.3)	0.030^a
unknown, n(%)	10(8.7)	26(20.0)	-
Intrauterine adhesion after abortion, n(%)	3(2.6)	9(7.8)	0.109
PAS: placenta accreta spectrum; SC: spontaneous conception; RPOC: retained products of conception;
^a The Chi-square test was conducted in the patients with detailed time of RPOC follow-up ( 26/105 vs. 36/89).

The outcomes of the termination pregnancy between the fresh embryo transfer group and the cryopreserved embryo transfer group

According to the type of implanted embryos, the patients in the IVF-ET group were divided into the fresh embryo transfer (ET) group (n = 44) and the cryopreserved ET group (n = 69). Two cases were excluded in this part because the embryo was transferred in the other centre without details. The incidence of the PAS was significantly higher (30/69,43.5%) in the cryopreserved ET group than in the fresh ET group (4/44, 9.1%), as well as the incidence of morbid PAS (20.3% vs. 4.5%, P = 0.006). The distribution of the PAS grades was not significantly different between the fresh ET group and the cryopreserved ET group(P = 0.817). The postpartum haemorrhage volume [165.0(100.0-417.5) ml vs. 280.0(100.0-550.0) ml, P = 0.268), and intrauterine adhesion after abortion (9.1% vs. 7.2%, P = 0.734) in the two groups were not significant. The sharp curettage times were relatively higher in the cryopreserved ET group than in the fresh ET group [1(0–1) vs.0(0–1), P = 0.056]. The results are shown in Table 3.

Table 3

The analysis between the fresh embryo transfer group and the cryopreserved embryo transfer group
	Fresh ET n = 44	Cryopreserved ET n = 69	P
Hysteroscopy history,n(%)	14(31.8)	19(27.5)	0.625
PAS,n(%)	4(9.1)	30(43.5)	< 0.001
Degree of PAS			0.817
Placenta adherenta, n(%)	2(4.5)	10(14.5)
Placenta increta, n(%)	2(4.5)	20(29.0)
Placenta percreta, n(%)	0	0
Morbid PAS, n(%)	1(4.5)	14(20.3)	0.006
Intrauterine tamponade balloon, n	1	7	-
Percutaneous transcatheter embolization, n	0	4	-
Hysteroscopic resection, n	0	1	-
Methotrexate intramuscular injection,n	0	2	-
Postpartum haemorrhage, n(%)	9(20.5)	19(27.5)	0.395
Volume of Blood loss(ml), median (25th -75th quartiles)	165.0(100,417.5)	280(100.0,550.0)	0.268
Postpartum haemorrhage >1000ml, n(%)	4(9.1)	5(7.2)	0.734
Curettage times(n), median(25th -75th quartiles)	0(0–1.0)	1.0(0–1.0)	0.056
Intrauterine adhesion after abortion, n(%)	4(9.1)	5(7.2)	0.734
PAS: placenta accreta spectrum; ET: embryo transfer;

The risk factors of PAS

In multivariate analysis, which used logistic analysis, gravidity, IVF-ET, uterine condition, uterine surgical history, hysteroscopy history, and placenta previa were included in the final model. IVF-ET [odds ratio (OR) = 2.42, 95% CI 1.10–5.28, P = 0.027] and hysteroscopy history (OR = 2.67, 95%CI 1.11–6.43, P = 0.028) were the independent risk factors for the PAS (Table 4). In the IVF-ET group, after controlling the factors such as uterine condition, hysteroscopy history, and prenatal placenta previa, cryopreserved ET (OR = 4.26, 95% CI 1.62–11.20, P < 0.001) was still an independent risk factor for the PAS (Table 5).

Table 4

Logistic regression analysis of the risk factors for placenta accreta spectrum.
	PAS (n = 49)	No PAS (n = 181)	P	Univariate OR(95%CI)	P	Multivariate^b OR(95%CI)
Gravidity, per women^a	2(1–3)	2(1–3)	0.857	0.98(0.76–1.26)	0.669	1.06(0.80–1.41)
IVF-ET,n(%)	34(69.4)	81(44.8)	0.003	2.80(1.43–5.50)	0.027	2.42(1.10–5.28)
Uterine condition,n(%)	9(18.4)	9(5.0)	0.004	4.30(1.60-11.53)	0.111	2.51(0.81–7.77)
Uterine surgery history,n(%)	11(22.4)	27(14.9)	0.211	1.65(0.75–3.62)	0.138	1.98(0.80–4.88)
Hysteroscopy history,n(%)	17(34.7)	19(10.5)	< 0.001	4.53(2.13–9.65)	0.028	2.67(1.11–6.43)
Placenta previa,n(%)	5(10.2)	12(6.6)	0.400	1.60(0.54–4.78)	0.625	1.34(0.41–4.35)
OR odds ratio; CI confidence interval; IVF-ET in vitro fertilization and embryo transfer;
^a Data present as median(25th -75th quartiles).
^bMultivariate analysis included gravidity, IVF-ET, uterine condition, uterine surgery history, hysteroscopy history and placenta previa.

Table 5

Logistic regression analysis of the risk factors for placenta accreta spectrum among the patients in the IVF-ET group.
	PAS (n = 34)	No PAS (n = 81)	P	Univariate OR(95%CI)	P	Multivariate^b OR(95%CI)
Uterine condition, n(%)	7(20.6)	4(4.9)	0.016	4.99(1.35–18.39)	0.141	3.23(0.68–15.38)
Hysteroscopy history, n(%)	14(41.2)	19(23.5)	0.058	2.28(0.97–5.37)	0.133	2.25(0.78–6.47)
Placenta previa, n(%)	3(8.8)	6(7.4)	0.797	1.21(0.28–5.15)	0.421	2.00(0.37–10.85)
Cryopreserved ET, n(%)	30(88.2)	39(49.4)^a	< 0.001	7.69(2.48–23.88)	< 0.001	4.26(1.62–11.20)
OR: odds ratio; CI: confidence interval; IVF-ET: in vitro fertilization and embryo transfer; ET:embryo transfer
^a Assessed in 79/81(97.5%) patiants, miss values for 2.
^bMultivariate analysis included uterine condition, uterine surgery history,placenta previa and cryopreserved ET.

Follow-up of PAS by ultrasound

There were 105 patients in the spontaneous conception group and 89 patients in the IVF-ET group who completed follow-up after the abortion. The proportion of patients without RPOC in the uterus for more than 4 weeks based on ultrasound was significantly higher in the IVF-ET group than in the spontaneous conception group [40.4%(36/89) vs.24.8%(26/105), P = 0.030]) (Table 2). An unclear boundary with the myometrium and the intrauterine residues was found by ultrasound in 21 cases, and 17 of them confirmed the PAS during the abortion course, with 13 cases in the IVF-ET group with cryopreserved ET and 4 cases in the spontaneous conception group. Only 11 of these 17 patients underwent MRI to further assess the invasion depth of the residue.

In our studies, we reported the association between IVF-ET and the PAS in the population with mid-trimester induced labour, and we also followed up on the subsequent prognosis of these patients. We found that the IVF-ET group still had a significantly higher incidence of the PAS, even though the spontaneous conception group had a higher rate and quantity of caesarean sections. The patients in the IVF-ET group also had a significantly higher risk of postpartum haemorrhage, more times of uterine curettage and longer time of RPOC than the spontaneous conception group. According to the results of logistic regression analysis, IVF-ET, especially cryopreserved embryo transfer (CET), were the independent risk factors in women with mid-trimester termination of pregnancy. In the IVF-ET group, 61.1% (69/113) of women underwent cryopreserved ET. Nearly no PAS was found prenatally in our termination of pregnancy cases. Most of the PAS were diagnosed by abnormal placental separation, or more than 4 weeks RPOC with unclear boundary with the myometrium by ultrasound follow-up. Moreover, the hysteroscopic surgery was also an independent risk factor for the PAS in the second trimester. These women might have a greater chance of defects in the endometrial-myometrial interface, leading to the development of the PAS. Normally, the decidua that develops into the placenta is called the decidua basalis. There are many extravillous trophoblast cells and fibrin-like substances in the decidua basalis, which act as a barrier to prevent the invasion of placental villi. If the endometrium at the implantation site of the placenta is defective or poorly developed, the villi are directly implanted into the myometrium or even deep into the myometrium, which becomes a pathological phenomenon[11]. This pathophysiological process presents hyperplastic blood vessels in the placenta accreta region by ultrasound scan. Even though the degree of vascularization and the number of blood vessels were higher in the third trimester than in the second trimester, PAS can also appear in the second trimester[12].

Placenta previa is known as an independent risk factor for the PAS [13]. A multiple-centre study showed that more than 50% of the PAS patients had placenta previa prenatally[14]. The PAS can also occur in 3% of women with placenta previa and no prior caesarean deliveries. As the limited volume of the uterus during the second trimester, the incidence of the placenta previa before 28 weeks of gestation, was relatively higher in our study cohort. Therefore, placenta previa showed no significant effect on the PAS in the logistic regression analysis.

The classification of PAS is according to the adhesion or invasion of villi. These grades include abnormal adhesion to the superficial muscular layer (placenta adherenta, grade 1), invasion of the muscular layer (placenta increta, grade 2), and penetration of the serosa (placenta percreta, grade 3)[1]. In our study, all of the PAS cases were grade 1(20/230,8.7%) and grade 2 (29/230,12.6%), and no placenta percreta was found. Due to the limitations of the included population, placental development and villus invasion were only observed during the second trimester, and no cases of penetrative placental implantation were found in our study. However, it is also possible that some of these patients may have placental percreta if they enter the third trimester of pregnancy. Even though significantly higher incidence of PAS in the IVF-ET group, the distribution of the PAS grades was no different between the IVF-ET group and the SC group. A systematic review also showed that the severity of the PAS was not compared between the IVF-ET group and the spontaneous conception group[9], which was consistent with our study findings.

Prenatal diagnosis of the PAS mainly depended on the results of the ultrasound scan. For the asymptomatic PAS patients, American College of Obstetricians and Gynaecologists (ACOG) guidelines recommend ultrasound screening for placenta accreta at 18 ~ 20 weeks, 28 ~ 30 weeks, and 32 ~ 34 weeks of gestation[13, 15]. Placental lacunae, abnormal uteroplacental interface, bridging vessel, and abnormal uterine contour (placental bulge) were recommended as ultrasound markers of PAS among the patients with high risk. These markers and approaches can find out the morbid PAS, especially with placenta previa[16]. In fact, during the second trimester of pregnancy, the placenta echoes are weak and close to the uterine muscle, which easily ignores the interface between the uterus and placenta[17]. The partial PAS or the posterior placenta with PAS were difficult to diagnose. Moreover, the patients in the IVF-ET group had less parity and a lower rate of caesarean section history. These patients were regarded as lower risk of PAS, which might lead to not enough attention to the interface between the uterus and placenta during the ultrasound scan.

Different hemodynamic changes presented a more aggressive trend of placenta development in patients with cryopreserved ET. A study showed that in the second and third trimesters, pregnancies after frozen-thawed ET had a strong decline in uterine arterial-pulsatility index(Uta-PI) and uterine arterial resistant index(Uta-RI) compared to pregnancies after fresh ET, suggesting lower distal vascular resistance and better placental vascular development[6], which indicated higher invasion of the placenta during the second trimester. This evidence suggests that women with IVF-ET have a higher risk of PAS in the second trimester. Residual trophoblastic tissue is more frequent after the second-trimester demise. A prospective observational study showed that residual trophoblastic tissue after miscarriage or delivery was observed more frequently after second-trimester demise (40%) than after first-trimester miscarriage (17.8%) or after third-trimester delivery (2.7%) [8]. The pathogenic residual trophoblastic tissue might cause a higher risk of postpartum haemorrhage and abnormal adherent of the myometrium, which needs more measures of stopping bleeding and cleaning the trophoblastic tissue. Therefore, the incidence of PAS and morbid PAS does not appear to be low in this population. Moreover, as the ultrasound scan after the postpartum period lacked specific signs, atypical ultrasound signs were found variously between patients, as well as the examiner. The initial follow-up ultrasound might lead to a misdiagnosis because of the interference with intrauterine blood clots. When the patients had more than 2 weeks or 4 weeks of retained products of conception, patients with a small range of PAS were finally scanned out by ultrasound, but the diagnosis of PAS was delayed.

PAS can lead to severe postpartum bleeding, postpartum curettage, and other operations aggravated endometrial damage, affecting the subsequent fertility of women of childbearing age. Patients with IVF-ET, especially cryopreserved ET, were at higher risk of PAS and postpartum haemorrhage during mid-trimester abortion, which needs more attention to avoid severe complications during labour and postpartum endometrial protection and repair. This result evokes further study on placenta development and placenta vascular development to resolve the mechanism of the PAS during the mid-trimester. As the ultrasound signs of PAS in the second trimester usually lack specificity, abnormal invasion of the placenta is underestimated prenatally. We should pay full attention to the IVF-ET patients of termination of pregnancy with medical indication during the mid-trimester, and do the blood preparation. Ultrasound is the most economical examination for patients with termination of pregnancy. A scoring system of the PAS prediction from the second trimester is needed.

We still have some limitations. The incidence of PAS was relatively higher in our centre, no matter in the IVF-ET group or in the SC group. One of the reasons is the bias of the population. As our centre is the territorial tertiary obstetrics and gynaecological centre, more intractable cases were selected in our cohort, which indicated these patients had more complications, more uterine surgery history and more complicated infertile factors. As our study is a retrospective study, the information on the postnatal follow-up was incomplete. Some patients prefer their community clinic for return visits. An additional sample size was needed for further study.

Patients with IVF-ET, especially cryopreserved embryo transfer, were at high risk of PAS during mid-trimester abortion, which needs more attention to avoid severe complications during labour. More experience with ultrasound scans of the PAS markers among these patients in the second trimester is needed. When an abnormal placenta is found during labour, fertility-preserving placental treatments are used as much as possible.

PAS: placenta accreta spectrum

IVF-ET: in vitro fertilization and embryo transfer

PPH: postpartum haemorrhage

RPOC: retained products of conception

OR: odds ratio

CI: confidence interval

Ethics approval and consent to participate

All procedures performed in the study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. All the patients indicated consent by written informed consent before the medical intervention.The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Ethics Committee of the Sixth Affiliated Hospital of Sun Yat-sen University (protocol code 2022ZSLYEC-5558) for studies involving humans. Data was collected from part of routine antenatal management and neonatal care, and personal information was only accessible to the study team.

Consent for publication

Not applicable.

Availability of data and materials

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

Competing interests

The authors declare that they have no competing interests.

Funding

This research was funded by the Project of Guangzhou Science and Technology Plan, grant number 202102080063, and the Basic and Applied Basic Research Foundation of Guangdong Province, grant number 2021A1515110418.

Authors' contributions

S. L. & MC. L. designed and performed the research, analysed the data and wrote the main manuscript text; L.Z, YX.Z. &F.G. performed the research; CY. G. & Y. G. designed the research and made major revisions to the manuscript. All authors have read and agreed to the published version of the manuscript.

#Si LI and Mancheng Liu contributed equally to this study.

Acknowledgements

Not applicable.

Conflict of Interest

The authors declare no conflicts of interest.

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No competing interests reported.

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In vitro fertilization and embryo transfer is an independent risk factor of the placenta accreta spectrum in the termination of pregnancy during the mid-trimester：a retrospective cohort study on perinatal management

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