Sarcoidosis in pregnancy

Sarcoidosis is an uncommon multi‐system disorder characterised by the presence of non‐caseating granulomas. It has a peak incidence between the ages of 20–40 years old. The pathogenesis of sarcoidosis is uncertain; however, it is known to be associated with an exaggerated T helper 1 (TH1) immune response leading to systemic inflammation and granuloma formation. Suppression in TH1 responses in pregnancy leads to disease remission in the majority of pregnancies. Nevertheless, the potential for decompensation in a subgroup remains, and consideration should be given to the pre‐pregnancy state. Sarcoidosis is associated with increased risk of maternal‐fetal morbidity, including growth restriction and pre‐eclampsia. Clinical management should focus on medication optimisation and mitigation of this increased risk.


Introduction
Sarcoidosis is a systemic disease characterised by the presence of non-caseating granulomatous lesions.It predominantly occurs as a multisystem disease.The aetiology remains uncertain, although infectious and genetic contributors to its pathogenesis have been proposed. 1The prevalence is thought to be 19 per 100 000 with a reported prevalence in pregnancy of 1 in 2000 to 1 in 10 464. 2,3 ore recent studies have, however, reported a lower prevalence in pregnancy than was previously believed. 2Despite this, the overall the incidence is thought to be increasing, possibly owing to better detection rates. 2 The condition is more common in women, with a peak age of incidence between 20-40 years old.Women of a Black African origin are more likely to experience severe disease. 4The mortality of sarcoidosis varies from <5-10% dependent on disease stage. 5Maternal deaths secondary to neuro-or cardiac sarcoidosis have previously been reported. 6,7There remains a paucity of guidance on the management of sarcoidosis in pregnancy.This review aims to outline the clinical features of sarcoidosis, its impact in pregnancy and the management of the condition.A key overview can be seen in Figure 1.

Clinical features of sarcoidosis
The clinical presentation of sarcoidosis is dependent on the site of presentation.Many patients may remain asymptomatic.Pulmonary involvement is the most common presentation in >90% of those affected. 8Pulmonary sarcoidosis is predominantly an interstitial lung disease (ILD) with progressive parenchymal fibrosis in up to 20% of people with the condition. 9A significant subset of patients will also develop pulmonary artery hypertension, a contraindication to pregnancy. 10Pulmonary disease can be radiologically staged using Scadding staging, as seen in Table 1.Extra-pulmonary symptoms of sarcoidosis are common and include those affecting the joints, liver, skin, heart, brain and eyes (Table 2).Skin disease is the most common extra-pulmonary manifestation of sarcoidosis; 11 it may be specific and associated with granulomas, such as lupus pernio, or nonspecific, including erythema nodosum, erythema multiforme and nummular eczema. 11Up to 50% of patients will experience cardiac symptoms, which can manifest as syncope in women with no cardiac history. 12,13This is due to infiltrative myocardial disease, which can cause life-threatening arrhythmias in 2-7% of patients with sarcoidosis and lead to sudden maternal, and subsequent fetal, death. 6,13Central nervous system involvement of sarcoidosis can occur in 5-13% of cases. 14The most common site for involvement is the cranial nerves.Common symptoms of neurosarcoidosis include facial nerve palsy, optic nerve dysfunction and papilloedema.

Pathogenesis of sarcoidosis
The pathogenesis of sarcoidosis is uncertain.The disease represents an exaggerated immune response to an unknown trigger. 1 Acute sarcoidosis is associated with an increased influx of CD14 macrophages. 1,15These have increased responsiveness to distinct pattern-recognition receptor ligands. 1 Organs affected by sarcoidosis display an influx of T helper 1 (T H 1) cells with increased cytokine production, including interferon-c and tumour necrosis factor-a (TNF-a). 16This T H 1 cytokine response is unattenuated, as reduced expression of regulatory T cells (T regs ) has been demonstrated within sarcoidosis. 1 Granulomas composed of epitheloid cells develop within affected tissue. 17The development of clusters of sarcoidosis is thought to be evidence of the potential of an antigen-driven disease.Notable clusters of cases include those affecting the metal-processing industries and emergency responders following the 2001 World Trade Center attacks. 18,19

Diagnosis of sarcoidosis
The diagnosis of sarcoidosis is predominantly one of exclusion, although multiple diagnostic scoring systems exist.The principle of diagnosis is based on three major criteria: clinical presentation, non-caseating granulomas in tissue samples and the exclusion of other granulomatous disease. 10Initial investigations depend on the presenting feature of concern.During pregnancy, investigations need to be rationalised based on clinical risk in an attempt to minimise fetal radiation exposure and reduce risks associated with obtaining samples for histopathological analysis. 20Chest radiographs are considered safe during pregnancy and most commonly will demonstrate bilateral hilar lymphadenopathy, or fibrosis secondary to pulmonary infiltration.Sometimes the infiltration is not apparent on chest radiograph, and highresolution computerised tomography (CT), bronchoalveolar lavage and transbronchial biopsy are required to confirm ILD.The decision to perform these investigations during pregnancy would require discussion in a multidisciplinary team and consideration of the risks and benefits to the pregnant patient and fetus.More advanced imaging including magnetic resonance imaging (MRI) may be considered.In non-pregnant patients, serum angiotensin converting enzyme (ACE) levels can be used for disease monitoring; however, as ACE levels can be altered in pregnancy, they cannot be used in pregnant patients. 21f cardiac symptoms are present, an electrocardiogram and echocardiography are recommended to rule out other differential diagnoses, but often non-specific changes are seen in sarcoidosis.Cardiac MRI is useful in pregnant patients and may demonstrate fibrosis, oedema and scarring. 13In pregnant women, gadolinium-based contrast enhancement may aid diagnosis, but as it can cross the placenta, its use is controversial and a risk-benefit analysis should be performed. 22f symptoms are suggestive of neurosarcoidosis, a brain MRI may be useful; however, given the need for contrast, an individualised approach to risk should be taken.Alternatively, cerebrospinal fluid analysis may provide additional information. 10The use of electromyography (EMG) can be used to diagnose myopathy secondary to sarcoidosis. 23f the sarcoidosis is thought to affect other systems, consideration needs to be given to the safety of additional testing and whether it will change current management.For example, malignancy may be a differential diagnosis which needs to be ruled out in a timely fashion during pregnancy.Histopathological confirmation on tissue biopsy may need to be delayed until after pregnancy.

The effects of pregnancy on sarcoidosis
Pregnancy is widely believed to have no effect on or improve the course of disease progression in sarcoidosis.Immune changes associated with pregnancy result in an interaction of pregnancy with sarcoidosis.Pregnancy induces a shift in immune cytokine profile, traditionally thought to be from a T H 1-expression pattern to a T h 2-expression pattern. 24While this view is likely simplistic and a more complex interplay between T h cells has been proposed, the resulting alterations lead to an improvement in disorders characterised by a T H 1 response, including rheumatoid arthritis, multiple sclerosis and sarcoidosis. 24,25This immune-mediated improvement has borne out in the clinical data on sarcoidosis in pregnancy.An early 1958 case series assessing 17 pregnancies in 10 women demonstrated no consistent effect of pregnancy on the disease. 26Similarly, a case series by Agha et al. 27 assessed 35 pregnancies across 18 women with known sarcoidosis and demonstrated one-third of the women had an improvement in their symptoms, 9 of 18 showed no change in their disease, and the remaining three women had a deterioration of their disease.A more recent case report and review of the literature reported on radiological regression of sarcoidosis in a 32-year-old woman with sarcoidosis. 28A review of the literature demonstrated contradictory reports on the clinical course of sarcoidosis, with the majority of reported cases demonstrating an improvement.Although the literature in this area is now dated, it remains robust in illustrating a clinical improvement in sarcoidosis in pregnancy in the majority, with risk of deterioration, however, remaining.It has further been proposed that this improvement may be secondary to endogenous corticosteroid production occurring in pregnancy. 28As with other T H 1-mediated disease, a postnatal flare of sarcoidosis is often seen.This increased risk may be secondary to a reduction in endogenous maternal corticosteroids or to a reversion to a T H 1-mediated cytokine state.Selroos et al. 29 assessed 252 women presenting with sarcoidosis over a 29-year period; 38 pregnancies were noted within this cohort.Of note, 25 of these diagnoses were made within a year of delivery, highlighting the clinical importance of this postnatal flare.Careful postnatal planning is therefore required in this cohort with use of flare suppression.
In addition to the disease process itself, consideration should be given to the effect of pregnancy on the sequelae of sarcoidosis, in particular that of severe disease.A common sequela is ILD.Severe ILD based on a forced vital capacity (FVC) <1-1.5 L is thought to be associated with increased risk of maternal mortality. 30,31It has been suggested that in women with severe ILD the increased oxygen demand in pregnancy may result in decreased oxygen saturations due to parenchymal fibrosis. 30This has led to the traditional recommendation of avoidance of pregnancy in this cohort.A cohort study of women presenting in pregnancy with pre-existing ILD assessed 86 pregnancies in 60 women. 30The majority of women in the study (71%) had a diagnosis of sarcoidosis; 30 of these women underwent echocardiography, which demonstrated evidence of pulmonary hypertension in 4 women.No maternal deaths were reported but 11% required supplemental oxygen at delivery.This led the authors to conclude that in women without heart failure, pulmonary hypertension or severely active disease, pregnancy could be considered.
Similarly, cardiac sarcoidosis affects up to 39% of patients. 10he majority are asymptomatic; however, congestive heart failure, arrhythmia and pericardial effusion may develop.Cardiac sarcoidosis has a greater maternal risk than other forms of the disease.While previous, now dated, case series have demonstrated improvement in cardiac sarcoidosis in pregnancy, several case reports of adverse cardiac outcome suggest the need for caution and careful multi-disciplinary management in this cohort. 6,13,32Agrawal et al. 13 reported on the occurrence of syncopal attacks in a 43 year old at 21 weeks' gestation.A diagnosis of cardiac sarcoidosis was made, and an implantable cardiac defibrillator (ICD) was implanted to manage intermittent runs of ventricular arrhythmia.Despite this, the patient progressed into clinical heart failure.Similarly, Wallm€ uller et al. 6 reported on a case of maternal cardiac arrest at 32 weeks' gestation in a woman with known pulmonary sarcoidosis.The post-mortem demonstrated a fibrotic mid-ventricular wall scar secondary to sarcoidosis.These cases reinforce the importance of vigilance in the management of women at risk in pregnancy.Women with cardiac sarcoidosis may have an ICD in-situ.Previous work has demonstrated that pregnancy does not increase the risk of ICD discharges or ICD-related complications. 33Indeed, the importance of ICD management remains, and regular device interrogation and consideration of device deactivation in labour are advised. 34Although a mainstay of treatment, the use of corticosteroids in cardiac sarcoidosis outside of pregnancy has not demonstrated a reduction in the incidence of ventricular arrhythmias. 35,36While there is no evidence for their use in pregnancy, it is unlikely to have a differential impact in comparison to the disease outside of pregnancy and therefore may be used for similar indications.The use of anti-TNF agents in refractory cardiac sarcoidosis is increasing.

The effects of sarcoidosis on pregnancy
The presence of sarcoidosis in pregnancy is associated with adverse pregnancy outcome.Although data are limited by small numbers, it is likely this effect is most marked in those with active disease.The majority of current data stems from two large cohort studies originating from the USA and Sweden. 2,37These studies demonstrate relatively large sample sizes for studies assessing sarcoidosis, representing 678 and 182 sarcoidosis cases, respectively.Nevertheless, the registry-based approach limits conclusions on reproductive outcomes or the impact of treatment.The studies are summarised in Table 3.Further prospective registries collecting this data in the sarcoidosis population would improve knowledge in this area.
There is limited evidence on pregnancy outcome in sarcoidosis.A 1999 consensus statement by the American Thoracic Society reported no increased risk of miscarriage in sarcoidosis. 20This finding, however, was based on a limited evidence base of dated studies.A 1998 case series assessed 33 pregnancies in 11 women with sarcoidosis. 38The study reported five miscarriages across the group, giving a miscarriage rate of 15%, in keeping with the general population.Nevertheless, there remains a paucity of current studies assessing miscarriage risk in the sarcoidosis cohort.Similarly, there is no evidence of an increased risk of intra-uterine death (IUD) or stillbirth in cases of sarcoidosis.Hadid et al. 2 in their US registry study assessed the rate of IUD in their population amd demonstrated a non-significant adjusted odds ratio of 1.23 (95% CI 0.61-2.48),while the Swedish cohort showed <5/182 stillbirths, limiting the power to definitively establish that there was no effect on stillbirth rates. 37n increased risk of pregnancy-associated conditions is seen in sarcoidosis.In K€ ocher et al.'s Swedish registry study, 37 an increased risk of pre-eclampsia was identified in women with sarcoidosis (RR 1.6; 95% CI 1.0-2.6).A similar finding was also seen in Hadid et al. 2 with a reported adjusted OR of 1.62 (95% CI 1.18-2.22).No significant difference was, however, seen for pregnancy-induced hypertension, further suggesting this relationship to be pathological in nature.No significant difference was seen in the development of gestational diabetes in either cohort.
An increased risk of maternal thromboembolism was seen in women with sarcoidosis in the Hadid et al. study, with both the risk of deep vein thrombosis (adjusted OR 4.92; 95% CI 1.58-15.33)and pulmonary embolus (adjusted OR 6.68; 95% CI 3.99-11.21). 2 A similar increase in risk was not, however, seen in K€ ocher et al.'s study, which reported no cases of venous thromboembolism.These differences may be secondary to differences in case selection, as Hadid et al. selected cases with a registry label at the time of delivery, suggesting a higher proportion with active disease. 2,37An increased thromboembolic effect has previously been seen in other systemic inflammatory conditions with active disease, suggesting the importance of this confounder in clinical decision making. 39arcoidosis has also been associated with increased fetal risk.A single-centre case series over 11 years assessed 20 pregnancies, and a 10% risk of intrauterine growth restriction was seen. 40This translates to the findings of larger cohort studies, with Hadid et al. identifying a significantly increased risk of fetal growth restriction (adjusted OR 1.62; 95% CI 1.08-2.43) 2 .An increased risk of preterm delivery was also seen in both cohorts in women with sarcoidosis in comparison to without, with an adjusted OR 1.73 (95% CI 1.40-2.15)and adjusted RR 1.7 (95% CI 1.1-2.5) in the US and Swedish cohort, respectively. 2,37It is unclear, however, the extent to which this finding was iatrogenic in origin due to the development of secondary complications.
A similar increase in caesarean section rates was demonstrated across cohorts with an adjusted OR of 1.20 (95% CI 1.03-1.40)and an adjusted RR of 1.3 (95% CI 1.0-1.6) in the US and Swedish cohort, respectively. 2,37K€ ocher et al. further evaluated this risk, demonstrating the increase stems from emergency caesarean sections, as opposed to elective procedures with an adjusted RR of 1.4 (95% CI 1.0-1.9) in comparison with an adjusted RR of 1.3 (95% CI 0.8-2.0).Of note, however, Hadid et al. assessed the odds of fetal distress in the US cohort and no increased risk was identified (adjusted OR 0.53; 95% CI 0.07-3.75). 2 The increased risk may, therefore, relate to alternate fetal or maternal concerns.
The risk of postpartum haemorrhage (PPH) was assessed in both cohorts.Hadid et al. demonstrated an increased risk of PPH in women with sarcoidosis (adjusted OR 1.69 [1.18-2.43]).A similar increased risk was not demonstrated in the Swedish cohort. 37This may be secondary to the presence of confounders.A selection bias in favour of active disease has already been described for the Hadid et al. study.Furthermore, this study had a higher proportion of African American women, with an associated independent increased risk of PPH. 41 tendency to increased risk of fetal structural differences was seen in K€ ocher et al., with 6.1% affected compared with 3.7% in the control population, although this difference was not statistically significant when adjusted (RR 1.6; 95% CI 0.9-2.8). 37No other increased neonatal risk has been reported.

Management of sarcoidosis in pregnancy
Given its systemic nature, the obstetric management of sarcoidosis necessitates a multidisciplinary approach.There is a paucity of guidelines focused on management in pregnancy, and the evidence on pregnancy-specific management is currently scarce.The principles of management, however, are consistent with other high-risk maternal disorders.
Firstly, this is to optimise current disease management, preferably in a pre-conception setting.Baseline review should consist of establishing current function and disease activity.Selected use of pulmonary function tests may be undertaken, however, these may not reflect disease activity, and, therefore, use should be based on symptomatic pulmonary disease or where clinical suspicion of reduced function exists. 42Baseline investigations should include a full blood count, urea and electrolytes, liver function tests, serum calcium and ACE levels.A baseline electrocardiogram may be of benefit. 42omen with a suspected or confirmed diagnosis of cardiac sarcoidosis should undergo an echocardiogram to exclude structural disease. 42A 24-hour Holter monitor should be undertaken in those symptomatic with palpitations. 13A personalised multidisciplinary risk discussion, including the woman, should be undertaken in those with severe ILD or symptomatic cardiac sarcoidosis to determine the risk-tobenefit ratio of embarking on or continuing with a pregnancy.Secondly, optimisation of medical management should be undertaken.A range of medication are used to manage sarcoidosis outside of pregnancy, not all of which are safe in pregnancy.A standard management regime would be to manage flares of sarcoidosis with suppressive immunotherapy, the most common regime being the use of high-dose oral corticosteroids. 42nce flare repression is achieved, maintenance management is through the use of a lower dosage corticosteroid regime.Use of disease-modifying drugs for both disease suppression and maintenance is not unusual.These include methotrexate, mycophenolate mofetil (MMF), leflunomide and azathioprine.Rarely, biological therapy with anti-TNF agents such as infliximab is used in refractory sarcoidosis.
The safety profile of long-term corticosteroid use in pregnancy has previously been well described. 43Dated research has suggested a potential increase in fetal cleft palate with corticosteroid use. 44This has not, however, been seen in more recent studies. 42,44,45Additionally, there is no increased risk of fetal growth restriction or preterm delivery. 44An increased risk of gestational diabetes is seen with long-term use and therefore an oral glucose tolerance test is indicated.
Azathioprine has demonstrated a good safety profile both in pregnancy and breastfeeding.A review conducted for the British Society of Rheumatology demonstrated no increased risk of fetal structural differences or adverse effect on birthweight. 45either methotrexate nor MMF are safe for use in pregnancy or breastfeeding.Methotrexate is a known teratogen associated with both miscarriage and fetal structural differences. 45There is some suggestion that low-dose methotrexate may carry a lower risk profile but further data is required. 46MMF has been associated with both fetal structural differences, including microtia, facial clefts and micrognathia, and miscarriage. 47etal growth restriction has also been seen with MMF therapy. 45oth drugs are secreted in breastmilk and associated with a theoretical risk to the neonate. 45In the absence of strong evidence of safety these should be avoided in the breastfeeding period.Importantly, these drugs also have a washout period prior to pregnancy which should be considered.MMF should be stopped at least 6 weeks prior to pregnancy, and methotrexate should be stopped 4 weeks prior to pregnancy.Where methotrexate is stopped within 4 weeks of conception, high-dose folate (5 mg once daily) should be continued up to 12 weeks of pregnancy. 45Leflunomide is also contraindicated in pregnancy.Animal studies have demonstrated teratogenicity in those exposed. 48Limited evidence suggests a low risk in humans but given lack of clarity in the data it is best avoided. 49A washout period of 11 days with a cholestyramine washout procedure is required.It is suggested that when possible women of reproductive age are switched to an alternate such as azathioprine.If pregnancy occurs on leflunomide, the drug should be stopped, a cholestyramine washout procedure given and onward referral to fetal medicine considered. 45inally, regarding the use of biologics in pregnancy, the evidence demonstrates no difference in pregnancy outcome, including that of fetal structural differences, in those on biologic treatment, suggesting these as a safe third-line alternative in the management of disease remission in pregnancy. 50Anti-TNF agents including adalimumab or infliximab are commonly used in the management of sarcoidosis.Their use is nuanced by concern around neonatal immunological effects, particularly the risk of immunosuppression with avoidance of live vaccines in early life.This has led to guidance suggesting discontinuation of infliximab after 20 weeks' and adalimumab after 28 weeks' gestation.It is, however, widely acknowledged that continuation across the pregnancy is safe and usually favourable on a riskbenefit balance. 45,51A more detailed discussion on the use of biologics is outside the scope of this review; these are well summarised by Soh and Moretto. 51

Suggested guideline for antenatal, intrapartum and postnatal care
The obstetric management of women with sarcoidosis is dependent on the stage of the disease, level of activity and presence of complications secondary to sarcoidosis.The majority will be asymptomatic, with disease suppression throughout pregnancy.Management therefore focuses on risk stratification with those presenting with complications managed in a multi-disciplinary fashion.

Pre-conception
Pre-conception care of sarcoidosis involves the optimisation of management of the disease, including baseline tests, as outlined previously.Consideration for underlying function should be taken in making recommendations on proceeding with pregnancy based on underlying physiological reserve as discussed.

Antenatal
Women with a history of sarcoidosis should be managed within a high-risk care pathway.Given the increased risk of pre-eclampsia and fetal growth restriction, women should be commenced on prophylactic aspirin from 12-weeks' gestation.The use of calcium and vitamin D-based supplements to mitigate the risk of pre-eclampsia should be avoided in sarcoidosis owing to abnormal calcium metabolism which occurs in the disease. 52Serial ultrasound growth surveillance should be undertaken.Given the increased risk of pre-eclampsia, an enhanced monitoring regime built around increased regularity of assessment of blood pressure and urine should be considered antenatally.One model would be fortnightly assessment from 24 weeks' gestation followed by weekly from 32 weeks' gestation.The development of maternal tachycardia or palpitations should be actively investigated with thyroid function tests, a 24-hour Holter monitor, maternal echocardiogram and maternal cardiac MRI considered, dependent on the clinical presentation.As there is an increased risk of thromboembolism, active sarcoidosis should be considered a risk factor for VTE.This should be taken into account in the provision of thromboprophylaxis.

Intrapartum
Intrapartum management in women with medical complications such as ILD, heart failure or neurosarcoidosis should be personalised and planned in conjunction with the multidisciplinary team.Timing of delivery should be determined based on disease control within pregnancy and the emergence of complications of pregnancy such as preeclampsia.Consideration of early delivery should be taken in cases of severe active disease requiring more aggressive medical therapy.While sarcoidosis alone is not an indication for caesarean section, the underlying maternal physiological reserve relating to both cardiac and respiratory disease should be considered when discussing mode of delivery.An alternative of vaginal delivery with a shortened second stage may also be considered.In addition, certain presentations of neurosarcoidosis may present with features of raised intracranial pressure; in these cases, a vaginal delivery may be contraindicated.The use of intrapartum oxygen may be of benefit in those with known ILD. 31 Careful fluid management in labour is required in those with ILD to ameliorate the risk of peri-or postpartum heart failure secondary to the fluid shifts that occur following delivery. 3

Postnatal
Postnatal planning should account for the increased risk of disease flare in the postnatal period.Continuation or resumption of maintenance therapy should be encouraged with consideration of the safety profile of the medication in breastfeeding mothers as outlined previously.Early follow-up by the medical team should be arranged.Counselling on postnatal contraception should be undertaken with clinical decision-making on type based on maternal wishes and accounting for maternal sequelae of sarcoidosis.

Conclusion
In conclusion, while women with sarcoidosis are likely to experience remission within pregnancy, they remain at increased risk of developing serious complications of the disease both within pregnancy and in the immediate postnatal period.In addition, they present higher obstetric risk.Careful multidisciplinary management is therefore required.There remains, however, a paucity of high-quality evidence on the management of sarcoidosis in pregnancy, and further studies are required.

Disclosure of interests
JO has no financial interests to declare.RCOG roles include: RCOG Elearning Editor (Trainee) and Member of the RCOG Learners Working Group.
FM has no financial interests to declare.RCOG roles include: RCOG Elearning Editor (Trainee).
ST has no financial interests to declare.Author on British Society for Rheumatology guideline on prescribing drugs in pregnancy.
SG has no financial interests to declare.RCOG role: Part 3 MRCOG Clinical Assessment Sub-committee.
EK has no financial interests to declare.

Contribution to authorship
FM, ST, SG and EK conceived the manuscript.FM undertook early design.JO undertook further design and manuscript composition.All authors provided critical feedback on the manuscript and approved the final version.

Figure 1 .
Figure 1.The inter-relationship between pregnancy and sarcoidosis.Upper panel: Regulation of sarcoidosis in pregnancy with increased stimulation of T-regulatory cells resulting in suppression of T H 1-based responses.Higher disease risk in those with pre-existing severe disease.Lower Panel: Effect of active sarcoidosis on pregnancy.

Table 3 .
Key studies on the effect of sarcoidosis on pregnancy Abbreviations: BMI = body mass index; DVT = deep vein thrombosis; OR = odds ratio; PE = pulmonary embolus; RR = relative risk.ª 2024 The Authors.The Obstetrician & Gynaecologist published by John Wiley & Sons Ltd on behalf of Royal College of Obstetricians and Gynaecologists.71