Intra-partum and perinatal outcomes in fetuses exhibiting ZigZag pattern on cardiotocography trace: a systematic review and meta-analysis

Protocol, information sources and literature search

This review was performed according to an a-priori designed protocol and recommended for systematic reviews and meta-analysis [31], [32], [33]. Medline, Embase and Cochrane databases were searched electronically on the 10/09/2024 utilizing combinations of the relevant medical subject heading (MeSH) terms, key words, and word variants for “ZigZag”, “Saltatory” patterns, “increased variability” and “outcome”. The search and selection criteria were restricted to the English language. Reference lists of relevant articles and reviews were hand-searched for additional reports. The PRISMA guidelines were followed [34].

Outcomes measures, study selection and data collection

We included studies reporting the intra-partum and perinatal outcome of fetuses showing compared to those not showing ZZP, defined as a rapid, repetitive oscillations in the FHR baseline, most of the times at a variability above 25bpm for at least 1 min, at CTG trace during labour (Figure 1).

Figure 1:

Zig-Zag pattern on a CTG trace during labour.

The outcomes observed were:

1. Operative vaginal delivery

2. Caesarean delivery

3. Umbilical artery pH<7.1

4. Base excess <−11

5. Mean pH and base excess

6. Admission to neonatal intensive care unit (NICU)

7. Abnormal post-natal brain imaging, defined as the presence of intra-ventricular haemorrhage or periventricular leukomalacia or at post-natal imaging

8. Occurrence of late decelerations later on the CTG trace

We also reported the distribution of different pregnancy and fetal characteristics including:

1. Maternal age

2. Gestational age at birth

3. Nulliparity

4. Spontaneous or induced labor

5. Term pregnancies

6. Prolonged or post-term pregnancies, defined as pregnancies progressing beyond 41 and 42 weeks of gestation respectively

Data extraction, quality assessment, risk of bias and statistical analysis

Two independent investigators (LF, GO) selected studies in two stages. The abstracts of all potentially relevant papers were examined individually for suitability. Papers were excluded at this stage only if they did not meet the inclusion criteria. The remaining papers were obtained in full text and were assessed independently for content, data extraction and analysis. Disagreements between the two original reviewers were resolved by discussion with a third investigator (FDA). Study characteristics were extracted using a predesigned data extraction protocol. 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.

Only full-text articles were considered eligible for inclusion. Studies not reporting the comparison between fetuses showing and those not showing ZZP on CTG trace during labour, those including only the role of CTG in specific pregnancy complications (such as those affected by infection or medical conditions complicating pregnancy) and those not reporting the occurrence of the observed outcomes were excluded. Case reports, conference abstracts and case series with<10 cases were also excluded to avoid publication bias. We excluded studies published before 2010 because we think that advances in the comprehension of CTG trace during labour make them less relevant.

Quality assessment of the included studies was performed using the Newcastle-Ottawa Scale (NOS) for case-control studies [35]. 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 of the outcome of interest.

Random-effect meta-analyses were used to combine data and results reported as pooled odd ratios (OR) and pooled mean differences (MD) for categorical continuous variables respectively [36], 37]. Funnel plots displaying the outcome rate from individual studies vs. their precision (1/standard error) were carried out with an exploratory aim, but were not used when the total number of publications included for each outcome was less than 10. In this case, the power of the tests is too low to distinguish chance from real asymmetry [37].

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. All analyses were performed using StatsDirect Statistical Software (StatsDirect Ltd Cambridge, United Kingdom).

Study selection and characteristics

The literature search identified 320 articles, 10 of which were assessed for eligibility for inclusion, and six studies were included in the systematic review (Table 1, Figure 2, Supplementary Table 1) [19], [21], [22], [23], [24, 30]. These six studies included (after removing the studies including overlapped cases) 18,136 fetuses.

Figure 2:

Prisma flow-diagram.

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 an overall moderate score 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 design, and heterogeneity of outcomes observed.

Synthesis of the results

When comparing the maternal and pregnancy characteristics, there was no difference in maternal age (p=0.878) and term labor between cases showing and those not showing ZZP on CTG. Conversely, there was a higher prevalence of nulliparity (p<0.001), prolonged or post-term pregnancies (p<0.001) and women undergoing induction of labor (p=0.002) between women showing compared to those not showing ZZP at CTG assessment during labor (Table 3).

Fetuses showing ZZP on CTG trace during labor had a higher risk of operative vaginal delivery (OR: 2.22, 95 % CI 1.69–2.91; p<0.001), cesarean delivery (OR: 1.71, 95 % CI 1.37–2.15; p<0.001), umbilical artery pH<7.1 (OR: 2.48, 95 % CI 1.56–3.94; p<0.001), Apgar score <7 at 5 min (OR: 2.13, 955 CI 1.05–4.31; p=0.004) and the occurrence of late decelerations later on during labor (OR: 9.51, 95 % CI 7.80–11.61; p<0.001) compared to those not showing this pattern, while there was no difference in the risk of NICU admission (p=0.209) and respiratory support after birth (p=0.755), while it was not possible to performed a comprehensive pooled data synthesis for abnormal brain imaging as only one study reported this outcome (Table 4). When considering the continuous variables, umbilical artery pH was significantly lower in fetuses showing compared to those not showing ZZP during labour (pooled MD: −0.10, 95 % CI −0.11 to −0.09; p<0.001), while there was no difference in the value of mean base excess between the two groups (p=0.156) (Table 4).

Summary of the main findings

The findings from this systematic review showed that fetuses showing ZZPon CTG trace during labor had a higher risk of operative vaginal delivery, cesarean section, abnormal Apgar score, pH<7.1 compared to those not showing this pattern during labour. The observed increase in the ZZP in post-term fetuses (p<0.001) who have reduced placental reserves and increased likelihood of umbilical cord compression due to relative reduction in amniotic fluid volume, and in fetuses who were exposed to induction of labor (p=0.002), supports the hypothesis that ZZP reflects a rapidly evolving hypoxic stress. This is because increased umbilical cord compression and reduced utero-placental insufficiency in the former and increased uterine activity in the latter would increase the likelihood of a rapidly evolving hypoxic stress in late first or second stage of labor, leading to the onset of ZZP on the CTG trace.

Comparison with other systematic reviews, strengths and limitations

The multitude of outcomes observed, and thorough literature search are main strengths of the present systematic review, while the small number of included cases, retrospective study design and lack of standardised criteria for intra-partum management in case of ZZP represents its main weaknesses. Furthermore, some maternal and pregnancy characteristics were unbalanced between the two different study groups, including nulliparity, induction of labour and post-term pregnancies, thus potentially representing a source of bias for the reported results.

Clinical and research implications

The American College of Obstetricians and Gynaecologists (ACOG) and the FIGO classification system [4], 7], 14] for CTG was developed to standardize the interpretation of FHR patterns during labor, grouping tracings into three primary categories based on specific criteria:

1. Category I (FIGO=Normal): Patterns with a low risk of hypoxia, typically requiring no intervention.

2. Category II (FIGO=Suspicious): Patterns that are inconclusive and warrant closer monitoring.

3. Category III (FIGO=Pathological): Patterns with a high likelihood of fetal hypoxia, necessitating prompt intervention.

While these frameworks support labor management by establishing universal categories, these categories, being too rigid, may overlook the complexity of individual cases. For example, a growth restricted fetus may not have sufficient physiological reserves to be rigidly classified into these “fixed categories”. However, exposure to chronic utero-placental insufficiency or an intraamniotic inflammation and/or chorioamnionitis may lead to multiple pathways of compromise. More importantly, its focus on technical criteria can limit a deeper understanding of the underlying pathophysiology, as it does not differentiate the causes of FHR variations or consider fetal adaptation to potentially hypoxic stress. This limitation may restrict clinicians’ insights into the physiological context of specific FHR patterns. These classification systems also do not address features of fetal inflammation, and therefore, may have some limitations when interpreting atypical patterns that do not fit neatly within these three categories.

The Saltatory pattern, for instance, has historically remained a controversial and poorly understood entity, with no established consensus on its pathophysiology and management. The saltatory pattern, as defined by FIGO guideline has been reported to occur rarely during labour. More recently, a new CTG feature during labor, the ZZP, which has been defined as a rapid, erratic, oscillations in FHRV with an amplitude of >25 bpm has been reported to be a transient sign suggesting a higher risk of fetal hypoxemia and/or an ongoing fetal inflammation. Recently, an international expert consensus has provided the definition and the maximum duration of the ZZP to be considered as abnormal [3]. Furthermore, the interpretation tools recommended by this international expert consensus panel classify the CTG traces based on the types of hypoxia and fetal inflammation and have included the ZZP both in subacute hypoxia (rapidly evolving hypoxic stress) and in chorioamnionitis (neuroinflammation).

Although the pathophysiology of ZZP has not been clearly described yet, it is likely to reflect a disordered or hyperactive autonomic response potentially triggered by rapidly evolving hypoxia or acidosis. When hypoxia progresses quickly, the fetus may not maintain baseline heart rate long enough to oxygenate critical organs, leading to erratic sympathovagal responses aimed at balancing oxygen delivery and cerebral perfusion. The sympathetic nervous system rapidly attempts to increase the FHR to obtain oxygenated blood while the parasympathetic nervous system tries to reduce the heart rate to protect the myocardial workload. This autonomic imbalance, likely caused by a sudden drop in oxygenation or acidosis, produces the pronounced FHR fluctuations seen as the ZZP, signalling that the fetus’s regulatory system may be under strain.

This rapid increase and decrease in the FHR may be seen on the CTG as variability exceeding 25 bpm in a shape of an irregular ZZP, defined by many authors as variability >25 bpm lasting at least 1 min. The appearance of this pattern during labor may represent an early sign of fetal hypoxia or acidosis, particularly when accompanied by other concerning signs, such as decreased long-term variability or late decelerations. A recent study has concluded that in the presence of features of fetal neuroinflammation on the CTG tracer which includes the ZZP, the levels of IL-6 in the umbilical cord, which is a marker of ongoing fetal inflammation is increased approximately 4-fold [29]. Moreover, it has been shown that injection of boluses of LPS (bacterial toxins) in sheep was associated with increased fetal heart rate variability, which also coincided with episodes of fetal hypotension [37]. Therefore, ZZP in chorioamnionitis may signify a late stage in fetal inflammatory response, requiring an urgent intervention.

We have reported a higher risk of operative delivery, abnormal Apgar score and umbilical artery pH in fetuses showing compared to those not showing ZZP during labour, thus highlighting the potential role of such sign in identifying fetuses at higher risk of progressive hypoxemia and acidosis.

Identification of fetuses exposed to a rapidly evolving hypoxic stress during labour is crucial as potential interventions, stopping the oxytocic drugs, administration of tocolytics, and intra-venous fluids if appropriate, cessation of active maternal pushing and changing maternal position, may help restore fetal oxygenation. This may not only help avoid poor perinatal outcomes due to the progression of the rapidly evolving fetal hypoxemia leading to fetal metabolic acidosis., but also unnecessary intrapartum operative interventions by normalising the CTG trace. Therefore, our systematic review, first in our best knowledge which determined the association between the ZZP and perinatal outcomes may have important clinical impact and help modify clinical practice.