In Chapter 6, we assessed the association between severe oligohydramnios and the risk of adverse pregnancy outcome. Although the finding was associated with the risk of SGA, it was not strongly predictive of SGA, and associations with neonatal morbidity were difficult to assess as > 95% of the patients included in the meta-analysis participated in studies in which the results of the ultrasound scan were revealed. The aim of this element of the work was to determine the association between borderline oligohydramnios and adverse pregnancy outcome. First, we aimed to determine whether there was indeed a gradient in the strength of association comparing severe with borderline oligohydramnios. Second, we were able to analyse previously unpublished data obtained from the POP study of unselected nulliparous women using a blinded assessment of the presence or absence of borderline oligohydramnios. This allowed us to address the true association between the finding and the risk of adverse outcome while avoiding associated biases, for example treatment paradox and ascertainment bias.
As severe oligohydramnios is defined as AFI of < 5 cm, borderline oligohydramnios can be defined as AFI of 5–8 cm or 5–10 cm. To establish the predictive associations, we analysed unpublished data from the POP study (as described in Chapter 4) and a systematic review of other studies of diagnostic effectiveness.
Methods
Analysis of data from the Pregnancy Outcome Prediction study
In the systematic review we included unpublished data from a prospective cohort study, the POP study, as described in Chapter 4. The present analysis excluded women who delivered prior to their 36 weeks’ gestation scan appointment. Screen positive was defined as an AFI between 5 and 8 cm and screen negative was defined as an AFI between 8 and 24 cm. Outcome data have been defined previously.8
Sources for meta-analysis
The protocol for the review was designed a priori and registered with the international Prospective Register of Systematic Reviews PROSPERO (registration number CRD42017064093). We searched MEDLINE, EMBASE, CDSR and CENTRAL from inception to June 2019. The studies were identified using a combination of words related to ‘ultrasound’, ‘pregnancy’, ‘amniotic fluid index’, ‘AFI’, ‘liquor volume’ and ‘prenatal diagnosis’. No restrictions on language or geographical location were applied.
Study selection
Selection criteria allowed the inclusion of cohort or cross-sectional studies involving singleton pregnancies in which an ultrasound scan was performed at ≥ 24 weeks’ gestation. We included studies that used a matched design based on the ultrasound finding (borderline oligohydramnios vs. normal AFI) but excluded case–control studies (matched on outcome). We included all studies in which ultrasound was performed as part of universal screening (i.e. ultrasound was offered to women regardless of indication), studies that were performed in low-risk populations (i.e. those that excluded pregnancies with any maternal or fetal complication) and studies in a mixed-risk population (i.e. those that did not specify the indication for the ultrasound). We included studies defining borderline oligohydramnios as an AFI of either 5–8 cm or 5–10 cm and included both studies in which the result was revealed (i.e. the result of the scan was reported to the clinician) and those in which the result was not revealed (i.e. clinicians were masked to the result). We excluded studies that were focused on high-risk populations only (e.g. pregnancies known to be complicated by FGR) and those in which the scan was performed during labour.
Study quality assessment and data extraction
The literature search, study selection and analysis were performed independently by two authors (AM and IA) using Review Manager 5.3. Any differences were resolved in discussion with the senior author (GS). The risk of bias in each included study was assessed using the QUADAS-2 tool37 as outlined in the Cochrane Handbook of Diagnostic Test Accuracy Studies. We used a predesigned data extraction form to extract information on study characteristics (i.e. year of publication, country, setting, study design, blinding), patient characteristics (i.e. inclusion and exclusion criteria, sample size), the index test (i.e. gestational age at scan, cut-off values used) and reference standard (i.e. pregnancy outcome, gestation at delivery, and interval from scan to delivery).
Statistical and meta-analysis methods
The statistical and meta-analysis methods employed are described in Chapter 4.
Results
The Pregnancy Outcome Prediction study
Initially, we analysed the previously unpublished data from the POP study.88 Applying the inclusion criteria described above yielded a total of 3387 women with a blinded scan at 36 weeks’ gestation out of the 4512 women recruited (see Appendix 4, ), and 108 (3.2%) of these women had borderline oligohydramnios (AFI of 5–8 cm, Appendix 4). Maternal age, socioeconomic deprivation, ethnicity, BMI, and rates of alcohol consumption and smoking were similar in the two groups (see Appendix 4, Table 22). Moreover, the groups had similar rates of pre-existing hypertension and pre-eclampsia. The median birthweight was 200 g lower in the cases of borderline oligohydramnios, with a small difference in the gestational age at delivery. The rates of IOL were similar in both groups but women with borderline oligohydramnios had higher rates of spontaneous vaginal delivery. The screening performance of borderline AFI in the POP study88 is presented in . Borderline AFI was associated with an increased risk of delivering a severely SGA infant but was not associated with SGA or an increased risk of a range of indicators of neonatal morbidity in the POP study.88
Diagnostic performance of borderline AFI (5–8 cm) in predicting adverse pregnancy outcome at term in the POP study (n = 3387)
Meta-analysis
The literature search flow chart is presented in Appendix 4, . We identified 11 studies88–98 (including the POP study) that met our inclusion criteria, which involved a total of 37,848 patients. The study characteristics are presented in Appendix 4, Table 23. Only the POP study88 (n = 3387) included unselected pregnancies, three studies91,97,98 (n = 1890) included low-risk pregnancies only and seven studies89,90,92–96 (n = 32,571) included mixed-risk pregnancies. Two studies97 (n = 3817) were prospective and nine studies89–96,98 (n = 34,031) were retrospective. Seven studies91,93–97 (n = 36,293) defined borderline oligohydramnios as AFI of between 5 and 8 cm and four studies89,90,92,98 (n = 1555) defined it as between 5 and 10 cm. The majority of patients in all the studies delivered at term. However, four studies89,92,95,97 reported a significantly higher rate of preterm delivery among those with borderline oligohydramnios.
The assessment of study quality was performed using the QUADAS-2 tool and is summarised in Appendix 4, . The main risk of bias was from the lack of blinding of the ultrasound result (which we defined as high risk for reference standard), which affected all studies except the POP study.88 We classified one study93 as being at high risk for selection bias as it used only low-risk patients for the comparison group and we classified two studies89,90 as being at unclear risk of selection bias as they did not specify whether they enrolled a consecutive or random sample of patients. Moreover, we classified five studies89,92,94,96,98 as having an unclear risk of bias for flow and timing because they did not report gestational age at ultrasound or delivery.
The summary diagnostic performance of borderline AFI at predicting adverse pregnancy outcome is presented in . The most commonly reported outcomes were SGA < 10th centile (nine studies), NICU admission (eight studies), 5-minute Apgar score of < 7 (eight studies), meconium-stained amniotic fluid (seven studies) and caesarean section for fetal distress (six studies). The meta-analysis demonstrated a statistically significant association between borderline oligohydramnios and all of the outcomes, and the strongest association was with delivery of a SGA infant (positive LR = 2.6). The summary ROC curves are presented in . Forest plots of the DORs () demonstrated statistically significant heterogeneity for SGA and NICU admission. Two studies (POP and Petrozella et al.95) reported SGA below the third centile and three studies reported perinatal death. However, we could not generate summary results for outcomes that were reported in fewer than four studies. Finally we used Deeks’ funnel plot asymmetry test to assess the risk of publication bias using the outcome of SGA < 10th centile for the analysis (see Appendix 4, ). The test showed no evidence of publication bias (p = 0.33).
Summary diagnostic performance of borderline AFI in predicting adverse pregnancy outcome
Summary ROC curves of borderline AFI at predicting (a) SGA < 10th centile; (b) NICU admission; (c) 5-minute Apgar score of < 7; and (d) caesarean section for fetal distress.
The diagnostic odd ratios of borderline AFI at predicting: (a) SGA < 10th centile; (b) NICU admission; (c) 5-minute Apgar score of < 7; and (d) caesarean section for fetal distress. a, Alexandros A Moraitis, Ilianna Armata, (more...)
Discussion
The main finding of the present study is that borderline oligohydramnios is moderately predictive of SGA babies. This was observed in the meta-analysis of multiple studies of variable quality. There was also a comparable association between borderline oligohydramnios and severe SGA in the only study in which researchers were blinded to the scan results, namely the POP study.
The observation that borderline oligohydramnios was associated with severe SGA only in the POP study is of interest. One possible explanation for this is that the scan result was not revealed; hence, the finding did not lead to changes in clinical management. The success from blinding the result is evidenced by the fact that borderline oligohydramnios was not associated with increased rates of IOL in the POP study. A previous RCT of routine early term induction compared with expectant management of pregnancies in which ultrasonic fetal biometry indicated a SGA infant demonstrated that early delivery was associated with a significantly decreased risk of the infant being delivered with a birthweight < 3rd percentile.99 A possible explanation for the POP study’s association with severe SGA and the meta–analysis association with all SGA is that a finding of borderline oligohydramnios may have led to increased rates of early delivery in studies in which the result was revealed, whereas the lack of intervention in the POP study led to growth-restricted fetuses becoming progressively smaller for gestational age as the pregnancy advanced.
The other major difference between the meta-analysis and the POP study may also relate to the lack of blinding in the other studies. Borderline oligohydramnios was associated with increased rates of neonatal morbidity in the meta-analysis but none of the outcomes of neonatal morbidity was associated with this finding in the POP study. However, the CIs were wide and one explanation could be the lower statistical power of the POP study. However, plotting the DORs demonstrates that, in relation to NICU admission, the 95% CI observed in the POP study excluded the point estimate of the meta-analysis. This result could also be explained by the absence of blinding in the other studies. If the scan result is revealed, the only disease-modifying intervention available in late pregnancy is early delivery, and this could be late preterm or early term. It is well recognised that both are associated with increased rates of neonatal morbidity and NICU admission. Hence, the association between borderline oligohydramnios and neonatal morbidity in the meta-analysis could be because the finding led to iatrogenic prematurity and the absence of the finding in the POP study could be due to the lack of this effect. Assessment of individual studies in the meta-analysis is consistent with this interpretation. Gumus et al.92 reported higher rates of IOL in women with borderline oligohydramnios, which was associated with higher rates of preterm and early term delivery, and higher rates of NICU admission. Similarly Asgharnia et al.,89 who offered screening after 28 weeks’ gestation, found that those with borderline AFI had a rate of preterm delivery of 40.4% (compared with 14.9% for those with normal AFI) and this is the likely explanation for the strong association between borderline oligohydramnios and NICU admission. This association was not found in studies that offered ultrasound later in pregnancy such as that by Sahin et al.97
In conclusion, we provide strong evidence that borderline oligohydramnios is associated with an increased risk of delivering a SGA infant. However, when the finding of borderline oligohydramnios is revealed to clinicians, it may lead to increased risks of neonatal morbidity as a result of earlier delivery. Given that the prediction of SGA was not strong and that revealing the result may have led to increased risks of neonatal morbidity, the observed association with SGA does not necessarily mean that screening unselected nulliparous women near term with this method will result in better clinical outcomes.
