Medical Management of GDM – following the evidenceMini Commentary on 21-0353.R1 - “Changing Patterns in Medication Prescription for Gestational Diabetes During a Time of Guideline Change in the USA: A Cross-sectional Study ”Aaron B. Caughey, MD, PhDDepartment of Obstetrics and Gynecology; Oregon Health & Science University; Portland, ORCorrespondence:Aaron B. Caughey, MD, PhDProfessor and ChairDepartment of Obstetrics and GynecologyOregon Health & Sciences UniversityP: 503-494-2999F: 503-494-2391E: email@example.comGestational diabetes mellitus (GDM) is one of the most common pregnancy complications and is associated with numerous pregnancy complications including preeclampsia, preterm birth, stillbirth, cesarean delivery, fetal macrosomia, birth injury, neonatal hypoglycemia, childhood obesity in the offspring and other short- and long-term complications.(Sweeting AN, et al. Diabetes Care. 2016;39:75-81) Many of these complications appear to be associated with hyperglycemia, so tight control of maternal plasma glucose is the primary approach to management during pregnancy. The first line approach is usually a strict carbohydrate-controlled diet and exercise, but when this fails, medical therapy is indicated.For many years, the first-line medical approach was injectable insulin. However, an oral hypoglycemic agent, glyburide, was increasingly adopted after a trial of glyburide versus insulin demonstrated no statistical difference in the outcomes, though it was underpowered to do so.(Langer O, et al. N Engl J Med 2000;343:1134-8) Another oral agent, metformin, was studied in an adequately powered randomized trial that found no differences in outcomes between pregnancies treated with metformin versus insulin.(Rowan JA, et al. N Engl J Med 2008;358:2003-15) Perhaps because glyburide was already being used, or that metformin crosses the placenta, or an odd finding of a higher rate of preterm birth in the metformin group, there was little adoption of metformin after this trial. Other trials of these medications have been conducted and a systematic review in 2015 demonstrated that a number of outcomes were worse in women randomized to glyburide whereas there are no differences in women randomized to metformin.(Balsells M, et al. BMJ 2015;350:h102) These findings led the American College of Obstetricians and Gynecologists (ACOG) to change their recommendations to encourage insulin to be first-line treatment in 2017.(ACOG. Obstet Gynecol. 2017;130:e17-e37) A follow-up recommendation from ACOG broadened to include metformin as well.(ACOG. Obstet Gynecol. 2018 Feb;131(2):e49-e64)So, how have these data and the recommendations from ACOG changed practice patterns? In a paper published in BJOG this month, the authors examined the pharmacologic approaches to management in GDM.(Venkatesh KK, et al. BJOG, 2021) In a large cohort of over 10,000 individuals with GDM requiring medical therapy, they found that from 2015 to 2018, the use of insulin increased from 26% to 44%, the use of metformin increased from 17% to 29%, and the use of glyburide decreased from 58% to 27%. These data are from either side of the 2017 ACOG recommendation, but end in the same year as the follow-up recommendation. Given how long it can take for recommendations to be adopted by clinicians, one wonders how the practice patterns may have continued to evolve in 2019 and 2020.Recalling that the 2017 ACOG recommendation was to have insulin be first line for GDM, while the trend is in the right direction, it was still less than 50% as of 2018. While it is understandable that clinicians and patients want to prescribe an oral agent, insulin remains an effective medication with great safety data. Likely this is why it is recommended as first-line treatment by many organizations and hopefully, further trends towards its primary use will be seen.
Mini-Commentary on Manuscript # BJOG-20-2493A Biomarker for Amniotic Fluid Embolism: The Search ContinuesWord count: 495Research into the pregnancy associated cytokine storm-like condition historically known as amniotic fluid embolism (AFE) has been hampered by a lack of unique diagnostic criteria. In its classic form, the clinical presentation of this condition is unmistakable. In less classic presentations, each of the clinical hallmarks of AFE (depressed ventricular function, lung injury and coagulopathy) may, in isolation, be seen in other obstetric conditions. Indeed, much of the confusion arising from previously published case series purporting to describe women with AFE appears to be the result of the inclusion of patients with other conditions. (Clark SL et al Obstet Gynecol 2014:123: 337-48) Identification of a reliable, objective biomarker specific to AFE is badly needed.It is against this background that the work of Bouvet et al is especially welcome. These investigators examined the use of insulin-like growth factor binding protein -1, a protein found in high concentration in amniotic fluid, as a potential biomarker of AFE in women suspected to have this condition. Unfortunately, the results were negative, leading the authors to question the usefulness of this assay.Although the results were negative, the major importance of this study may be as an example of how to properly conduct a search for AFE biomarkers. These authors avoided several pitfalls that have invalidated most previous biomarker publications. First, they used 2 objective, internationally recognized clinical criteria sets for identifying women with AFE. Their finding that only about half of women suspected to have AFE actually had the condition based on either of the identified criteria sets emphasizes the importance of insisting on inclusion criteria more stringent than “someone thought the patient had AFE,” so common in current literature. Secondly, in their use of women with suspected AFE these investigators avoided another common pitfall in biomarker research, namely the use of normal pregnant women, rather than critically ill women as controls. Presumably the women without AFE had some other form of critical illness. This distinction is particularly important in investigating the potential of various inflammatory mediators as specific markers for AFE.Finally, the authors’ data support 2 additional important conclusions beyond the original intent of the paper. The finding that 100% of AFE patients identified by the SMFM criteria also met the UK diagnostic criteria serve as additional validation of the ability of the former criteria to reliably identify a group of women who, for research purposes, do have the disease, while excluding some others with less typical forms of AFE. (Clark et al, Am J Obstet Gynecol 2016:408-12.) Secondly, the authors’ findings of no difference in levels of ILGFBP-1 in women with and without clinical AFE, despite high levels of this protein in amniotic fluid, supports the current belief that amniotic fluid per se is unrelated to the condition known as amniotic fluid embolism.It is generally accepted by the scientific community that AFE is unpreventable. It is hoped that additional quality research such as that of Bouvet et al may someday change this unfortunate fact.
Professor PEP Petros DSc DS (UWA) PhD (Uppsala) MB BS MD (Syd) FRCOG (Lond)31/93 Elizabeth Bay Rd, Elizabeth Bay NSW 2011 AUSTRALIAReconstructive Pelvic Floor Surgeon and Certified Urogynaecologist (retired)Formerly University of NSW Professorial Dept of Surgery, St Vincent’s Hospital Sydney (retired)Adjunct Professor, University of Western Australia School of Mechanical and Chemical Engineering, Perth WA (current)Tel 61 2 9361 3853 Cellphone (AUST) 61 411 181 731Email firstname.lastname@example.org website www.integraltheory.org
BJOG-20-2353.R2 What should we believe when systematic reviews disagree?For many years, uterine balloon tamponade (UBT) has been used to treat severe postpartum haemorrhage (PPH), despite a lack of randomised trials to demonstrate its effectiveness. With commercial devices being expensive, clinicians in low resource settings have made their own using 2 low-cost, widely available items (Foley catheters and condoms). Public health experts have been so confident of their benefit that large programmes have been set up to disseminate the necessary skills worldwide.Recently, however, the global maternal health community has been thrown into disarray when not one, but two randomised controlled efficacy trials suggested that outcomes with condom catheter UBTs were actuallyworse than normal care in low resource settings. The Cochrane meta-analysis concluded that “in [low resource] settings, balloon tamponade [should be] only introduced alongside multi‐system improvements in PPH care” (Kellie et al. Cochrane Database of Systematic Reviews 2020(7): CD013663).Systematic reviews may be the pinnacle of evidence-based medicine, but even they can differ in how to interpret evidence. And so, proponents of the condom catheter conducted their own systematic review with far wider inclusion criteria – they not only included the randomised trials but examined success rates from 15 non-randomised trials and 69 case series (Suarez et al. Am J Obstet Gynecol 2020;222(4):293.e1–e52). Furthermore, the primary outcome was the success rate of the technique (overall 86%) rather than the risk of morbidity and mortality compared to controls, as used in the Cochrane review. This is problematic, as reported ‘success rates’ without controls can be very difficult to interpret: in initial case series misoprostol showed similar success rates against life-threatening haemorrhage before RCTs eventually showed it to be less effective than oxytocin.A third version of the same review is published today by a WHO team (Pingray et al. BJOG 2021;XXX,XXX). This time they include only 4 high quality studies in which UBT was compared to standard care. With a composite maternal morbidity / mortality outcome, they found no evidence of benefit and concluded that “the effect … is unclear, as is the role of the type of device and the setting”. WHO studies are now underway to address this uncertainty.But why is this all so important? The difficulty comes because the World Health Organisation has been updating its guidance on PPH management, and had to declare a position on UBT. The recently-published guideline, drawn up by independent experts, accepts the validity of the RCTs but recognises that there is wide acceptability of the technique and that the evidence of harm is only for condom catheters and onlyin resource-poor settings. They put a high emphasis on minimising harm and conclude that UBTs should only be used in settings where there is already a good standard of care, including recourse to blood transfusion and surgery if needed (WHO. Geneva: World Health Organization; 2021).Until further studies are published, the debate will continue. But this episode shows how the choice of inclusion criteria and outcomes in systematic reviews are critical, both for their conclusions, and for global policy.
Anaemia in pregnancy remains a global health problem In this issue of BJOG Hull et al …… et al report on an important study from South Africa regarding anaemia in pregnancy and the response to iron therapy. They report that in HIV-positive women the response was slower than in HIV-negative women. The underlying causes of anaemia varied and included iron deficiency (as assessed by ferritin levels) as well as concurrent infections (urinary tract infections and tuberculosis)Anaemia in pregnancy (blood haemoglobin Hb<11.0g/dl) occurs in > 40% of women living in low- and middle-income countries (LMIC) and in some settings in Asia prevalence is >60%. (McCauley et al, BMJ Global Health, 2018; 3(3):e000625) The latest WHO recommendations on antenatal care consider anaemia as the world’s second leading cause of disability and one of the most serious global public health problems (WHO Geneva 2016 ) .Although globally the focus has largely been on anaemia in pregnancy resulting from either iron deficiency or malaria, this is an incomplete approach at best. Iron deficiency is hard to measure and confirm as; i) this requires a functioning laboratory to be in place, ii) indicators for iron deficiency are influenced by the presence of concurrent infection, or, iii) repeated measures of Hb are needed to check whether the anaemia is responsive to treatment with iron. By contrast, malaria is relatively easy to diagnose via rapid diagnostic tests or microscopic examination of a stained blood smear slide. The handful of studies which have comprehensively assessed aetiology of anaemia in pregnant women demonstrate that anaemia is most commonly the result of complex multiple underlying factors including nutritional deficiencies as well as infectious diseases. Both nutritional deficiency and other infections (malaria, tuberculosis) are more likely with HIV-infection which itself can lead to anaemia probably through direct suppression of erythropoiesis.Hull et al show what was possible in a real-life clinical practice setting. This example of integration of research into clinical practice is laudable and is illustrative of how such integration could result in better services being made available for women in LMIC where burden of disease is high, but diagnostic tests are largely unavailable. It is sobering to realise that the majority of women world-wide will still only be screened for anaemia during pregnancy using ‘conjunctival inspection’ which is highly inaccurate. (van den Broek et al. Bull WHO 1999; 77(1):15-21) Rapid diagnostic tests are available for Hb, malaria, syphilis, HIV and, more recently, for tuberculosis. We are doing women a dis-service if we cannot offer at least these basic diagnostic tests as part of antenatal care.To prevent anaemia during pregnancy, the ‘fall-back’ position is to offer all women daily iron prophylaxis (30-60mg elemental iron) - with luck tablets are available that include folic acid (0.4mg) - along with presumptive treatment of malaria (various regimes) in endemic areas. Multi-micronutrients (including the required amount of iron and folic acid) might actually be better but cannot be recommended because of lack of evidence and they are still three times as expensive as iron and folic acid supplementation alone (3$ vs 1$ approximately).WHO recently recommended a better understanding of the aetiology of anaemia. A search on PubMed shows a clear lack of papers on the topic and more good research is needed. Investment in the antenatal care package offered to women is also much needed if we are aiming for a global ‘Health for All’.
Episiotomy and operative vaginal delivery- Do we need more evidence?A.H. Sultan- Urogynaecology and Pelvic Floor Reconstruction Unit, Croydon University Hospital, London Road, Croydon CR7 7YE- Honorary Reader, St George’s University of LondonEmail:email@example.comTel: 00 44 7961386840(ORCID 0000-0001-8979-2304)J.W. de Leeuw, Department of Obstetrics and Gynaecology, Ikazia Ziekenhuis, Rotterdam, the Netherlands(ORCID 0000-0001-5028-8055)DISCLOSURE of INTERESTAbdul Sultan is the co-director of the Croydon Perineal and Anal Sphincter Trauma courses (www.perineum.net)Operative vaginal delivery (OVD) is recognised as a major risk factor in the occurrence of obstetric anal sphincter injuries (OASIs), particularly during first vaginal deliveries. Randomised controlled trials (RCTs) have shown the merits of adopting a policy of restrictive mediolateral episiotomy during normal vaginal delivery, although no RCT to date has included measurements of the angle or size of the episiotomy. The benefits of episiotomy performed during OVD demonstrated in large observational studies are overwhelming (Sultan et al. Eur J Obstet Gynecol Reprod Biol. 2019;240:192-196) .Ankarcrona et al have added another study to this collection and have confirmed the results of most such publications. In their study, based on 11 years of data from the Swedish Medical Birth Register, they have emulated a RCT using propensity scores. Ultimately, both methods used showed an almost identical risk reducing effect as the commonly used logistic regression analysis. demonstrating a significant reduction in OASIs during vacuum extraction associated with the use of mediolateral or lateral episiotomies. The Number Needed to Treat to prevent one OASI was 27, which is known to be fourfold lower in forceps delivery.Is the episiotomy a treatment for a certain condition or disease? In reality, episiotomy is an intervention to reduce the risk for an unwanted side effect of birth. Consequently, the impact is one of risk modification as opposed to treatment. Similar to the study by Ankarcrona et al risk factors are commonly established with the use of observational studies (RCOG Greentop guideline No 29, 2015) . In the last decade, several large observational studies Involving more than 2 million women showed a significantly lower rate of OASI in nulliparous women undergoing OVD with an episiotomy.Given the availability of such studies, based on registered databases, showing significantly lower OASI rates, is there still a need for further evidence? Ankarcrona et al acknowledge Lund et al who have shown in their systematic review that there is an association between the risk reduction for OASI with episiotomy rates; the greatest reduction was shown in studies with episiotomy rates over 70%.Obstetricians opposing the use of routine episiotomy during OVD highlight the lack of a definitive RCT. RCT’s are commonly used to address the treatment effect of an intervention on a particular condition with a well described outcome. However, RCT’s of episiotomy during OVD have proven to be very difficult and usually compare no more than the liberal versus the restricted use of episiotomy. As Ankarcrona et al mention, there is only one pilot RCT of IVD and episiotomy indicating that 1600 OVD will need to be included for a definitive study. However, we believe that the design of such a study should be two separate arms for forceps and vacuum delivery as the inherent risks with/without an episiotomy is different. Such a study with vacuum extraction is currently underway in Sweden.The challenge now is to identify prior to labour which women are at high risk of sustaining OASIS using prediction models based on the pre-existing large national databases.
Letter to the Editor, BJOG Title:Deceleration Area and Deceleration Capacity: Promising predictors of fetal acidaemia in human labour? Visual versus computerised cardiotocographyRe: Georgieva A, Lear CA, Westgate JA, Kasai M, Miyagi E, Ikeda T, Gunn AJ, Bennet L. Deceleration area and capacity during labour-like umbilical cord occlusions identify evolving hypotension: a controlled study in fetal sheep. BJOG 2021; https://doi.org/10.1111/1471-0528.16638.Author: Mr. Shashikant L SHOLAPURKARMD, DNB, MRCOGDept of Obstetrics & Gynaecology,Royal United Hospital, Bath, BA1 3NG, UKEmail:firstname.lastname@example.org; email@example.com; Tel: 07906620662Short Running Title: Deceleration area and capacity in labourWord count: 500Corresponding Author: Mr. Shashikant L SHOLAPURKARMD, DNB, MRCOGDept of Obstetrics & Gynaecology,Royal United Hospital, Bath, BA1 3NG, UKStatement of interest: The author has no conflict of interest or funding to declare.
Objective To test the hypothesis that there is seasonal variation in the rates of gestational diabetes (GDM) diagnosed using a 2 hour oral glucose tolerance test. Design Monthly assessment of the percentage of women screened from 1st April 2016 to the 31st December 2020 who were diagnosed as having gestational diabetes Setting London Teaching Hospital Population 28,128 women receiving antenatal care between April 1st 2016 and 31 December 2020. Methods Retrospective study of prospectively collected data. Main Outcome Measures Proportion of women screened diagnosed as having gestational diabetes. Results The mean (SD) percentage of women diagnosed with GDM was 14.78 (2.24) in summer (June, July, August) compared with 11.23 (1.62) in winter (p < 0.001), 12.13 (1.94) in spring (p = 0.002), and 11.88 (2.67) in autumn (p = 0.003). There was a highly significant positive correlation of the percentage testing positive for GDM with the mean maximum monthly temperature (R2 = 0.248, p < 0.001). There was a statistically significant 33.8% increase in the proportion of GDM diagnoses from June 2020 onwards, possibly related to a reduction in exercise secondary to the Covid-19 pandemic. Conclusions There is a 23.3% higher rate of GDM diagnoses in the warmer summer months. There has been a 33.8% rise in GDM diagnoses associated with the Covid-19 pandemic.
Background Pregnancy and liver cirrhosis is a rare but increasing combination. Liver cirrhosis can raise the chance of maternal and fetal mortality and morbidity, although the exact risks remain unclear. Objective To provide a systematic literature review and meta-analysis on maternal, fetal and obstetric complications among pregnant women with liver cirrhosis. Search strategy We performed a systematic literature search in the databases PubMed/MEDLINE and EMBASE (Ovid) from inception through 25 January 2021. Selection criteria Studies including pregnancies with liver cirrhosis and controls were eligible. Data collection and analysis Two reviewers independently evaluated study eligibility. We used the random-effects model for meta-analysis. Main results Our search yielded 3118 unique papers. We included 11 studies, including 2912 pregnancies in women with cirrhosis from 1982-2020. Seven studies were eligible for inclusion in the meta-analysis. The overall maternal mortality rate was 0.89%. Maternal mortality and variceal hemorrhage decreased comparing recent and older studies. Most cases of maternal mortality due to variceal hemorrhage (70%) occurred during vaginal delivery. Pregnant women with liver cirrhosis had a higher chance of preterm delivery (OR 6.7 95% CI 5.1- 9.1), cesarean section (OR 2.6, 95% CI 1.7-3.9), preeclampsia (OR 3.8, 95% CI 2.2-6.5) and small for gestational age neonates (OR 2.6, 95% CI 1.6-4.2) compared to the general obstetric population. Subgroup-analyses could not be conducted. Conclusions Liver cirrhosis in pregnant women is associated with serious increases in maternal mortality and obstetric and fetal complications. Large international prospective studies are needed to identify risk factors for unfavorable outcome.
Placenta accreta spectrum: Welcome progress and a call for standardization.Mini-commentary for BJOG on Kayem et al 2021 BJOG-20-1462R3Placenta accreta spectrum (PAS) is among the most feared causes of maternal morbidity worldwide, and yet few prospective data are available to inform best practice. PAS is rare enough that rigorous study in a single center is difficult, but common enough that most obstetric hospitals now encounter PAS. Management and outcomes vary strikingly between hospitals and best practice, regrettably, is guided more by expert consensus than by level I evidence. In fact, most clinical questions regarding management of PAS are informed by essentially no prospective data (Collins et al. Am J Obstet Gynecol. 2019;220:511-526).Into this data void has come the PACCRETA cohort (Kayem et al. Act Obstet Gynecol Scand 2013;92:476-482) and some of its first results, published in this issue of BJOG (Kayem et al. BJOG 2021). PACCRETA is a prospective population-based study from 176 hospitals in France, capturing 30% of all French deliveries, from from 2013 to 2015. The study investigators identified 249, or 4.8 per 10,000, cases of PAS.Of all PAS patients, Kayem and colleagues found that a full half did not have the classic combination of risk factors for PAS (previa with history of cesarean). This group had lower morbidity and milder disease than those with the classic combination. Only 17% of those without classic risk factors were diagnosed antenatally. The message here is mixed: those without classic PAS risk factors are less likely to be diagnosed antenatally (bad) but appear to suffer less morbidity overall (good).But did these patients actually have PAS? Only 21% of those without prior cesarean and previa had a hysterectomy. Although this could be due to a regional preference for conservative treatments, the presence of false positives seems likely. Without a hysterectomy specimen, the diagnosis of PAS is difficult, controversial, and (in our opinion) highly susceptible to overdiagnosis. The authors define “strict” criteria for true cases of PAS, but several criteria depended entirely on the subjective assessment of a clinician faced with a difficult placental removal and the flawed principle of PAS as diagnosis of exclusion . Difficulty in manual placental removal or massive bleeding from an implantation site does not always indicate that microscopic PAS was present. Similarly, areas of prior cesarean section scar dehiscence (windows) where the placenta can be seen through the serosa are often diagnosed as percreta (Figure) without any histological evidence of the villous tissue having invaded through the serosa or beyond (Hecht et al. Modern Pathol 2020;33:2382-2396).We congratulate Kayem and colleagues for the current study and all of their important contributions to our understanding of PAS. However, these data illustrate the need for standardization of the definition of PAS, especially in conservatively managed cases with considerable potential for misdiagnosis. There is a desperate need for controlled studies of patients with antenatally suspected PAS with detailed and objective documentation of imaging, intra-operative findings, and when available, histopathological examination. In absence of such studies, the void of definitive data to guide treatment options will remain wide open.