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England and Wales High Court (Queen's Bench Division) Decisions
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Cite as:  EWHC 1408 (QB)
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QUEEN'S BENCH DIVISION
Strand, London, WC2A 2LL
B e f o r e :
| LUC JONES (BY HIS MOTHER AND LITIGATION FRIEND MRS LYNN HARRIS)
|- and -
|TAUNTON AND SOMERSET NHS FOUNDATION TRUST
Angus Moon QC & Eleanor Morrison (instructed by Bevan Brittan Solicitors) for the Defendant
Hearing dates: 1st, 2nd, 3rd, 4th, 8th & 22nd May 2019
Crown Copyright ©
Mr Justice Stewart:
i) his mother was not in preterm labour;
ii) Nifedipine should only have been administered as part of a clinical trial and the safety of the drug was not confirmed;
iii) the drug was administered contrary to the Defendant's own protocol.
• Doctor Bett. Her witness statement is dated 22nd November 2017. Doctor Bett is now a general practitioner. In November 1995 she was a senior house officer (SHO) at the Defendant hospital.
• Mr Eki Emovon. Mr Emovon is a consultant obstetrician and gynaecologist. In November 1995 he was a registrar at the Defendant hospital. His witness statement is dated 17th April 2018.
• Mr John Hare. Mr Hare qualified as a medical practitioner in 1964. He was a consultant obstetrician and gynaecologist from 1976 until April 1998 when he took early voluntary retirement. He has provided reports dated 22nd June 2018 and 1st March 2019.
• Professor Steven Thornton. Professor Thornton has been a clinical academic since 1986. He spends about 50% of his working week on clinical work and the remainder on academic work. He is an obstetrician and gynaecologist. At present he is Vice Principal (Health), Queen Mary University of London, and Executive Dean of the Bart's and London School of Medicine and Dentistry. His report is dated 4th February 2019.
Breach of Duty
"…he is not guilty of negligence if he has acted in accordance with a practice accepted as proper by a responsible body of medical men skilled in that particular art……Putting it the other way round, a man is not negligent, if he is acting in accordance with such a practice, merely because there is a body of opinion who would take a contrary view."
"Differences of opinion and practice exist, and will always exist, in the medical as in other professions. There is seldom any one answer exclusive of all others to problems of professional judgment. A court may prefer one body of opinion to the other: but that is no basis for a conclusion of negligence."
"……the court is not bound to hold that a defendant doctor escapes liability for negligent treatment or diagnosis just because he leads evidence from a number of medical experts who are genuinely of opinion that the defendant's treatment or diagnosis accorded with sound medical practice……The use of these adjectives - responsible, reasonable and respectable - all show that the court has to be satisfied that the exponents of the body of opinion relied upon can demonstrate that such opinion has a logical basis. In particular in cases involving, as they so often do, the weighing of risks against benefits, the judge before accepting a body of opinion as being responsible, reasonable or respectable, will need to be satisfied that, in forming their views, the experts have directed their minds to the question of comparative risks and benefits and have reached a defensible conclusion on the matter…….
…… if, in a rare case, it can be demonstrated that the professional opinion is not capable of withstanding logical analysis, the judge is entitled to hold that the body of opinion is not reasonable or responsible."
"25. ……….It seems to me that in the light of the case law the following principles and considerations apply to the assessment of such expert evidence in a case such as the present:
i) Where a body of appropriate expert opinion considers that an act or omission alleged to be negligent is reasonable a Court will attach substantial weight to that opinion.
ii) This is so even if there is another body of appropriate opinion which condemns the same act or omission as negligent.
iii) The Court in making this assessment must not however delegate the task of deciding the issue to the expert. It is ultimately an issue that the Court, taking account of that expert evidence, must decide for itself.
iv) In making an assessment of whether to accept an expert's opinion the Court should take account of a variety of factors including (but not limited to): whether the evidence is tendered in good faith; whether the expert is "responsible", "competent" and/or "respectable"; and whether the opinion is reasonable and logical.
v) Good faith: A sine qua non for treating an expert's opinion as valid and relevant is that it is tendered in good faith. However, the mere fact that one or more expert opinions are tendered in good faith is not per se sufficient for a conclusion that a defendant's conduct, endorsed by expert opinion tendered in good faith, necessarily accords with sound medical practice.
vi) Responsible/competent/respectable: In Bolitho Lord Brown Wilkinson cited each of these three adjectives as relevant to the exercise of assessment of an expert opinion. The judge appeared to treat these as relevant to whether the opinion was "logical". It seems to me that whilst they may be relevant to whether an opinion is "logical" they may not be determinative of that issue. A highly responsible and competent expert of the highest degree of respectability may, nonetheless, proffer a conclusion that a Court does not accept, ultimately, as "logical". Nonetheless these are material considerations….The following are illustrations…."Competence" is a matter which flows from qualifications and experience. In the context of allegations of clinical negligence in an NHS setting particular weight may be accorded to an expert with a lengthy experience in the NHS……..This does not mean to say that an expert with a lesser level of NHS experience necessarily lacks the same degree of competence; but I do accept that lengthy experience within the NHS is a matter of significance. By the same token an expert who retired 10 years ago and whose retirement is spent expressing expert opinions may turn out to be far removed from the fray and much more likely to form an opinion divorced from current practical reality…..A "responsible" expert is one who does not adapt an extreme position, who will make the necessary concessions and who adheres to the spirit as well as the words of his professional declaration (see CPR35 and the PD and Protocol).
vii) Logic/reasonableness: By far and away the most important consideration is the logic of the expert opinion tendered. A Judge should not simply accept an expert opinion; it should be tested both against the other evidence tendered during the course of a trial, and, against its internal consistency…….There are 2 other points which arise in this case which I would mention. First, a matter of some importance is whether the expert opinion reflects the evidence that has emerged in the course of the trial. Far too often in cases of all sorts experts prepare their evidence in advance of trial making a variety of evidential assumptions and then fail or omit to address themselves to the question of whether these assumptions, and the inferences and opinions drawn therefrom, remain current at the time they come to tender their evidence in the trial. An expert's report will lack logic if, at the point in which it is tendered, it is out of date and not reflective of the evidence in the case as it has unfolded. Secondly, ……..it is good practice for experts to ensure that when they are reciting critical matters, such as Clinical Notes, they do so with precision……Having said this, the task of the Court is to see beyond stylistic blemishes and to concentrate upon the pith and substance of the expert opinion and to then evaluate its content against the evidence as a whole and thereby to assess its logic. If on analysis of the report as a whole the opinion conveyed is from a person of real experience, exhibiting competence and respectability, and it is consistent with the surrounding evidence, and of course internally logical, this is an opinion which a judge should attach considerable weight to."
Mr Moon QC had some concern about subparagraph (vii) above. It is correct that the critical test of logic is that set out in Bolitho. The factors referred to by Green J may well be of assistance in deciding whether an opinion is logical. I do not read him as saying that the mere fact of (e.g.) some internal inconsistency in an expert's evidence means that his opinion must be regarded as illogical.
Mrs Harris' witness statement
"9. I have two other children; Judy 'Jude' Harris aged 37, and Kimberley 'Kim' Harris aged 27. Neither of my other children suffer from celebral palsy or any other serious illness. When I gave birth to Judy I had an episiotomy to help with the birth. When I gave birth to Kimberley I had an episiotomy and a suction cup was also used.
12. The first two trimesters of my pregnancy were unremarkable. During my third trimester I experienced a number of 'false alarms' where I would believe I was going into labour. On each occasion I would attend Musgrove Park Hospital, Taunton. The false alarms occurred over a period of several weeks.
13. Following the last of my false alarms I was treated by a nurse who told me I would have to go the full term (emphasis added). The nurse provided me with an injection which I was told would stop the onset of false alarms. I did not recall the name of the drug, however I have since been advised that it was called Nifedipine. I cannot remember the exact date of the injection, though I do recall it was several weeks before I eventually gave birth to Luc. It was during the third trimester and I now understand that I was given two doses.
14. I remember after I was given the injection I was not on the planet, I am able to recall that the bed was tipped up to a near vertical position I understand that this was to restore my blood pressure to an appropriate level.
15. I did not experience any further false alarms following the injections…"
The medical records
2nd November 1995
One record for this date is not in Doctor Bett's handwriting. She is mentioned in the note under her then maiden name, Doctor Garner. The note records that Mrs Harris was admitted from home at 19:15 hours. By dates she was 31+4 weeks pregnant but by USS 27/40. The record shows that premature labour and urinary tract infection were considered as possible diagnoses, Mrs Harris was complaining of abdominal pain/contractions. The pain/contractions were one every three to five minutes, irregular since early morning and more regular since 14:00 hours. A CTG was commenced and the fetal heart baseline was 140 beats per minute (bpm). At 20:05 hours Doctor Garner was asked to review.
Doctor Bett's note records that Mrs Harris was complaining of abdominal pain with a 24-hour history of lower abdominal pains. The pains were now one in five minutes. There was no radiation of the pain. The pain was cramp like. There was no per vaginam loss of liquor. There were no urogenital symptoms and bowel opening was normal. Doctor Bett recorded the history of recent chest infection. Mrs Harris had started that day on Augmentin. She also recorded four previous pregnancies. The first in 1980, a term pregnancy where a girl was born, the second in 1989 when there was a spontaneous miscarriage, the third in 1991 when a girl was born at 38 weeks, and a spontaneous miscarriage in 1992. There is a diagram indicating the area of pain in the lower abdomen. The lower abdomen is described as soft and not tender on palpation. There is cephalic presentation and longitudinal lie. Dr Bett did a speculum examination and determined that Mrs Harris was not in labour. In her statement she says the cervical os was noted to be closed. The notes record: "Speculum: Closed Cx". The midwife noted that the plan was to arrange for an ultrasound scan and await the results of a urine sample sent to the laboratory to exclude urinary infection. Mrs Harris however wanted to go home and said she would phone if she was worried.
9th November 1995
Doctor Bett did not see Mrs Harris on 9th November 1995. However, the midwifery notes (M Dinsdale) record that she was admitted via the GP surgery with possible preterm labour. She had been experiencing pains since the evening before which continued until 5 a.m. and were sometimes as frequent as 1:5. She had had diarrhoea the day before and a feeling of pressure and that something had dropped. Ultrasound had showed breech presentation the week before. The baby was very active and there was no offensive vaginal discharge. The abdomen was palpated. Abdominal CTG was commenced. It appeared reactive. There were good fetal movements. Mrs Harris complained of needing to go to the toilet and then not passing stream of urine. She had just completed a course of antibiotics for chest infection and had been receiving physiotherapy for back problems.
Later at 14:15 there is a note by an SHO which records the presenting complaint as "abdo pains" and refers to the similar admission a week before. It said that she had had a busy day yesterday and reported abdominal pains in the evening which settled. She slept and again had abdominal pains in the morning. There was no per vaginam loss or show. There was no urinary frequency or dysuria. She had loose stools four times the evening before. She admitted to feeling 'a bit uptight' at present. Her pulse was regular, her blood pressure 120/85 and urine showed a trace of protein only. Her abdomen was soft and non-tender. There were no palpable tightenings. Fetal movements were felt. CTG was reactive. The impression was that she was not obviously in labour, so she was reassured and sent home with midwife follow up.
25th November 1995 – first admission
At 17:20 Mrs Harris phoned in feeling unwell with lower abdominal pain.
A note, not written by Doctor Bett and probably written by a midwife (not Mrs Dinsdale), shows:-
At 18:40 Mrs Harris was readmitted from home with a history of backache and abdominal pain since yesterday. It was becoming more uncomfortable today. ? bearing down sensation. Finished course of antibiotics ? a month ago for UTI. ? 'show' yesterday……..On palpation: fundus = 30 weeks. Feels soft. Long lie ? cephalic presentation free. ? LOA fetal heart 140 R. CTG monitoring commenced. Doctor Garner asked to see.
Doctor Bett saw Mrs Harris on the labour ward and recorded that in the last 24 hours she had worsening lower abdo pain which came once in five minutes, now from both sides to pubic area. ? had the show yesterday – pink/mucousy loss. No blood loss. No liquor lost. No UGSx. Bowels opening normally. Good fetal movements. On examination her temperature was 36°C. She was noted as 'well looking'. Pulse 80. BP 110/70. Mrs Harris had a soft abdomen with tenderness over the suprapubic area. Cephalic presentation, longitudinal lie 3/5 palp. Vaginal examination was performed and the cervix noted as 1cm dilated, soft and approximately 1 cm long. The fetal head was not felt and there were no membranes. The note continues: "Speculum multips os'. There was no pooling liquor. Amnistix were negative. The CTG was reactive. The impression was 'early labour' and Doctor Bett prescribed 'betamethasone'. The note continues that the patient was requesting to leave, was strongly advised to stay, but still wished to go. The registrar was informed and the self-discharge form was to be signed. It is recorded that betamethasone was administered at 20:40.
25th November 1995 – second admission
23:56: Midwifery notes record that Mrs Harris arrived from home again complaining of contractions occurring one every two minutes. She was quite distressed at home. She needed to be reassessed and probably given analgesia. The notes says '? in established labour'. Blood pressure was 130/75, pulse 100. The note continues
"Abdo does tense for short periods quite frequently, doesn't seem to be as often as 2 minutes, but Lynn very uncomfortable."
On palpation the fundus was 32/40. The lie was longitudinal. 'Pres cephalic, position ROL presentation in brim. Fetal movements active.'
At midnight Mrs Harris returned to the labour ward. Doctor Bett wrote that Mrs Harris was complaining of "pains every two minutes now, worsening." There was no per vaginam loss. 'To re-examine cervix please'. The midwife examination was recorded as "soft 1cm dilated. PP 4cm." The notes then records 'Nifedipine if dilatation of cervix less than 4cm as per protocol. Discussed with registrar and agrees.
The remainder of the relevant notes, save one are not made by Doctor Bett. They show:
At 00:41 abdo CTG commenced – reactive trace. For vaginal assessment for management of care as discussed with Doctor Garner. Doctor Emovon aware of admission. External genitalia normal, vagina moist, cervix sl(ightly) posterior. Thick partially effaced – very gentle examination external os admits a finger – presentation – 4cm above spines. No cord/placenta felt. For Nifedipine regimen as per directions. Baseline BP 133/70. p87.
At 01:00 10mg of Nifedipine were administered. Blood pressure was 112/68. Pulse 88.
At 01:03 Pethidine 100mg was administered. Maxolon 10mg. I.M for analgesia.
At 01:15 blood pressure was 128/69. Pulse 96. Fetal heart rate very reactive – good accelerative periods.
01:20 Lynn in a light sleep. When awake a few minutes earlier complained of abdomen still being painful (in waves).
01:30 blood pressure 137/67. Pulse 36.
01:35 Nifedipine 10mg S.L.
01:45 blood pressure 108/53. Pulse 97.
01:49 109/55. Pulse 97.
01:56 101/46. Pulse 120. Doctor Garner alerted. Tx – do not give any more Nifedipine.
• a letter from the legal services manager at the Defendant's Hospital dated 17th September 2010. This letter was written with the assistance of Mr Bidgood, consultant obstetrician and gynaecologist who was working in the Trust at the time of Mrs Harris' pregnancy. Mr Bidgood advised that a protocol must have been followed. Doctor Bett in the notes wrote: 'Nifedipine if dilatation of cervix greater than 4cm 'as per protocol'. The notes therefore imply a protocol was followed for Nifedipine. Mr Bidgood's recollection was that this was a recipe for the dosage and regimen based on the experience of the staff working in Bristol, and using their protocol as the guide. He did not think it was ever printed on separate Musgrove Park based paper, as in those days the Trust was still using guides based on local hospital handbooks.
• Doctor Bett in her witness statement says that due to the passage of time she was unable to recall the exact nature of the protocol to which she was referring.
• Mr Emovon in his witness statement said that he cannot recall a protocol being referred to, but it must have existed otherwise it would not have been agreed.
• There is a witness statement from Alison Garrett, associate solicitor in the employ of the Defendant's solicitors. This is dated 28th March 2018. Ms Garrett sets out the attempts made to locate the 1995 protocol and says that none has been located. Her concluding paragraph says that '… despite the Defendant's best efforts, it has not been possible to confirm the existence of a formal protocol relating to Nifedipine and we have to date, unfortunately not been able to establish any certainty, the source for the entry in the records.'
The diagnosis of preterm labour is difficult. Early symptoms may be very subtle and the cervix may dilate with minimal contractions if infection is present.
Preterm labour has several causes. The management differs greatly according to the cause and so it is imperative to consider carefully why a woman has gone into labour.
PRINCIPALS (sic) OF MANAGEMENT
Encourage women with any symptoms suggestive of preterm labour to present early.
Admit all women presenting with symptoms to delivery suite for assessment.
Establish or refute diagnosis of labour (this may take hours/days).
Consider need for tocolysis.
On Admission to Delivery Suite
In addition to any standard management of labour:
Abdominal pain & APH.
Abdominal palpation for tenderness
Cervix for effacement/dilatation/presentation
6. Insert venflon If APH or suspect occult abruption.
If instituting tocolytic therapy.
8. Consider need for corticosteroids to enhance fetal lung maturity.
The overall value of tocolysis for the fetus is unclear and it carries some important risks for the mother. It should, therefore, be instituted with care.
The main value of tocolysis is that it gives time for any cortiscosteroid therapy to take effect. It also may allow … utero transfer with greater safety.
Contraindications to Tocolysis
>2 cms dilated and contracting strongly
>3 cms dilated
There are various agents available with differing side effects.
Nifedipine (calcium channel blocker)
Salbutamol and ritodrine (B-mimetic agents)
In general, nifedipine is as good as any other agent and is probably the safest drug for mother and baby.
Salbutamol and ritodrine are poorly tolerated by the women and carry a risk of pulmonary oedema.
Site a venflon and start infusion of Hartmann's solution (1 litre over 4 hours)
Check maternal history and auscultate heart for evidence of cardiac disease
Institute electronic fetal monitoring
Give 10mg nifedipine ORALLY
Monitor blood pressure and pulse 5 minutes for 15 mins and then every 10 mins for 45 minutes.
If contractions reduce substantially, repeat nifedipine (10mg orally) every 4 hours for 48 hours.
If little or no effect on contractions, repeat nifedipine at 30 mins and monitor blood pressure again.
If no effect on contractions with 2nd dose, repeat nifedipine at 30 mins (1 hour total).
If no effect again, repeat VE. May be in established labour.
If not in advancing labour at this point, discuss care with consultant.
NB Blood pressure may fall precipitously.
Try to keep the woman lying for fist four hours after initial therapy.
Do not allow her to stand up suddenly or walk unaided.
If BP fails sharply, infuse Hartmann's solution rapidly to resuscitate.
Remember diagnosis of labour is difficult preterm.
Use tocolysis cautiously.
Doctor Bett's evidence
Mrs Harris' previous history
2nd November 1995
9th November 1995
25th November 1995 – first admission
25th November 1995 – second admission
"26/11/95 – if Cx dilation <4 cms Nifedipine 10mg s/l
26/11/95 30 minutes later Nifedipine 10mg s/l
26/11/95 60 minutes later Nifedipine 10mg s/l
- Call if BP less then 100/50 mmHg
- If contractions cease then no further Nifedipine."
It appears the midwife has written against the third prescription: "hypotensive and not contracting so not given."
Mr Emovon's evidence
"13. Doctor Bett has recorded that Nifedipine should be given as per protocol. More than 22 years after the events I cannot now recall what protocol this is referring to, but it must have existed otherwise it would not have been agreed. I can confirm however, it would have been my standard practice to prescribe Nifedipine or other tocolysis to a mother who is 30 weeks in preterm labour with a view to suppressing labour. This would have been in line with my training and general practice at this time.
14. I understand it is alleged that the second dose of Nifedipine should not have been given at 01:35 on 26th November 1995. I see from the notes that I discussed the case with Doctor Bett at midnight but it is not noted whether we also discussed what the next steps in the mother's care should be. I would have expected Doctor Bett to have called me if the clinical picture significantly changed. Otherwise, I would have expected her to continue to treat the mother as per our protocol and this must have included the second dose of Nifedipine if this was indicated. Had Doctor Bett called me to discuss giving a second dose of Nifedipine I am likely to have agreed that this was indicated because at 01:20 she has noted 'abdomen still being painful (in waves)'. As there was evidence that Ms Harris was still experiencing contractions, I would have recommended continuing with Nifedipine to try and suppress the labour."
Mr Hare's evidence: general
Professor Thornton's evidence – general
i) For the SGI in Atlanta in 1999 he was symposium organiser for 'calcium and myometrial contractility.' The SGI is the Society for Gynaecological Investigations. It is the major clinically based research organisation in the United States. This was acknowledged worldwide as a major conference. The subject matter was in relation to contractions and the effect of calcium.
ii) In 2014 there was a presentation in Jordan heading 'Preterm Delivery Prevention'. This was dedicated to tocolysis.
Was Mrs Harris in threatened preterm labour?
"The term threatened preterm labour is often used to describe pregnancies complicated by episodes of clinically significant uterine activity but without cervical change."
Mr Hare's opinion was that if the court decides that the notes in the present case record significant uterine contractions (i.e. not Braxton Hicks contractions) then the criteria for threatened preterm labour were satisfied.
i) the criteria for diagnosis of preterm labour required (a) gestation 20-37 weeks and (b) documented uterine contractions (four in twenty minutes or eight in sixty minutes) and (c) if membranes are intact then documented cervical change by a single examiner or cervical effacement of greater than 75% or cervical dilatation of greater than 2cm.
ii) Mrs Harris was in the period of 20-37 weeks gestation;
iii) As to uterine contractions, the note at 23:56 reading 'c/o contractions occurring 1:2' has to be read in the context of the midwife's examination where she wrote 'abdomen does tense for short periods quite frequently. Doesn't seem to be as often as every few minutes but Lynn very uncomfortable.' Mr Hare says that he has never known a midwife to make a positive diagnosis of labour without recording the strength and frequency of the contractions, and that the phraseology indicates to him that the midwife was far from convinced that labour had started. His opinion is that the only acceptable way to clarify this position would have been to set up a CTG tracing and look for evidence of contractions. The short section of CTG trace obtained before Nifedipine was given showed no evidence of regular uterine contractions.
iv) As to the changing condition of the cervix, the 25th November 1995 note at about 19:00 performed by Doctor Bett read '1cm dilated cervix about 1cm long. Head not felt'. On visualisation with the speculum multips os was recorded. The midwife's examination at 00:41 on 26th November 1995 shows the cervix as slightly posterior, thick, partially effaced, external os admits a finger, presentation 4cm above the spine.' According to Mr Hare, this is not any different, apart from in the form of words, from the first examination. Therefore, Mr Hare says that there was no cervical change.
v) The diagnosis of preterm labour requires skill and experience. The senior resident obstetrician should have assessed the case, rather than the diagnosis being made by the SHO on the basis of history and without the confirmation of the examination findings obtained by the midwife.
Mr Hare's evidence
Doctor Bett's examination findings
a) as to the length of the cervix Mr Hare said that in a multigravid woman, the cervix can start from a length of 2-3cms. He agreed that a cervix of less than 1.5 centimetres at 30 weeks, if a matter of measurement, is a risk factor for early delivery.
b) dilatation is another sign that a woman might be going into labour;
c) if the cervix is soft that is a characteristic of early labour;
d) Mr Hare did not accept any of these findings as being accurate from a junior SHO. In respect of the cervical os he said that that was probably multips os rather than true dilation. He said the assessment of the cervix being soft, hard or in between is a difficult one. It was pointed out to Mr Hare that he had not previously suggested that the measurement of the length of the cervix or the assessment of its softness was inaccurate; therefore this had not been put in cross examination to Doctor Bett;
e) in the joint statement Professor Thornton had said that a cervix at 30 weeks described as soft and admitting a finger is characteristic of a change associated with early labour and not a multip os. Mr Hare agreed that if the two observations were in fact correct then he would agree with Professor Thornton's conclusion.
f) Professor Thornton had further said 'it is not usual for the cervix to admit a finger at 30 weeks suggesting that it was not a multip os.' As to this, Mr Hare said that depended on whether the finger was through the external or internal os.
a) Mr Hare said that contractions were an essential description for early labour. In relation to Doctor Bett's entry, Mr Hare said that there was rhythmic pain every five minutes and contractions were a possibility but there were other explanations. At 23:56 the complaint was of more frequent contractions occurring once every two minutes;
b) the midwife's examination at 23:56 suggested that she did lay her hands on Mrs Harris' abdomen and felt the tension and the frequency. He also accepted that these were probably uterine contractions, but not necessarily those of labour. He said that the notes suggested a degree of indecision. He interpreted the note as the midwife not believing that she was feeling meaningful contractions. He said that a midwife would not write in this way if recording such contractions. She would record the word 'contractions' and would write how long, how strong and how frequent the contractions were. As to note at 01:20, he regarded this as history, not an examination by palpation.
c) Mr Hare acknowledged, when he was taken to it, the fact that the next morning the same midwife had written 'contractions (irregular)' in the antenatal inpatient care plan. He said he would have expected her to use the word contractions at the time of the original entry;
d) after exploration of the matter, Mr Hare accepted that the most likely explanation is that Mrs Harris had uterine contractions, though he thought they were probably Braxton Hicks rather than true early labour contractions. Mr Hare said that Braxton Hicks contractions are normal uterine contractions of which the mother is aware. It is variable whether they demonstrate a change in frequency. Generally, they would not be associated with cervical change. Professor Thornton explained that the uterus in pregnant, and in non-pregnant, women undergoes contractions. Towards the end of a pregnancy the mother feels these contractions. They are usually irregular, and are a normal finding not indicative of labour. They are usually felt later in pregnancy than the stage at which Mrs Harris was, i.e. 30+ weeks. His reading of the notes was that Mrs Harris was not having Braxton Hicks contractions.
e) Mr Hare was asked whether if rhythmic contractions were palpated there was sufficient evidence to justify tocolysis. He refuted this, saying that it was important to take into account the frequency, duration and strength and that these were not recorded or estimated. Further, CTG lower tracing showed no evidence of uterine activity;
f) Mr Hare's opinion was that to diagnose preterm labour it is essential to have a record of the frequency duration and estimated strength of contractions. Also, that these would usually show on a CTG trace which was not the case here. As regards the recording of frequency, duration and estimated strength of contractions, he accepted that he could not point to any literature to support this.
Mrs Harris' History
In final submissions the Claimant relied on the earlier admissions to say that Mrs Harris had previously been attended by Mrs Disdale who had noted 'contractions', yet no tocolytic was given and the contractions settled after observation. The most relevant notes in this regard are on 8th January and 9th January 1991. However: (i) A finding of contractions does not necessarily lead to a diagnosis of threatened preterm labour – though it may do; (ii) a doctor has to make a judgment, based on contractions and other indicators. Medicine is an art, not a science; (iii) Doctor Bett had made a number of relevant findings on the 1st admission on 25th November 1995 which had given her an impression that Mrs Harris was in early labour, such that she was very concerned when Mrs Harris discharged herself; (iv) the fact that Mrs Harris had settled without tocolysis is unremarkable, since as repeated below, it is not possible in advance to identify which women, even if they can properly be diagnosed as having threatened preterm labour, will then progress to established labour.
Mr Hare accepted that in neither of the two textbooks which he had cited was it suggested that there needs to be CTG confirmation of contractions before making a diagnosis. Nor was this in the 2015 NICE Guidelines. He also accepted that there were some circumstances in which a CTG would not pick up changes in the contours of the abdomen. The CTG does not measure contractions themselves but the secondary effects of the contractions. Nevertheless, he was of the opinion that it was essential to use CTG tracing to diagnose preterm uterine contractions in clinical practice. It is common ground in the present case that the CGT does not show any contractions.
a) Thornton et al (2015). Mr Moon QC suggested that the requirement for CTG was to decide who should be in the study. Mr Hare said that it was the criterion for the methodology which allowed the diagnosis to be made; that was essentially the same as to whether to diagnose in the clinical situation. Mr Hare did not accept that this 'proof of concept' study, requiring CTG as an entry criterion, was totally different from the position in clinical practice.
b) The second paper was Kragt and Keirse. Mr Moon QC suggested that there is nothing in this article which supports what Mr Hare said about the need for a confirmatory CTG. Mr Hare referred to two passages. The first says that abdominal pains were defined as 'vague' if they were not of a rhythmic character, if there were no clinically recognisable contractions on palpation and cardiotocography, and if there was no watery or bloody discharge. Mr Hare said that this was an assessment of clinical practice with a view to giving advice. Abdominal pains would not be vague if they were rhythmic and clinically recognisable as contractions on palpation and/or CTG. The second said:
"clinical assessment on arrival was always complemented with cardiotocography. Urine analysis, laboratory investigations and ultrasound were performed when deemed appropriate."
Mr Hare did not accept that this was because it would be important to know the fetal heart rate, not to know about contractions. He said that, on the contrary, heart rate monitoring and the sensation of contractions go together. The CTG is an invaluable tool in the assessment of both. The fact that the last sentence was about the well-being of the fetus did not change his opinion on this. It seems to me that the paper does not support Mr Hare's statement in the joint statement that it stresses that CTG should always be used.
(c) Mr Hare said he would wish to qualify other passages in the Kragt and Keirse paper. This was where they said their study indicated that women were reasonably accurate in their diagnosis of threatened preterm delivery, and that there is little room for improving the woman's own diagnosis of threatened preterm delivery. The paper concludes with the following:
"This implies that a considerable amount of research will be necessary before the obstetrician's diagnosis of preterm labour will become substantially better than the woman's own diagnosis."
Mr Hare pointed out that this study was a prospective observational study i.e. with no controls. It was testing the proposition in another paper (O'Driscoll 1977) that suggested that about 80% of diagnoses of signals of impending preterm birth by the mother herself, were erroneous. He said that from his experience an 80% error rate was a little harsh; he would put it at somewhat under 50%.
Tocolysis prescription – general considerations
"…because of the need for early management of suspected preterm labour, the diagnosis is commonly made in clinical practice before the above criteria are met, and hence the reported incidence of threatened and actual preterm labour may be open to question."
Professor Thornton added in evidence that the risks of not treating with tocolysis are high. A baby born at 30 weeks has a 4-5% chance of dying. If a baby is born at less than 32 weeks, the risk of brain injury is high. Therefore, when thinking whether to give tocolysis, the decision is heavily weighted in favour of treatment, and that is standard practice. Such is the perceived advantage that some US studies will not do placebo controlled trials on the basis that it is unethical not to treat with tocolysis in threatened preterm labour. Professor Thornton agreed that tocolysis should not be used prophylactically. He said one should look at the symptoms and signs and investigations (if applicable) in each individual case to see if tocolytic treatment was or was not appropriate. However, it is not possible to identify in advance which women will progress from threatened preterm labour into established labour.
Post 2nd dose - evidence
(i) At 0212 on 26th November there is a note "not contracting". The use of the word 'contracting' may imply either that the midwife would normally use that word explicitly if there were contractions; alternatively, that this was in contradistinction to earlier and therefore connotes that what was felt earlier were contractions. Professor Thornton said this note was not explicit as to whether it was as a result of an examination or Mrs Harris' complaint. In any event, this was after two doses of Nifedipine.
(ii) Later, at 0305-0320, Mrs Harris complained of extreme back pain. As part of the examination, no contractions were palpable
(iii) At 0920 is a note: "Remains uncomfortable – tightenings intermittent".
(iv) Professor Thornton's interpretation of these notes was that Mrs Harris had been having contractions which had then stopped at about 0212 after two doses of Nifedipine
(v) On 3rd December 1995 Mrs Harris was admitted with a presenting complaint of "Tightenings every 2 minutes….staying same intensity". On examination the contractions were noted as not registering a great deal on the CTG. Vaginal examination was "multips os, not effaced, posterior." The impression was "Braxton Hicks contractions. ? threatening preterm labour". The plan was to admit, give Betamethasone 12 mg 12 hourly. It was recorded that when she was given Nifedipine on the last admission she had low blood pressure.
Professor Thornton said that one would not give tocolysis a second time. Steroids were given because the doctor was perhaps still worried about preterm labour. As to the cervical findings, he said he was not sure what, if anything, they added, though they did make him wonder if Mrs Harris just has a sensitive uterus. He said that one could not look back from these notes for assistance on whether Mrs Harris was or was not in threatened preterm labour on 25th/26th November 1995. I accept this evience.
Mrs Dinsdale - Midwife
"(1) In certain circumstances a court may be entitled to draw adverse inferences from the absence or silence of a witness who might be expected to have material evidence to give on an issue in an action.
(2) If a court is willing to draw such inferences they may go to strengthen the evidence adduced on that issue by the other party or to weaken the evidence, if any, adduced by the party who might reasonably have been expected to call the witness.
(3) There must, however, have been some evidence, however weak, adduced by the former on the matter in question before the court is entitled to draw the desired inference: in other words, there must be a case to answer on that issue.
(4) If the reason for the witness's absence or silence satisfies the court then no such adverse inference may be drawn. If, on the other hand, there is some credible explanation given, even if it is not wholly satisfactory, the potentially detrimental effect of his/her absence or silence may be reduced or nullified."
"30. There are three aspects to the claimant's submissions that demonstrate the difficulty that she has on this issue. First, Wisniewski is not authority for the proposition that there is an obligation to draw an adverse inference where the four principles are engaged. As the first principle adequately makes plain, there is a discretion i.e. "the court is entitled [emphasis added] to draw adverse inferences". An appellate court will be hesitant to interfere with the exercise of such a discretion given that it is being exercised in the knowledge of all the nuances of evidence that are in the knowledge of the judge who receives that evidence. Second, the judge in this case did not conclude that an absent witness had to be central to the case, he merely and correctly identified that the doctor in Wisniewski was central to that claim as the person who had failed to defend his clinical judgment. By comparison, the judge decided that Dr Hooper's role and hence evidence was tangential for the reasons I have summarised…. Third, there was an explanation for absence and that was a decision on proportionality grounds taken by the defendant i.e. this was not a case where a defendant or witness deliberately prevents or avoids the admission of evidence that would undermine their case.
31. There is also a further difficulty that the claimant must face. On 21 August 2015 Master Roberts gave case management directions. The claimant sought a direction for disclosure of information about Dr Hooper but did not seek an order that she file and serve a witness statement. They could have asked for the latter. If the claimant was of the view that Dr Hooper's evidence was as important to her case as is now asserted and that an adverse inference would be appropriate in Dr Hooper's absence, they could have asked for a direction which contained the warning that an adverse inference may be drawn if the evidence was not provided. Even without such a direction, the claimant could have made arrangements to obtain evidence from Dr Hooper themselves."
(i) Doctor Bett recorded a history of worsening lower abdo pain coming every 5 minutes now and from both sides to the pubic area. Professor Thornton said that Doctor Bett had said that she felt this was consistent with contractions; he agreed that this was a reasonable assumption.
(ii) As to the possible show, this has to be distinguished from just bleeding. Doctor Bett had entered a description of the show as a "pink/mucousy loss". Professor Thornton said that a true show can herald the onset of preterm labour. The fact that Mrs Harris in fact went to term does not suggest that she probably did not have a show, since it is possible to have an early show and still go to term.
(iii) Doctor Bett palpated the abdomen. She recorded "tender+". Professor Thornton agreed that she had not recorded contractions or tension. There was no note of uterine activity being discovered.
(iv) On vaginal examination the cervix was recorded as 'soft', 1 cm dilated and about 1 cm long. Professor Thornton said that these, if correct, are signs that labour may be coming.
At that stage the Doctor Bett did not make a diagnosis of preterm labour, though Professor Thornton's opinion was that a case could be made for prescribing tocolysis. It appears that she did not because there was still a possibility that Mrs Harris was complaining of abdominal pain which might settle. Professor Thornton said that his concerns were a little heightened because of the cervical findings, the complaint of pain radiating to the pubic area and the history of a possible show.
(i) A complaint of contractions every two minutes (allowing for the fact that the midwife did not think the tensions were as often as that) did not sound like a bowel or bladder problem. It indicates that something is happening and, on that history and finding on examination, in conjunction with the earlier history and findings) he would make a diagnosis of preterm labour.
(ii) The midwife did not use the term contractions, but in his mind there was little doubt that she was describing contractions. He asked rhetorically what else was causing Mrs Harris to tense? He could not think of another reason for tensing other that voluntary tensing. The tensing was suprapubic. If Mrs Harris was tensing intentionally or because of pain, it would not just be felt suprapubically.
(iii) The midwife did not record the strength of the contractions. It is not possible to determine the strength of contractions from palpation. Palpation can only detect movement of the lower abdomen. Midwives can make an estimate based on palpation and complaint of the woman so as to assess whether the contractions are important enough to make labour progressive.
(iv) Although the note might be regarded as "marginally inadequate" in terms of what is actually written down, and could have been better expressed, in practice the midwife would discuss with the doctor and a diagnosis would be made together.
(v) The description of the findings on palpation and the complaint made by Mrs Harris is not consistent with Braxton Hicks contractions. Women do not come in complaining of contractions every two minutes if they are Braxton Hicks.
(i) In general I accept the above evidence of Professor Thornton. I find that as at 23.56 Mrs Harris was complaining of, and found by the midwife on palpation to have, contractions which were not Braxton Hicks. I also find that it was, or would have been, reasonable to diagnose threatened preterm labour.
(ii) On no abdominal examination in this pregnancy prior to 25th November 1995 had tenderness been found.
(iii) On no occasion in this pregnancy prior to 25th November 1995 had the presenting complaint clearly been one of contractions on a regular basis. Here the complaint was of contractions every two minutes and the finding was of quite frequent tensing, albeit not seeming to be as often as every two minutes; also Mrs Harris was described as 'very uncomfortable'. Professor Thornton said that by regular contractions he meant contractions occurring consistently; if he had to put a frequency on it, which perhaps he should not, he would say once every 5 minutes or more often.
(iv) Shortly afterwards the SHO prescribed Nifedipine. Her note is succinct. However, I accept what Professor Thornton said, namely that it would be standard practice for the doctor to communicate with the midwife. Doctor Bett did not record a complaint or finding of contractions in her note at midnight, but if there had been contractions that would have been communicated to Doctor Bett. Therefore I agree with Professor Thornton that the absence of a recording of contractions or tensing in Doctor Bett's note is not that important – though it would undoubtedly have been better to have recorded contractions. That she understood that Mrs Harris was contracting is apparent from her note on the drug chart, to which I shall turn in a moment. The note on the drug chart evidences that Doctor Bett appreciated that tocolysis was to be used only in the presence of contractions. Also, if a doctor wanted to prescribe and a midwife disagreed, Professor Thornton said he would expect that to be recorded.
(v) The Drug chart written up by Doctor Bett after midnight but prior to the administration of Nifedipine stated: "..if contractions cease then no further Nifedipine". We know that, later, Mrs Dinsdale followed the instructions in terms of the doses of Nifedipine which should be administered and when she did not give a 3rd dose. Is it at all likely that Mrs Dinsdale would have administered two doses of Nifedipine if she did not believe that what she had found at 23.56 were contractions? I find that to be very unlikely. In addition, when she wrote up why she was not administering the 3rd dose she wrote: "Hypotensive and not contracting so not give." This, too, indicates that Mrs Dinsdale considered that Mrs Harris had been contracting at the time of the 1st and 2nd dose. She was following the mandate of Doctor Bett. Therefore the probabilities strongly favour the fact that the midwife found, and told Doctor Bett, that Mrs Harris was having contractions and that they were more regular than earlier, even if not quite as regular as the complaint of 1:2.
(vi) The evidence of Mr Emovon, now a consultant obstetrician, was essentially in agreement with Professor Thornton's opinion. Doctor Bett herself said it appeared from the midwife's note that she felt tension, that she did palpate a contraction.
(vii) Mrs Dinsdale recorded on the Antenatal in-patient care plan at sometime before 0615 on 26th November 1995: "Contractions, (irregular) settled whilst on labour ward with nifedipine/pethidine treatment given breakfast". This is a difficult note. Doing the best I can, it appears that the note is recording a historical position, i.e the position earlier that morning. This follows from the fact that the contractions are recorded to have settled with nifedipine/pethidine. Thus the fact that Mrs Dinsdale uses the word 'contractions' here suggests that what she described earlier were, in her opinion, contractions. This is entirely consistent with my above finding. The difficulty is that those contractions were described as 'irregular'. The Claimant says that it is supportive of them being Braxton Hicks. What did Mrs Dinsdale mean by 'irregular'? The problem is that there is nothing in the 23.56 (or 0120) notes to suggest irregularity; the suggestion is, if anything, rather to the contrary. This is especially so when one has regard to Professor Thornton's evidence that by regular contractions he meant contractions occurring consistently. Also, a midwife would be expected to know about Braxton Hicks and their distinction from true uterine contractions. There may be other explanations of what Mrs Dinsdale meant: unfortunately she did not give evidence, so we are in the dark. However, this one word is not sufficient to undermine the other evidence on which I have relied to find that Mrs Harris was having true uterine contractions when Nifedipine was administered. Further, Professor Thornton said that although the note says 'irregular', his reading is that the contractions were uterine, even though Braxton Hicks tend to be irregular. Looking at the note, Mrs Dinsdale did not find the contractions to be as regular as the complaint of 1:2; this may be why she later used the word "irregular'. However in her note she then added: "but Lynn very uncomfortable". This may explain why she considered them to be true contractions, not Braxton Hicks
(viii) Contractions are the key element in making a diagnosis of threatened preterm labour. If they were not present, generally speaking tocolysis should not therefore be administered. However, other signs, taken together with contractions, would be part of the picture of the diagnosis. So:
(i) As to the CTG, this did not demonstrate contractions. I accept Professor Thornton's evidence that CTG is not diagnostic of preterm labour and that there is no literature which says it is. There is no good way of measuring uterine contractions. The 'toco' line of the CTG (the bottom line) is not used in the diagnosis of preterm labour as there are often false positives and false negatives. In the studies the position is very different from in clinical practice. The purpose of the studies is to develop drugs and it is necessary to understand if contractions reduce. Therefore, in order to be admitted to the study, the subjects have to be restricted to those where the CTG in fact did show contractions, so as to see if they changed in frequency. Professor Thornton was not persuaded that the tocodynanometer (the bottom line sensor) had been properly applied as it was very flat at times.
(ii) As to the examination, (a) the cervix admitted a finger. It was described as (b) slightly posterior and (c) partially effaced. According to Professor Thornton, (a) would not be expected in a woman 30 weeks pregnant, (b) suggested that it might be starting to move, as happens at the start of labour, (c) suggested that the cervix was starting to be taken up.
Was it negligent to prescribe Nifedipine?
"Brief History of Tocolysis
12. As nifedipine increased in popularity in the 1990's, ritodrine was essentially phased out. The Royal College Guidelines from 2002 state that if a tocolytic drug is used ritodrine no longer seemed the best choice…
13……………Thus, in the 1990's the only licenced treatment was ritodrine which was considered to be associated with more adverse effects than nifedipine……..
General comments on case
16………..She was given nifedipine which was standard practice at the time. Although ritodrine was licenced for use as a tocolytic, it was associated with marked maternal side effects and was falling into disrepute……I consider that nifedipine should have been used in preference to ritodrine at this time given the data available. Indeed I consider that a significant proportion of obstetricians would have used nifedipine in this situation. Given the major competitor for nifedipine (atosiban) was not licenced until 2000, nifedipine was the first choice tocolytic at the time. I therefore consider that the management of Mrs Harris with nifedipine was appropriate and consistent with standard practice……
Comments on amended particulars of claim (undated)
(ii) it was contrary to the 1997 Protocol to use tocolysis continually
The administration of nifedipine was favoured over the use of ritodrine given the marked maternal side effects of the latter. Therefore, even if the protocol had been available and it suggested that ritodrine should be used, I consider that it would have been outdated and nifedipine should have been administered as was widely undertaken at the time…..
(c) Despite the fact that the Defendant was not part of (or conducting its own) clinical trial
Atosiban was not licenced until 2000 so this was not a viable alternative. It follows that the only alternatives in 1995 were to give ritodrine (associated with marked side effects), nifedipine (which required further evaluation), or no treatment which was considered (and still considered by some) not to be ethical. Thus, nidfedipine was the only sensible option at the time despite there being no high quality evidence of efficacy or improved outcomes…
(d) (ii) Failed, negligently and in breach of the 1997 Protocol, to start an intravenous infusion running before instituting Nifedipine treatment….
In 1995 it was considered that maternal fluids were relatively contraindicated in preterm labour. This was because ritdorine was falling into disrepute and there had been a number of serious maternal side effects (including maternal deaths) reported. It was considered that this was in part due to pulmonary oedema which was exacerbated by administration of maternal fluids…."
Review of the literature
Post 1995 Literature
The RCOG Yearbook 1995 – Item 16
Professor Thornton's evidence as to the use of Nifedipine in 1995
"These guidelines were produced under the direction of the Scientific Advisory Committee of the Royal College of Obstetricians and Gynaecologists as an educational aid to obstetricians and gynaecologists. These guidelines do not define a standard of care, nor is it intended to dictate an exclusive course of management. It presents recognised methods and techniques of clinical practice for consideration by obstetricians/gynaecologists for incorporation in to their practices. Variations of practice taking into account the needs of the individual patient, resources and limitations unique to the institution or type of practice may be appropriate"
This endorsement may properly be taken as some support for Professor Thornton's view that the 1994 and 1997 Guidelines were limited in their intended remit. Their purpose was not to evaluate different tocolytics, much less to recommend a course of treatment i.e Ritodrine over Nifedipine.
(i) Mr Hare and Professor Thornton are both obstetricians who acted in good faith. Both are responsible, competent and respectable experts. Is the evidence of both of them logical and reasonable?
(ii) It is fair to say that they approach the issue from different standpoints. Mr Hare gave the impression that he was more conservative, Professor Thornton more prepared to be avant garde, in approach. This may reflect the fact that Mr Hare was a consultant in a District General Hospital. He has not published or carried out any research into tocolysis. Professor Thornton has spent much of his life researching the subject and working in a teaching hospital. What is troubling is that, despite the recommendation from the RCOG since 2002, and NICE since 2015, Mr Hare still does not believe that Nifedipine should be prescribed. This is internally consistent with his opinion that Nifedipine was not proven to be safe in 1995 and is not proved to be safe now, there having been no high quality double-blind studies. However, on the evidence available to me it seems much more probable that Nifedipine is now properly regarded as a safe tocolytic and therefore could properly have been regarded as such in 1995.
(iii) An unusual feature of this case is that it is common ground that by 2002 at the latest it would not have been negligent to prescribe Nifedipine in preference to Ritodrine. In clinical negligence cases the question is often whether a clinician kept up with advancements in treatment/knowledge, and whether s/he should be held in breach of duty for seeing matters through the eyes of a clinicians at the time of the alleged negligence. This case is the opposite. The question in effect is whether the clinicians were ahead of their time in prescribing a drug about which it is alleged insufficient was known to prescribe it in late 1995, but which, seen through the eyes of clinicians from (at least) 2002 onwards, would have been an entirely appropriate treatment. This is despite the fact that then, as now, it remains unlicensed for the purpose for which it is used and there have still been no convincing double-blind studies or further primary research. Though the claim, when so analysed, may seem strange, yet it is an entirely logical proposition. I shall consider the claim by looking at the state of knowledge in November 1995.
(iv) When considering the expert evidence I remind myself in particular of the comments of Green J in C v North Cumbria University Hospitals NHS Trust at [25(vii)], namely that a Judge should not just accept an expert opinion; it should be tested both against the other evidence tendered during the course of the trial, and against its internal consistency. If the evidence is from a person of real experience, exhibiting competence and respectability, and it is consistent with the surrounding evidence and internally logical, a judge should attach considerable weight to it.
(v) Nifedipine was unlicensed for tocolytic use in 1995. It is still unlicensed in 2019. Nevertheless, the 2002 RCOG Clinical Guidance (Item 14) and the NICE Guidelines recommend its use. In the former it is described as preferable to Ritodrine. In the latter "Full Guideline" on "Preterm labour and birth", some 60 pages are devoted to tocolysis. In the recommendations it is said that Nifedipine should be considered/offered to women between 26 and 33+6 weeks of pregnancy who have intact membranes and are in suspected or diagnosed preterm labour. As to Ritodrine (a betamimetic) it says: "Do not offer betamimetics" for tocolysis. There are many reasons why a drug may remain unlicensed for a particular use. Regards must nowadays be had to the GMC Guidance of 2013 (Item 15). Nevertheless the fact that Nifedipine was unlicensed is merely one factor, and I find, not a strong factor, in the light of the other evidence.
(i) the Defendant was using Nifedipine as the tocolytic of choice
(ii) Mr Bidgood's recollection in 2010 was that "..my memory is that this was a recipe for the dosage and regimen based on the experience of staff working in Bristol and using their Protocol as a guide….in those days we were still using guides based on the local hospital handbooks and the practice as far as I remember it was that most of the doctors having worked in Bristol used the Bristol Handbook. I had provided access to the St Mary's Handbook and also the Bristol one which was available on the delivery suite. This was not a formal guideline or protocol in the sense that we follow now but provided a commentary and recipe for the management of things like preterm labour".
(iii) In the Netherlands (Item 7) 3 hospitals used nifedipine between February 1002 and February 1995, the results of which were published in 1997
(iv) In 1987 Nifedipine "was introduced as an alternative tocolytic agent…at St Joseph's Hospital", Denver, Colorado, In the light of concerns raised by some animal studies a systematic review of all patients was undertaken of 102 patients. The conclusion was: "Nifedipine was a well-tolerated and safe tocolytic in this population and warrants further investigation".
"Studies comparing ritodrine with nifedipine in the management of preterm labour suggest a similar tocolytic efficacy but fewer maternal side effects and no adverse fetal side effects with nifedipine."
This large-scale study then examined this finding, effectively corroborated it and found other advantages of Nifedipine over Ritodrine.
Administration of Nifedipine
The second dose of Nifedipine
(i) Although Mrs Harris' abdomen was probably not palpated at 0120, on the balance of probabilities she was complaining of continuing contractions. This is based on the fact that she complained of her abdomen still being painful in waves. If the contractions had stopped, then it can properly be inferred that the midwife would have followed Doctor Bett's instruction – see previously in this judgment.
(ii) In any event, I accept Professor Thornton's evidence that, even if the contractions had ceased, it was reasonable to give a second dose in the circumstances obtaining. This is notwithstanding that the Protocol probably recommended against another dose.
(2) There was no breach of duty in prescribing Nifedipine in 1995
(3) Failure to set up intravenous infusion prior to administration of Nifedipine was not a breach of duty
(4) The administration of a second dose of Nifedipine was not a breach of duty
Nifedipine versus Ritodrine for suppressing preterm labor. Meyer et al. 1988 The Journal of Reproductive Medicine.
"Fifty eight women in preterm labor were selected randomly to receive either oral nifedipine or intravenous ritodrine hydrochloride. In comparison to ritodrine, nifedipine had similar tocolyltic efficacy with fewer adverse maternal and fetal side effects … Preliminary data suggest that nifedipine is a safe, effective and well-tolerated tocolytic agent. It may prove to be a suitable alternative to ritodrine hydrochloride, especially for women in whom beta-sympathomimetics are contraindicated.
The efficacy of sympathomimetics, including Ritodrine hydrochloride, is generally well accepted, yet the potential side effects have lessened enthusiasm for its use. Currently, interest centres on the tocolytic use of calcium channel blockers. The aim of the present investigation was to compare the tocolytic efficacy and safety of nifedipine and ritodrine hydrochloride.
Between August 1986 and February 1987, 34 women were randomly selected to receive nifedipine, while 24 received ritodrine hydrochloride …
Our study lent support to the clinical use of nifedipine for preterm labor. In comparison to ritodrine hydrochloride, nifedipine demonstrated similar tocolytic efficacy with less severe maternal side effects and metabolic alterations. Fetal homeostasis as measured by external fetal monitoring … appeared unaltered. Prematurity, with its inherent dangers, seems a much greater risk to the fetus than does nifedipine tocolysis."
The safety and efficacy of Tocolytic Agents for the treatments of preterm labor: Besinger and Niebyl. Obstetrical and Gynaecological survey 1990, by Williams and Wilkins (USA) Vol 45 No. 7, page 415.
"… a diverse variety of tocolytic medications have been proposed for clinical use, with betamimetics and magnesium sulphate being the common therapeutic agents of choice in the United States today. The clinician using these agents should be aware of the significant maternal and fetal side effects associated with these particular medications. New classes of pharmacological agents, including … calcium channel blockers … have been proposed as tocolytic agents and are currently undergoing critical evaluation. The purpose of this review is to provide a compilation of the available clinical studies that document the safety and efficacy of these various tocolytic agents.
In 1980 the United States Food and Drug Administration approved Ritodrine hydrochloride … for inhibition of preterm labor. Among all the tocolytic agents to be discussed in this article, this is the only one so approved and the other agents should be considered experimental. However, the use of approved drugs for nonlabelled indications may be entirely appropriate based on medical advances extensively reported in the medical literature … the purpose of this article is to provide a compilation of the available clinical studies that document the efficacy and safety of these various tocolytic agents
The intravenous administration of betamimetic agents can stimulate beta-receptors in multiple organ systems and is responsible for the various clinically significant side effects associated with these medications (33). Maternal cardiovascular side effects are most frequently seen with beta-adrenergic agonists, including hypotension, tachycardia, and arrhythmia.
As the clinical use of beta-adrenergic agonists has become more widespread, more than 80 cases of pulmonary edema have been reported in the literature (39, 51-70). This life-threatening complication has been reported in up to 5% of patients receiving intravenous betamimetic therapy (35, 39).
Several maternal deaths have been associated with administration of betamimetic therapy (57, 77, 78). While most of these maternal debts were not directly attributable to the drug, a majority of these patients had a history of cardiac disease or pulmonary hypertension, pointing out the importance of pre-treatment screening for cardiopulmonary disease.
A more recent multicentre European study of 99 patients randomised to receive either intramuscular Ritodrine or placebo followed by oral therapy did not show long term efficacy … these more recent studies raise serious questions regarding the efficacy of Ritodrine in the treatment of preterm labor.
Oral maintenance therapy with Ritrodrine appears to be successful in preventing recurrent preterm labor. In one randomised double-blind study of oral maintenance therapy with Ritodrine, 70 patients were initially treated intramuscularly with Ritodrine and 59 patients received successful tocolysis beyond 24 hours …
Calcium Channel Blocking Agents
The clinical experience in the treatment of preterm labor with this group of tocolytic agents has been limited. To date, no controlled, randomised clinical studies have been reported to confirm the efficacy of these tocolytic agents …
The major concern restricting the clinical use of calcium channel blocking agents is the effect upon uteroplacental blood flow … In the 65 patients who have received Nifedipine during pregnancy, no adverse fetal or neonatal side effects have been described …
In summary, calcium channel blocking agents represent an apparently powerful class of tocolytic drugs. However, the concern over their effect upon the fetus and newborn, as well as their unproven efficacy, should limit the clinical use of these agents pending further investigation.
As our clinical experienced with these various medications increases, it becomes readily apparent there is no ideal tocolytic agent available at this time. …"
Comparison of Nifedipine and Ritodrine for the Treatment of Preterm Labor. Bracerio et al. American Journal of Perinatology/Volume 8, number 6, November 1991.
Treatment of preterm labor with beta-sympathomimetics has been questioned because of the many maternal and fetal complications associated with its use. Nifedipine, a calcium antagonist, has been shown to suppress uterine activity in vitro and in vivo. A randomised prospective study was performed to compare the efficacy of Nifedipine to Ritodrine in the suppression of preterm labor. Data obtained from 42 women, of which 19 were randomised to the Ritodrine group and 23 to the Nifedipine group, were analysed. Ritodrine and Nifedipine were proved to be equally effective in the suppression of perterm labor. However, the Nifedipine group had fewer maternal and fetal complications.
There is a need to find a tocolytic agent that is efficacious and has fewer side effects than the agents currently in use. The most widely used agents are beta-sympathomimetics. These agents are associated with several side effects in both mother and fetus …
… therefore, calcium antagonists seem ideally suited to suppress premature uterine smooth muscle contractions. On the other hand, the wisdom of using beta-sympathomimetics to treat preterm labor is being questioned. A review article on the treatment of preterm labor includes that the use of Ritodrine should be discouraged because of its questionable efficacy and life-threatening maternal adverse side effects. …
Harake and associates report that on pregnant sheep Nifedipine decreases uterine blood flow and fetal arterial oxygen content. In published human studies there has been no indirect confirmation of Harake's finding in sheep. In our study antepartum fetal heart rate monitoring did not reveal any significant abnormalities…
Most encouraging of all, neonatal RDS and other morbidities were lower in the Nifedipine group, resulting in a significantly lower hospital stay for these infants. Additionally, women who receive Nifedipine experienced fewer subjective and objective drug side effects.
This is a small randomised trial in which both Nifedipine and Ritodrine prove to be effective in suppressing preterm labor. Nifedipine, however, had fewer maternal side effects and less neonatal morbidity."
Best Practice in Labour and Delivery, 2nd edition (2016). Chapter 21 The Management of Preterm Labour.
In 1982 the Food and Drug Administration approved Ritodrine for use in the USA … There followed a mark increase in pulmonary oedema and in 1986 in the USA and Japan, post marketing surveillance advice recommended the cessation of preloading with intravenous fluids prior to initiation of ß2-agonist treatment. In 1992, the Canadian Preterm Labour Investigators group reported similar findings to the Keirse meta-analysis, namely that ß2-agonists were able to stop contractions and delay delivery for a short time, albeit that they had not been shown to be associated with a reduction in neonatal, mortality or morbidity. In the same issue of the journal, Leveno and Cunningham published an editorial in which they called for a reappraisal of the use of the ß2-agonists. There followed a decline in use of ß2-agonists in the USA and Europe, and in 1999 atosiban was launched in Europe (Austria first). Because of the cost of atosiban, there followed a drift towards the use of cheaper tocolytic alternatives such as magnesium sulphate and calcium channel blockers (CCBs), mainly nifedipine………."
Nifedipine versus Ritodrine for Suppression of Preterm Labor. Kupferminc et al. British Journal of Obstetrics and Gynaecology December 1993, vol 100 pp 1090-1094.
Objective To compare the efficacy of tocolysis with specific regimens of Nifedipine and Ritodrine. Maternal side effects and neonatal outcome also were evaluated.
Design A prospective, randomised trial.
Subjects 71 women, including 11 with twin pregnancies, who had uterine contractions and observed cervical changes.
Conclusions Nifedipine is as effective as Ritodrine in suppressing preterm labour. Its uses are associated with less frequent side effects.
Preterm delivery is a common obstetric problem. The incidence of preterm delivery is about 7 to 9% of pregnancies, and it accounts for as much as three quarters of the mortality and morbidity among newborns without congenital abnormalities … Therefore major emphasis has been placed on perinatal and neonatal research directed at preventing and lessening the consequences of preterm birth …
The pharmacological choices limited by the number of drugs available and by their safety and side effects, thus necessitating a continuous search for effective drugs with minimal side effects. Currently the most commonly used tocolytic agents are beta-adrenergic drugs, particularly Ritodrine. However, the incidence of troublesome, and occasionally fatal, side effects associated with this drug are of serious concern.
There is a growing body of evidence that Nifedipine is effective in suppressing preterm labour with minimal maternal and fetal side effects. In this paper we present the results of a prospective randomised study which was designed to compare the efficacy of oral Nifedipine with our existing regimen for administration of Ritodrine.
This study shows that Nifedipine is an effective tocolytic agent, comparable to Ritodrine, but it causes fewer side effects and less haemodynamic compromise.
Since calcium channel blockers are known to have both a vasodilatory effect and a negative inotropic effect on the myocardium …, haemodynamic side effects are of concern … Ferguson et al … reported a statistically significant increase in maternal heart rate and decrease in both diastolic blood pressure and MAP after sublingual and oral administration of Nifedipine, but they considered these changes unlikely to be of physiological importance. Our findings are consistent with theirs. The decrease in blood pressure which we observed after oral administration of Nifedipine, although statistically significant, was unlikely to be of clinical importance and was significantly less than the decrease associated with Ritodrine.
Nifedipine caused an increase in maternal heart rate following each dose, but this was transient and much less pronounced compared with women treated with Ritodrine. Similar observations were reported by Ferguson et al … No significant changes were noted in the fetal heart rate.
Consistent with previous reports (Ulmsten et al 1980, 1984), we found that other side effects associated with oral Nifedipine were trivial, and less common than with Ritodrine even in women who received a 2nd dose of Nifedipine. Treatment with Ritodrine, however, often requires discontinuation due to severe side effects and complications …
We conclude that Nifedipine is a useful tocolytic agent comparable in efficacy to Ritodrine, but with a lower frequency of side effects."
Holmes Childress and Katz Obstetrics and Gynaecology, Volume 83, number 4, April 1994, page 616.
"Objective: to review studies and investigations regarding the safety and efficacy of Nifedipine.
Data sources and methods: we reviewed the published literature on calcium channel blockers and their pharmacology and therapeutic applications in obstetrics and gynaecology. We paid particular attention to methods of animal research and recent clinical evaluations.
Conclusions: the dihydropyridine group of calcium channel blockers … and, specifically, Nifedipine are safe for use in pregnancy. They have little teratogenic or fetotoxic potential. Nifedipine's mechanism of action is through smooth-muscle relaxation secondary to blockage of the slow calcium channels into the cells. In vivo, there is minimal effect on the cardiac conducting system. Multiple studies in women have demonstrated the effectiveness and safety of Nifedipine as an antihypertensive. … Nifedipine is as effective as beta-mimetics in decreasing uterine activity. As a tocolytic agent, it is more effective as there are fewer patients who have to discontinue with Nifedipine because of side effects. …
Numerous investigators have reported positively on the fetal and neonatal effects of Nifedipine over prolonged periods during pregnancy. Studies comparing maternal treatment with Nifedipine and other agents have found that fetuses treated with Nifedipine fared at least as well and sometimes better (because of fewer maternal side effects) than fetuses exposed to other medications. Short-term fetal effects from Nifedipine have also been examined. The fetal heart rate during labour, fetal heart rate shortly after maternal ingestion, and umbilical artery Doppler flow studies have not been adversely affected by Nifedipine.
Animal studies have shown varying effects from the dihydropyridine agents. Harake et al, Parisi et al, and Ducsay et al found deleterious effects from high doses of Nifedipine, including declines in fetal arterial oxygen content, acidosis, and fetal deaths in lambs after maternal Nifedipine and Nicardipine treatment. These early reports caused widespread concern among physicians. In contrast, other investigators did not find adverse fetal effects. The contrasting results of animal and human study may be related to maternal haemodynamic effects, changes in the distribution in placental blood (an effect which is unlikely to occur in humans), and the dosages used. Taking all the studies together the large number of women treated with Nifedipine without adverse fetal effects suggests that the animal studies may not be applicable to pregnant women. Nifedipine has not been shown to affect birth weights, even with prolonged fetal exposure. There are fewer studies of Nitrendipine and Nicardipine, but abnormal effects have not been found with these agents, either.
The use of Nifedipine for tocolysis
In all the studies on women, Nifedipine has been as successful as or better than Ritodrine in stopping pre-term contractions. Negative fetal effects have not been found. Long-term use has not been associated with decreased birth weight or neonatal problems. Infants exposed to Nifedipine in utero have shown no untoward effects after one year. Perhaps most important, the maternal side effects have been much worse with Ritodrine, leading to more morbidity and greater discontinuation of the drug. Thus, in summary of the animal and human studies, Nifedipine is an effective agent to decrease uterine contractions, and because of fewer side effects, it has distinct advantages over current tocolytics."
Nifedipine and Ritodrine in the management of pre-term labor: a randomised multicenter trial. Papatsonis et al., Obstetrics and Gynaecology Volume 90(2) August 1997
"Objective: to compare the efficacy of Nifedipine with Ritodrine in the management of preterm labor.
Methods: 185 singleton pregnancies with preterm labour were assigned randomly to either Ritodrine intravenously (n = 90) or Nifedipine orally (n = 95)…
Conclusion: Nifedipine in comparison with Ritodrine in the management of preterm labour is significantly associated with a longer postponement of delivery, fewer maternal side effects, and fewer admissions to the NICU…
Studies comparing Ritodrine with Nifedipine in the management of preterm labor suggest a similar tocolytic efficacy but fewer maternal side effects and no adverse fetal side effects with Nifedipine …
Ferguson et al, Meyer et al, and Kupferminc et al all found Nifedipine to be associated with significantly fewer maternal side effects as compared with Ritodrine, and our results concur. The higher efficacy of Nifedipine and the lower incidence of maternal side effects are not the only advantages. The lower neonatal intensive care unit admission rate with Nifedipine is probably the most relevant finding. Nifedipine has the ease of oral administration. Other theoretical advantages are the (relative) lack of influence on maternal cardiac output and carbohydrate metabolism, which is in contrast with the beta-adrenergic agents. In addition, Nifedipine does not interfere with the interpretation of fetal heart rate tracings as does Ritodrine, which may be important in the timely diagnosis of an intra-uterine infection in patients with preterm PROM."
Dewhurst's Textbook of Obstetrics and Gynaecology for Postgraduates 5th edition, 1995, Chapter 22
"The early onset of labour
Treatment with Ritodrine by intravenous fusion for 24-48h, followed by oral administration for 5-7 days, has been described by Wesselius de Casparis et al. (1971). The drug is now used quite frequently in clinical practice, though its efficacy appears to remain unverified by controlled clinical trials (Hemminki and Starfield 1978; O'Connor et al, 1979). Furthermore, there have been disturbing reports of pulmonary oedema in mothers following its use in conjunction with betamethasone to supress premature labor (Elliot et al, 1978; Tinga & Aarnoudse 1979), and one of Ritodrine-induced acidosis in pregnancy (Desir et al 1978).
Calcium agonists such as Nifedipine (probably magnesium sulphate also) are being investigated currently, but only limited data are so far available (Read and Wellby 1986; Odum & Pipkin, 1988). …
Probably the beta-adrenoagic tocolytic drugs are the agents most widely used, but they are not without significant risk to the mother in some circumstances, and in most women are associated with unpleasant side effects, including flushing, tremor, headache, sweating and tachycardia. Alternative agents such as prostaglandin inhibitors, calcium antagonists and oxytocin inhibitors, have as yet been insufficiently tested to be introduced into routine use."
Turnbull's Obstetrics 2nd edition 1995, Chapter 33. Preterm labour and delivery of the preterm infant
"3a. Therapies to improve outcome: delaying delivery
Several drugs are now available to delay delivery in spontaneous preterm labour and where possible these should be utilised to allow other therapies which may improve outcome to be given. There are few complete contraindications to the inhibition of preterm labour … Current drugs used are betamimetics, prostaglandin synthetase inhibitors, magnesium sulphate, Calcium Channel Blockers and antibiotics.
Safety. Maternal side effects of betamimetics are well documented …
Most of the concern over the use of beta-agonists centres on the severe cardiovascular side effects…
The greatest controversy has been reserved for the risk of pulmonary oedema which occurs in 0.3% of cases (Canadian Preterm Labour Investigators Group 1992) … Whatever the cause, the injudicious use of beta-agonists can be lethal and appropriate monitoring needs to be in place…
Beta-agonists should only be used where there is good evidence of preterm labour …
Safety. … Severe side effects are extremely rare. Initial concerns over fetal welfare have been largely dispelled (Hanretty et al 1989).
Efficacy. Clinical experience is limited with Nifedipine. Trials to date have not been of high quality, and have not demonstrated any benefit over Ritodrine in the prolongation of pregnancy (Bracero et al, 1990; Ferguson et al., 1990; Meyer et al., 1990). It appears well tolerated, and no adverse fetal or neonatal effects have been reported. Its use should be confined to appropriate trials at present but its apparent safety justifies continuing investigation.
RCOG April 1994 Guidelines "For The Use of Ritodrine"
The risk-benefit ratio of Ritodrine hydrochloride …, a beta-agonist licensed to inhibit preterm uterine activity, has been reviewed recently following a series of events. These include the publication in July 1992 of a paper in the New England Journal of Medicine by the Canadian Pre-term Labor Investigators Group that indicated that the drug had no beneficial effects on perinatal mortality but was associated with increased maternal morbidity – particularly the potential to cause pulmonary oedema in the mother. Shortly after this publication a further two fatal cases of complications relating to pulmonary oedema were reported to the Committee on Safety of Medicines (CSM); the pharmaceutical company circulated a letter to doctors reminding them of this side effect and emphasising measures to minimise the risks; and the data sheet has been reviewed and revised.
Ritodrine hydrochloride is a beta-agonist … The drug was introduced in the UK in 1974 and has been widely used for the inhibition of preterm labour in the UK, rest of Europe and the USA. …
3. Effectiveness of Ritodrine
The Canadian Pre-term Labour Investigators Group represents the largest placebo-controlled investigation conducted on any tocolytic agent. Seven hundred and eight women were randomised to intravenous Ritodrine … The results indicate that Ritodrine significantly reduced the proportion of women who delivered within 24 and 48 hours after treatment, but there was no significant difference in birth weight or neonatal morbidity overall. …
The management of preterm labour will depend upon the cause of the problem (if determined), the gestation and degree of cervical dilatation at presentation, and the availability of neonatal intensive care facilities. The increased likelihood of being able to delay delivery by 24-48 hours by administration of intravenous Ritodrine may allow the possibility of in-utero transfer to a referral centre and facilitate time to administer corticosteroids to promote increased fetal lung maturity…
Drugs and Therapeutics Bulletin, Volume 30, number 25, 7th December 1992: Prescribing unlicensed drugs or using drugs for unlicensed indications
"Unlicensed use –
….even when the prescriber is fully aware of the contents of the data sheet there are occasions when non-adherence seems justified, for example where:
• the licensed indications do not reflect current knowledge. The data sheet for prednisolone … recommends that the drug be given in 'divided doses' through the day but clinical evidence strongly favours once daily or even alternate-day dosing.
• the indications do not include well proven uses of a drug. Mountain sickness, a recognised use for acetazolamide, is not mentioned in the data sheet, nor is treatment of dystonia with benzhexol or more recently the use of magnesium sulphate for acute myocardial infarction.
• the licensed indications are over restrictive. Junifen and Brufen syrup both contain 100 milligrams Ibuprofen in 5ml liquid yet for Brufen the indications include use as an anti-inflammatory, and for Junifen as an antipyretic. Brufen costs much less than Junifen, and on cost grounds doctors would be justified in prescribing Brufen syrup for both indications.
Such anomalies may arise if the manufacturer does not wish to alter the product's market niche and/or is unwilling to sponsor the trials necessary to support an application for a licence change."
A Guide to Effective Care in Pregnancy and Childbirth, 2nd edition, (1995). Enkin et al.
"3 Treatment of active preterm labour.
3.7 Other drug treatments
Apart from trials in which calcium antagonists were used mainly to supplement labour-inhibiting treatment with betamimetic drugs, there have been few attempts to evaluate these agents in preterm labour. There are not enough data on any of these agents to justify their use outside the context of well-designed and carefully monitored randomised trials."
RCOG Guideline January 1997. Beta-agonists for the care of women in preterm labour.
A wide variety of agents have been advocated as suppressing uterine contractions. Currently the most widely used is Ritodrine hydrochloride, a beta-agonist………. The aim of this guideline is to summarise the evidence about the effectiveness of beta-agonists for prevention and treatment of preterm labour and to provide guidance as to how to incorporate this evidence into clinical practice.
2. Evidence from systematic reviews
… Taken together, these studies show that beta-agonists reduce the proportion of deliveries occurring within the first 48 hours after beginning treatment. This is not reflected in any decrease in perinatal mortality or serious morbidity…
3.Risks and side effects
The most common symptoms associated with beta-agonist use are palpitations, tremor, nausea, vomiting, headache and restlessness … Beta-agonists are also associated with hypotension, although this is less of a problem with Ritodrine than some of the earlier agents …
Rare but serious side effects have also been reported following beta-agonist use. These are potentially life threatening and there have been a small number of maternal deaths associated with the use of beta-agonists. Pulmonary oedema is a well-documented complication and most cases are associated with aggressive intravenous hydration. Myocardial ischaemia is another uncommon but serious side effect and is a consequence of the increased cardiac output associated with beta-agonist administration. Women with known cardiac disease should not be given a beta-agonist. Other drugs, such as calcium antagonists and beta blockers, have been tried as adjuncts to beta-agonists in an attempt to reduce the cardiovascular side effects. None have been shown to have the desired effects and the available data do not justify their use…"
Royal College of Obstetricians and Gynaecologists Clinical Guideline No. 1(B) October 2002: Tocolytic drugs for women in preterm labour
"1.Purpose and scope
A wide variety of agents have been advocated as supressing uterine contractions. Those in current use include beta-agonists, calcium channel blockers, prostaglandin synthetase inhibitors, nitrous oxide donors and oxytocin receptor antagonists. There is little reliable information about current clinical practice but it is likely that Ritodrine hydrochloride, a beta-agonist, remains the most widely used. …
… The aim of this guideline is to summarise the evidence about the effectiveness of tocolytic drugs for preterm labour and to provide guidance as to how to incorporate this evidence into clinical practice.
4.Choice of tocolytic drug
If a tocolytic drug is used, Ritodrine no longer seems the best choice. Atosiban or Nifedipine appear preferable as they have fewer adverse effects and seem to have comparable effectiveness. Atosiban is licensed for this usage in the UK but Nifedipine is not.
There is still no clear evidence that tocolytic drugs improve outcome following preterm labour and so it is reasonable not to use them. … There is insufficient evidence for reliable conclusions about more substantive effects on perinatal or infant mortality or on serious neonatal morbidity. It remains plausible that, for selected women such as those who require transfer for neonatal care or time to complete a course of corticosteroids, there may be benefit associated with tocolysis. However, this benefit has not been formally evaluated in randomised trials.
If a tocolytic agent is used, Ritodrine no longer seems the best choice. Alternatives such as Atosiban or Nifedipine appear to have comparable effectiveness in terms of delaying delivery for up to 7 days and are associated with fewer maternal adverse effects. Atosiban is licensed for use as a tocolytic but the purchase price is relatively expensive. Nifedipine is not licensed for use as a tocolytic and the ideal dosage and formulation are unclear. For both these agents, further evidence is required about their relative effects on substantive outcomes such as neonatal mortality and morbidity, and on safety and long-term outcome for the child.
In view of the current lack of evidence for any substantive benefit for the baby from tocolysis, and the possibility of hazard for the mother, the available evidence should be discussed with the woman and her partner and their preferences taken into account in determining her care."
General Medical Council (2013)
"Prescribing unlicensed medicines.
68. You should usually prescribe licensed medicines in accordance with the terms of their licence. However, you may prescribe unlicensed medicines where, on the basis of an assessment of the individual patient, you conclude, for medical reasons, that it is necessary to do so to meet the specific needs of the patient.
69. Prescribing unlicensed medicines may be necessary where:
a) there is no suitably licensed medicine that will meet the patient's need …
70. When prescribing an unlicensed medicine you must:
a) be satisfied that there is sufficient evidence or experience of using the medicine to demonstrate its safety and efficacy
b) take responsibility for prescribing the medicine and for overseeing the patient's care…
Information for patients about the licence for their medicines
71. You must give patients … sufficient information about the medicines you propose to prescribe to allow them to make an informed decision."
The Yearbook of the Royal College of Obstetricians and Gynaecologists 1995.
"The treatment of preterm labour: physiological and clinical considerations
Steven Thornton and Gerald A Hackett
PHARMACOLOGICAL MANIPULATION OF UTERINE ACTIVITY
The effect of ritodrine in clinical practice is variable, possibly due to the multiple underlying pathophysiological processes. …
… it is therefore currently recommended (Royal College of Obstetricians and Gynaecologists 1994) that ritodrine should be administered to delay delivery in order to implement measures which may improve fetal health, such as to:
(1) Promote fetal lung maturity by administration of steroids;
(2) Enable in utero transfer to a centre with appropriate neonatal facilities; or
(3) Delay delivery at a gestation which is normally associated with a very poor fetal outcome.
The administration of ritodrine for the treatment of preterm labour is associated with pulmonary, cardiac and pancreatic side effects (Clesham 1994). Many patients have mild symptoms of palpitations, anxiety, sweating, tremor or chest discomfort which limit the administration dose. The more serious side effects are pulmonary oedema, myocardial ischaemia, cardiac arrhythmia, hypotension and hyperglycaemia. There appears to be little difference in efficacy and side effects of ritodrine compared to other ß-sympathomimetics.
… there is good in vitro evidence that human myometrial, contractility is reduced by the dihydropyridines … The in vivo evidence also supports a tocolytic effect. … In clinical studies (Keirse 1994c) the use of nifedipine was associated with fewer deliveries of babies less than 2500g and an increase in admissions to the neonatal intensive care unit.
Although some degree of myometrial relaxation has been demonstrated without major systemic side effects in the rat … in other species there are marked side effects. The most notable are due to l-type channel blockade in vascular smooth muscle. This causes vasodilatation with a fall in maternal blood pressure, increase in heart rate and reduction in uterine blood flow … In the primate, administration of nifedipine leads to a fall in fetal pO2 and pH with an increase in pCO2 … This is particularly worrying, since a similar effect in the human fetus would be likely to result in a deleterious effect on neonatal outcome. Nevertheless, clinical human studies have failed to demonstrate any effect of nifedipine on uterine blood flow in normotensive … or hypertensive … subjects, although an increase in admissions to the neonatal intensive care unit following maternal nifedipine … may be relevant.
Potassium channel openers
Repolarisation of the myometrial membrane is associated with the efflux of potassium through specific channels …
There are, as yet, no clinical trials which report the effect of potassium channel opening drugs administered to women in preterm labour. Evidence from in vitro experiments on human myometrium … support the use of these drugs as effective tocolytics and in vivo animal data suggests that spontaneous uterine activity is reduced by administration of potassium channel openers …
The diversity of pharmacological agents which are currently promoted for the treatment of preterm labour testify to our lack of understanding of the basic process. Progress can only be made if the physiological and pathophysiological processes in the human are elucidated further. This area, with a few notable exceptions, has largely been neglected.
At present, only the ß-sympathomimetic ritodrine is licensed for the treatment of preterm labour. Administration is not without maternal risk and may not improve neonatal outcome. Nevertheless, it is an effective tocolytic since it causes a delay in delivery…
The … calcium channel blockers may be associated with adverse fetal effects and are not recommended for clinical use at present. However, in the rush to develop new tocolytics, it is important that we do not abandon existing drugs before the risks and benefits are fully determined…
In addition to the physiological and pathophysiological investigation of preterm labour, attention should be focused on obtaining useful information from clinical trials…
The judicious use of tocolysis is thus of paramount importance and these drugs must be administered in clinical practice with the same rigour that is required in research"
Note 1 Originally this comprised two allegations (i) that Nifedipine should have been administered orally, not sub-lingually; (ii) that there should have been an intravenous line set up prior to the administration of Nifedipine. During the trial the Claimant abandoned allegation (i). [Back] Note 2 This section on authorities relating to breach of duty is essentially reproduced from my judgment in Keh v Homerton University Hospitals NHS Foundation Trust  EWHC 548 (QB). [Back] Note 3  1WLR 583
[Back] Note 4  1WLR 634
[Back] Note 5  AC 232
[Back] Note 6  EWHC 61
[Back] Note 7 Doctor Bett said this showed that the fetal head had descended somewhat but was not engaged. [Back] Note 8 In the multigravid woman the cervix tends to shorter than in the primigravid state and, although the internal os (opening into the uterine cavity) is closed, the external os (opening into the vagina) may allow a fingertip to be inserted into it. This condition is known as ‘multips os’. See later [Back] Note 9 Betamethasone is a steroid. [Back] Note 10 The self-discharge form is in the medical notes and is signed by Mrs Harris. [Back] Note 11 From this it appears that Dr Bett’s examination was shortly prior to this. [Back] Note 12 Seemingly Mrs Dinsdale [Back] Note 13 The pp of 4cm is the distance between the head to the ischial spines. [Back] Note 14 Doctor Bett said that the midwife examination note followed the examination at 00:41. [Back] Note 15 This is the drug prescription sheet which is signed by Dr Bett. [Back] Note 16 Mr Bidgood’s letter of 6 September 2010 was disclosed. This was the basis of the 13 September 2010 letter. [Back] Note 17 Doctor Bett said that ‘s/l’ meant ‘sub-lingually’. [Back] Note 18 This was brought out in re-examination. [Back] Note 19 Professor Jane Norman was the Chair of the NICE Guideline Committee which reported in 2015. [Back] Note 20 Turnbull’s Obstetrics 1995 (Walkinshaw) [Back] Note 21 Besinger and Niebyl cited as authority in the Defendant’s 1997 protocol; agreed by Walkinshaw in the chapter ‘Preterm labour and delivery of the preterm infant’ pages 609-627 from Turnbull’s Obstetrics 2nd edition 1995. [Back] Note 22 In fact probably nearer to 20:40 [Back] Note 23 See later. It was not put to Doctor Betts that her finding that the cervix was 1 cm dilated was an inaccurate finding or that it was in effect a finding of multips os. [Back] Note 24 About 20:40 on 25th November 1995. [Back] Note 25 Mr Hare accepted that in his Report he had missed (paragraph 13.3 and 29.1) inserting Doctor Bett’s finding at about 20:40 on 25th November 1995 of a worsening lower abdominal pain over the previous 24 hours with the pain coming every one in five minutes and from both sides to the pubic area. In the joint report he had not opted for Braxton Hicks contractions as being the probability. He had suggested the possibility of bladder or bowel as the pain source – a possibility he did not maintain in cross-examination. [Back] Note 26 Turnbull’s Obstetrics 1995 (Walkinshaw); James and others ‘High Risk Pregnancy Management Options’ 1994 Chapter 11. [Back] Note 27 ‘Treatment of spontaneous preterm labour with retosiban: a phase 2 proof-of-concept study’. 2015: Brtitish Journal of Pharmacology 740 [Back] Note 28 British Journal of Obstetrics and Gynaecology 1990 Volume 97 pp. 317-323. [Back] Note 29 How accurate is a woman’s diagnosis of threatened preterm delivery? High Risk Pregnancy Management of Contractions. [Back] Note 30 See also the 1997 Protocol and an extract from Vatish et al (2005): Management of threatened preterm labour” of which Professor Thornton was a co-author. [Back] Note 31 E.g, see RCOG Guidelines 2002. [Back] Note 32 Mr Hare was not asked about these notes. They were substantially reproduced in his Report, though he appears not to have drawn specific conclusions from them.. [Back] Note 33 This note also needs to be read in the context of the notes by Mrs Dinsdale on the drug chart and also later that morning on the Antenatal In-Patient Care Plan – see below. [Back] Note 34 He also referred to the midwife’s Antenatal In-Patient care Plan Note at a time before 0615 – see above [Back] Note 35  PIQR 324 [Back] Note 36  EWCA Civ 1882 [Back] Note 37 See also the recent Supreme Court case of Prest v Prest  UKSC 34 at . [Back] Note 38 The Claimant in written submissions relied on the duty of candour under Regulation 20 of the Health and Social Care Act (Regulated Activities) Regulations 2014. The Defendant said it was not applicable. The Claimant accepted it added nothing to the common law position in these circumstances. I therefore do not deal with it further. [Back] Note 39 Professor Thornton was criticised for this expression and other similar expressions about his impressions of the notes. It was said that this is hopelessly vague, falls far short of satisfying a reasonable criterion for diagnosis, speculative and is not evidence-based. While it is not, and was not presented as powerful evidence, it is nonetheless evidence of some weight and demonstrates that Professor Thornton was careful not to exaggerate in this regard. [Back] Note 40 He was shown a table prepared by Mr Hare of recorded findings throughout Mrs Harris’ pregnancy between 2nd November 1995 until 30 January 1996. These findings showed some variability after 25th November 1995 in these signs, and in effacement. Professor Thornton said it was not known whether, in a single pregnancy, signs could in effect reverse. [Back] Note 41 It is not known how many tensings for short periods the midwife felt. However, some supportive evidence that they were happening frequently, even if not every two minutes, is that her note is timed at 23.56 and Dr Bett’s note is timed only 4 minutes later, at midnight – however there may be some discrepancy in precise timings e.g. Mrs Dinsdale may have written her note at 23.56 rather than begun the examination at that time. [Back] Note 42 Professor Thornton was shown the Partogram of Mrs Harris’ subsequent labour. This contains a box with key diagrams of mild, moderate or strong contractions for filling in the form. Professor Thornton said midwifes do assess the strength, but cannot really do so by palpation. [Back] Note 43 In cross examination, Professor Thornton said that if dilatation had reached 1cm an hour he would have been extremely concerned because labour would then have been fully established and may not have been capable of being stopped. He said that it did not matter hugely what the state of the cervix was unless it was dilated such that it was too late to administer tocolysis. [Back] Note 44 This was not the language he used but it was the gist of his evidence. [Back] Note 45 I have reviewed some of the evidence as to the finding by Doctor Bett on the 1st 25th November admission that the cervix was 1cm dilated and her recording after Mrs Dinsdale’s 0041 examination that the cervix was 1cm dilated. This may have been a finding of multips os, as Mr Hare’s table of earlier and later findings does not suggest cervical dilatation on other examinations. As I have previously stated it was not put to Doctor Bett that her finding of 1cm dilatation was multips os. On balance I am persuaded that the cervix was 1cm dilated. The note of the 1st 2th November 1995 admission makes it clear that Doctor Bett made two findings (i) on VE 1cm dilated; (ii) speculum: multips os – thereby suggesting that, though junior, she appreciated the difference. In any event, some dilatation would not be necessary for a diagnosis of threatened preterm labour. [Back] Note 46 Other drugs have been considered for inhibiting preterm labour. These are Indomethacin (a cyclo-oxygenase inhibitor/prostaglandin inhibitor), Glyceryl nitrate (a nitric oxide donor), magnesium sulphate, Atosiban (an oxytocin receptor antagonist) and Acebutolol (a Beta adrenergic receptor blocking agent). Some of these have come more prominently into play since 1995. [Back] Note 47 It was probably less thorough than a protocol because Mr Bidgood in the solicitor’s letter had apparently referred to it as a ‘recipe’. For full details of Mr Bidgood’s letter, see below. [Back] Note 48 There is a reading list attached to the 1997 protocol. Mr Hare said this was a skeletal list. If writing a protocol a consultant should fully acquaint himself or herself with the literature. [Back] Note 49 He relied on the RCOG 1994 Guidelines (Item 10) in support of this [Back] Note 50 On the above extracts up to and including the ‘General Comments on case’ [Back] Note 51 1992-1995 [Back] Note 52 Based on animal, not human, studies. [Back] Note 53 The statement that there were no randomized clinical studied to confirm their efficacy remains the case even today. Despite that, they have been recommended for use by the Royal College of Obstetricians and Gynaecologists since 2002 and by NICE since 2015. [Back] Note 54 This is taken from the Introduction to the 1994 RCOG Guidleines (Item 10 in the Appendix). See also the Historical Perspective set out in Item 4 of the Appendix. [Back] Note 55 As recorded in the paragraph of this judgment relating to Item 5. [Back] Note 56 Earlier it seems to suggest that it is in current use: “Current drugs used are beta-mimetics….calcium channel blockers…” [Back] Note 57 It says that the comments in the Guidelines could be deemed to be other beta-agonists [Back] Note 58 It must be appreciated that Nifedipine is still unlicensed as a tocolytic but has been recommended for that use by the RCOG since 2002 and NICE since 2015. (See later in the judgment). [Back] Note 59 And another tocolytic drug, Atosiban [Back] Note 60 The relevant extracts are in the Appendix. [Back] Note 61 Item 5 is the BJOG paper. The reading list also included a 1990 American paper by Ferguson et al, not produced in court but referred to in other articles in the Appendix, namely Items 5, 7 and 9. It was entitled: A comparison of tocolysis with nifedipine or ritodrine: analysis of efficacy and maternal, fetal, and neonatal outcome. [Back] Note 62 See letter referring to UK survey. Johnson & Mason BJOG 112, pp 1582-1584 [Back] Note 63 Nifedipine is still unlicensed for use as a tocolytic [Back] Note 64 It is always a possibility that he will be shown to be correct and the RCOG and NICE to be wrong. However, I have to work on the quality of the evidence available to me at this point in time. [Back] Note 65 Though see Epilogue to this judgment [Back] Note 66 Both Item 6 and the 1994 RCOG document (Item 10) were published in April 1994 [Back] Note 67 Indeed as time progressed, the viewpoint became the one endorsed by the RCOG and NICE> [Back] Note 68 Letter 6 September 2010 [Back] Note 69 In submissions Mr Moon QC said he had been told that there were two St. Mary’s obstetric hospitals, one in London (Paddington) and one in Manchester. His instructions were that Mr Bidgood had previously worked in the London St Mary’s. [This is not in evidence]. [Back] Note 70 Murray et al: Nifedipine for Treatment of preterm labor: A historic prospective study.” Am J Obstet Gynecol 1992; 167:52-6 [Back] Note 71 And it was not negligent to fail to do so [Back] Note 72 That is also how both Doctor Bett and Mr Emovon interpreted the note – see above. [Back] Note 73 The 1997 Protocol is not so stark or clear in its recommendation. It says: “If contractions reduce substantially repeat Nifedipine...” [Back] Note 74 This includes Ritodrine. [Back] Note 75 There is then reference to some animal studies, [Back] Note 76 Respiratory Distress Syndrome [Back] Note 77 Causative of congenital abnormality. [Back] Note 78 References given are all 1995 or prior. [Back] Note 79 There is also discussion of treatment of premature labour with Orciprenaline and Salbutamol. [Back] Note 80 There is then a discussion about side effects. [Back] Note 81 This appears to be inaccurate. Perhaps Professor Thornton had not read the endorsement to the Report – see main judgment. [Back]
Note 1 Originally this comprised two allegations (i) that Nifedipine should have been administered orally, not sub-lingually; (ii) that there should have been an intravenous line set up prior to the administration of Nifedipine. During the trial the Claimant abandoned allegation (i). [Back]
Note 2 This section on authorities relating to breach of duty is essentially reproduced from my judgment in Keh v Homerton University Hospitals NHS Foundation Trust  EWHC 548 (QB). [Back]
Note 3  1WLR 583 [Back]
Note 4  1WLR 634 [Back]
Note 5  AC 232 [Back]
Note 6  EWHC 61 [Back]
Note 7 Doctor Bett said this showed that the fetal head had descended somewhat but was not engaged. [Back]
Note 8 In the multigravid woman the cervix tends to shorter than in the primigravid state and, although the internal os (opening into the uterine cavity) is closed, the external os (opening into the vagina) may allow a fingertip to be inserted into it. This condition is known as ‘multips os’. See later [Back]
Note 9 Betamethasone is a steroid. [Back]
Note 10 The self-discharge form is in the medical notes and is signed by Mrs Harris. [Back]
Note 11 From this it appears that Dr Bett’s examination was shortly prior to this. [Back]
Note 12 Seemingly Mrs Dinsdale [Back]
Note 13 The pp of 4cm is the distance between the head to the ischial spines. [Back]
Note 14 Doctor Bett said that the midwife examination note followed the examination at 00:41. [Back]
Note 15 This is the drug prescription sheet which is signed by Dr Bett. [Back]
Note 16 Mr Bidgood’s letter of 6 September 2010 was disclosed. This was the basis of the 13 September 2010 letter. [Back]
Note 17 Doctor Bett said that ‘s/l’ meant ‘sub-lingually’. [Back]
Note 18 This was brought out in re-examination. [Back]
Note 19 Professor Jane Norman was the Chair of the NICE Guideline Committee which reported in 2015. [Back]
Note 20 Turnbull’s Obstetrics 1995 (Walkinshaw) [Back]
Note 21 Besinger and Niebyl cited as authority in the Defendant’s 1997 protocol; agreed by Walkinshaw in the chapter ‘Preterm labour and delivery of the preterm infant’ pages 609-627 from Turnbull’s Obstetrics 2nd edition 1995. [Back]
Note 22 In fact probably nearer to 20:40 [Back]
Note 23 See later. It was not put to Doctor Betts that her finding that the cervix was 1 cm dilated was an inaccurate finding or that it was in effect a finding of multips os. [Back]
Note 24 About 20:40 on 25th November 1995. [Back]
Note 25 Mr Hare accepted that in his Report he had missed (paragraph 13.3 and 29.1) inserting Doctor Bett’s finding at about 20:40 on 25th November 1995 of a worsening lower abdominal pain over the previous 24 hours with the pain coming every one in five minutes and from both sides to the pubic area. In the joint report he had not opted for Braxton Hicks contractions as being the probability. He had suggested the possibility of bladder or bowel as the pain source – a possibility he did not maintain in cross-examination. [Back]
Note 26 Turnbull’s Obstetrics 1995 (Walkinshaw); James and others ‘High Risk Pregnancy Management Options’ 1994 Chapter 11. [Back]
Note 27 ‘Treatment of spontaneous preterm labour with retosiban: a phase 2 proof-of-concept study’. 2015: Brtitish Journal of Pharmacology 740 [Back]
Note 28 British Journal of Obstetrics and Gynaecology 1990 Volume 97 pp. 317-323. [Back]
Note 29 How accurate is a woman’s diagnosis of threatened preterm delivery? High Risk Pregnancy Management of Contractions. [Back]
Note 30 See also the 1997 Protocol and an extract from Vatish et al (2005): Management of threatened preterm labour” of which Professor Thornton was a co-author. [Back]
Note 31 E.g, see RCOG Guidelines 2002. [Back]
Note 32 Mr Hare was not asked about these notes. They were substantially reproduced in his Report, though he appears not to have drawn specific conclusions from them.. [Back]
Note 33 This note also needs to be read in the context of the notes by Mrs Dinsdale on the drug chart and also later that morning on the Antenatal In-Patient Care Plan – see below. [Back]
Note 34 He also referred to the midwife’s Antenatal In-Patient care Plan Note at a time before 0615 – see above [Back]
Note 35  PIQR 324 [Back]
Note 36  EWCA Civ 1882 [Back]
Note 37 See also the recent Supreme Court case of Prest v Prest  UKSC 34 at . [Back]
Note 38 The Claimant in written submissions relied on the duty of candour under Regulation 20 of the Health and Social Care Act (Regulated Activities) Regulations 2014. The Defendant said it was not applicable. The Claimant accepted it added nothing to the common law position in these circumstances. I therefore do not deal with it further. [Back]
Note 39 Professor Thornton was criticised for this expression and other similar expressions about his impressions of the notes. It was said that this is hopelessly vague, falls far short of satisfying a reasonable criterion for diagnosis, speculative and is not evidence-based. While it is not, and was not presented as powerful evidence, it is nonetheless evidence of some weight and demonstrates that Professor Thornton was careful not to exaggerate in this regard. [Back]
Note 40 He was shown a table prepared by Mr Hare of recorded findings throughout Mrs Harris’ pregnancy between 2nd November 1995 until 30 January 1996. These findings showed some variability after 25th November 1995 in these signs, and in effacement. Professor Thornton said it was not known whether, in a single pregnancy, signs could in effect reverse. [Back]
Note 41 It is not known how many tensings for short periods the midwife felt. However, some supportive evidence that they were happening frequently, even if not every two minutes, is that her note is timed at 23.56 and Dr Bett’s note is timed only 4 minutes later, at midnight – however there may be some discrepancy in precise timings e.g. Mrs Dinsdale may have written her note at 23.56 rather than begun the examination at that time. [Back]
Note 42 Professor Thornton was shown the Partogram of Mrs Harris’ subsequent labour. This contains a box with key diagrams of mild, moderate or strong contractions for filling in the form. Professor Thornton said midwifes do assess the strength, but cannot really do so by palpation. [Back]
Note 43 In cross examination, Professor Thornton said that if dilatation had reached 1cm an hour he would have been extremely concerned because labour would then have been fully established and may not have been capable of being stopped. He said that it did not matter hugely what the state of the cervix was unless it was dilated such that it was too late to administer tocolysis. [Back]
Note 44 This was not the language he used but it was the gist of his evidence. [Back]
Note 45 I have reviewed some of the evidence as to the finding by Doctor Bett on the 1st 25th November admission that the cervix was 1cm dilated and her recording after Mrs Dinsdale’s 0041 examination that the cervix was 1cm dilated. This may have been a finding of multips os, as Mr Hare’s table of earlier and later findings does not suggest cervical dilatation on other examinations. As I have previously stated it was not put to Doctor Bett that her finding of 1cm dilatation was multips os. On balance I am persuaded that the cervix was 1cm dilated. The note of the 1st 2th November 1995 admission makes it clear that Doctor Bett made two findings (i) on VE 1cm dilated; (ii) speculum: multips os – thereby suggesting that, though junior, she appreciated the difference. In any event, some dilatation would not be necessary for a diagnosis of threatened preterm labour. [Back]
Note 46 Other drugs have been considered for inhibiting preterm labour. These are Indomethacin (a cyclo-oxygenase inhibitor/prostaglandin inhibitor), Glyceryl nitrate (a nitric oxide donor), magnesium sulphate, Atosiban (an oxytocin receptor antagonist) and Acebutolol (a Beta adrenergic receptor blocking agent). Some of these have come more prominently into play since 1995. [Back]
Note 47 It was probably less thorough than a protocol because Mr Bidgood in the solicitor’s letter had apparently referred to it as a ‘recipe’. For full details of Mr Bidgood’s letter, see below. [Back]
Note 48 There is a reading list attached to the 1997 protocol. Mr Hare said this was a skeletal list. If writing a protocol a consultant should fully acquaint himself or herself with the literature. [Back]
Note 49 He relied on the RCOG 1994 Guidelines (Item 10) in support of this [Back]
Note 50 On the above extracts up to and including the ‘General Comments on case’ [Back]
Note 51 1992-1995 [Back]
Note 52 Based on animal, not human, studies. [Back]
Note 53 The statement that there were no randomized clinical studied to confirm their efficacy remains the case even today. Despite that, they have been recommended for use by the Royal College of Obstetricians and Gynaecologists since 2002 and by NICE since 2015. [Back]
Note 54 This is taken from the Introduction to the 1994 RCOG Guidleines (Item 10 in the Appendix). See also the Historical Perspective set out in Item 4 of the Appendix. [Back]
Note 55 As recorded in the paragraph of this judgment relating to Item 5. [Back]
Note 56 Earlier it seems to suggest that it is in current use: “Current drugs used are beta-mimetics….calcium channel blockers…” [Back]
Note 57 It says that the comments in the Guidelines could be deemed to be other beta-agonists [Back]
Note 58 It must be appreciated that Nifedipine is still unlicensed as a tocolytic but has been recommended for that use by the RCOG since 2002 and NICE since 2015. (See later in the judgment). [Back]
Note 59 And another tocolytic drug, Atosiban [Back]
Note 60 The relevant extracts are in the Appendix. [Back]
Note 61 Item 5 is the BJOG paper. The reading list also included a 1990 American paper by Ferguson et al, not produced in court but referred to in other articles in the Appendix, namely Items 5, 7 and 9. It was entitled: A comparison of tocolysis with nifedipine or ritodrine: analysis of efficacy and maternal, fetal, and neonatal outcome. [Back]
Note 62 See letter referring to UK survey. Johnson & Mason BJOG 112, pp 1582-1584 [Back]
Note 63 Nifedipine is still unlicensed for use as a tocolytic [Back]
Note 64 It is always a possibility that he will be shown to be correct and the RCOG and NICE to be wrong. However, I have to work on the quality of the evidence available to me at this point in time. [Back]
Note 65 Though see Epilogue to this judgment [Back]
Note 66 Both Item 6 and the 1994 RCOG document (Item 10) were published in April 1994 [Back]
Note 67 Indeed as time progressed, the viewpoint became the one endorsed by the RCOG and NICE> [Back]
Note 68 Letter 6 September 2010 [Back]
Note 69 In submissions Mr Moon QC said he had been told that there were two St. Mary’s obstetric hospitals, one in London (Paddington) and one in Manchester. His instructions were that Mr Bidgood had previously worked in the London St Mary’s. [This is not in evidence]. [Back]
Note 70 Murray et al: Nifedipine for Treatment of preterm labor: A historic prospective study.” Am J Obstet Gynecol 1992; 167:52-6 [Back]
Note 71 And it was not negligent to fail to do so [Back]
Note 72 That is also how both Doctor Bett and Mr Emovon interpreted the note – see above. [Back]
Note 73 The 1997 Protocol is not so stark or clear in its recommendation. It says: “If contractions reduce substantially repeat Nifedipine...” [Back]
Note 74 This includes Ritodrine. [Back]
Note 75 There is then reference to some animal studies, [Back]
Note 76 Respiratory Distress Syndrome [Back]
Note 77 Causative of congenital abnormality. [Back]
Note 78 References given are all 1995 or prior. [Back]
Note 79 There is also discussion of treatment of premature labour with Orciprenaline and Salbutamol. [Back]
Note 80 There is then a discussion about side effects. [Back]
Note 81 This appears to be inaccurate. Perhaps Professor Thornton had not read the endorsement to the Report – see main judgment. [Back]