Timing and mode of birth for women with sickle cell disease: A systematic review

Porjai Pattanittum; Chetta Ngamjarus; Apiwat Jongjakapun; Termtem Waidee; Nampet Jampathong; Yaneve Fonge; Pisake Lumbiganon; Jen Sothornwit

doi:10.1002/pmf2.70031

. 2025 May 14;1(3):e70031. doi: 10.1002/pmf2.70031

Timing and mode of birth for women with sickle cell disease: A systematic review

Porjai Pattanittum ¹, Chetta Ngamjarus ¹, Apiwat Jongjakapun ², Termtem Waidee ², Nampet Jampathong ³, Yaneve Fonge ⁴, Pisake Lumbiganon ², Jen Sothornwit ^2,^✉

PMCID: PMC13344830 PMID: 42597071

Abstract

Introduction

Sickle cell disease (SCD) is a significant global health issue. Pregnant women with SCD are at high risk of maternal and fetal morbidity and mortality. Among considerations in the management of women with SCD during pregnancy is the increased risk of placental insufficiency and the potential need for induction of labor or cesarean section to reduce risks to the woman and baby. In two separate reviews, we aimed to evaluate the effect of timing of birth (induction of labor at early term [37–38 weeks’ gestation] or term [39–40 weeks’ gestation] vs. spontaneous labor or induction of labor at 41–42 weeks’ gestation) and the impact of mode of birth (cesarean section or vaginal birth) among women with SCD on neonatal and maternal outcomes.

Methods

We systematically searched for relevant studies in PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), Scopus, and CINAHL. We searched without language restriction from inception to July 29, 2023. We planned to include randomized controlled trials and cohort studies and to use standard methodological procedures as described in the Cochrane Handbook for Systematic Reviews of Interventions. Primary review outcomes included maternal death, pre‐eclampsia, stillbirth and neonatal death. Secondary outcomes included maternal outcomes, for example, thromboembolic events, and fetal outcomes, for example, admission to neonatal intensive care.

Results

No studies on timing of birth met the eligibility criteria. One retrospective, cross‐sectional study, which included 255 pregnant women with SCD, was eligible for inclusion in the mode of birth review. Due to high risk of bias and imprecision in the study, we have very little confidence that the effect estimates represent the true effect. Compared to vaginal birth, cesarean birth may be associated with a reduction in risk of stillbirth (OR 0.03, 95% CI 0.00 to 0.45; 1 study, 255 women) and neonatal death (OR 0.31, 95% CI 0.11 to 0.84; 1 study, 255 women) in women with SCD, but the evidence is very uncertain. Conversely, cesarean birth may be associated with an increase in risk of pre‐eclampsia (OR 2.32, 95% CI 1.17 to 4.58; 1 study, 255 women), postnatal infection (OR 1.86, 95% CI 1.07 to 3.23; 1 study, 255 women), and the need for blood transfusion (OR 2.67, 95% CI 1.38 to 5.14; 1 study, 255 women) in this population but, again, the evidence is very uncertain.

Conclusions

As no studies relevant to timing of birth met our eligibility criteria, we are unable to comment on the optimal timing of birth for women with SCD. Based on a single observational study, we remain uncertain about whether vaginal or cesarean birth is more appropriate for women with SCD. Further research is necessary to thoroughly evaluate the effect of timing and mode of birth on maternal and fetal outcomes in this population.

PROSPEERO Registrations

CRD 42023461767; CRD 4202346175.

Keywords: mode of birth, perinatal outcomes, pregnancy outcomes, sickle cell disease, systematic review, Timing of birth

1. INTRODUCTION

1.1. Description of the condition

Sickle cell disease (SCD) is the most common inherited condition worldwide with the number of people living with SCD rising from 5.46 million in 2000 to 7.74 million in 2021 [1]. While the prevalence is highest in sub‐Saharan Africa, the Middle East/North Africa, India, Latin America, and Mediterranean countries are also affected [1]. Further, global modernization and increased migration has changed the landscape of SCD such that the burden of SCD transcends geographic borders [2].

SCD is a group of autosomal recessive hemoglobin disorders that results from a gene mutation in the β‐subunit of hemoglobin A [3]. Several subtypes of SCD exist depending on the exact mutation in the hemoglobin A β‐subunit. Homozygous SCD (HbSS) is the most common type. Other variants include hemoglobin C, D, E, O, and heterozygous conditions (e.g., HbSC, HbSβ‐thalassemia) [4]. It is important to distinguish SCD from sickle cell trait, a benign condition in which there is only one abnormal gene of the β‐subunit [4]. In contrast, the two abnormal β‐subunits in SCD result in abnormal hemoglobin variants that change shape under low oxygen states [2]. The red blood cells become rigid, fragile, and prone to sticking together, leading to the clinical phenotype of hemolytic anemia and intermittent attacks of vascular occlusion that cause pain, infections, and end‐organ damage [2]. The subtypes vary in severity, but life expectancy is reduced in all people with SCD [2, 5, 6]. Early diagnosis and improved pediatric care have, however, increased the number of people with SCD who reach reproductive age [2, 5, 6].

As more women with SCD live to reproductive age, pregnancy complications directly or indirectly related to SCD might become more widespread [2]. Pregnancy is a time of particular concern for women with SCD as the increased metabolic demands, hypercoagulable state, and physiologic anemia of pregnancy can exacerbate their condition [6, 7]. Pregnancies with SCD are at increased risk of vaso‐occlusive episodes, acute chest syndrome, osteonecrosis, hepatic necrosis, leg ulcers, and thromboembolic events [2]. Vaso‐occlusion may also impair placenta function, increasing the risk of fetal growth restriction, fetal loss, and other adverse outcomes [2, 6, 7].

SCD is also associated with fetal growth restriction (pooled odds ratio [OR] 2.79), perinatal mortality (pooled OR 3.76), stillbirth (pooled OR 4.05) and low birthweight (pooled OR 2.00) [8]. These outcomes are consistent across low‐ and high‐income settings. The pathophysiology behind these adverse outcomes is multifactorial, but is likely due in part to placental insufficiency [9].

1.2. Description of the interventions

1.2.1. Induction of labor at early term or term

WHO recommends that induction of labor should only be performed when there is a clear medical indication, and when the expected benefits outweigh the potential risks. It must be carried out with caution, as it carries the risk of uterine hyperstimulation, rupture, and fetal distress. Adequate facilities for monitoring both maternal and fetal well‐being should be available. Whenever possible, induction should take place in settings where a cesarean section can be performed if necessary [10]. In 2022, WHO released updated recommendations on induction of labor at or beyond term. Most women will give birth by the end of the 41st week of gestation. Spontaneous onset of labor minimizes interventions, reduces the potential for over‐medicalization of a physiological process, and may lead to a more positive birth experience. Induction of labor is recommended for women who are certain to have reached 41 weeks (greater than or equal to 41 weeks + 0/7 days) of gestation. Routine induction of labor for women with uncomplicated pregnancies before 41 weeks is not recommended [10].

1.2.2. Cesarean section

Cesarean sections can prevent maternal and neonatal mortality when medically indicated [11]. However, whether indicated or not, cesarean section is associated with a higher risk of severe maternal outcomes (e.g., mortality, blood transfusion, hysterectomy, etc.) compared with vaginal birth [12, 13]. Organ injury, infection, venous thromboembolism, anesthetic complications, and neonatal respiratory complications are also more frequent in women undergoing cesarean section [14, 15, 16, 17, 18]. Women who give birth vaginally experience fewer complications, both in the short‐ and long‐term. Early breastfeeding initiation, continuation, and exclusive breastfeeding are higher among mother–child dyads who experience vaginal birth [19, 20].

Pregnancies subsequent to a cesarean section are more likely to result in a repeat cesarean section, due to the risk of rare adverse events such as uterine rupture [21]. Repeat cesarean sections increase the risk of placenta previa, placenta accreta, placental abruption, uterine rupture, hysterectomy, organ injury, critical care admission, blood transfusion, preterm birth, and stillbirth [22, 23]. Trial of labor after cesarean section (TOLAC) is an accepted alternative to elective repeat cesarean section. Successful, vaginal birth after cesarean section (VBAC) is associated with a reduction in maternal morbidity, uterine rupture, and hysterectomy when compared with elective repeat cesarean section [24]. However, this practice continues to decline as many institutions cease to offer this choice as concern over liabilities rises [25]. Moreover, candidate selection for TOLAC is critical as a failed TOLAC is associated with an increase in maternal morbidity [24]. Consequently, current clinical practice guidelines recommend that TOLAC should only be offered to women with one prior cesarean section with a uterine incision in the lower segment [26, 27].

1.3. How the interventions might work

1.3.1. Induction of labor at early term or term

Evidence from high‐income countries suggests that, for the general pregnant population, the risk of stillbirth increases with gestational age, from 0.11 per 1000 births at 37 weeks' gestation to 3.18 per 1000 births at 42 weeks' gestation [28]. The risk of neonatal death is nearly doubled for pregnancies continuing beyond 41 weeks, compared with those at 38–41 weeks' gestation [28].

Women with SCD are at higher risk of adverse outcomes associated with placental insufficiency, which has implications for timing of birth. A recent study found that women with SCD and pregnancies of more than 20 weeks’ gestation had high rates of placental pathology (69%) and maternal vascular malperfusion (MVM) (40%) [9]. Placental insufficiency was associated with small for gestational age, iatrogenic preterm birth, and stillbirth in 79% of women with SCD and MVM. In contrast the risk of adverse outcomes in a low‐risk pregnant population with MVM has been reported at ∼47% [29]. Appropriate timing of birth in this population therefore has potential to reduce adverse outcomes, as a prolonged pregnancy can give rise to health complications arising from both pregnancy‐related issues and SCD. Induction of labor at early term or term may reduce the risk of these health complications. However, early induction also has potential to increase risks of neonatal morbidity and mortality.

1.3.2. Cesarean section

While cesarean section may be indicated due to obstetric complications, it may also increase complications associated with SCD compared to vaginal birth. Studies indicate that women with SCD undergoing cesarean section are at higher risk of postnatal infection, sepsis, venous thromboembolism, and blood transfusion [30, 31]. Furthermore, anesthetic complications are more frequent in women in the general pregnant population undergoing cesarean birth [18]. However, recent observational research suggests that vaginal birth for women with SCD may increase the risk of postpartum hemorrhage [32]. Conversely, cesarean birth may elevate the risk of postnatal infections and hypertensive disorders [32]. These benefits and disadvantages add complexity to the decision‐making process regarding the most suitable mode of birth for women with SCD.

1.4. Why it is important to do this review

The appropriate timing of birth for women with SCD has not been firmly established. There is a need for systematic review of the evidence to assess the optimal timing of birth for women with SCD, with the aim of minimizing neonatal and maternal morbidity and mortality.

It is well established that without medical indications for cesarean section, vaginal birth is appropriate [11]. However, evidence specifically in women with SCD is scarce. Current literature favoring planned vaginal birth is based on observational data [2, 33, 34]. In accordance with United Nations Sustainable Development Goals (SDGs), robust evidence is needed to determine the appropriate mode of birth in women with SCD, as it is crucial to reduce maternal and neonatal mortality associated with this non‐communicable disease (SDG 3.1, 3.2 and 3.4) [35].

2. OBJECTIVES

To compare the effects of different timings of induction of labor at early term (37–38 weeks’ gestation) or term (39–40 weeks’ gestation) versus spontaneous labor or induction of labor at 41–42 weeks’ gestation on maternal and neonatal outcomes.
To determine the effectiveness and safety of cesarean section compared to vaginal birth (including vaginal birth after cesarean [VBAC]) in pregnant women with SCD.

3. MATERIALS AND METHODS

Two protocols were registered on PROSPERO — one specific to timing of birth (CRD42023461767) and the other to mode of birth (CRD42023461757). The reviews were undertaken to support the development of a new World Health Organization guideline on the management of SCD during pregnancy, childbirth and the interpregnancy period [36]. The methods for the reviews followed those outlined in the Cochrane Handbook for Systematic Reviews of Interventions [37].

3.1. Criteria for considering studies for this review

Randomized controlled trials (RCTs), cluster RCTs, quasi‐experimental studies, and cohort studies were eligible for inclusion in the reviews, with no publication date or language restriction.

Eligible populations included women with any type of homozygous or compound heterozygous SCD who were due to give birth between gestational ages of 37 and 42 weeks (timing review) or had outcomes reported by mode of birth (mode of birth review).

Interventions and comparators for the reviews were:

Timing of birth: Early term (37–38^6/7 weeks of gestation) or term (39–40^6/7 weeks of gestation) birth compared to spontaneous labor or induction of labor at 41–42 weeks’ gestation.
Mode of birth: All planned elective cesarean births versus all planned vaginal births and all actual cesarean section versus all actual vaginal births

We planned to evaluate maternal death, pre‐eclampsia, stillbirth and neonatal death as primary outcomes. Secondary outcomes included maternal outcomes, for example, thromboembolic events, and fetal outcomes, for example, admission to neonatal intensive care. The full set of outcomes considered in the reviews is listed in the appendix.

3.2. Search methods for identification of studies

We searched for relevant studies in PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), Scopus, and CINAHL. We searched without language restriction from inception to July 29, 2023. The search terms we used are listed in Appendix 1. We reported the literature searches using the PRISMA‐S reporting guidelines [38].

Reference lists of relevant studies were manually searched for other potentially relevant articles. We planned to contact authors of the studies to confirm additional details if necessary.

3.3. Data collection and analysis

No studies were eligible for inclusion in the timing of birth review. The following methodologies relate to the mode of birth review.

3.4. Selection of studies

All titles and abstracts retrieved through both electronic and manual searches were transferred to Covidence (www.covidence.org), where duplicated or clearly irrelevant studies were excluded. Full texts of potentially relevant articles were independently assessed for eligibility by two review authors (JS and AJ). Disagreements were resolved by discussion and/or consultation with a third reviewer (PL). We developed PRISMA flow diagrams to visually represent the study selection process for the reviews [39].

3.5. Data extraction and management

Using Covidence software, study characteristics and outcomes were independently extracted from the eligible studies by two authors (JS and AJ). Whenever possible, data were extracted based on intention‐to‐treat analysis. Disagreements were resolved through discussion to reach consensus or consultation with a third author (PL). One author (AJ) transferred data to Review Manager 5 software [40]. and another author (JS) assessed the extracted data for accuracy against the trial reports.

3.6. Assessment of risk of bias in included studies

We evaluated the risk of bias on the data provided in the included study in accordance with the Cochrane Handbook for Systematic Review of Interventions [37]. As we retrieved only one observational study, we used the Risk of Bias In Non‐randomized Studies of Interventions (ROBINS‐I) assessment tool [41]. This tool assesses seven domains that could introduce bias into the study, categorized as pre‐intervention (such as confounding and selection bias), at intervention (like intervention classification), or post‐intervention (including deviations from intended interventions, missing data, outcome measurement, and selection of reported results). The assessments within each domain are analyzed and aggregated across domains to produce an overall determination of risk of bias for the specific outcome under evaluation. Responses to signaling questions help determine domain‐specific risk of bias, classified as no information, low, moderate, serious, or critical [41]. We considered maternal age, gestational age, previous uterine scar, pre‐pregnancy body mass index (BMI), hemoglobin at booking, and fetal weight (< 4000 g versus ≥4000 g) as confounding factors. Judgement was done independently by two authors (JS and AJ). Disagreement was resolved through discussion or consultation of the third reviewer (PL). Data were summarized into a risk of bias ‘graph’ and ‘table’.

3.7. Measurement of treatment effect

Although we initially planned to present the effect estimate for dichotomous outcomes (e.g., maternal death, neonatal death, etc.) as relative risk (RR) in the protocol, this was not feasible due to the design of the included study. Therefore, we used odds ratio (OR) and 95% confidence interval (CI) to estimate the treatment effect. For continuous outcomes (e.g., length of hospitalization, hemoglobin level, etc.), we planned to use mean difference (MD) and 95% CI.

3.8. Dealing with missing data

We planned to contact authors of studies with missing data for further information. If not possible, and where missing data were substantial, we planned not to perform the analysis.

3.9. Assessment of heterogeneity

We planned to perform visual inspection of the forest plot and assess heterogeneity using statistical methods. We considered the heterogeneity to be high if I² value was greater than 50% or P value of Chi‐squared test was less than 0.10. We planned to carry out subgroup analysis to explore the cause of heterogeneity. However, this was not performed as only one study met our inclusion criteria.

3.10. Assessment of publication bias

We planned to assess publication bias using funnel plots where sufficient studies were available. However, given that only one study was identified, funnel plot asymmetry could not be evaluated.

3.11. Data synthesis

We planned to perform meta‐analysis if there was no meaningful heterogeneity. The analysis was conducted in Review Manager 5.4 software [40]. The results were reported as ORs for dichotomous data with their respective 95% CIs. For all outcomes, the certainty of the evidence was assessed using the GRADE approach in GRADEpro GDT software [42]. The GRADE framework considers the risk of bias, inconsistency, indirectness, imprecision, and publication bias to classify the certainty of evidence as high, moderate, low, or very low. A ‘summary of findings’ table was presented according to The Cochrane Handbook for Systematic Review of Interventions (Table 1) [37].

TABLE 1.

Summary of findings: Cesarean section compared to vaginal birth for pregnancy with sickle cell disease.

Patient or population: Pregnant women with sickle cell disease Setting: Hospital Intervention: Cesarean section Comparison: Vaginal birth
	Anticipated absolute effects ^* (95% CI)
Outcomes	Risk with cesarean section	Risk with vaginal birth	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)
Stillbirth	147 per 1000	5 per 1000 (20 to 527)	OR 0.03 (0.00 to 0.45)	255 (1 study)	⨁◯◯◯ (Very low) ^a , ^c
Neonatal death	140 per 1000	48 per 1000 (18 to 120)	OR 0.31 (0.11 to 0.84)	255 (1 study)	⨁◯◯◯ (Very low) ^a , ^c
Pre‐eclampsia	113 per 1000	229 per 1000 (130 to 369)	OR 2.32 (1.17 to 4.58)	255 (1 study)	⨁◯◯◯ (Very low) ^a , ^c
Blood transfusion	120 per 1000	267 per 1000 (158 to 412)	OR 2.67 (1.38 to 5.14)	255 (1 study)	⨁◯◯◯ (Very low) ^a , ^c
Maternal death	7 per 1000	29 per 1000 (3 to 223)	OR 4.38 (0.45 to 42.72)	255 (1 study)	⨁◯◯◯ (Very low) ^a , ^b
Deep vein thrombosis	13 per 1000	10 per 1000 (1 to 97)	OR 0.71 (0.06 to 7.95)	255 (1 study)	⨁◯◯◯ (Very low) ^a , ^b

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The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: confidence interval; OR: odds ratio.

GRADE Working Group grades of evidence

High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.

Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.

Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.

Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

^{^a}

Serious risk of bias.

^{^b}

Wide confidence interval including appreciable harm and appreciable benefit. Estimate based on small sample size and few events.

^{^c}

Estimate based on small sample size.

3.12. Sensitivity analysis

We intended to conduct a sensitivity analysis by excluding unpublished data, quasi‐RCTs, and studies exhibiting a high or unclear risk of bias. However, this analysis was not feasible owing to the inclusion of only one study.

4. RESULTS

4.1. Database search results

One conference abstract [43] initially appeared to meet the eligibility criteria for the timing of birth review, but was excluded due to the use of a theoretical cohort. There were no ongoing studies or studies awaiting classification for the review. The study selection process is illustrated in Figure 1.

PRISMA flow diagram for timing of birth review. *Consider, if feasible to do so, reporting the number of records identified from each database or register searched (rather than the total number across all databases/registers). **If automation tools were used, indicate how many records were excluded by a human and how many were excluded by automation tools. *Source*: Page MJ, et al. *BMJ* 2021;372:n71. doi: 10.1136/bmj.n71. This work is licensed under CC BY 4.0. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/.

Eighty records were obtained from the database search. Seven duplicated articles were removed, resulting in 73 records available for title and abstract screening. Of these, eight studies relevant to mode of birth were selected for full text review. One was deemed eligible for inclusion and seven were excluded due to wrong study design—three were not a comparative study [44, 45, 46], two were studies in a different population [47, 48], one studied the wrong intervention [49], and one was a commentary [50] (Figure 2).

PRISMA flow diagram for mode of birth review.

4.2. Characteristics of the included study

The only included study was a retrospective, cross‐sectional study intended to evaluate pregnancy outcomes by mode of birth in women with SCD (HbSS) compared with women with normal hemoglobin [32].

Labor records of 255 HbSS women who gave birth after 24 weeks gestation at the university hospital in Jamaica between 1992 and 2020 were compared with the records of 252 age‐matched women with normal hemoglobin.

Modes of birth were vaginal and cesarean section. In this review, we considered only the 255 women with SCD. Of these, 150 (59 %) gave birth vaginally and 105 (41%) had a cesarean section. Among women who had a vaginal birth, 59% had their labor induced or augmented and only 2% underwent operative delivery. In the cesarean section group, 39% had a primary cesarean section without a trial of Labor. Almost all (84%) women with a previous cesarean section had repeat cesarean section without a trial of labor. There was no information on whether cesarean section was elective or emergency.

4.3. Outcomes

The primary outcomes of the included study encompassed both maternal and neonatal mortality. In terms of secondary maternal outcomes, the study specifically reported incidences of blood loss exceeding 500 mL, requirement for blood transfusion, postnatal infections, and thrombotic events. Secondary fetal outcomes were limited to stillbirth.

4.4. Risk of bias in included studies

We considered the outcomes maternal death, pre‐eclampsia, stillbirth, and neonatal death to have a serious risk of bias due to potential confounders. The women in the cesarean section group appeared to have lower gestational ages compared to those in the vaginal birth group. Although the authors performed adjusted analyses for some factors (maternal age, gestational age at delivery and hemoglobin at booking), other important factors such as BMI or fetal status were not considered. Furthermore, the study authors did not employ suitable analytical methods for some important outcomes. We also judged the included study to have serious risk of selection bias, based on variables that influence selection such as neonatal death. Other domains including classification of intervention, deviations from intended intervention, missing data, outcome measurement, and selective reporting were deemed low risk. The overall risk of bias for all outcomes was judged to be serious (Figure 3).

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages for the included study for primary outcomes (maternal death, pre‐eclampsia, stillbirth, and neonatal death).

4.5. Effects of interventions

Compared to vaginal birth, cesarean section may reduce the odds of stillbirth (OR 0.03, 95% CI 0.00 to 0.45; 1 study, 255 women; very‐low certainty evidence; Figure 4) and neonatal death (OR 0.31, 95% CI 0.11 to 0.84; 1 study, 255 women; very‐low certainty evidence; Figure 5), but the true effect of cesarean section may substantially differ. Cesarean section may increase the odds of pre‐eclampsia (OR 2.32, 95% CI 1.17 to 4.58; 1 study, 255 women; very‐low certainty evidence; Figure 6), postnatal infection (OR 1.86, 95% CI 1.07 to 3.23; 1 study, 255 women; very‐low certainty evidence; Figure 7), and the need for blood transfusion (OR 2.67, 95% CI 1.38 to 5.14; 1 study, 255 women; very‐low certainty evidence; Figure 8). The evidence is also very uncertain about the effect of mode of birth on maternal death (Figure 9), deep vein thrombosis (Figure 10), pregnancy‐induced hypertension (Figure 11), and blood loss more than 500 mL (Figure 12), and there may be little to no difference in effect. Meta‐analysis was not feasible as only one study was included in this review. See summary of findings Table 1.

Forest plot of caesarean section versus vaginal birth, still‐birth.

Forest plot of caesarean section versus vaginal birth, neonatal death.

Forest plot of caesarean section versus vaginal birth, pre‐eclampsia.

Forest plot of caesarean section versus vaginal birth, postnatal infection.

Forest plot of caesarean section versus vaginal birth, blood transfusion.

Forest plot of caesarean section versus vaginal birth, maternal death.

Forest plot of caesarean section versus vaginal birth, deep vein thrombosis.

Forest plot of caesarean section versus vaginal birth, pregnancy‐induced hypertension.

Forest plot of caesarean section versus vaginal birth, blood loss more than 500 mL.

5. DISCUSSION

5.1. Summary of main results

There were no eligible studies investigating timing of birth for women with SCD. The evidence presented in this review is constrained by the inclusion of only one study relating to mode of birth, which involved a moderate number of participants. It is also important to note that the single included study is at serious risk of bias due to its observational design. Insufficient data preclude the reliable demonstration of the superiority of either mode of birth in relation to maternal and neonatal outcomes (maternal and neonatal mortality, preeclampsia, stillbirth, or blood loss), or on the optimal timing of birth for women with SCD.

5.2. Overall completeness and applicability of evidence

No studies were identified providing evidence on timing of birth for women with SCD. Only one observational study met the inclusion criteria for this review. While the study provided some insight into maternal outcomes regarding mode of birth, evidence regarding admission rates, length of hospitalization and the cost of care remains limited. Moreover, there was a notable scarcity of data on neonatal outcomes, with only neonatal death and stillbirth being reported.

5.3. Quality of the evidence

Our review revealed a lack of randomized studies on the optimal timing of birth or directly comparing cesarean section to vaginal birth for women with SCD. The sole included study was a retrospective cross‐sectional study. We downgraded the level of evidence to “very low” for all outcomes due to the high risk of bias, imprecision due to a small number of events and wide confidence intervals, failing to definitively exclude significant benefits or harms. In summary, we concluded that the included study provided evidence of very low certainty according to GRADE methods.

5.4. Agreements and disagreements with other studies or reviews

5.4.1. Timing of birth

There are no systematic reviews on the timing of birth for women with SCD. As mentioned, one conference abstract relevant to the timing of birth in women with SCD was identified, but it did not meet our study's inclusion criteria. The abstract described a decision‐analytic model designed to compare six different strategies for planned birth at 36, 37, 38, 39, 40, and 41 weeks of gestation, using a theoretical cohort of 1600 women with hemoglobin SS disease in the United States. The authors found that, compared to planned birth at 39 weeks, induction of labor at 38 weeks resulted in four fewer stillbirths and one less maternal death [43].

A recent publication aimed to investigate the optimal gestational age for birth in pregnant women with chronic hypertension. This was a planned secondary analysis of a randomized controlled trial examining different blood pressure treatment goals for chronic hypertension. Participants included women with term, singleton pregnancies. The authors concluded that, compared to expectant management, planned birth during the early‐term period was not associated with a reduction in adverse maternal outcomes. However, it was associated with increased odds of respiratory distress syndrome (RDS) and neonatal hypoglycemia. The timing of birth for women with mild chronic hypertension should consider both maternal and neonatal outcomes at each gestational week, with birth at 39 weeks potentially offering optimal outcomes [51].

The WHO recommendations on induction of labor at or beyond term state that induction is recommended for women who are certain to have reached 41 weeks of gestation. Routine induction of labor for women with uncomplicated pregnancies before 41 weeks is not recommended [10]. A recently published guideline by the SMFM recommended that induction of labor between 39 0/7 and 39 6/7 weeks of gestation for women with uncomplicated SCD, normal BP, and a normally grown fetus [52]. A British Society for Hematology (BSH) Guideline published in 2021 concluded that there were no randomized controlled trials to support the appropriate timing of birth. This guideline recommended that pregnant women with SCD who have a normally growing baby should give birth between 38 and 40 weeks of gestation [2].

5.4.2. Mode of birth

One existing systematic review and meta‐analysis aimed to identify the differences in complications between pregnancies with SCD and those without [53], but did not explore the relationship between mode of birth and maternal and perinatal outcomes. Our systematic search yielded one observational study that indirectly provided outcome data stratified by mode of birth. Our analysis of this data suggests that, compared to cesarean section, vaginal birth may be associated with an increase in stillbirth and neonatal death in women with SCD. One possible explanation for this finding is that vaginal birth is the preferred mode of birth in pregnant women whose fetus has died in utero [54]. However, we assessed evidence for both outcomes to be of very low‐certainty and therefore we are not confident that this represents the true effect of cesarean section versus vaginal birth for women with SCD.

Our finding contrasts with earlier studies in non‐SCD women which suggested an association between repeat cesarean section and stillbirth [55, 56]. Another systematic review, which included eight studies encompassing 703,562 women, also suggested an elevated likelihood of stillbirth with repeat cesarean section in the general pregnant population (OR 1.27, 95% CI 1.15 to 1.40) [22].

We are uncertain whether cesarean section is associated with pre‐eclampsia in women with SCD compared to those giving birth vaginally. The authors of the included study did not explicitly specify whether preeclampsia occurred antepartum or postpartum. We are uncertain about the causal effect, as patients with preeclampsia may be more likely to undergo cesarean section due to obstetricians being less willing to allow prolonged labor in potentially unstable patients. A previous study showed that prior cesarean section is a risk factor for pre‐eclampsia in a subsequent pregnancy in the general pregnant population [57]. Although vaginal birth has been recommended for women with pre‐eclampsia unless a cesarean section is obstetrically indicated, cesarean section rates in women with pre‐eclampsia with severe features was higher than in women without [58]. A recent study conducted at tertiary hospital in Thailand in 2023 showed that preeclampsia was associated with a significantly increased overall cesarean section rate [59].

There is uncertainty regarding the association between blood transfusion and puerperal fever with cesarean section in women with SCD. Nevertheless, numerous large‐scale epidemiological studies have demonstrated a clear correlation between cesarean section and adverse perinatal outcomes in the general pregnant population. These include maternal death, blood transfusion, hysterectomy, admission to the intensive care unit (ICU), and postoperative infections [12, 13, 15].

In terms of current guidelines for pregnant women with SCD, the BSH recommends that women with SCD can be offered vaginal delivery and vaginal birth after previous cesarean section if there are no other contraindications [2].

6. CONCLUSION

6.1. Implications for practice

The evidence regarding the optimal timing and mode of birth for pregnant women with SCD is extremely limited. Due to the scarcity of high‐quality evidence, there remains uncertainty regarding the effects of early term or term induction of labor compared to spontaneous delivery or induction labor at 41–42 weeks’ gestation, and cesarean section compared to vaginal birth, on adverse maternal and neonatal outcomes in this population.

6.2. Implication for research

As the review identified no studies relevant to timing of birth and only one observational study relevant to mode of birth, further research evaluating the effects of timing and mode of birth for women with SCD is imperative. Well‐designed and meticulously conducted RCTs should be pursued. These trials are essential for minimizing bias, particularly concerning confounders and the selection process.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflicts of interest.

Supporting information

Supporting Information

PMF2-1-e70031-s001.docx^{(158KB, docx)}

ACKNOWLEDGMENTS

The authors would like to extend their sincere gratitude to Myfanwy Williams and Jenny Ramson for their invaluable contributions to the development of this systematic review. Their expertise, dedication, and support were instrumental in shaping the quality of this work.

REFERENCES

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[pmf270031-bib-0015] 15. Villar, J. , Carroli G., Zavaleta N., Donner A., Wojdyla D., Faundes A., Velazco A., et al. 2007. “Maternal and Neonatal Individual Risks and Benefits Associated with caesarean Delivery: Multicentre Prospective Study.” BMJ 335(7628): 1025. 10.1136/bmj.39363.706956.55. [DOI] [PMC free article] [PubMed] [Google Scholar]

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PERMALINK

Timing and mode of birth for women with sickle cell disease: A systematic review

Porjai Pattanittum

Chetta Ngamjarus

Apiwat Jongjakapun

Termtem Waidee

Nampet Jampathong

Yaneve Fonge

Pisake Lumbiganon

Jen Sothornwit

Abstract

Introduction

Methods

Results

Conclusions

PROSPEERO Registrations

1. INTRODUCTION

1.1. Description of the condition

1.2. Description of the interventions

1.2.1. Induction of labor at early term or term

1.2.2. Cesarean section

1.3. How the interventions might work

1.3.1. Induction of labor at early term or term

1.3.2. Cesarean section

1.4. Why it is important to do this review

2. OBJECTIVES

3. MATERIALS AND METHODS

3.1. Criteria for considering studies for this review

3.2. Search methods for identification of studies

3.3. Data collection and analysis

3.4. Selection of studies

3.5. Data extraction and management

3.6. Assessment of risk of bias in included studies

3.7. Measurement of treatment effect

3.8. Dealing with missing data

3.9. Assessment of heterogeneity

3.10. Assessment of publication bias

3.11. Data synthesis

TABLE 1.

3.12. Sensitivity analysis

4. RESULTS

4.1. Database search results

FIGURE 1.

FIGURE 2.

4.2. Characteristics of the included study

4.3. Outcomes

4.4. Risk of bias in included studies

FIGURE 3.

4.5. Effects of interventions

FIGURE 4.

FIGURE 5.

FIGURE 6.

FIGURE 7.

FIGURE 8.

FIGURE 9.

FIGURE 10.

FIGURE 11.

FIGURE 12.

5. DISCUSSION

5.1. Summary of main results

5.2. Overall completeness and applicability of evidence

5.3. Quality of the evidence

5.4. Agreements and disagreements with other studies or reviews

5.4.1. Timing of birth

5.4.2. Mode of birth

6. CONCLUSION

6.1. Implications for practice

6.2. Implication for research

CONFLICT OF INTEREST STATEMENT

Supporting information

ACKNOWLEDGMENTS

REFERENCES

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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