Introduction

Premature placental abruption (PPA) is a rare obstetric pathology complicating approximately 1% of births. The prevalence of PPA varies from 0.5% in Scandinavian countries to 5% in developing countries [1]. Each case of PPA is potentially dangerous for the mother and fetus due to high risk of preterm birth, maternal and perinatal morbidity and mortality. Adverse maternal outcomes of PPA mainly include the consequences of massive blood loss: hemorrhagic shock, disseminated intravascular coagulation syndrome, hysterectomy. Postpartum cerebrovascular disorders, acute respiratory, cardiac, renal failure, pulmonary edema, myocardial infarction, cardiomyopathy, thromboembolic complications, sepsis and death are rarer [1, 2].

One of the most significant risk factors of PPA is hypertensive disorders [3] including gestational arterial hypertension (GAH), preeclampsia, eclampsia and chronic arterial hypertension [4]. All these abnormalities are closely related to each other, complicate approximately 5-10% of pregnancies [5] and lead to significant maternal, fetal and neonatal morbidity and mortality [6].

Incidence of preeclampsia during pregnancy ranges from 2% to 8% [4]. Despite a significant number of studies devoted to prevention of preeclampsia, incidence of this complication has not changed over the past decades and has increased in some countries [7, 8]. Chronic arterial hypertension occurs in 1-5% of pregnant women [9] and tends to increase [10]. It is a significant risk factor of preeclampsia [11]. According to statistical data (2016), patients with chronic arterial hypertension have a 5-fold higher risk of preeclampsia [12].

The purpose of the meta-analysis was to study the effect of hypertensive disorders during pregnancy on the risk of premature placental abruption.

Material and methods

Searching strategy and selection criteria

The protocol for this meta-analysis was developed in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) standards and guidelines for meta-analysis [13]. We analyzed the PubMed, Google Scholar and Cochrane Research databases between January 1, 2016 and April 30, 2022 using the following keywords in all languages: placental abruption, abruptio placentae, ischemic placental disease, preeclampsia, hypertensive disorders in pregnancy.

Selection criteria

The meta-analysis included prospective and retrospective cohort and case-control studies devoted to relationship between PPA and arterial hypertension. Inclusion criteria were PPA and hypertension (any other indicators).

Exclusion criteria

Systematic reviews and meta-analyses, case reports and case series, comments, experimental trials and studies without control group.

Selection of studies

Two researchers (Rudakova I.S., Pylaeva N.Yu.) analyzed databases and extracted potentially relevant studies. The experts (Shifman E.M., Tikhova G.P.) assessed full-text articles regarding inclusion criteria. Disputes were resolved by consensus. In total, we found 340 articles. However, we excluded 323 manuscripts with exclusion criteria (Fig. 1). The meta-analysis was based on 17 studies. The largest sample included 27,796,465 patients, the smallest one included 80 people. Of these, there were only 5 small case-control studies (n=3955), where the number of PPAs was close to the number of patients in the control group. Other studies were cohort. A total of 30,184,624 patients were analyzed including 286,485 (0.95%) cases of PPA, 1,943,227 (6.4%) cases of gestational hypertensive disorders and 514,182 (1.7%) cases of chronic arterial hypertension. These data correspond to the world statistics.

Fig. 1. PRISMA flow diagram.

Results

Influence of gestational hypertensive disorders (gestational arterial hypertension, preeclampsia, eclampsia) on the risk of placental abruption

In this part of meta-analysis, we studied the effect of hypertension on the mother's body over a short period (between the 20^th week of gestation and delivery). There were 15 studies (Table 1) [14–28].

Table 1. Characteristics of studies devoted to correlation of gestational hypertensive disorders and premature placental abruption

Risk of bias is shown in Fig. 2, risk of bias in non-randomized controlled trials — in Fig. 3.

Fig. 2. Assessing the risk of bias in non-randomized controlled trials.

Fig. 3. Assessing the risk of bias in non-randomized controlled trials

According to our data (Fig. 4, 5), odds ratio (OR) of cumulative effect is 2.79 (95% CI 2.37; 3.27). Thus, our meta-analysis indicates that gestational hypertensive disorders significantly increase the risk of PPA by 2.79 times (95% CI 2.37; 3.27).

Fig. 4. Forest plot analysis of the impact of gestational hypertensive disorders on the risk of placental abruption.

Fig. 5. Funnel chart shows 99% significance of 14 studies and less than 90% significance of 1 study.

Symmetry of studies is disturbed that can be explained by significant heterogeneity; its causes are described in the text; ln (OR) — natural logarithm of the odds ratio

The vast majority of large and small studies revealed significant increment of the risk of PPA in women with gestational hypertensive disorders/preeclampsia by 38-700% (Fig. 4). Only one study found no significant effect of gestational hypertensive disorders/preeclampsia on PPA (Eubanks A.A., 2019; n=7958) (Fig. 4, 5) [24]. The results of other 14 studies are within significant effect (≥99%) (Fig. 5). Fourteen out of 15 reports revealed significant effect of pregnancy-related hypertensive disorders including preeclampsia on the risk of PPA (odds ratio 1.38-8.22). Cumulative effect value (OR) was 2.79.

Effect of chronic arterial hypertension on the risk of premature placental abruption

In this part, we analyzed the effect of long-standing hypertension (more than gestational period). In total, 9 studies were included in meta-analysis (Table 2) [14–16, 20, 21, 24, 27, 29, 30].

Table 2. Characteristics of studies devoted to correlation of chronic hypertension and premature placental abruption

Risk of bias is shown in Fig. 6, risk of bias in non-randomized controlled trials — in Fig. 7.

Fig. 6. Assessing the risk of bias in non-randomized controlled trials.

Fig. 7. Assessing the risk of bias in non-randomized controlled trials.

According to our data (Fig. 8, 9), OR of cumulative effect was 2.22 (95% CI 1.67; 2.96). Thus, chronic hypertension increases the risk of PPA by 2.2 times (no less than 1.7 and no more than 3.0 times).

Fig. 8. Forest plot analysis of the impact of chronic hypertension on the risk of placental abruption.

Fig. 9. Funnel chart shows 99% significance of 4 studies 95% significance of 1 study. Three studies are in zone of significance less than 90%.

Symmetry of studies is disturbed that can be explained by significant heterogeneity; its causes are described in the text;ln (OR) — natural logarithm of the odds ratio

Slightly more than half of the studies obtained significant increase of the risk of PPA by 62-500% in case of concomitant chronic hypertension (Fig. 8). In 4 studies, the effect of chronic hypertension on PPA was insignificant (Fig. 8, 9) [21, 24, 27, 29]. Results of one study (n=100495) are within significance range (95-99%) [15]. Other data indicate significance level ≥ 99% [14, 16, 20, 30] (Fig. 8). Importantly, 5 out of 9 studies revealed significant effect of chronic hypertension on the risk of placental abruption. The odds ratio for PPA was 1.62-6.01. Cumulative value was 2.22.

Discussion

According to our data, gestational hypertensive disorders including gestational arterial hypertension, preeclampsia and eclampsia increase the risk of PPA by almost 3 times (OR 2.79, 95% CI 2.37; 3.27). A similar study was performed more than 25 years ago [31]. Ananth C. V. et al reported almost 2-fold increase of the risk of PPA in pregnant women with preeclampsia (OR 1.76, 95% CI 2.59, 3.80) and more than 3-fold increase in case of chronic hypertension (OR 3.13, 95% CI 2.04, 4.80). The role of preeclampsia in PPA has increased compared to the data of the earlier meta-analysis (1996). Higher incidence of preeclampsia may be associated with decrease of health index and increase of age and body mass index in pregnant women [7]. According to our data, the influence of such a risk factor as chronic hypertension significantly decreased (OR 2.22, 95% CI (1.67; 2.96) compared to previous data (1996). Despite higher incidence of chronic hypertension among pregnant women, our data suggest less influence of this risk factor on PPA [32]. Possible cause is difficult differential diagnosis between chronic hypertension and preeclampsia developed on the background of chronic hypertension [32]. Moreover, preeclampsia occurs in 20% of pregnant women with chronic hypertension, and the last one may be missed during data processing. However, antihypertensive agents approved during pregnancy have significantly improved over the past 25 years. Therapy with modern drugs ensures target blood pressure and reduces the likelihood of obstetric complications [33].

Study limitations

We analyzed various types of hypertension (chronic and gestational) without specifying severity and time of occurrence. Only one study provided information on severity of preeclampsia [14]. A recent study of preeclampsia phenotypes in PPA revealed that severe preeclampsia is more often associated with PPA [34]. However, PPA per se can determine preeclampsia as severe complication of pregnancy despite the absence of other criteria of severe preeclampsia. According to the 2021 clinical guidelines, the criteria of severe preeclampsia include not only certain maternal indicators, but also fetal abnormalities such as intrauterine growth retardation (IUGR) and antenatal death [4]. However, the third important participant (placenta) is implied, but not mentioned, although placenta is important in pathogenesis of preeclampsia. In the foreign literature, preeclampsia, IUGR and PPA are combined under the general term — ischemic placental disease. All these obstetric complications are closely related, often combined with each other and have common pathophysiological mechanisms [35]. Severity of chronic hypertension was also described in only one study [29].

There was no information about early and late preeclampsia. Probably, preeclampsia within 34 weeks of gestation has the greatest impact on PPA that may be indirectly confirmed by a large proportion of preeclampsia in patients with PPA [3, 36, 37]. Han M. et al. [38] reported early preeclampsia in 87% of patients with PPA [38]. Information about eclampsia was only in two reports without specifying the number of cases [16, 21].

We analyzed only the risk factors of PPA associated with hypertension during pregnancy without adjusting for other characteristics such as older reproductive age, smoking, race and parity. Moreover, only one study described prophylactic measures with acetylsalicylic acid [24]. This was the only report indicating no effect of gestational hypertensive disorders on PPA. Other reports provided no data on appointment of acetylsalicylic acid.

Advantages of our research

We have analyzed a significant number of studies devoted to the effect of hypertensive disorders during pregnancy on PPA. Limitations and prospects for further researches are outlined.

Conclusion

We compared the effect of chronic and gestational arterial hypertension on the risk of premature placental abruption. Our meta-analysis enrolled observational retro- and prospective studies, so odds ratio was chosen as effect size. Significant heterogeneity of studies (I²>85%, p<0.01) necessitated the use of random effect model. Heterogeneity was caused by the following reasons:

— wide range of sample sizes (from tens to millions of patients);

— features and some differences in study design;

— racial, ethnic and geographical differences of samples;

— difference between primary and secondary objectives of the study.

Our meta-analysis convincingly indicates that chronic and gestational arterial hypertension significantly increase the risk of premature placental abruption by 2 and 2.8 times, respectively.

Author contribution:

Concept and design of the study — Rudakova I.S., Shifman E.M.

Collection and analysis of data — Rudakova I.S., Pylaeva N.Yu.

Statistical analysis — Tikhova G.P., Rudakova I.S.

Writing the text — Rudakova I.S.

Editing — Shifman E.M.

Financing. The study was not sponsored.

The authors declare no conflicts of interest.