Outcome of fetal congenital pulmonary malformations: a systematic review and meta-analysis

Protocol, eligibility criteria, information sources and search strategy

This review was performed according to a priori designed protocol recommended for systematic reviews and meta-analysis. Medline, Embase and Cochrane databases were searched electronically in 2018 and updated in December 2022, utilizing combinations of the relevant medical subject heading (MeSH) terms, key words, and word variants for “congenital pulmonary airways obstruction” and “outcome” (Supplementary Table 1). The search and selection criteria were restricted to English language.

Reference lists of relevant articles and reviews were hand searched for additional reports. PRISMA and MOOSE guidelines were followed. The study was registered with the PROSPERO database (Registration number: CRD42018107238).

Study selection, data extraction and data items

The primary outcome to report was in-utero natural history of prenatally diagnosed CLM by describing the reduction (reduction or disappearance) or the increase in size of the lesions.

The secondary outcomes were:

1. Intrauterine death (IUD), defined as fetal loss after 20 weeks’ gestation;

2. Neonatal death (NND), defined as death occurring up to 28 days after birth;

3. Perinatal death (PND), defined as IUD or NND;

4. Overall neonatal morbidity (including respiratory distress syndrome (RDS), Neonatal Intensive Care Unit (NICU) admission, respiratory morbidity).

5. Need for surgery.

6. Type of surgery: elective or emergency (i.e. in the neonatal period and/or for respiratory symptoms).

Furthermore, we planned to perform sub-group analysis according to the sonographic appearance of the lesion (microcystic, macrocystic, mixed and hyperechoic) and in those presenting with hydrops at ultrasound. Finally, we planned to report the role of fetal therapy (any, cyst drainage or thora-coamniotic shunt placement) in improving the outcome of these anomalies.

Only studies including fetuses with a prenatal diagnosis of isolated CLM confirmed at birth were considered eligible for the inclusion in the present systematic review. Studies reporting prenatal information on paediatric or pathologic series were excluded if no information on the natural history and perinatal mortality of these fetuses could be extrapolated.

Case reports, conference abstracts and case series with fewer or equal to three cases were excluded to avoid sampling bias. Studies published before 2010 were also excluded as we believe that the recent important advances in prenatal diagnosis (better resolution of ultrasound machines, improvement in knowledges of these pathologies, etc.) have increased the diagnosis also of small lesions while, on the other hand, it is likely that only more severe forms were prenatally diagnosed in the past. Therefore, by including only papers from 2010 onward, this review will best reflect the natural history and the current management of these lesions.

Three authors (FGS, SA and DAI) reviewed all abstracts independently. Agreement regarding potential relevance was reached by consensus. Full text copies of those papers were obtained, and the same reviewers independently extracted relevant data regarding study characteristics and pregnancy outcomes. Inconsistencies were discussed by the reviewers and consensus reached or by discussion with a senior author (FDA). If more than one study was published on the same cohort with identical endpoints, the report containing the most comprehensive information on the population was included to avoid overlapping populations.

Assessment of risk of bias

Quality assessment of the included studies was performed using the Newcastle-Ottawa Scale (NOS) for cohort and/or case-control studies [14]. According to NOS, each study is judged on three broad perspectives: the selection of the study groups, the comparability of the groups, and the ascertainment outcome of interest. Assessment of the selection of a study includes the evaluation of the representativeness of the exposed cohort, selection of the non-exposed cohort, ascertainment of exposure and the demonstration that outcome of interest was not present at the start of study. Assessment of the comparability of the study includes the evaluation of the comparability of cohorts based on the design or analysis. Finally, the ascertainment of the outcome of interest includes the evaluation of the type of the assessment of the outcome of interest, length and adequacy of follow-up. According to NOS a study can be awarded a maximum of one star for each numbered item within the Selection and Outcome categories. A maximum of two stars can be given for Comparability [14].

Data synthesis

We used meta-analyses of proportions to combine data and reported pooled proportions and their 95 % confidence intervals (CI). Between-study heterogeneity was explored using the I2 statistic, which represents the percentage of between-study variation that is due to heterogeneity rather than chance. A value of 0 % indicates that no heterogeneity was observed, whereas values >50 % are associated with substantial heterogeneity. Due to the clinical heterogeneity among studies, a random effects model was used for all meta-analyses [15]. Egger’s test was used to assess potential publication bias and funnel plots were created for visual inspection [16]. Tests for funnel plot asymmetry were not used when the total number of publications included for each outcome was less than 10, as the tests lack power to detect real asymmetry in this scenario [17]. The analysis was performed using Statsdirect 3.0.171 (Stats Direct Ltd) and Revman 5.3 (The Nordic Cochrane Centre, The Cochrane Collaboration, 2014) statistical software.

Study selection and study characteristics

A total of 1787 studies were identified, 173 were assessed with respect to their eligibility for inclusion and 39 studies were included in this systematic review (Table 1 and Figure 1) [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54], [55], [56].

Figure 1:

Systematic review flowchart.

These 39 studies included 2,638 fetuses with an antenatal diagnosis of CPAM (Table 1). No randomized controlled trial was available for inclusion; data for this review were derived only from observational cohort studies or case series. Thirty-nine studies were retrospective [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38, 40], [41], [42], [43], [44], [45], [46], [47], [48], [49, 51], [52], [53], [54], [55], [56] and only three [18, 39, 50] were prospective in nature. Diagnosis occurred mainly in the second trimester at the time of the anomaly scan and reported at its earliest at 19.5 weeks’ gestation [19].

The sonographic appearance of the lesions (i.e. microcystic, macrocystic, mixed or hyperechoic) was reported by 19 studies [18, 21, 22, 24, 25, 29], [30], [31], [32, 37, 38, 42], [43], [44, 47, 50, 53, 55]. Type of lesions (i.e. CPAM or CCAM or Bronchopulmonary sequestration or hybrid lesions) was reported by 34 studies [18], [19], [20], [21], [22], [23], [24], [25, 27], [28], [29], [30], [31], [32, 34], [35], [36], [37], [38], [39], [40, 43], [44], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54, 56]. Among the included studies, 15 studies [19, 23, 26, 30, 33, 37, 38, 43, 45, 46, 48, 49, 52, 55, 56] reported also data on fetal therapy: four studies performed a cyst drainage [37, 38, 49, 52], 10 studies positioned a thoraco-amniotic shunt [19, 23, 30, 33, 37, 38, 45, 46, 55, 58], seven studies performed other types of fetal therapy including amniodrainage, laser therapy of the feeding artery, maternal steroids or EXIT procedure [19, 26, 37, 38, 43, 45, 56]. Finally, 17 studies reported data on hydropic fetuses separately from the whole cohort [19, 25, 26, 30, 31, 34, 35, 38, 43, 45], [46], [47, 49, 51, 52, 54].

Risk of bias of included studies

The results of the quality assessment of the included studies using the NOS scale are presented in Table 2. Most of the included studies showed average scores regarding the selection and comparability of study groups, and for ascertainment of the outcome of interest. The main weaknesses of these studies were their retrospective non-randomized design, small sample size, heterogeneity of outcomes observed and lack of stratification of the observed outcomes according to the ultrasound appearance of the lesions for most of the included studies.

Synthesis of results

Regression or reduction in size of the lung lesion during pregnancy was reported in 30.90 % (95 % CI 20.09–42.88) of cases, while its increase in 8.47 % (95 % CI 2.93–16.46). Intra-uterine death complicated 1.53 % (95%CI 0.89–2.34) of pregnancies, while the corresponding figures for neonatal and perinatal death were 2.21 % (95 % CI 1.21–3.50) and 2.97 % (95 % 1.77–4.46). 20.57 % (95 % CI 15.66–25.97) of newborns with CLM experienced postnatal morbidity and 18.50 % (95 % CI 8.60–31.10) had radiological signs of mediastinal shift at birth. 46.29 % (95 % CI 33.96–58.86) of newborns with a prenatal diagnosis of CLM had surgery; elective surgical intervention was performed in 67.13 % (95 % CI 54.05–78.99), while 32.87 % (95 % CI 21.01–45.95) required emergency surgery for the presence of respiratory symptoms (Table 3). The occurrence of the explored outcomes when not considering studies including cases of fetal hydrops is reported in Table 3. Unfortunately, a comprehensive assessment of the observed outcomes according to the ultrasound appearance of the lesion was not possible due to the very small number of studies reporting these sub-group analyses.

Sub-group analyses: fetuses with hydrops and fetal therapy

Fetal or perinatal loss occurred in 42.38 % (95 % CI 26.84–58.74) of fetuses with hydrops, while reduction of the size during pregnancy was reported in 4.42 % (95 % CI 1.26–9.39) as presented in Table 4. Assessment of the role of fetal therapy in improving the outcomes of pregnancies complicated by CLM was hampered by the small number of included cases and even smaller number of events which precluded a comprehensive assessment of the role of fetal therapy in these anomalies. Furthermore, different interventions for fetal CLM were reported in the published literature, including insertion of thoraco-amniotic shunt, drainage of the lesion in case of cystic malformation and laser coagulation of the feeding vessel of the lesion. For the purpose of the analysis and in view of the small number of cases included, we reported the analysis for fetuses undergoing drainage of the lesion or insertion of thoraco-amniotic shunt. When considering all fetuses undergoing intervention (Table 5), regression or reduction in size of the lesion was reported in 61.73 % (95 % CI 13.99–97.86), perinatal death in 21.51 % (95 % CI 11.88–33.07) and preterm birth in 29.42 % (95 % CI 14.57–46.95), while 70.37 % (95 % CI 55.18–83.55) of newborns underwent surgery. Finally, when considering only fetuses presenting with hydrops at ultrasound, regression or reduction in size of the lesion was reported in 84.02 % (95 % CI 47.60–99.98) of cases and 78.76 % (95 % CI 43.62–98.82) had resolution of the hydrops after fetal therapy. Perinatal death occurred in 21.91 % (95 % CI 9.37–37.88) of pregnancies complicated by CLM presenting with hydrops and PTB in 52.73 % (95 % CI 25.54–79.06).

Main findings

The findings from this study showed that fetuses with CLM diagnosed on prenatal ultrasound have a generally good outcome. Regression or reduction in size of the lesion occurred in 31 % of cases, while its increase in size in about 8.5 %. The risk of fetal or neonatal mortality was also low. Conversely, in fetuses presenting with hydrops the risk of perinatal loss was high while the regression or resolution of the lesion was less frequent. Assessment of the role of fetal therapy in improving the outcomes of pregnancies complicated by CLM was impaired by the small number of included cases and heterogeneity of interventions explored which precluded a comprehensive assessment of the role of fetal therapy in these anomalies.

Strengths and limitations

This is, to the best of our knowledge, the first systematic review and meta-analysis on congenital lung malformations and their natural in-utero history. The main strengths of this study include the systematic literature search and the large number of included studies. Nevertheless, the retrospective design and differences among the included populations, the different definitions adopted, the different management protocols and criteria to perform fetal therapy represent the main limitation of this review.

Subgroup analysis according to the sonographic appearance of the lesions were conducted although only few studies reported outcomes according to this while the majority of them only described the sonographic appearance of the lesions and then reported the outcomes for the whole population.

Similarly, despite most of the studies included hydropic fetuses in their cohorts, data on these fetuses were frequently aggregated to the whole cohort limiting the number of studies included in the sub-group analysis on hydrops.

Furthermore, we decided to include only studies reporting data on prenatally identified cohort or paediatric cohort with comprehensive prenatal data in order to avoid the selection bias introduced by including pediatric surgical series. The latter, in fact, reported only data on children undergoing surgery and consequently excluded the most severe cases (i.e. pregnancies complicated by IUD or where parents opted for TOP).

Finally, the outcomes reported were not consistent among studies both in prenatal and post-natal reported information. In particular, the post-natal imaging technique and/or its timing were not consistent as well as the indication and type of surgery performed with high heterogeneity among studies.

However, despite these limitations, this review represents the most up-to-date assessment of this important congenital pathology.

Comparison with existing literature

This is, to the best of our knowledge, the first systematic review and meta-analysis reporting the outcome of fetuses with CLM diagnosed prenatally. Another systemic review assessing the diagnostic accuracy of congenital airway malformation lung volume (CVR) ratio in identifying those fetuses who will develop hydrops, reported a sensitivity and specificity of this ultrasound parameter in detecting hydrops of 86 and 90 % respectively [57]. Compared to this review, the present meta-analysis reported the natural history of fetuses with CLM in utero, perinatal and post-natal outcome of these anomalies.

Implications for clinical practice and research

This review updated the knowledge on prenatally diagnosed CLM with the most recently published studies showing a very favorable outcome for fetuses with this diagnosis. In fact, up to one third of the lesions decreased in size or disappeared in utero while only in 8.5 % of them the lesion increased in the prenatal period. Furthermore, the perinatal outcome of uncomplicated (i.e. without hydrops) CLM is good, being these pregnancies complicated by perinatal death in only 3.5 % of the cases while previous studies have produced highly variable rates of perinatal death from 9 to 49 % [58]. This is likely to be explained by the fact that the rate of prenatal diagnosis of CLM has been increasing over recent years thanks to the improvement in prenatal imaging with an increased identification also of small lesions without additional anomalies or without hydrops at presentation.

The CVR has already been described as a possible a tool to predict the development of hydrops in these fetuses two decades ago. However, since then, no clear international consensus has been reached to define the optimal CVR thresholds and, as recently shown by Kane et al. [59] in their systematic review, further large-scale studies are still required to confirm and define the utility of this index.

The possible role of fetal therapy in these fetuses still needs to be clarified. In fact, the number of included fetuses was small and differences in techniques, protocols and management impairs our ability to produce robust evidence on the use of thoracoamniotic shunt or cyst drainage in these fetuses although cyst drainage can be offered for macrocystic lesion occupying space and shunting is frequently offered in CLM complicated by hydrothorax and/or hydrops [9].

Looking at post-natal outcomes, the rate of neonatal morbidity was only 20.6 %, confirming the fact that most of the fetuses with prenatal diagnosis of CLM are likely to be asymptomatic at birth. However, around 33 % of these fetuses required an emergency surgery due to neonatal symptoms. Moreover, more than half (67 %) of the fetuses with CLM underwent surgery in the series included in this review. In fact, prophylactic elective surgery is usually recommended to avoid the long-term risk of pulmonary infections and to prevent the development of malignancy, despite the true incidence of these adverse outcomes remains debated [10], [11], [12]. Therefore, the results of this review should help guiding the counseling with parents of fetuses with a prenatal diagnosis of CLM, who should be reassured of the good prognosis of the lesions when the pregnancy is not complicated by the occurrence of hydrops.