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The last specialty using racist charts

January 11, 2022

Deriving normal ranges from abnormal patients

Doctors do millions of different tests on patients – bloods, imaging, exercise tolerance – and always define the range of normal values on healthy people. The normal haemoglobin concentration is based on healthy participants. Even in countries where malaria is common, and many people anaemic, the same normal ranges are used.

With two exceptions, renal function and fetal biometry. Until recently some kidney doctors used different estimated glomerular filtration rate (eGFR) ranges for people with black skins, who tend to have lower values, i.e. slightly worse renal function. And some obstetricians still use special “customised” fetal size charts, for short, underweight, or ethnic minority mothers, who tend to have smaller babies.

However the lower black eGFR values are not “normal”, they reflect more pathology, raised blood pressure etc. In 2021 NICE recognised that using different normal ranges for black people was racist. It deprived them of effective treatment, and NICE revised its guidelines to a single set of normal ranges for all adults (click here).

Most obstetricians also know that being short, under or over-weight, or having dark skin, is also associated with adverse outcomes, so using special charts for such women tends to normalise pathology. Their use is heightist, weightist and racist. The WHO, and the Intergrowth-21 group, have produced unified charts based on healthy pregnancies, which most obstetricians worldwide now use.

But the UK has been slow to adjust. About half of UK maternity units still use customised charts and the RCOG, in its Green Top guidelines, still endorses them (click here).

In the 1970s Archie Cochrane awarded obstetrics the “wooden spoon” as the last specialty to implement evidence-based medicine. We’ve done better in that department since.

But right now we are the last specialty using racist charts. Fortunately the Green Top guidelines are due for revision. It’s time to put this right.

Jim Thornton

Two maternal deaths from surgical herpes

January 6, 2022

Avoidable with blunt needles

Last year a BBC investigation suggested that two young women in Kent had died from generalised surgical herpes infection, contracted from an infected surgeon, due to a needlestick injury at Caesarean section (click here).

The evidence was compelling. Herpes contracted this way is rare, but often fatal. Neither woman had a previous history of herpes, so would likely not have had prior immunity. Both were operated on in the same trust, albeit different hospitals, by the same unnamed surgeon. Kim Sampson gave birth on 3 May 2018, and Samantha Mulcahy on June 26 the same year. Both developed overwhelming herpes infections shortly after birth and died soon after.

According to emails seen by the BBC, the partial viral genome from both infections was not only identical, but also “rare”, compared with the previous 10 years of herpes samples collected by Public Health England’s North London lab. Although the surgeon was questioned, and denied having a herpetic lesion (a whitlow) on his finger, such lesions can be small and missed.

Needlestick injuries at Caesarean are common – the BBC quotes a 50 percent glove perforation rate. It was not reported whether the surgeon used a sharp or blunt needle, but the former is likely. If so, an easy opportunity to prevent the deaths of two young women was missed.

There is overwhelming evidence that blunt needles reduce needlestick injuries. It not only accords with common sense, but there have been ten randomised trials, two involving Caesarean section, and 2,961 operations included in the latest Cochrane review in 2011 (click here).

The use of blunt needles reduced the risk of glove perforations (RR 0.46; 95% CI, 0.38 to 0.54) compared to sharp needles, and self‐reported needle stick injuries (RR of 0.31; 0.14 to 0.68). It is unlikely that future research will change this conclusion.

This was followed by a Cochrane editorial (click here) in which the review was cited as an example of one “that can and should change practice”. The authors wrote “where they can be used they should be used”. They are recommended by the US Centers for Disease Control, the US Food and Drug Administration (click here), and the National Institute for Occupational Safety and Health (click here)”.

However, for some reason, NICE (click here for the March 2021 guidance), still doesn’t recommend them, and in my experience, few UK obstetricians use them. Despite the FDA and CDC recommendations things are not much better in the US. In a recent survey only 17% of fetal medicine trainees used them, and many were not even aware such needles existed (click here).

The reason for such reluctance to implement a simple safety step is unclear. They need a little more pressure to penetrate tissue, and some surgeons argue, mistakenly, that needlestick injuries matter less when everyone is screened for Hep B, Hep C and HIV. Nothing could be further from the truth. Each of these viruses caused many surgical infections until screening caught up, and if the last two years have taught us anything, new viruses are appearing all the time!

The inquest opened this week (click here) and has been adjourned to February 21. Let’s hope the coroner, Ms Katrina Hepburn, asks if the surgeon used blunt needles, and if not, why not.

This is an avoidable harm. If NICE’s recommenation had been evidence-based, maybe two young women would be alive today.

Jim Thornton

Sharp tender shock

December 20, 2021

An Arundel Tomb

Coming across it in Chichester cathedral recently, was a shock. My friends had misled me. “It’s not here” they had said. “It’s in Arundel.”

Afterwards, walking outside, a young couple asked for a photo. I told them about the tomb and poem – they didn’t know either – so I recited the final line. They promised to check it out. I started to explain how people misread it, or maybe don’t, but got “a bit o’ grit in me eye”, so had to turn away instead.

An Arundel Tomb

Side by side, their faces blurred,   
The earl and countess lie in stone,   
Their proper habits vaguely shown   
As jointed armour, stiffened pleat,   
And that faint hint of the absurd—   
The little dogs under their feet.

Such plainness of the pre-baroque    
Hardly involves the eye, until
It meets his left-hand gauntlet, still   
Clasped empty in the other; and   
One sees, with a sharp tender shock,   
His hand withdrawn, holding her hand.

They would not think to lie so long.   
Such faithfulness in effigy
Was just a detail friends would see:
A sculptor’s sweet commissioned grace   
Thrown off in helping to prolong   
The Latin names around the base.

They would not guess how early in
Their supine stationary voyage
The air would change to soundless damage,   
Turn the old tenantry away;
How soon succeeding eyes begin
To look, not read. Rigidly they

Persisted, linked, through lengths and breadths   
Of time. Snow fell, undated. Light
Each summer thronged the glass. A bright   
Litter of birdcalls strewed the same
Bone-riddled ground. And up the paths   
The endless altered people came,

Washing at their identity.   
Now, helpless in the hollow of   
An unarmorial age, a trough
Of smoke in slow suspended skeins   
Above their scrap of history,   
Only an attitude remains:

Time has transfigured them into   
Untruth. The stone fidelity
They hardly meant has come to be   
Their final blazon, and to prove   
Our almost-instinct almost true:   
What will survive of us is love.

Philip Larkin

Evie Toombes’ Wrongful Birth

December 14, 2021

Spina bifida and folic acid

Many were startled last week to learn that Evie Toombes, who has a type of occult spinal lesion, a lipomyelomeningocele, which would not have been prevented by her mother taking folic acid, will be awarded damages against Dr Mitchell, her mother’s GP, who had failed to advise her correctly about taking folic acid. Evie is “an occasional wheelchair/Zimmer frame user”, and needs to self catheterise, but is also “a para-horse rider, a campaigner for hidden disabilities and together with her mother, the author of a book”. Click here for the news story, and here or here for the full judgment.

An earlier court had already ruled on the principle; if, with correct advice, Evie’s mother would have delayed conception, Evie would never have been born and another healthy child replaced her, Evie would be entitled to damages.

There are parallels here with abortion for fetal abnormality. In the 1970’s the Oxford philosopher, Richard Hare, argued that parents considering abortion should decide in the interests of all their potential future children. A mother carrying a fetus with spina bifida should abort in the interests of her, unconceived, but likely to be healthy, replacement child (click here). In my experience this is how many parents think, and I guess the legal arguments follow this sort of logic too. I find the earlier court’s decision rather congenial.

But the judge’s ruling that the doctor’s advice was so bad that no responsible body of GPs would have advised Evie’s mother that way, does seem harsh.

Imagine Dr Mitchell, back when the claim started, getting a lawyer’s letter presumably alleging that he’d failed to advise Evie’s mum to take folic acid. Imagine him pulling his 27 February 2001 note to read “Preconception counselling. adv. Folate if desired discussed” (judgment para 31). He must have felt out of the frame.

But here’s para 61. Both sides agree that Mrs Toombes had attended for preconception counselling at her own instigation.

“I find that Dr Mitchell’s note is completely inadequate. As I have found, Mrs Toombes’ main concern was with regard to stopping the pill and that is not referred to in the note at all. I find that Dr Mitchell’s assumption that “Folate if desired,” means that he gave his usual standard advice, but that Mrs Toombes raised an issue as to whether or not the supplement was necessary and he explored details of her diet, informed her of the risks and then left it to her to choose, is nothing but speculation after the event. The note gives the impression without more discussion that Mrs Toombes was told that she should take folic acid if she wanted to. I accept Mrs Toombes’ evidence that she came away from the consultation under the impression that if she had a healthy diet, folic acid supplements were not necessary. In the circumstances, I prefer the evidence of Mrs Toombes and find that she was not told about the recommended dose or the reason why folic acid supplementation was recommended or that it should be taken before conception and for the first 12 weeks of pregnancy.”

Nothing wrong with the judge making findings of fact. But we can now see the aspects of Dr Mitchell’s advice, that were so bad that apparently no responsible body of GPs would follow them. Here they are.

  1. Qualifying his advice with a comment that folic acid was not necessary if her diet was good
  2. Not telling her the exact dose
  3. Not saying that the reason was to prevent spina bifida
  4. Not saying that it should be given pre-conception

To a woman who was knowledgable enough to arrange preconception counselling! We used to think obstetricians had it tough.

Jim Thornton

Gynaecological effects of Covid

November 1, 2021

Scientific papers reporting short and long-term effects of Covid-19 on menstruation, menarche and menopause, fertility, genital tumours, uterovaginal prolapse, female sexual function, urinary and vulval disorders, endometriosis and other miscellaneous gynaecological problems. Primary sources only. Updated regularly. Most recent first. Curated by Jim Thornton, Keelin O’Donoghue & Kate Walker.

For Covid-19 in pregnancy (click here), indirect effects on pregnancy (click here), news reports (click here) and effects of Covid-19 vaccines (click here).

26 January 2022 – GP 16 to 22 added. GP 13 transferred to vaccines & fertility (click here)

Gynae paper 22 – vaccine response in 36 women with ovarian cancer

Centres not reported, but approved by the research ethics comttee of Alexandra Hospital, Athens, Greece (click here or paper). Citation: Liontos, M.; Terpos, E.; Markellos, C.; Zagouri, F.; Briasoulis, A.; Katsiana, I.; Skafida, E.; Fiste, O.; Kunadis, E.; Andrikopoulou, A.; Kaparelou, M.; Koutsoukos, K.; Gavriatopoulou, M.; Kastritis, E.; Trougakos, I.P.; Dimopoulos, M.-A. Immunological Response to COVID-19 Vaccination in Ovarian Cancer Patients Receiving PARP Inhibitors. Vaccines 2021, 9, 1148. https://doi.org/10.3390/vaccines9101148

Gynae paper 21 – 46 cases from Argentina

Women, aged 21–41, undergoing assisted reproductive technology procedures between November 2020 and April 2021 at the following clinics; PREGNA Medicina Reproductiva, IVI Buenos Aires, Fertilis, and InVitro, all in Buenos Aires (click here or paper). Citation: Herrero Y, Pascuali N, Velázquez C, Oubiña G, Hauk V, de Zúñiga I, Peña MG, Martínez G, Lavolpe M, Veiga F, Neuspiller F, Abramovich D, Scotti L, Parborell F. SARS-CoV-2 infection negatively affects ovarian function in ART patients. Biochim Biophys Acta Mol Basis Dis. 2022 Jan 1;1868(1):166295. doi: 10.1016/j.bbadis.2021.166295. Epub 2021 Oct 27. PMID: 34718118; PMCID: PMC8550892. – Control study

Gynae paper 20 – 9 couples from Israel

Seven with female partner covid, and two with male partner, teated at Chaim Sheba Medical Center, Ramat Gan, both before the pandemic and after infection (click here or paper). Citation: Orvieto R, Segev-Zahav A, Aizer A. Does COVID-19 infection influence patients’ performance during IVF-ET cycle?: an observational study. Gynecol Endocrinol. 2021 Oct;37(10):895-897. doi: 10.1080/09513590.2021.1918080. Epub 2021 May 11. PMID: 33974475.

Gynae paper 19 – case report from Turkey

From author affiliations the Atasehir Memorial IVF Center, Istanbul (click here or paper). Citation: Demirel C, Tulek F, Celik HG, Donmez E, Tuysuz G, Gökcan B. Failure to Detect Viral RNA in Follicular Fluid Aspirates from a SARS-CoV-2-Positive Woman. Reprod Sci. 2021 Aug;28(8):2144-2146. doi: 10.1007/s43032-021-00502-9. Epub 2021 Feb 22. PMID: 33616884; PMCID: PMC7899067.

Gynae paper 18 – 2 case reports from Spain

From author affiliations the Clinica EUGIN, Carrer de Balmes 236, Barcelona (click here or paper). Citation: Barragan M, Guillén JJ, Martin-Palomino N, Rodriguez A, Vassena R. Undetectable viral RNA in oocytes from SARS-CoV-2 positive women. Hum Reprod. 2021 Jan 25;36(2):390-394. doi: 10.1093/humrep/deaa284. PMID: 32998162; PMCID: PMC7543480.

Gynae paper 18 – 9 cases from Israel

See vaccination source 23 here.

Gynae paper 17 – 14 cases from France

From the ART unit of Tenon Hospital, Paris, between June and December 2020 (click here or paper). Citation: Kolanska K, Hours A, Jonquière L, Mathieu d’Argent E, Dabi Y, Dupont C, Touboul C, Antoine JM, Chabbert-Buffet N, Daraï E. Mild COVID-19 infection does not alter the ovarian reserve in women treated with ART. Reprod Biomed Online. 2021 Dec;43(6):1117-1121. doi: 10.1016/j.rbmo.2021.09.001. Epub 2021 Sep 10. PMID: 34711516; PMCID: PMC8432972.

Gynae paper 16 – 70 cases from China

From the Reproductive Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology between May 2020 and February 2021 (click here or paper). Citation: Wang M, Yang Q, Ren X, Hu J, Li Z, Long R, Xi Q, Zhu L, Jin L. Investigating the impact of asymptomatic or mild SARS-CoV-2 infection on female fertility and in vitro fertilization outcomes: A retrospective cohort study. EClinicalMedicine. 2021 Aug;38:101013. doi: 10.1016/j.eclinm.2021.101013. Epub 2021 Jul 6. PMID: 34250457; PMCID: PMC8259363.

25 January 2022 – GP 15 added

Gynae paper 15 – 78 cases from China

Women of reproductive age with Covid between January 28 and March 8, 2020 from Tongji Hospital in Wuhan (click here or paper). Citation: Ding T, Wang T, Zhang J, Cui P, Chen Z, Zhou S, Yuan S, Ma W, Zhang M, Rong Y, Chang J, Miao X, Ma X, Wang S. Analysis of Ovarian Injury Associated With COVID-19 Disease in Reproductive-Aged Women in Wuhan, China: An Observational Study. Front Med (Lausanne). 2021 Mar 19;8:635255. doi: 10.3389/fmed.2021.635255. PMID: 33816526; PMCID: PMC8017139.

7 January 2022 – GP 14 added

Gynae paper 14 – vaccination & menstrual cycle length

US resident participants enrolled in the fertility-awareness application “Natural Cycles”, who recorded menstrual cycle data from October 2020 to September 2021, and were vaccinated between December 2020 and July 2021, and an unvaccinated control group (click here or paper). Citation: Edelman, Alison MD, MPH; Boniface, Emily R. MPH; Benhar, Eleonora PhD; Han, Leo MD, MPH; Matteson, Kristen A. MD, MPH; Favaro, Carlotta PhD; Pearson, Jack T. PhD; Darney, Blair G. PhD, MPH Association Between Menstrual Cycle Length and Coronavirus Disease 2019 (COVID-19) Vaccination, Obstetrics & Gynecology: January 5, 2022 – Volume – Issue – 10.1097/AOG.0000000000004695 doi: 10.1097/AOG.0000000000004695

23 December – GP 13 added

Gynae paper 13 – no effect of mRNA vaccine on AMH levels

129 women given two doses of the Pfizer-BioNTech vaccine (click here or paper). Citation: Mohr-Sasson A, Haas J, Abuhasira S, Sivan M, Amdurski HD, Dadon T, Blumenfeld S, Derazne E, Hemi R, Orvieto R, Afek A, Rabinovici J. The effect of Covid-19 mRNA vaccine on serum anti-Müllerian hormone levels. Hum Reprod. 2021 Dec 22:deab282. doi: 10.1093/humrep/deab282. Epub ahead of print. PMID: 34935913. 26 January update – transferred to Covid-19 vaccines, pregnancy & fertility, source 95 (click here).

13 December – GP 12 added

Gynae paper 12 – 8,538 vaccinated women

Volunteers participating in The Covid-19 Pandemic and Women’s Reproductive Health registry (click here or paper). Citation: Alexandra Alvergne, Gabriella Kountourides, Austin Argentieri, Lisa Agyen, Natalie Rogers, Dawn Knight, Gemma C Sharp, Jacqueline A Maybin , Zuzanna Olszewska. COVID-19 vaccination and menstrual cycle changes: A United Kingdom (UK) retrospective case-control study. MedRxiv posted December 6, 2021

30 November – GP 10 and 11 added

Gynae paper 11 – RCT of estadiol Rx in post menopausal women with Covid in India

Recruited at the Government Institute of Medical Sciences, Greater Noida, from September 10 to December 31, 2020 (click here or paper). Citation: Seth S, Sharma R, Mishra P, Solanki HK, Singh M, Singh M. Role of Short-Term Estradiol Supplementation in Symptomatic Postmenopausal COVID-19 Females: A Randomized Controlled Trial. J Midlife Health. 2021 Jul-Sep;12(3):211-218. doi: 10.4103/jmh.JMH_57_21. Epub 2021 Oct 16. PMID: 34759703; PMCID: PMC8569453.

Gynae paper 10 – 14 cases undergoing ART in France

From Tenon Hospital, Paris (click here or paper). Citation: Kolanska K, Hours A, Jonquière L, Mathieu d’Argent E, Dabi Y, Dupont C, Touboul C, Antoine JM, Chabbert-Buffet N, Daraï E. Mild COVID-19 infection does not alter the ovarian reserve in women treated with ART. Reprod Biomed Online. 2021 Sep 10:S1472-6483(21)00431-4. doi: 10.1016/j.rbmo.2021.09.001. Epub ahead of print. PMID: 34711516; PMCID: PMC8432972.

18 November – GP 8 and 9 added

Gynae paper 9 – case report (ectopic & Covid) from USA

From University of Miami, Health Systems, Jackson Memorial Hospital, Miami, Florida (click here or paper). Citation: Millan NM, Morano J, Florez L, Carugno J, Medina CA. Management of tubal ectopic pregnancy with methotrexate in the setting of symptomatic Coronavirus disease 2019 (COVID-19): A case report. Facts Views Vis Obgyn. 2021 Sep;13(3):277-281. doi: 10.52054/FVVO.13.3.030. PMID: 34555882.

Gynae paper 8 – Case report (ectopic & Covid) from Japan

From Gifu Prefectural Tajimi Hospital (click here or paper). Citation: Hayashi S, Takeda A. Gasless laparoendoscopic single-site surgery for management of unruptured tubal pregnancy in a woman with moderate COVID-19 pneumonia after administration of remdesivir and casirivimab-imdevimab: A case report. Case Rep Womens Health. 2022 Jan;33:e00368. doi: 10.1016/j.crwh.2021.e00368. Epub 2021 Nov 11. PMID: 34786352; PMCID: PMC8580554.

9 November – GP 7 added

Gynae paper 7 – Endometriosis survey from Italy

468 women diagnosed with endometriosis at Dipartimento di Scienze Mediche e Chirurgiche, Sant’Orsola-Malpighi Hospital, University of Bologna, and surveyed in May 2020 (click here or paper). Citation: Arena A, Orsini B, Degli Esposti E, Raimondo D, Lenzi J, Verrelli L, Iodice R, Casadio P, Seracchioli R. Effects of the SARS-CoV-2 pandemic on women affected by endometriosis: a large cross-sectional online survey. Ann Med. 2021 Dec;53(1):1924-1934. doi: 10.1080/07853890.2021.1991589. PMID: 34714186; PMCID: PMC8567944.

1 November 2021

Gynae paper 6 – 507 women with, & 520 without, endometriosis in Iran

No difference in rates or severity of Covid (click here or paper). A case–control study at Pars general hospital, Tehran, from May 21st to July 3rd, 2020. Citation: Moazzami B, Chaichian S, Samie S, Zolbin MM, Jesmi F, Akhlaghdoust M, Pishkuhi MA, Mirshafiei ZS, Khalilzadeh F, Safari D. Does endometriosis increase susceptibility to COVID-19 infections? A case-control study in women of reproductive age. BMC Womens Health. 2021 Mar 22;21(1):119. doi: 10.1186/s12905-021-01270-z. PMID: 33752656; PMCID: PMC7983080.

Gynae paper 5 – Haemothorax after IVF & Covid

From Conceber Centro de Medicina Reprodutiva, Curitiba, Paraná, Brazil (click here or paper). Citation: Rahal D, Kozlowski IF, Rosa VBD, Schuffner A. Hemothorax after oocyte retrieval in a patient with a history of COVID-19: a case report. JBRA Assist Reprod. 2021 Oct 4;25(4):647-649. doi: 10.5935/1518-0557.20210043. PMID: 34415132; PMCID: PMC8489828.

Gynae paper 4 – Covid, menopause & hormone therapy

Covid was more common among postmenopausal women and, within the latter group, more common among those taking menopausal hormone therapy (click here or paper). Women using the “Zoe” Covid Symptom Study app. Citation: Costeira R, Lee KA, Murray B, Christiansen C, Castillo-Fernandez J, Ni Lochlainn M, et al. (2021) Estrogen and COVID-19 symptoms: Associations in women from the COVID Symptom Study. PLoS ONE 16(9): e0257051. https://doi.org/10.1371/journal.pone.0257051

Gynae paper 3 – 237 women with Covid from China

Women aged 18 to 45 with confirmed COVID-19 who were hospitalized in Tongji Hospital, Wuhan, from 19 January to 1 April 2020 (click here or paper). Citation: Li K, Chen G, Hou H, Liao Q, Chen J, Bai H, Lee S, Wang C, Li H, Cheng L, Ai J. Analysis of sex hormones and menstruation in COVID-19 women of child-bearing age. Reprod Biomed Online. 2021 Jan;42(1):260-267. doi: 10.1016/j.rbmo.2020.09.020. Epub 2020 Sep 29. PMID: 33288478; PMCID: PMC7522626.

Gynae paper 2 – Mobile app ovulation & menstruation

No overall changes before and during pandemic in 214,426 cycles from 18,076 app users, primarily from Great Britain (29.3%) and the United States (22.6%) (click here or paper). Women using the “Natural Cycles” mobile app. Citation: Nguyen BT, Pang RD, Nelson AL, Pearson JT, Benhar Noccioli E, Reissner HR, Kraker von Schwarzenfeld A, Acuna J. Detecting variations in ovulation and menstruation during the COVID-19 pandemic, using real-world mobile app data. PLoS One. 2021 Oct 20;16(10):e0258314. doi: 10.1371/journal.pone.0258314. PMID: 34669726; PMCID: PMC8528316.

Gynae paper 1 – Menstrual symptoms in 127 self-selected women with Covid

From the Arizona CoVHORT study (click here or paper). Citation: Khan SM, Shilen A, Heslin KM, Ishimwe P, Allen AM, Jacobs ET, Farland LV. SARS-CoV-2 infection and subsequent changes in the menstrual cycle among participants in the Arizona CoVHORT Study. Am J Obstet Gynecol. 2021 Sep 20:S0002-9378(21)01044-9. doi: 10.1016/j.ajog.2021.09.016. Epub ahead of print. PMID: 34555320; PMCID: PMC8452349.

Jim Thornton, Keelin O’Donoghue & Kate Walker

Identical FSH & LH values at baseline in two different trials

August 1, 2021

My first PubPeer comment

As anyone who’s tried to expose fraudulent research by writing a “letter to the editor” will know, it can be fustrating. Editors prevaricate, authors obfuscate, and time ticks by.

PubPeer (click here) is an alternative. Publish the facts, let the author reply, and readers, editors, regulators and employers can judge for themselves. If you enter the author’s email when you submit, PubPeer automatically notifies them that one of their papers has been commented on.

It has been a powerful way to expose fabricated laboratory research, where authors have manipulated images. It can also be used for fabricated clinical studies.

To protect whistleblowers, comments can be anonymous – they just need to stick to verifiable facts – but I’ll be signing mine. Here’s my first. To read it on PubPeer (click here).

It refers to this paper:

Rezk M, Shaheen AE, Saif El-Nasr I. Clomiphene citrate combined with metformin versus letrozole for induction of ovulation in clomiphene-resistant polycystic ovary syndrome: a randomized clinical trial. Gynecol Endocrinol. 2018 Apr;34(4):298-300. doi: 10.1080/09513590.2017.1395838. Epub 2017 Oct 27. PMID: 29076376.

Table 1 has identical values for FSH and LH as Table 1 in a different paper in the same journal from 2016.

Rezk M, Sayyed T, Saleh S. Impact of unilateral versus bilateral laparoscopic ovarian drilling on ovarian reserve and pregnancy rate: a randomized clinical trial. Gynecol Endocrinol. 2016;32(5):399-402. doi: 10.3109/09513590.2015.1124262. Epub 2015 Dec 15. PMID: 26670076.

Present paper
file

Rezk et al 2016
file
The earlier paper reported a trial comparing two surgical treatments with 105 participants, and the present paper a trial of two medical treatments with 202 participants. The earlier paper recruited “from October 2014 to July 2015”. The present paper recruited “between the middle of October 2016 and the beginning of May 2017”. The later paper does not reference the earlier one.

Both have the same first author, and originate from Menoufia university, Egypt.

Jim Thornton

Why use ripe-tomato as a Covid in pregnancy source?

July 30, 2021

People often ask us “What’s different about ripe-tomato? Why not use WHO (click here), Cochrane (click here), or PubMed (click here) Covid-19 databases instead?”

Serious systematic reviewers, or guideline authors, should indeed use all those. But it will be a lot of work, searching, accessing, reading and deduplicating.

Ripe-tomato has done it for you, for primary sources in pregnancy. It isn’t perfect, but we’ve not missed much. Friends and colleagues soon tell us if we have!

But haven’t the WHO/Cochrane Living Systematic Review (LSR) team and Johns Hopkins each done the work too? Yes and no.

Shakila Thangiratinam and her WHO/Cochrane LSR team (click here) have a more complete, and better indexed, database. Dozens of people update it full time – and check ripe-tomato. But it’s not publicly accessible. The reference lists and appendices of their publications reveal the sources they used, but they keep the master database to themselves.

Johns Hopkins Center for Humanitarian Health has two related repositories. COVID-19, Maternal and Child Health, and Nutrition (click here) and COVID-19, Breastfeeding, Infant Feeding, and Breast Milk (click here). Both broader in topic than ripe-tomato and not limited to primary sources. Update 1 May 2021. The two John Hopkins repositories ceased updates from 30 April. They remain publicly available but are no longer updated.

Ripe-tomato’s unique features

Primary sources only. Anyone whose ever studied Covid-19 realises that secondary sources, reviews, editorials, comments and opinion pieces outnumber the primary sources many times. Not on ripe-tomato.org

Duplicate publications noted. Another major problem for all Covid evidence synthesisers. If you’re writing a review, creating a reference list for an article, or refereeing a paper on Covid-19 in pregnancy, ripe-tomato is your friend. We’ve caught and recorded most of the obvious duplicates. Use us.

Easy access. Some sources are behind paywalls, and some difficult to access. Don’t ask how we do it. But where possible, beside a link to the source website, we also provide a direct link to our own uploaded copy.

Newspaper reports (click here). A deduplicated list of primary newspaper stories about people with Covid-19 in pregnancy. From Italy’s “patient one”, the partner of Juventus footballer, Daniele Rugani, and the wife of the British Prime Minster, to a transgender man who caught Covid during his pregnancy. The list of nearly 700 heartbeaking and heartwarming stories is unique. It’s not complete – English language reports are over represented – but there’s nothing else like it in the world.

Click here for Ripe-tomato.org’s Covid-19 in pregnancy navigation page.

Jim Thornton

Bloody awful tripe?

July 10, 2021

This Be The Verse and The Trees

This Be The Verse is Philip Larkin’s most famous poem. In his latest book, Inside Story, (p 117) Martin Amis notes that it has a technically near identical sister, The Trees, which is more optimistic. Although Larkin apparently wrote “Bloody awful tripe” on the manuscript of the latter, he published it in High Windows, and it’s not.

This Be the Verse

They fuck you up, your mum and dad.
They may not mean to, but they do.
They fill you with the faults they had
And add some extra, just for you.

But they were fucked up in their turn
By fools in old-style hats and coats,
Who half the time were soppy-stern
And half at one another’s throats.

Man hands on misery to man.
It deepens like a coastal shelf.
Get out as early as you can,
And don’t have any kids yourself.

The Trees

The trees are coming into leaf
Like something almost being said;
The recent buds relax and spread,
Their greenness is a kind of grief.

Is it that they are born again
And we grow old? No, they die too.
Their yearly trick of looking new
Is written down in rings of grain.

Yet still the unresting castles thresh
In fullgrown thickness every May.
Last year is dead, they seem to say,
Begin afresh, afresh, afresh.

(Not) Giving Women Good Sex

April 5, 2021

Is this fraud?

My colleague, Susan Bewley, drew my attention to the Journal of Sex Research last week (click here or Spielmans 2020 Re Analyzing Phase III Bremelanotide Trials for Hypoactive Sexual Desire Disorder in Women). The author, Glen Spielmans, Professor of Psychology at Metropolitan State University in Minnesota, dissects two pivotal phase-3 trials (click here or Kingsberg Obstetrics & Gynecology November 2019), which had led the US Federal Drug Administration (FDA) to license bremelanotide, trade name Vyleesi, to treat women with hypoactive sexual desire disorder (HSDD).

One of the original co-primary outcomes in each trial was switched, many pre-specified outcomes went unreported and new ones appeared, scores were reported as dichotomous rather than as the prespecified means, cut-off values varied for no apparent reason, and other outcomes were claimed as supportive without data. Spielmans also noted that more women (18 or 19% bremelanotide v 3 or 9% placebo) dropped out of the active groups, and questioned whether the various shifts in subsets of sexual behaviour scores, even in the unlikely event they were real, were of clinical significance.

He is correct on all counts. But altered co-primary outcomes in two drug licensing trials? How did that get past the FDA?

Background

Bremelanotide is a polypeptide, related to melanocyte stimulating hormone (MSH). Ever since someone noticed in the 1960s that MSH caused rats to become sexually aroused, chemists have been fiddling with the pharmacology in the hope of creating a female Viagra. In 2016, Palatin Technologies, who own the rights, convinced themselves in a phase-2 dose-finding trial (PT-141-54 in the FDA report) (click here or clayton 2016) that the stuff worked at higher doses. The planned sample size was 100 per group. The pre-specified primary outcome was change in satisfying sexual events (SSE) per month.

PlaceboLow doseMediumHigh dose
No. randomised 99 100 9999 
Analysed (at least 1 dose & 1 follow-up visit)  91 87 7574 
Dropped out 8 1324 25 
Additional satisfying sexual events per month 0.2 0.6 0.7 0.8

The authors claimed a dose response relationship (bottom row) but were coy about the row above – I’ve extracted it for you. Without knowing what they were getting, three times as many women on the higher doses dropped out. In a double-blind trial this can only mean one thing, side effects. There were many more, mainly nausea, flushing and headache, in the active treatment groups

Such non-random differential drop out pretty much invalidates the results. If women who stayed the course were more stoical, or had a greater desire for their sexual problems to be sorted, it’s hardly surprising to see a small increase in SSEs.

But what do I know? These data were judged sufficiently promising to set up two pivotal efficacy trials for FDA approval. 

The trials

Both had the same title “Study to Evaluate the Efficacy/Safety of Bremelanotide in Premenopausal Women With Hypoactive Sexual Desire Disorder (HSSD)” on Clinicaltrials.gov.

They both studied the allegedly most effective, high dose of bremelanotide, 1.75mg, from the dose-finding study.

They were both reported in the same paper (click here or Kingsberg Obstetrics & Gynecology November 2019). For the FDA analysis (click here or FDA bremelanotide).

Study 1 (labelled BMT-301 in Kingsberg and FDA papers) had a planned sample size of 550 (actual 723) and ran from December 2014 to July 2016, (registry here). Study 2 (labelled BMT-302) had the same planned sample size of 550 (actual 714) and ran from January 2015 to August 2016, (registry here). I could find no explanation for the 30% sample size increases, in either the Kingsberg paper or the FDA report.

Despite their identical eligibility criteria, and almost identical recruitment periods, both trials appear to have been run in the same 91 centres.

The original co-primaries for both trials were:

1.       Change in Female Sexual Function Index–desire domain (FSFI-D). The desire domain is the sum of; “Over the past 4 weeks, how often did you feel sexual desire or interest?” – responses range from 1 “Almost never or never” to 5 “Almost always or always” – and; “Over the past 4 weeks, how would you rate your level (degree) of sexual desire or interest?” – responses range from 1 “Very low or none at all” to 5 “Very high”.

2.       Change in absolute number of sexually satisfying events (SSE) per month.

Of thirteen planned secondary outcomes, the twelfth was this question from the Female Sexual Distress Scale–Desire/Arousal/Orgasm (FSDS-DAO); “are you bothered by low sexual desire?” Responses range from 0 “never” to 4 “always”.

Both trial results would have been negative had the co-primary outcomes remained unchanged. Although absolute numbers of SSEs are not reported in either the paper nor the FDA report, the latter states “neither treatment nor placebo arm showed any improvement” (p 126).

This looks suspicious. SSEs are more meaningful than “bothered by low sexual desire” which is little more than a different aspect of the other co-primary.

But on 27 October 2014 (click here) the FDA had held a workshop with patients about Female Sexual Dysfunction.

The company claimed that workshop participants had stated that SSEs were a poor efficacy outcome. Some quotations e.g. “Several [participants] stressed the importance of feeling desire regardless of whether it is accompanied by a satisfying sexual event” (p6), could be interpreted this way, although others e.g. “Participants largely appeared to believe that having satisfying sexual events was important to them” (p13) suggest the opposite. Even on its own terms this is hardly a convincing argument.

But the workshop had been captured by pharma. Here’s what independent experts, Leonore Tiefer, Ellen Laan and Rosemary Basson wrote about it at the time (click here or Tiefer),

Participants had their expenses paid by [a group funded by] pharmaceutical companies, […] had met the morning of the first day in their hotel to hear presentations and prepare their talking points.

They had each received a green shawl, identifying them with the ‘’even the score’’ campaign that accused the FDA of sexism in handling [female sexual disorder] drug applications [and] arrived at and departed together by chartered bus.

It looks like the FDA was pressured into agreeing the switch, to avoid accusations of sexism in the way they treated applications for female and male sexual treatments.

And the timing of the switch? The alteration was requested on 10 October 2016. Study BMT-301 had been completed on July 26 that year, and study BMT-302 on Aug 4th.

Let’s summarise. More than two months after the studies had been completed, on the basis of a dodgy, pharma-captured workshop conducted two years earlier, the trial sponsors persuaded the FDA to allow the co-primary endpoints to be switched. They were changed from a meaningful predefined outcome justified by the pilot dose-finding study, the number of satisfying sexual events, to the twelfth of thirteen secondary outcomes. And guess what? Bremelanotide, which did not alter the number of satisfying sexual events, magically improved this suddenly important secondary outcome.

Spielmans doesn’t say it, but I do. This must be a data-driven outcome switch. If so, that’s fraud. 

Jim Thornton

Update 10 April 2021

Yesterday Dr Kingsberg and her colleagues replied to Dr Spielmans’ critique (click here or paper), and Dr Spielmans replied to her reply (click here or paper). Despite much bluster, in my opinion, she failed to deal with any of his substantive points. But judge for yourself.

With regard to whether the co-primary outcome switch was data driven, Kingsberg writes;

He also alludes to “data peeking” in his introduction and that the FDA allowed the “sponsor’s request for satisfying sexual events (SSEs) to move from the co-primary to the key secondary outcome …. a year after the trials had begun.” What Spielmans omitted is that the FDA published a guidance document (2016) for designing clinical trials in which SSEs were no longer required to be a primary endpoint for HSDD treatment trials. Instead, trials could now include measures reflecting the hallmark criteria of the condition: loss of (i.e., deficiency or absence of) sexual desire (i.e., FSFI-D) and distress about lack of desire (i.e., FSDS-DAO #13). The approval from the FDA to change the primary endpoint, after discussion with the FDA review division, came prior to the data lock [my emphasis] in these well-conducted, randomized, double-blind, multicenter placebo-controlled trials, with pre-established statistical analysis plans. 

Note the non-denial choice of words. No-one doubts that the outcome switch came “prior to the data lock”. The issue is whether the sponsor had seen the data prior to the outcome switch request.

Philosophy for children P4C2 – clarification

March 11, 2021

The power of randomisation

Mistake in my P4C-2 post yesterday (click here). The result is still negative, and the report still turgid, but when describing the distribution of the pooled reading and maths scores, I suggested that the authors had not shown them by group, and made the snide comment “Perish the thought that an educationalist would ever show you anything remotely near to the raw data!”

Forgive me. Further down appendix I of the main report (click here) are “intervention” (p 100) and, controls (p 102). But different pages? This is a randomised trial where half the pupils got philosophy teaching and half did not. Readers want to compare the two groups side by side. Come on EEF!

To help I’ve reordered the graphs here p4c2 result histograms p number. Intervention group left, control right. Page one, free school meal (FSM) pupils and page two all pupils. Reading scores before maths scores.

It’s rather revealing. For each outcome and for each subgroup not only are the means and ranges almost identical but also the shapes of the distributions. Not exactly identical – these are different populations – but remarkably similar. Go on, check. Click the link above and then scroll down comparing left to right. The shape of the control distribution of reading scores among FSM pupils is different from the shape of the control maths scores, but both are almost identical to the respective reading and maths scores for the intervention group.  Same for the whole sample.

Not only did the intervention, Philosophy for Children, have no effect on maths or reading but, since it had no effect, we can see how beautifully, when you have a large sample size, randomisation really does generate comparable groups.

Well I think it beautiful.

Jim Thornton

 

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