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Factors and outcomes for placental anomalies: An umbrella review of systematic reviews and meta-analyses

Dazhi Fan1,2, Dongxin Lin1, Jiaming Rao1, Pengsheng Li1, Gengdong Chen1, Zixing Zhou1, Li Sun3, Li Liu4, Yubo Ma5, Xiaoling Guo1,2, Zhengping Liu1,2

1 Foshan Fetal Medicine Research Institute, Foshan Women and Children Hospital, Foshan, Guangdong, China
2 Department of Obstetrics, Foshan Women and Children Hospital, Foshan, Guangdong, China
3 Department of Library, Foshan Women and Children Hospital, Foshan, Guangdong, China
4 Department of Library, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
5 Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China

DOI: 10.7189/jogh.14.04013

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Abstract

Background

Placental anomalies, including placenta previa (PP), placenta accreta spectrum disorders (PAS), and vase previa (VP), are associated with several adverse foetal-neonatal and maternal complications. However, there is still a lack of robust evidence on the pathogenesis and adverse outcomes of the diseases. Through this umbrella review, we aimed to systematically review existing meta-analyses exploring the factors and outcomes for pregnancy women with placental anomalies.

Methods

We searched PubMed, Embase, Web of Science, and the Cochrane Library from inception to February 2023. We used AMSTAR 2 to assess the quality of the reviews and estimated the pooled risk and 95% confidence intervals (CIs) for each meta-analysis.

Results

We included 34 meta-analyses and extracted 55 factors (27 for PP, 22 for PAS, and 6 for VP) and 16 outcomes (12 for PP, and 4 for VP) to assess their credibility. Seven factors (maternal cocaine use (for PP), uterine leiomyoma (for PP), prior abortion (spontaneous) (PP), threatened miscarriage (PP), maternal obesity (PP), maternal smoking (PAS), male foetus (PAS)) had high epidemiological evidence. Twelve factors and six outcomes had moderate epidemiological evidence. Twenty-two factors and eight outcomes showed significant association, but with weak credibility.

Conclusions

We found varying levels of evidence for placental anomalies of different factors and outcomes in this umbrella review.

Registration

PROSPERO: CRD42022300160.

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Placental anomalies are associated with several adverse foetal-neonatal and maternal complications. They have three principal types: placenta previa (PP), placenta accreta spectrum disorders (PAS), and vase previa (VP) [1]. According to existing systematic reviews, the prevalence of placental anomalies has been increasing over the past two decades due to the growing incidence of assisted reproductive technologies and caesarean section [25]. The cause of placental anomalies is multifactorial, as are the related adverse pregnancy outcomes [6]. In particular, several factors and adverse outcomes, such as smoking, endometriosis, caesarean delivery, and perinatal haemorrhage, preterm delivery, foetal death, have been proposed as being relate to placental anomalies [79]. However, robust evidence to the pathogenesis and adverse outcomes of the diseases remain largely unknown.

Numerous meta-analysis and systematic reviews have explored the factors and pregnancy outcomes linked to placental anomalies [911]. However, most are incomplete and controversial, as they are limited by excess significance and publication bias. To consolidate the data from these meta-analyses, two umbrella reviews reported the risk factors for PP [7] and PAS [8], respectively. Although they identified some risk factors, they were still incomplete due to limited environmental risk factors. They also did not evaluate other common factors for PP (alcohol, obesity, threatened miscarriage, etc.) and non-environmental factors for PAS (prior abortion, prior uterine artery embolization, smoking, etc.), nor did they summarise the adverse pregnancy outcomes for either placental anomaly type.

Therefore, to evaluate the strength of epidemiological evidence of the reported associations of various factors and pregnancy outcomes with placental anomalies, including PP, PAS, and VP, we conducted an umbrella review of the evidence across existing systematic reviews and meta-analyses. We formed the following PICO question (except for the intervention, which our study did not have): ‘How does the strength of epidemiological evidence for factors and outcomes (O) for placental anomalies (P) compared to normal pregnant women (C)’?

METHODS

We conducted an umbrella review using standardised methodology and reported our findings according to the PRISMA and MOOSE guidelines [12,13]. The protocol was registered in PROSPERO (CRD42022300160).

Search strategy

We searched PubMed, Embase, Web of Science, and the Cochrane Library from inception to 8 February 2023 to identify systematic reviews and meta-analyses of studies that analysed the association between factors and outcomes and placental anomalies, including PP, PAS, and VP. We conceptualised the search strategy around the following keywords: ‘morbidly adherent placenta,’ ‘abnormal placentation,’ ‘placenta previa,’ ‘placenta accreta spectrum disorders,’ or ‘vasa previa,’ combined with ‘systematic review’ or ‘meta-analysis’ (File S1 in the Online Supplementary Document). We did not impose any language limitations when choosing the appropriate studies. We also manually searched the reference lists of relevant reviews and performed forward and backward citation chaining. Two researchers (DF and LL) independently screened and evaluated the full texts of potentially eligible articles. Disagreements were resolved through discussion.

Inclusion and exclusion criteria

We included all meta-analyses of observational studies that investigated the causes and consequences of PP, PAS, and VP, irrespective of their publication date. We excluded systematic reviews without meta-analyses, animal studies, genetic studies, conference abstracts, letters, and editorials (File S2 in the Online Supplementary Document). If we found two similar articles, we included the most recent in the analysis, as it likely comprises more studies and/or is of the highest quality per the AMSTAR 2 tool [14].

Data extraction

Two researchers (DF and JR) extracted the following data independently: first author, journal and year of publication, factor(s) and outcome(s) of interest (PP, PAS, or VP), and number of studies analysed. Where possible, they extracted other data such as estimated value, 95% confidence intervals (CIs), P-values, the number of participants in each groups, analytical data model, heterogeneity, and small-study effects. Disagreements in the extraction process were resolved through consensus.

Quality of meta-analyses

Two investigators (DF and YM) assessed the methodological quality of each included meta-analysis using the AMSTAR 2 tool, a reliable and valid instrument facilitates the quality assessment of meta-analysis and systematic reviews [1416] (File S3 in the Online Supplementary Document). AMSTAR 2 categorises the quality of a meta-analysis on a scale from critically low to high, based on 16 predefined items [17]. Each item has three responses – yes, partial yes, and no; items 2, 4, 7, 9, 11, 13, and 15 are key to the evaluation. Overall, the included articles are ranked as high, moderate, low, or critically low.

Determining the credibility of evidence

We noted which associations met the following criteria to determine the strength of the epidemiologic evidence (i.e. the confidence in the effect estimate): Precision of the estimate (i.e. P-value <0.001, a threshold associated with significantly less false-positive results, and over 1000 cases with the disease); consistency of results (I2<50% and Cochran’s Q test P-value >0.10); and no evidence of small-study effects (P-value >0.10) [1820].

We ranked the strength of epidemiologic evidence as high (when all the above criteria were satisfied), moderate (if a maximum of one criterion was not satisfied and a P-value <0.001), or weak (P-value <0.05). If the P-value was not reported, we calculated the 95% CI of the pooled effect estimate using a standard method.

Statistical analysis

We displayed the derived random-effects estimates using forest plots to show the relationships between various factors or outcomes and PP, PAS, or VP. We computed and presented the random-effects estimate whenever a fixed-effects model was originally used. In practice, these different measures (rate ratio (RR), odds ratio (OR), and hazard ratio (HR)) of effect yield similar estimates, since PP, PAS, or VP is a rare occurrence. We converted these various measurements to ORs using a standardised methodology [21]. We used the Shapiro-Wilk test was used to test for normality of continuous variables and presented data with skewed distribution using medians and interquartile ranges (IQRs). We considered P-value <0.05 statistically significant, except for heterogeneity and small-study effects. All statistical analyses were conducted in Stata software, version 12.0 (StataCorp, College Station, Texas, USA).

RESULTS

Search results

We retrieved 689 studies, of which 34 met the eligibility criteria (Figure 1). They were published between 2003 and 2023. Twenty-seven articles focussed on PP [9,10,1517,2243], eight on PAS [10,11,25,4448], and only two on VP [9,49]. Two articles [10,25] focussed on PP and PAS and one [9] on PP and VP. We found 55 factors (27 for PP, 22 for PAS, and 6 for VP) and 16 outcomes (12 for PP, and 4 for VP) in the 34 included studies. No meta-analysis evaluated the outcomes for PAS. There was a median of six primary studies per evidence synthesis (IQR = 3–12) with a median number of 1772 cases (IQR = 359–9532) and 278 459 subjects (IQR = 48 209–1 055 206) (Table 1).

Figure 1.  Flowchart of literature search.

Table 1.  Characteristics, quantitative synthesis, and assessment of the included meta-analyses

Factors/outcomes Author (year) Number of studies Number of cases Number of subjects Random effects model Heterogeneity Small study effects AMSTAR 2 Credibility of the evidence
OR (95% CI) P-value I2P-value
Factors for PP
AMA (>45 y) Sugai et al. (2023) [41] 14 101 794 14 604 565 3.61 (2.70–4.81) 0.0001 81.4% 0.0001 0.459 High Moderate
ART (programmed frozen ET) Busnelli et al. (2022) [23] 10 642 75 973 1.12 (0.88–1.43) 0.342 37.3 0.0485 0.869 Low NS
IMH Zhuo et al. (2022) [42] 4 941 36 683 1.79 (0.64–5.01) 0.218 63.2 0.043 0.270 Low NS
Maternal alcohol Steane et al. (2021) [10] 4 16 071 6 984 743 1.27 (1.00–1.60) 0.047 62.5 0.046 0.482 High Weak
Endometriosis Matsuzaki et al. (2021) [24] 19 53 084 7 282 776 3.53 (3.00–4.16) 0.0001 72.6 0.0001 0.036 High Weak
Adolescent pregnancy Karacam Z, 2021 [26] 7 126 25 696 0.52 (0.31–0.88) 0.010 0 0.580 0.562 High Weak
Prior UAE Matsuzaki et al. (2021) [25] 4 2220 320 906 5.66 (1.78–18.02) 0.003 55 0.083 0.062 Low Weak
Anti-TNF in IBD Tandon et al. (2020) [27] 2 5 1188 1.58 (0.30–8.48) 0.591 0 0.554 - Low NS
Uterine leiomyoma Jenabi et al. (2019) [28] 9 1772 255 886 2.29 (1.64–3.20) 0.0001 33.2 0.152 0.281 Low High
ART (endometriosis) Horton et al. (2019) [15] 6 164 4646 3.31 (1.26–8.71) 0.020 80 0.0001 0.335 High Weak
AMA (>35 y) Martinelli et al. (2018) [31] 23 113 990 21 961 192 3.16 (2.79–3.57) 0.0001 96.5 0.0001 0.318 High Moderate
ART (singleton pregnancy) Karami et al. (2018) [32] 14 3846 965 379 2.80 (1.99–3.61) 0.0001 72.7 0.0001 0.986 Low Moderate
ART (twin pregnancy) Karami et al. (2018) [32] 9 87 17 063 2.56 (0.97–4.14) 0.002 0 0.990 0.706 Low Weak
ART (fresh ET) Sha et al. (2018) [30] 6 816 72 584 1.63(1.13–2.36) 0.009 65 0.014 0.026 Low Weak
Maternal smoking Shobeiri et al. (2017) [33] 21 16 878 9 094 443 1.35 (1.27–1.44) 0.0001 62.8 0.0001 0.026 Low Weak
Prior abortion (spontaneous) Karami et al. (2017) [16] 16 3036 58 713 1.77 (1.60–1.94) 0.0001 0 0.652 0.742 Low High
Prior abortion (induced) Karami et al. (2017) [16] 10 2946 62 459 1.36 (1.02–1.69) 0.0001 59.2 0.009 0.486 Low Moderate
HDP Yin et al. (2015) [17] 7 2583 505 738 0.53 (0.30–0.94) 0.029 85.5 0.0001 0.590 Critically low Weak
Maternal asthma Wang et al. (2014) [34] 8 3793 1 359 749 1.19 (1.04–1.37) 0.010 0 0.599 0.412 Low Weak
CHB infection Huang et al. (2014) [35] 7 9119 1 687 276 1.77 (0.69–4.59) 0.237 53.5 0.044 0.087 Low NS
eSET Grady et al. (2012) [36] 1 72 15 306 6.02 (2.74–13.25) 0.0001 - - - Low Weak
Prior CS Gurol-Urganci et al. (2011) [37] 37 9532 399 674 1.79 (1.60–1.98) 0.0001 82 0.0001 0.027 Low Weak
Miscarriage (threatened) Saraswat et al. (2010) [38] 6 229 64 365 1.62 (1.19–2.21) 0.0001 0 0.477 0.706 Low High
Maternal obesity Heslehurst et al. (2008) [39] 7 2647 756 217 0.83 (0.71–0.96) 0.0001 0 0.526 0.305 Low High
Maternal cocaine use Faiz et al. (2003) [40] 3 359 55 562 2.91 (1.90–4.29) 0.0001 0 0.526 0.448 Critically low High
Male foetus Faiz et al. (2003) [40] 7 3620 798 119 1.20 (1.12–1.31) 0.0001 41.9 0.215 0.0001 Critically low Weak
Preeclampsia Faiz et al. (2003) [40] 3 445 37 922 0.89 (0.51–1.41) 0.546 50.2 0.046 0.334 Critically low NS
Outcomes for PP
Blood transfusion (CS) Iqbal et al. (2022) [22] 17 10 903 384 949 7.62 (5.79–10.03) 0.0001 88.8 0.0001 0.141 Low Moderate
Preterm delivery (<37 weeks) Jansen et al. (2022) [43] 12 2 247 569 23 664 492 9.51 (7.60–11.91) 0.0001 97.1 0.0001 0.028 High Weak
Preterm delivery (<34 weeks) Jansen et al. (2022) [43] 5 611 191 22 444 795 6.12 (4.29–8.72) 0.0001 90.5 0.0001 0.999 High Moderate
Preterm delivery (<32 weeks) Jansen et al. (2022) [43] 4 337 186 22 861 089 8.58 (6.35–11.58) 0.0001 88.7 0.0001 0.377 High Moderate
Preterm delivery (<28 weeks) Jansen et al. (2022) [43] 4 98 186 22 792 315 5.61 (4.02–7.83) 0.0001 61.6 0.050 0.193 High Moderate
IUGR Balayla et al. (2019) [29] 13 10 575 1 593 226 1.31 (0.98–1.75) 0.071 92 0.0001 0.498 Low NS
NICU admission Vahanian et al. (2015) [9] 5 48 915 844 906 4.09 (2.75–6.09) 0.0001 96.6 0.0001 0.777 Low Moderate
Neonatal death Vahanian et al. (2015) [9] 3 57 765 22 929 501 5.43 (3.03–9.74) 0.0001 88.7 0.0001 0.594 Low Moderate
Perinatal death Vahanian et al. (2015) [9] 3 5422 597 163 3.00 (1.38–6.54) 0.006 88.6 0.0001 0.553 Low Weak
SGA Vahanian et al. (2015) [9] 5 146 039 1 137 103 0.97 (0.67–1.41) 0.875 90.5 0.0001 0.526 Low NS
APGAR-1 < 7 Vahanian et al. (2015) [9] 2 20 155 278 459 3.15 (1.69–5.88) 0.0001 93.9 0.0001 - Low Weak
APGAR-5 < 7 Vahanian et al. (2015) [9] 3 1839 635 703 2.73 (2.25–3.29) 0.039 98.7 0.0001 0.652 Low Weak
Factors for PAS
Maternal smoking Jenabi et al. (2022) [45] 14 9800 3 892 832 1.21 (1.02–1.41) 0.0001 4.7 0.400 0.439 Low High
HDP Li et al. (2022) [44] 6 816 126 224 0.74 (0.38–1.44) 0.379 54.1 0.054 0.317 Low NS
Prior UAE Matsuzaki et al. (2021) [25] 3 55 3236 25.83 (10.87–61.37) 0.0001 0 0.677 0.062 Low Moderate
ART Matsuzaki et al. (2021) [46] 9 1081 206 634 5.03 (3.34–7.56) 0.0001 76.4 0.0001 0.008 Low Weak
Maternal alcohol Steane et al. (2021) [10] 1 350 79 393 0.92 (0.46–1.86) 0.814 - - - High NS
Male foetus Hou et al. (2020) [47] 5 1856 804 043 0.79 (0.74–0.84) 0.0001 0 0.0001 0.953 High High
Multiple gestations Hou et al. (2020) [47] 7 147 30 458 1.79 (0.91–2.66) 0.0001 80.5 0.0001 0.310 High Moderate
Low SES Hou et al. (2020) [47] 3 390 244 792 0.47 (0.26–0.67) 0.0001 87.3 0.0001 0.162 High Moderate
Maternal obesity Iacovelli et al. (2020) [11] 5 516 554 106 1.33 (1.02–1.74) 0.038 0 0.543 0.893 High Weak
AMA Iacovelli et al. (2020) [11] 17 1152 1 055 206 2.40 (1.12–5.16) 0.024 96.1 0.0001 0.038 High Weak
Prior uterine surgery Iacovelli et al. (2020) [11] 34 1869 1 057 363 3.04 (2.16–4.29) 0.0001 77 0.0001 0.626 High Moderate
Prior CS Iacovelli et al. (2020) [11] 33 1662 656 168 3.12 (2.14–4.55) 0.0001 78.3 0.0001 0.956 High Moderate
PP Iacovelli et al. (2020) [11] 24 1694 1 057 222 4.75 (2.06–10.93) 0.0001 96.8 0.0001 0.145 High Moderate
Multiparity Iacovelli et al. (2020) [11] 19 1559 1 022 765 1.95 (1.43–2.65) 0.0001 70.9 0.0001 0.718 High Moderate
PP and prior CS Iacovelli et al. (2020) [11] 12 331 429 007 6.91 (1.29–37.08) 0.024 96.1 0.0001 0.037 High Weak
Prior curettage Iacovelli et al. (2020) [11] 16 644 10 886 1.54 (0.91–2.62) 0.109 78.9 0.0001 0.910 High NS
Prior myomectomy Iacovelli et al. (2020) [11] 9 309 938 0.76 (0.35–1.66) 0.486 0 0.617 0.557 High NS
Prior abortion Iacovelli et al. (2020) [11] 6 543 36 111 1.22 (0.87–1.71) 0.243 40.5 0.135 0.583 High NS
Prior CS (elective) Iacovelli et al. (2020) [11] 3 506 693 724 2.47 (0.17–36.67) 0.512 99.2 0.0001 0.290 High NS
Prior CS (emergency) Iacovelli et al. (2020) [11] 3 316 606 098 1.41 (0.33–6.03) 0.642 96.2 0.0001 0.101 High NS
SISP Iacovelli et al. (2020) [11] 2 143 820 1.60 (0.63–4.10) 0.324 78.3 0.032 - High NS
ART (frozen ET) Roque et al. (2018) [48] 2 149 48 209 3.51 (2.04–6.05) 0.0001 0 0.553 - Low Moderate
Factors for VP
STPP Ruiter et al. (2016) [49] 4 1231 202 296 18.97 (6.13–58.68) 0.0001 66 0.030 0.282 High Weak
VCI Ruiter et al. (2016) [49] 2 161 20 634 93.57 (25.29–346.21) 0.0001 0 0.580 - High Weak
ART Ruiter et al. (2016) [49] 2 1997 84 881 18.95 (6.61–54.34) 0.0001 29 0.240 - High Weak
Bilobed placenta Ruiter et al. (2016) [49] 2 72 19 776 55.84 (11.89–262.26) 0.0001 0 0.999 - High Weak
CILTTU Ruiter et al. (2016) [49] 2 61 5010 279.28 (1.51–51547.34) 0.030 86 0.007 - High Weak
Multiple gestations Ruiter et al. (2016) [49] 3 627 16 660 3.14 (0.97–10.11) 0.055 0 0.454 - High NS
Outcomes for VP
Preterm delivery Vahanian et al. (2015) [9] 1 21 743 246525 3.36 (2.76–4.09) 0.0001 - - - Low Weak
SGA Vahanian et al. (2016) [9] 1 5192 246 525 4.02 (2.64–6.12) 0.0001 - - - Low Weak
Perinatal death Vahanian et al. (2015) [9] 1 3463 246 525 4.52 (2.77–7.39) 0.0001 - - - Low Weak
APGAR-5 < 7 Vahanian et al. (2015) [9] 1 7651 246 525 2.18 (1.36–3.50) 0.003 - - - Low Weak
WordPress Data Table

AMA – advanced maternal age, APGAR – appearance, pulse, grimace, activity, and respiration, ART – assisted reproductive techniques, CHB – chronic hepatitis B, CS – caesarean section, eSET – elective single embryo transfer, ET – embryo transfer, HDP – hypertensive disorders of pregnancy, NS – not significant, OR – odds ratio, PAS – placenta accreta spectrum disorders, PP – placenta previa, SES – socioeconomic status, SGA – small for gestational age, SISP – short interval between prior caesarean section and subsequent pregnancy (<23 mo), STPP – second trimester placenta previa, TNF – tumour necrosis factor, UAE – uterine artery embolization, VCI – velamentous cord insertion, VP – vasa previa, wk – weeks.

Quality assessment of meta-analyses

Eleven studies were of ‘high’ (32.35%), twenty-one of ‘low’ (61.77%), and two of ‘critically low’ quality (6.45%). The most frequent flaw was the absence of a registered protocol (item 2: 23 meta-analyses (67.65%)) and inadequacy of the literature search (item 4: 2 meta-analyses (5.88%)) (File S3 in the Online Supplementary Document).

Strength of epidemiologic evidence

Seven factors (maternal cocaine use (for PP), uterine leiomyoma (for PP), prior abortion (spontaneous) (PP), threatened miscarriage (PP), maternal obesity (PP), maternal smoking (PAS), male foetus (PAS)) had high epidemiological evidence. Twelve factors (advanced maternal age (>45 years) (PP), advanced maternal age (>35 years) (PP), assisted reproductive techniques (singleton pregnancy) (PP), prior abortion (induced) (PP), prior uterine artery embolization (PAS), placenta previa (PAS), assisted reproductive techniques (frozen embryo transfer) (PAS), prior caesarean section (PAS), prior uterine surgery (PAS), multiparity (PAS), multiple gestations (PAS), low socioeconomic status (PAS)) and six outcomes (preterm delivery (<32 weeks) (PP), blood transfusion in caesarean section (PP), preterm delivery (<34 weeks) (PP), preterm delivery (<28 weeks) (PP), neonatal death (PP), neonatal intensive care unit (PP)) had moderate epidemiological evidence. Twenty-two factors (13 for PP, 4 for PAS, and 5 for VP) and eight outcomes (4 for PP, and 4 for VP) showed significant association, but with weak credibility. Other fourteen factors (5 for PP, 8 for PAS, and 1 for VP) and two outcomes (for PP) showed no statistically significant estimates (Table 1, Figure 2, and Figure 3; File S4 in the Online Supplementary Document).

Figure 2.  The results of factors and outcomes for placenta previa. AMA – advanced maternal age, ART – assisted reproductive techniques, CHB – chronic hepatitis B, CI – confidence interval, CS – caesarean section, eSET – elective single embryo transfer, ET – embryo transfer, HDP – hypertensive disorders of pregnancy, IBD – inflammatory bowel disease, IMH – isolated maternal hypothyroxinaemia, IUGR – intrauterine growth restriction, NICU – neonatal intensive care unit, NS – not significant, PP – placenta previa, SGA – small for gestational age, TNF – tumour necrosis factor, UAE – uterine artery embolization.

Figure 3.  The results of factors for placenta accrete spectrum disorders and the factors and outcomes for vasa previa. AMA – advanced maternal age, ART – assisted reproductive techniques, CI – confidence interval, CILTTU – cord insertion in the lower third of the uterus at first trimester ultrasound, CS – caesarean section, ET – embryo transfer, HDP – hypertensive disorders of pregnancy, NS – not significant, PAS – placenta accreta spectrum disorders, PP – placenta previa, SES – socioeconomic status, SGA – small for gestational age, SISP – short interval between prior caesarean section and subsequent pregnancy (<23 months), STPP – second trimester placenta previa, UAE – uterine artery embolization, VCI – velamentous cord insertion, VP – vasa previa.

DISCUSSION

In this umbrella review, we identified seven factors demonstrating high strength of epidemiologic evidence, as well as twelve factors and six outcomes demonstrating moderate strength of epidemiologic evidence. Meanwhile, the estimate of effect’s degree of confidence was weaker another 22 factors and 8 outcomes. The methodological quality across meta-analyses differed slightly.

A previous umbrella study has attempted to explore the risk factors for PP [7] and found seven high and two weak risk factors. We evaluated a further sixteen factors and found two which had two high epidemiological evidence (threatened miscarriage and maternal obesity). We also twelve outcomes – six moderate, four weak, and two of insignificant epidemiologic evidence. Compared to previous study [7], we not only explored risk factors, but also reported outcomes for PP, addressing the existing gap in the literature.

A previously published umbrella review evaluated and found seven environmental risk factors for PAS [8]; in our study, we found another 15 – one of high, five of moderate, three of weak, and six of statistically insignificant epidemiological evidence.

The factors found in the previous umbrella review and our study differ slightly. This includes four factors for PP (hypertensive disorders of pregnancy; assisted reproductive techniques (singleton pregnancy); assisted reproductive techniques (twin pregnancy); and endometriosis) and one for PAS (hypertensive disorders of pregnancy). This is mainly caused by the different included articles. For example – regarding hypertension in pregnancy in PAS, we selected the latest study by Li et al. [44] rather than the one by Wang et al. [50] study. For endometriosis in PP, we chose the study by Matsuzaki et al. [24], not the one by Zullo et al. [51]. We determined by detailed evaluation and comparison that the two studies by Li et al. [44] and Matsuzaki et al. [24] are more recent and have higher quality (per the AMSTAR 2 tool), and are also more in line with our inclusion criteria.

VP is a rare but life-threatening obstetric disease, with an incidence from 0.46 to 0.60 for every 1000 deliveries, according to two systematic reviews [5,49]. Each effect size is relatively large for the six factors and four outcomes in VP. However, the epidemiologic evidence for this estimation was weak, mainly because the sample size of the included studies was too small. Therefore, more research is needed for this rare obstetrical condition. While three other systematic reviews and meta-analyses assessed VP [5,52,53], their topics were not related to and could not be evaluated in this umbrella review.

The previous review noted antepartum haemorrhage, postpartum haemorrhage, and septicaemia (among others) as adverse pregnancy outcomes for placental anomalies [8]. However, we did not find several of these outcomes in our review. Therefore, more systematic reviews and meta-analyses are needed to evaluate the effect of placental anomalies on other adverse pregnancy outcomes in the future.

The AMSTAR 2 tool assisted us in evaluating the methodological quality of the included studies. The most common flaw and reason for downgrading the quality assessment was the lack of protocol (n = 23). The most recent registration among the included studies took place in 2016. While preregistration of study protocols was an uncommon practice until recently, especially in the field of obstetrics, we found that implementing it could improve the quality of published meta-analysis.

To our knowledge, this is the first umbrella review to provide a broad overview of the scope and validity of the reported associations of various factors and pregnancy outcomes with placental anomalies, including PP, PAS, and VP. However, some limitations should be considered. First, our results exclusively rely on meta-analyses of observational studies, and are thus subject to the same limitations – including over/under-reporting, recall bias, and reverse causation. Second, because most of included meta-analysis were of low quality according to the AMSTAR 2 assessment, the results should be interpreted with caution. Third, we found an uneven covariate mix across primary studies, which could have affected our findings so that it might be difficult to assess both the effect size or its direction. Fourth, the results may not necessarily correspond well with the clinical studies. Finally, due to the lack of raw data, we are not able to conduct further analyses.

CONCLUSIONS

In this review, we provide a comprehensive overview and critical evaluation of the contributing factors and outcomes of placental anomalies. Across 55 factors and 16 outcomes, seven (five for PP and two for PAS) and 12 factors (four for PP, and eight for PAS) and six outcomes (for PP) showed high/moderate epidemiologic evidence for placental anomalies. The results can be used to reassure women or refer them to to pre-conception counselling clinics or antenatal clinics. Clinicians should consider and communicate these factors and outcomes when counselling their patients. Regarding future research, more broadly implementing the reporting criteria and registering observational studies that test hypotheses could help strengthen the evidence. Likewise, new meta-analyses are needed to obtain, evaluate, and validate the novel and strongest evidence.

Additional material

Online Supplementary Document

Acknowledgments

We appreciate the efforts of all the researchers whose articles were included in this study.

Ethics statement: This study involved only literature review of previously published studies and the contained data. It involved no primary research on human or animal subjects, or medical records. As such, this work was considered exempt from ethical review.

Data availability: The study data are available from the corresponding author upon reasonable request.

[1] Funding: This work was supported by the 2023 Foshan Health Bureau Medical Scientific Research Project (No. 20230814A010028).

[2] Authorship contributions: DF, ZL and XG participated in the design and coordination of the study. DF conceived the study and drafted the manuscript. DF, LS, and LL searched the databases and checked them according to the eligibility criteria and exclusion criteria. YM, DL, PL, ZZ and JR help develop search strategies. GC and JR analysed the data. DF, ZL and XG did the data management. All authors read and approved the final manuscript.

[3] Disclosure of interest: The authors completed the ICMJE Disclosure of Interest Form (available upon request from the corresponding author) and disclose no relevant interests.

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Correspondence to:
Dazhi Fan
Foshan Fetal Medicine Research Institute, Foshan Women and Children Hospital
11 Renminxi Road, Foshan, Guangdong, 528000
China
[email protected]
Zhengping Liu
Foshan Fetal Medicine Research Institute, Foshan Women and Children Hospital
11 Renminxi Road, Foshan, Guangdong, 528000
China
[email protected]