UvA-DARE (Digital Academic Repository)
Bleeding in the first trimester of pregnancy
Wieringa-de Waard, M.
Publication date
2002
Document Version
Final published version
Link to publication
Citation for published version (APA):
Wieringa-de Waard, M. (2002). Bleeding in the first trimester of pregnancy.
General rights
It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons).
Disclaimer/Complaints regulations
If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible.
inn the first t r i m e s t e r
off pregnancy
Bleeding g
inn the first trimester
off pre
Bleedingg in the first trimester of pregnancy
Margrethee Wieringa-de Waard, the Netherlands, 2002 Thesiss University of Amsterdam
ISBN:: 90-9015349-7
Lay-outt and cover design
(Batikk impression, Indonesia): R.C.B. Kreuger, Medisch Illustratieve Dienst,, Divisie J, Academie Medical Center, Universityy of Amsterdam
Printedd by: Ridderprint, Ridderkerk
Thee study presented in this thesis was supported by grants from the Dutch Healthh Research and Development Council (ZON) and the Dutch Ministry of Health,, Welfare & Sports.
Bleedingg in the first trimester of pregnancy
ACADEMISCHH PROEFSCHRIFT
terr verkrijging van de graad van doctor aann de Universiteit van Amsterdam opp gezag van de Rector Magnificus
prof.mr.. P.F. van der Heijden
tenn overstaan vann een door het college voorr promoties ingestelde commissie,
inn het openbaar te verdedigen inn de Aula der Universiteit
opp donderdag 7 februari 2002, te 14.00 uur
Promotiecommissie e
Promotores:: Prof.dr. E. Schade Prof.dr.. O.P. Bleker Co-promotores:: Dr. W.M. Ankum
Prof.dr.. P.J.E. Bindels Prof.dr.. G.J. Bonsel Overigee leden: Prof.dr. M.P.M. Burger
Prof.dr.. W. Everaerd Prof.dr.. R.J. de Haan Prof.dr.. A.P.M. Heintz Prof.dr.. B. Meijboom- de Jong
Contents s
page page
C h a p t e rr 1
Generall introduction g
C h a p t e rr 2
Managementt of spontaneous miscarriage in the first trimester:
ann example of putting informed shared decision making into practice 15
C h a p t e rr 3
Threatenedd miscarriage in general practice;
diagnosticc value of history taking and physical examination 25
C h a p t e rr 4
Managementt of miscarriage: a randomised controlled trial of
expectantt management versus surgical evacuation 37
C h a p t e rr 5
Expectantt management versus surgical evacuation in
first-trimesterr miscarriage: health-related quality of life in randomised
andd non-randomised patients 49
C h a p t e rr 6
Patientt preferences for expectant management versus surgical evacuationn in first-trimester miscarriage; data from a randomised
studyy with patient preference arms 63
C h a p t e rr 7
Thee natural course of spontaneous miscarriage: analysis of signs
andd symptoms in 188 expectantly managed women 75
C h a p t e rr 8
Generall discussion and implications for future research 87
C h a p t e rr 9
CHAPTERR 1
Generall introduction
Introduction n
Twoo out of every ten pregnant women experience an episode of vaginal bleeding duringg the first trimester. In 50% of these women the pregnancy is viable and thee bleeding will stop after a certain period of time without further conse-quences.. In the remaining 50% of women, however, the pregnancy is non-viable andd the bleeding period heralds a miscarriage.1 In most countries surgical evacuationn is the preferred treatment for miscarriages.2 Some observational studiess and one randomised trial have also described expectant management ass a realistic alternative to surgical evacuation.3"5
Thee guideline on imminent miscarriage of the Dutch College of General Prac-titionerss (first issued in 1989, revised in 1997) advises women in the Nether-landss to first await the natural course of the bleeding, and to withhold from furtherr diagnostic investigations, i.e. ultrasonography.6,7 After one week, if thee diagnosis is still unclear, these women are referred for an ultrasonograph-icc assessment. In case of a non-viable pregnancy, the guideline then propa-gatess expectant management. The restrictive use of ultrasonography is based onn the premise that in either case, whether the bleeding results from a viable orr a non-viable pregnancy, the ultrasonographic findings will have no thera-peuticc consequences whatsoever.
Thee first Dutch guideline was based on a study, initiated by the Dutch College off General practitioners in the late 1950s, which resulted in two theses pub-lishedd in 1964 and 1966.6>8,9 This study was performed in a primary care set-tingg and included more than 1500 women with a miscarriage. The diagnosis wass solely based on patient histories. Spontaneous expulsion of products of conceptionn was verified by the GPs' inspection of any lost tissue. In the ab-sencee of both a urinary pregnancy test and transvaginal ultrasonography, cur-rentlyy the gold standard for establishing the cause of first-trimester bleeding, considerablee diagnostic errors were probably made. Clearly, a guideline to be usedd today cannot validly be based on the evidence from this study.
Inn the revised version of the guideline, the results of a recently performed randomisedd controlled trial were incorporated.7 This hospital-based trial comparedd expectant management with surgical evacuation in women with ultrasonographicallyy confirmed miscarriages, and suggested the outcomes to bee similar.5 However, the duration of expectant management in that study wass restricted to only three days, while the majority of included women had ann incomplete miscarriage. Three days of follow-up cannot seriously be
CHAPTERCHAPTER 1
regardedd as 'true expectant therapy', neither from a practical nor from an em-piricall point of view. The over-representation of women with an incomplete miscarriage,, thus excluding the vast majority of women with a non-viable pregnancy,, also limits the generalisability of these findings from this study for every-dayy practice.
Inn contrast to the Dutch GP guideline, the Dutch Society of Obstetrics and Gynaecologyy advises a sonographic assessment in all women with first-trimesterr bleeding, enabling a distinction between viable and non-viable pregnancies.. In case of a non-viable pregnancy the advice is 'to prevent pro-longedd bleeding and infection'.10 Consequently, curettage is often the pre-ferredd treatment in these cases.
Bothh recommendations are neither evidence-based nor representative for cur-rentt practice. In fact, a recent study showed no adherence of GPs to the guide-linee in 56% of cases of threatened miscarriage.11
First-trimesterr bleeding, being a problem which affects two out of every ten pregnantt women, needs management based on scientific evidence. The com-binationn of unsatisfactory evidence from the literature, the high incidence of thiss clinical problem, and the conflicting recommendations with respect to its management,, were the reasons to start the study presented in this thesis.1 2
Thee aim of the present study
Thee aim of the study presented in this thesis is to answer the following questions: 11 . What is the value of patient's medical history and physical examination in
diagnosingg the underlying cause of first-trimester bleeding during pregnancy? 22 . Which treatment is preferable in the management of first-trimester
mis-carriage:: expectant management or surgical evacuation?
33 . Are there any differences in health-related quality of life between expec-tantt or surgical management in the treatment of miscarriages?
4 .. Which treatment do women prefer in first-trimester miscarriage? 55 . What is the natural course of a first-trimester miscarriage?
Terminology y
Wee have used the term miscarriage instead of spontaneous abortion.13 First-trimesterr miscarriage is defined as 'a miscarriage occurring before the gestational agee of 16 completed weeks following the first day of the last menstrual period'.
GeneralGeneral introduction
Studyy design
Wee performed an observational study (to answer questions 1 and 5) as well as ann intervention study (questions 2 to 4). In order to cover the whole range of womenn with first-trimester bleeding we not only enrolled women attending the outpatientt clinics or the emergency departments because of pregnancy com-plicationss in the first trimester, but we also asked general practitioners and midwivess to refer all consecutive women with first-trimester vaginal bleeding forr an ultrasound assessment. All GPs/midwives working in the health district coveredd by two Amsterdam hospitals, the Academic Medical Center and the Onzee Lieve Vrouwe Gasthuis, were asked to participate in the study during a speciallyy organised seminar about first-trimester bleeding during pregnancy. Thee GPs/midwives were visited by the researcher and received information aboutt the study. Ultimately 74 GPs and 8 midwives agreed to participate and includedd one or more patients in the study. During the consultations of eligi-blee patients, the participating GPs/midwives used structured questionnaires andd registered signs and symptoms and findings of gynaecological examina-tions.. Referral of eligible patients was facilitated by direct telephone access too the researchers. A special daily ultrasonographic facility was created, enablingg referral to our unit within two days. To inform the participating GPs/midwivess about our project, and to remind them to send in patients, a newsletterr was sent out every four months.
Thee flow of participants is presented in the Figure below. Between April 19988 and September 2000 we enrolled 1101 women in the study. For the observationall part of the study we registered signs, symptoms and the final diagnosiss of all women. Women with a confirmed diagnosis of a viable
preg-Transvaginal l sonography y (n=1101) ) Non-viablee pregnancy (n=419) )
"
Incompletee miscarriage (n=30) )L* *
Excludedd (n=652) -- viable pregnancy complete miscarriage -- other diagnosis Randomisation n (n=122) ) Inclusionn I (n=427)) ' I Preference e (n=305) ) Excludedd (n=22) -- immediate curettage necessary y —WW Expectant (n=64) —fcc Curettage (n=58) - WW Expectant (n= 126) ) - kk Curettage (n=179)CHAPTERCHAPTER 1
nancyy were referred back to their GP or midwife. These women received a ques-tionnairee at term to check the outcome of the index pregnancy. Women with aa complete miscarriage, an ectopic pregnancy, or a molar pregnancy, were managedd according to the hospital protocol.
Womenn with a non-viable pregnancy or an incomplete miscarriage were asked too participate in the intervention study. Consenting women took part in the randomisedd controlled trial comparing expectant and surgical management. Womenn who refused to be randomised were managed according to their own treatmentt choice, and were asked to participate in the observational study.
Outlinee of this thesis
CHAPTERR 2 gives an overview of the history of the management of
first-trimes-terr miscarriage.
CHAPTERR 3 analyses the diagnostic accuracy of the patient's medical history
andd physical examination in predicting the underlying cause of the first-tri-mesterr vaginal bleeding. In addition, we analysed the accuracy of the GPs/mid-wivess in making a provisional diagnosis based on their clinical impression beforee referral (question 1).
CHAPTERR 4 AND 5 describe a randomised controlled trial comparing expectant
managementt and surgical evacuation in terms of safety, complications and successs rates (chapter 4). Health-Related Quality of Life issues are analysed inn chapter 5. The outcomes of the trial are compared with those of women treatedd according to their own preference (question 2 and 3).
CHAPTERR 6 provides information on treatment preferences for surgical
evac-uationn or expectant management in women with first-trimester bleeding or a non-viablee pregnancy (question 4).
CHAPTERR 7 describes the natural course of miscarriages (question 5).
CHAPTERR 8 discusses the results of the study. Implications for guidelines and
forr future research are indicated.
CHAPTERR 9: Summary, samenvatting.
References s
1.. Everett C. Incidence and outcome of bleeding before the 20th week of pregnancy: prospectivee study from general practice. BMJ 1997;315:32-4.
2.. Hemminki E. Treatment of miscarriage: Current practice and rationale. Obstet Gynecoll 1998;91:247-253
3.. Ambulatory Sentinel Practice Network. Spontaneous abortion in primary care. J Am Boardd Fam Pract 1988;1:15-23.
GeneralGeneral introduction
4.. Nielsen S, Hahlin M. Expectant management of first-trimester spontaneous abortion. Lancett 1995;345:84-6.
5.. Wiebe E, Janssen P. Management of spontaneous abortion in family practices and hospitals.. Fam Med 1998;30:293-6.
6.. Flikweert S, Ligtenberg WJJ, Sips AJBI. NHG-Standaard dreigende miskraam (Dutch Societyy of General Practitioners. Practice guideline threatened miscarriage). Huisarts Wett 1989;32:138-43.
7.. Flikweert S, Meijer LJ, De Haan M, Wiersma Tj. NHG-Standaard Miskraam, eerste herzieningg (Dutch Society of General Practitioners. Revised practice guideline mis-carriage).. Huisarts Wet 1997;40:661-70.
8.. Ligtenberg WJJ. Abortus in de huisartsenpraktijk. Dissertation, Leiden: Stenfort Kroese,, 1966.
9.. Roorda PA. De behandeling van de dreigende abortus. Dissertation, Utrecht, 1964. 10.. Oepkes D. Indicaties echoscopisch onderzoek in de zwangerschap. In: Nota
Echosopiee Gynaecologie/Verloskunde. NVOG. Utrecht, 1993:15-22.
11.. Fleuren M. Managing (imminent) miscarriage in primary health care. Dissertation, Amsterdam,, 1997.
12.. Ankum WM, Veen van der F. Management of first-trimester a b o r t i o n . Lancet 1995;345:1179. .
13.. The management of early pregnancy loss. Guideline no 25. Royal College of Obstetricianss and Gynaecologists. London, 2000.
CHAPTERR 2
Managementt of spontaneous miscarriage
inn the first trimester
anan example of putting informed shared decision
makingmaking into practice
Willemm M. Ankum, Margreet Wieringa-de Waard, Patrick J.E. Bindels BMJJ 2001;322:1343-6
Introduction n
Inn many parts of the Western world there is a strong preference among gynae-cologistss to rely on surgical evacuation for the management of miscarriages in thee first trimester. Why so many specialists have adopted surgery as the stan-dardd procedure seems determined by custom and habit and rooted in history ratherr than being an evidence based choice. During the first half of the 20t h centuryy the high rate of infections from retained products of conception with ensuingg mortality from septicaemia -often complications from criminal attemptss to terminate a pregnancy- resulted in the policy of immediate surgi-call evacuation whenever a diagnosis of inevitable abortion was made.1 Today thesee complications are rare, and their role in the justification of a universal tendencyy to perform surgery, has therefore expired.2
Expectantt management finds its main protagonists in general practice, where thee process of spontaneous miscarriage is acknowledged more readily as being aa well regulated natural process in human reproduction.
Relativelyy new is the medical approach to spontaneous miscarriages.3 The combinationn of the antiprogestagen mifepristone and the prostaglandin ana-loguee misoprostol is being used successfully for the termination of pregnan-ciess on a large scale. The use of these substances has also been tried in the managementt of spontaneous miscarriage.
Doctorss and patients are confronted with a situation where opinions about the properr management of spontaneous miscarriage differ widely. That the avail-ablee options are so diverse makes it even more complex. This paper aims to increasee the awareness of various management options and explores the availablee evidence.
CHAPTERCHAPTER 2
Methods s
Wee performed a search in Medline, Embase, the Cochrane Library, and PubMed too identify relevant literature, using spontaneous abortion and spontaneous miscarriagee as primary search conditions for titles and abstracts. We carried outt a crossover search from the obtained articles.
Studiess from primary care
Inn 1989 the Dutch College of General Practitioners issued a practice guideline basedd on the expectant management of spontaneous miscarriage. A revised guideline,, issued in 1997, confirmed expectant management as the strategy off first choice.4-5 Several observational studies from the United Kingdom, Canada,, and the United States have also advocated expectant management by doctorss as a feasible option.6 8 These studies showed that a major proportion of womenn with spontaneous miscarriages, a quarter in the United Kingdom and almostt half in the North American studies, were managed successfully by doctors,, either in the general practice or at home. Additionally, these studies showedd that virtually all women under specialist care were bound to undergo surgicall evacuation. Through an education programme focussing on both doc-torss and patients in Vancouver, British Columbia, surgical evacuations were reducedd from 46% to 32%, and the incidence of complications even decreased duringg the study.9
Thesee studies neither allow any conclusions about the differences between expectantt and surgical management nor between the management in primary andd secondary care, as it is likely that more serious cases were referred to hospital.. They do, however, illustrate that expectant management is being practisedd widely in primary care, even in communities with a high rate of sur-gicall intervention in the hospital environment.
Hospitall based studies
Severall hospital based randomised controlled trials comparing the various managementt options for spontaneous miscarriage are now available and pro-videe more solid ground for management decisions. The Table summarises the resultss of these trials.
Expectantt management versus surgical evacuation
Nielsenn and Hahlin published the first randomised study, which compared expectantt management, during a period of three days, with surgical evacua-tion.1 00 They included women with inevitable and incomplete abortions with anterior-posteriorr diameters greater than 15 mm at ultrasonography. Success
C C O O Ü Ü o o o o co o E E o o "O O c c co o CD' ' co o > > (0 0 c c OO CQ ii > == < Q. . E E o o o o a 75 5 > > 0)) - * V)V) ~ 4)) c WW (0 0) ) 0)) -~
SE E
33 -5 (00 co o» » c c o o EE «O caa * E S S o o o o LO O o o A A CO O LO O ö ö A A LO O ó ó A A CO O O O ó ó LO O ó ó A A CMM -—-LOO O - »» O CMM T -LOO >—' CDD — . , -- O - -- O coo , -f—— ' LO O O O o o V V r --CMM co" (OO o* CMM "*" LO O O O A A CO O i » » co o LO O ó ó A A LO O o o A A LO O o o A A OJ J i » » co o LO O o o ó ó V V LO O o o o o V V LO O 2» » *fr r LO O o o o o V V E E a> > *—* * o o co o LO O O O o o V V E E B B (^^ O) >> o o o CD D E E 2 o o CM co o co o cc g 2 S S 3> CMM co ~~ C CO —' ca a >. . IV)) c *-~~ E CDS-gg
5
E E EE CD >% COO c w ~~ E ® XX ? 5 E E coo c C OO CD CD ee CD o 5> > "cöö c £* oo CD CD TOO E a> E COO -^ CDD co coo ^ co ^ COO O ) ^ 0 0 COO >~ ' LO " " COO c ^ oo CD 0 T33 E P CMM ^ COO o CMM w co o a> > COO 3 E COO —' CDD co COO c JT OO CD CD T33 E P COO ^ CDD CO LO O ó ó A A CVJ J LO O LO O ó ó A A CMM h» ^^ co c* oT oo 5 i co o^ h -- o> .,_ _ £00 05" coo 92-o 92-o CO O o o t OO CM O)) 55. -*t t coo (F -'t t iSS g Ü Ü CDD = CO O O O EE =5 CD D E E co o 3 3 O O CD D C C co o < -c -c o o Q. . co o c c CD D E E CD D O) ) CO O c c ca a CAA . 2 o o a> > .EE O Q. COO 3 CD« ? ë ë
oo c a>> CD a ~ ~ >»» co I -- o. o o LO O o o c c COO cD«f-2 2
>> O o®® g E
.EE .E co E E E E LO O CM M CD DÜ Ü
. EE co CDD co NN . *'
55s
©© i -^^ v CD DII I
IS S
T 3 3 CO O o o CD D CD D (O O E E CD D CD D Q . . E E o o o o c c C C O O ^ ^ ^~ ~ ( J J o o CO O E E E E CM M V V E E b b h --CM M cv v E E o o LO O A A ^. . > > co o c c co o E E o o co o A A (Tl l CO O T 3 3 r r CO O o o CD D CO O CD D .3? ? a. . h h o o c c o o n n EE .E "OO <D cc +-caa £ c T33 Q- O CDD £ ï = ww o ^ «« 8 o EE .E « E E E E o o LO O " OO a) cc + -COO © c T33 O- O CDD E ï = ww O « «« 8 o E . EE "co Q. . (8 8 O) ) o o c c o o 4» » co o CDD coCHAPTERCHAPTER 2
ratess and complication rates were similar in both groups, as was the duration of vaginall bleeding, pain, sick leave and packed cells volume after 3 and 14 days. Twoo more recent papers from this study showed no differences in psychological reactionss and in subsequent fertility between both cohorts of women.11-12 Chipchasee and Jones did a similar but smaller study among women with retained productss of conception less than 50 mm on transvaginal sonography after spontaneouss miscarriages.1 3 They found no differences between expectant andd surgical management in complication rates, duration of bleeding, pain, or sickk leave.
Medicall treatment versus surgical evacuation
Dee Jonge et al compared medical treatment (a single dose of the prostaglandin analoguee misoprostol) with surgical evacuation.14 Women with inevitable mis-carriagess on clinical grounds were included. Several women were stabilised beforee randomisation: in each treatment arm about one third received blood transfusions.. Medical treatment was considered successful if a complete mis-carriagee occurred within 12 hours. Only 3 of 23 patients (13%) were treated successfullyy with misoprostol compared with 26 of 27 patients (96%) allocat-edd to surgery. Haemoglobin concentrations decreased significantly in women treatedd medically but were stable in those treated surgically. The study was discontinuedd after the present (interim) analysis. Patients entered in this studyy were apparently different from those in the other reports summarised inn this paper. The fairly large uterine size (mean 13 weeks) and considerable proportionn of women requiring blood transfusions before randomisation prob-ablyy explain the high failure rate of medical treatment in this study.
Johnsonn et al compared medical treatment with surgical evacuation in women withh miscarriages in the first trimester.1 5 Findings on ultrasonography were nott specified, and included patients were a mixture of symptomatic women withh non-vital pregnancies and incomplete or complete abortions. All patients weree treated successfully in both treatment groups. In each group one major complicationn occurred: a laparotomy was done for a bleeding perforation after surgicall evacuation, and a presumed ectopic pregnancy after medical treat-mentt also resulted in a laparotomy, which did not confirm the diagnosis. Hinshaww compared medical treatment with surgical evacuation in women with missedd and incomplete abortions.16 An open study design was used: patients weree either treated according to the randomised treatment allocation or a-ccordingg to their own preference. Pooled results were reported. Medical man-agementt comprised misoprostol in those with incomplete abortions, whereas thosee with missed abortions were treated with the antiprogestagen mifepris-tone,, followed by misoprostol after a priming phase. In women with small uterinee contents, no difference between medical treatment and surgery was foundd in the rate of complete evacuations. In those with larger uterine contents,
ManagementManagement of spontaneous miscarriage diagnosis* * ultrasonography y vaginall bleeding uterinee pain 22 3 4 5
1:: ultrasonography shows early anembryonic pregnancy or fetal death (missed miscarriage) 2:: vaginal bleeding occurs (threatened miscarriage)
3:: open cervical os (inevitable miscarriage)
4:: miscarriage (products of conception are expelled, cramps and bleeding soon subside) 5:: ultrasonography may show uterine contents: decidua, blood, and some villi
Figuree 2.1. Natural course of miscarriage, with opportunities for intervention.
thee complete evacuation rate was significantly lower in medically treated wom-enn compared with those undergoing surgical evacuation. Overall, three haem-orrhagess greater than 500 ml occurred during medical treatment. In the sur-gicallyy treated women three major complications occurred: one perforation necessitatingg laparotomy with bowel resection and one cervical tear requiring suturing.. The woman with the cervical tear developed sepsis and pelvic infec-tionn and was treated with high dose intravenous antibiotics. Chung et al com-paredd medical management (misoprostol every four hours) with surgical eva-cuationn in women with ultrasonographical evidence of retained products of conceptionn greater than 5cm2 (transverse plane) or greater than 6cm2 (sagit-tall plane).1 7 Patients allocated misoprostol underwent a surgical evacuation thee next day, whenever retained products of conception were still present (as wass the case in 50% of patients). In the group allocated surgical removal, 2% requiredd a second evacuation. There were significantly less short, medium, andd long term complication in the women treated medically. Drug related gastrointestinall side effects occurred in up to 48% of those women.
Expectantt management versus medical therapy
Nielsenn et al were the first to explore the efficacy of expectant versus medical managementt in a randomised trial of women with spontaneous miscarriages in thee first trimester.1 8 Women were either managed expectantly or received mifepristonee followed by misoprostol 48 hours later. After five days, women withh ultrasonographical evidence of retained products of conception greater than
CHAPTERCHAPTER 2
groups,, as were pain scores, vaginal bleeding, complications, and scores for patient satisfaction.. Convalescence was 1.8 days longer after medical treatment.
Observationall studies
Twoo observational hospital based studies are of special interest:
aa non-randomised study, performed by Cheung et al, provides detailed infor-mationn about short-term complications in a large series of patients.1 9 Women withh complete abortions (n = 297) were managed expectantly, whereas those showingg retained products of conception on ultrasonography (n = 470) were treatedd surgically. Treatment complications after surgery occurred in 6% of women:: two cervical lacerations and four uterine perforations, for which two laparoscopicss were done, whereas another patient needed an emergency hys-terectomyy for uncontrollable pelvic bleeding. Short term complications in thosee managed expectantly occurred in only 3% of women and were less severe,, but the difference did not reach significance compared with those treatedd primarily by surgery.
Inn another observational study by Jurkovic et al, 221 asymptomatic women withh a missed miscarriage diagnosed by ultrasonography were offered a choicee between surgical evacuation and expectant management.2 0 Among 85 womenn (38%) opting for expectant management, 25% experienced a com-pletee miscarriage, whereas 17% needed surgical evacuation because of incompletee miscarriages. The remaining 59% requested surgical evacuation att some later stage, mostly for psychological reasons. The authors conclude thatt the success of expectant management is too low to justify its use in rou-tinee clinical practice.
Conclusion n
Althoughh miscarriage is the most common complication in pregnancy, the availablee evidence on its management is extremely limited. A considerable proportionn of women with spontaneous miscarriages is being managed expec-tantlyy by doctors, even in communities where virtually all patients under sec-ondaryy care are treated by surgical evacuation.
Surgicall intervention in women with complete abortions is unnecessary and representss over treatment. Most studies in the Table simply excluded these patientss from further intervention. Even in women with ultrasonographical evidencee of retained products of conception in the aftermath of a spontaneous miscarriage,, immediate surgery is likely to be unnecessary in most cases, and medicall treatment offers no advantages either. Arguably, clinical rather than ultrasonographicall criteria should be used to indicate the necessity of surgical uterinee evacuation in these patients. In women with no history of passing any
ManagementManagement of spontaneous miscarriage
tissue,, however, an empty uterine cavity on ultrasonography should raise suspicionn of an ectopic pregnancy. In these women, measurements of serum humann chorionic gonadotropin concentrations together with repeated ultra-sonographyy should lead the way in differentiating between a complete mis-carriagee and ectopic pregnancy.21"23
Inn women still facing the process of spontaneous miscarriage there is strong evidencee to suggest expectant management to be a realistic alternative to surgicall evacuation, whereas medical treatment does not seem to offer any advantage.. As mifepristone and misoprostol cause gastrointestinal side effectss in up to 50% of patients and increase costs, these drugs probably deservee no place in the management of spontaneous miscarriage. Therefore, womenn with missed abortions or fetal death in the first trimester should be counselledd accordingly and offered a choice between expectant and surgical management.. This also seems true for women with evidence of non-vital pregnanciess on ultrasonography before the onset of any clinical signs.
Obviously,, patients' preferences should play a key part in these management decisions,, and more research is needed to elucidate the effect of these prefer-encess on the acceptance of different treatment options. There seems, however, noo point in denying a motivated well informed woman a fair chance to await thee natural course of events whenever she prefers to do so. If surgical evacua-tionn becomes necessary for medical or psychological reasons at some later stage,, nothing is lost and at least then the reasons for surgical intervention aree clear. Spontaneous miscarriage is a typical example of a condition, where informed-sharedd decision making should be put into practice thus replacing paternalismm by partnership.2 4"2 6
References s
1.. Ballagh SA, Harris HA, Demasio K. Is curettage needed for uncomplicated incomplete spontaneouss abortion? Am J Obstet Gynecol 1998;179:1279-82.
2.. Why mothers die. Report on confidential enquiries into maternal deaths in the United Kingdomm 1994-1996. The Stationary Office, London, 1998.
3.. El-Refaey H, Hinshaw K, Henshaw R, Smith N, Templeton A. Medical management of missedd abortion and anembryonic pregnancy. BMJ 1992;305:1399.
4.. Flikweert S, Ligtenberg WJJ, Sips AJBI. NHG-Standaard dreigende miskraam (Dutch Societyy of General Practitioners. Practice guideline threatened miscarriage). Huisarts Wett 1989;32:138-43.
5.. Flikweert S, Meijer LJ, De Haan M, Wiersma Tj. NHG-Standaard Miskraam, eerste herzieningg {Dutch Society of General Practitioners. Revised practice guideline mis-carriage).. Huisarts Wet 1997;40:661-70.
6.. Everett C. Incidence and outcome of bleeding before the 20th week of pregnancy: prospectivee study from general practice. BMJ 1997;315:32-4.
CHAPTERCHAPTER 2
7.7. Ambulatory Sentinel Practice Network. Spontaneous abortion in primary care. J Am Boardd Fam Pract 1988;1:15-23.
8.. Wiebe E, Janssen P. Management of spontaneous abortion in family practices and hospitals.. Fam Med 1998;30:293-6.
9.. Wiebe E, Janssen P. Reducing surgery in management of spontaneous abortions. Familyy physicians can make a difference. Can Fam Physician 1999;45:2364-9. 10.. Nielsen S, Hahlin M. Expectant management of first-trimester spontaneous abortion.
Lancett 1995;345:84-6.
1 1 .. Nielsen S, Hahlin M, Moller A, Granberg S. Bereavement, grieving and psychological morbidityy after first trimester spontaneous abortion: comparing expectant manage-mentt with surgical evacuation. Hum Reprod 1996;11:1767-70.
12.. Blohm F, Hahlin M, Nielsen S, Milsom I. Fertility after a randomised trial of sponta-neouss abortion managed by surgical evacuation or expectant treatment. Lancet 1997;349:995. .
13.. Chipchase J, James D. Randomised trial of expectant versus surgical management of spontaneouss miscarriage. Br J Obstet Gynaecol 1997;104:840-1.
14.. De Jonge ETM, Makim JD, Manefeldt E, De Wet GH, Pattinson RC. Randomised clinicall trial of medical evacuation and surgical curettage for incomplete miscarriage. BMJJ 1995;311:662.
15.. Johnson N, Priestnall M, Marsay T, Ballard P, Watters J. A randomised trial evaluat-ingg pain and bleeding after first trimester miscarriage treated surgically or medical-ly.. Eur J Obstet Gynecol Reprod Biol 1997;72:213-5.
16.. Hinshaw HKS. Medical management of miscarriage. In: Grudzinskas JG, O'Brien PMS, eds.. Problems in early pregnancy. London: RCOG Press, 1997:284-95.
17.. Chung TKH, Lee DTS, Cheung LP, Haines CJ, Chang AMZ. Spontaneous abortion: a randomized,, controlled trial comparing surgical evacuation with conservative man-agementt using misoprostol. Fertil Steril 1999;71:1054-9.
18.. Nielsen S, Hahlin M, Platz-Christensen J . Randomised trial comparing expectant withh medical management for first trimester miscarriages. Br J Obstet Gynaecol 1999;106:804-7. .
19.. Cheung LP, Sahota DS, Haines CJ, Chang AMZ. Spontaneous abortion: short term complicationss following either conservative or surgical management. Aust NZ J Obstett Gynaecol 1998;38:61-4.
20.. Jurkovic D, Ross JA, Nicolaides KH. Expectant management of missed miscarriage. Brr J Obstet Gynaecol 1998; 105:670-1.
2 1 .. Ankum WM, Van der Veen F, Hamerlynck JVTH, Lammes FB. Transvaginal sonogra-phyy and human chorionic gonadotrophin measurements in suspected ectopic preg-nancy:: a detailed analysis of a diagnostic approach. Hum Reprod 1993;8:1307-11.
ManagementManagement of spontaneous miscarriage
22.. Bannerjee S, Aslam N, Zosmer N, Woelfer B, Jurkovic D. The expectant management off women with early pregnancy of unknown location. Ultrasound Obstet Gynaecol 1999;14:231-6. .
23.. Ankum WM. Diagnosing suspected ectopic pregnancy; HCG monitoring and transvagi-nall ultrasound lead the way. BMJ 2000;321:1235-6.
24.. Towle A, Godolphin W. Framework for teaching and learning informed shared deci-sionn making. BMJ 1999;319:766-71.
25.. Charles C, Whelan T, Gafni A. What do we mean by partnership in making decisions aboutt treatment? BMJ 1999;319:780-2.
CHAPTERR 3
Threatenedd miscarriage in general practice
diagnosticdiagnostic vaiue of history taking and physical
examination examination
Margreett Wieringa-de Waard, Gouke J. Bonsel, Willem M. Ankum, Jeroenn Vos, Patrick J. E. Bindels
Submittedd for publication
Abstract t
OBJECTIVESS To determine the diagnostic value of history taking and physical exam-inationn in first-trimester bleeding, for differentiating between patients requiring im-mediatee further diagnostic examination from those in whom an expectant policy will initiallyy suffice.
DESIGNN Prospective population based cohort study. SETTINGG 74 General practices in Amsterdam.
PARTICIPANTSS Pregnant women with first-trimester bleeding.
RESULTSS 225 patients with first-trimester vaginal bleeding were referred for an early pregnancyy assessment and the data of 204 were analysed.
Threee approaches (models) were explored to identify diagnostic subgroups relevant too clinical practice. Model 1 distinguishes between viable pregnancies and complete miscarriagess on the one hand (expectant policy possible) and all other diagnoses on thee other (further diagnostics required). By using this model the pre-test probability off viable pregnancies and complete miscarriages combined, increased from 72% to 77%% post-test. Model 2, which separates viable pregnancies from other diagnoses, enabledd an increase from a 47% pre-test probability to a post-test probability of 70%.. Model 3, enabling the identification of complete miscarriages, showed a post-testt probability of 4 1 % of a complete miscarriage, given a pre-test sample probabili-tyy of 25%. The tentative diagnosis of the GP, based entirely on clinical judgement, turnedd out to be a poor predictor for the ultrasonographically confirmed diagnosis (pre-testt probability of 47% changed to a post-test probability of 58%).
CONCLUSIONSS This study shows that in first-trimester bleeding neither statistical predictionn models based on signs and symptoms, nor clinical judgement can validly replacee ultrasonographic assessment in establishing a diagnosis.
CHAPTERCHAPTER 3
Introduction n
First-trimesterr vaginal bleeding is the most common problem in pregnancy, al-mostt always leading to a consultation in the general or gynaecological practice. Thee problem occurs in about one-fifth of all pregnancies, with an estimated miscarriagee rate of about 50%, while the other 50% of pregnancies continue withoutt serious problems.1 Ultrasonography, the gold standard for establishing aa diagnosis in first-trimester vaginal bleeding, is not always immediately available.. In these circumstances, the patient's medical history and a gynae-cologicall examination are used to make a provisional diagnosis and to decide whetherr referral for any further clinical assessment, i.e. ultrasonographic examination,, is needed. To date virtually no information is available on the discriminativee capacity of clinical symptoms and gynaecological examination in differentiatingg between the various underlying diagnoses, e.g. viable or non-viablee pregnancy, complete or incomplete miscarriage or ectopic pregnancy.2 Inn this paper we present a prospective population-based cohort study of oth-erwisee unselected women, presenting in general practice with first-trimester bleeding,, who were referred to our unit for ultrasonographic assessment. We analysedd whether the patient's history and physical examination were of any usee in predicting the final diagnosis. In addition, we analysed the skills of the attendingg GPs in making a provisional diagnosis of a viable pregnancy on clinicall grounds before referring the patient.
Methods s
Patients Patients
Ourr study was conducted as part of a randomised trial on the management of miscarriagess in two Amsterdam hospitals, the Academic Medical Center and thee Onze Lieve Vrouwe Gasthuis, between April 1998 and September 2000. Seventy-fourr GPs working in the health district covered by these two hospi-talss participated in the study. They referred all women with vaginal bleeding, aa positive urinary pregnancy test result, and a gestational age of less than 16 weeks,, for ultrasonographic assessment. Oral informed consent was obtained inn all patients.
Thee study was approved by the medical ethics committees of both hospitals.
DataData collection
Duringg the first consultation, the participating GPs collected base line data onn a structured form on clinical signs and symptoms, obstetric history and gestationall age. Additional findings from the gynaecological examination weree recorded. With regard to the gynaecological examination GPs had the possibilityy to fill out 'not performed' on the form. A provisional diagnosis was thenn made, and the GP was asked to estimate the probability of a viable
ThreatenedThreatened miscarriage in general practice
nancyy being present on a 0-100% scale. Information on sociodemographic data wass collected by means of a patient questionnaire.
UltrasoundUltrasound examination
AA standardised transvaginal sonographic examination was performed by trained physicianss using a transvaginal 6.5 MHz sonographic probe (Hitachi Corpo-ration,, Tokyo, Japan). A viable pregnancy was diagnosed whenever fetal heart activityy could be detected. A non-viable pregnancy was diagnosed in case of ann immeasurable embryonic pole at a gestational sac diameter > 15 mm, an embryoo without cardiac activity, or an empty gestational sac at a diameter <
155 mm not showing any growth after a seven-day interval.3 , 4 An incomplete miscarriagee was diagnosed in case of sonographic evidence of retained prod-uctss of conception (RPOC) > 15 mm anteroposterior (AP) diameter. AA complete miscarriage was diagnosed in case of sonographic evidence of RPOCC < 15 mm (AP diameter) in combination with previous sonographic documentationn of an intra-uterine pregnancy (IUP) or with decreasing serum betaa human chorionic gonadotrophin (hCG) concentrations during follow-up. AA diagnosis of ectopic pregnancy was considered if no intra-uterine gestation-all sac was seen, or if an ectopic gestational sac was seen, or if an ectopic mass wass visualised, together with a serum hCG concentration > 1.500 IU/L.5 Thee ultrasonographic diagnosis of hydatidiform mole had to be confirmed by histopathologicall examination.
StatisticalStatistical analysis
Ourr prospective approach implies that we analysed all cases, including rela-tivelyy rare conditions, e.g. ectopic pregnancy and hydatidiform mole, which shouldd be considered in differential diagnosis of first-trimester bleeding. Wee analysed three models, which were constructed to classify women pre-sentingg with first-trimester bleeding into a group in whom an expectant policy cann be justified and a group in whom further ultrasonographic assessment is required. .
Modell 1 aims as the first step to separate viable pregnancies together with completee miscarriages from the rest of the study population, thereby assum-ingg that these women do not require immediate sonographic assessment. Afterr the first step model 1 would be further explored to separate viable pregnanciess from complete miscarriages.
Modell 2 tries to predict the presence of a viable pregnancy, while model 3 triess to separate complete miscarriages from all remaining diagnoses. Thee relationship between patient characteristics, clinical variables, findings fromm gynaecological examination and the diagnosis was analysed, starting withh an univariate regression analysis. All variables with a p-value < 0.10 weree selected for further multivariate analysis. Prior to multivariate mod-elling,, the multicollinearity of potential predictive variables was checked
CHAPTERCHAPTER 3
Tablee 3 . 1 . Patient characteristics according to the sonographically confirmed
diagnosis.3 3
Characteristic c
AgeAge - yr, mean Parity Parity 0 0 1 1 > 1 1 PriorPrior miscarriage 0 0 1 1 > 1 1 Prior Prior ectopicectopic pregnancy GestationalGestational age < 88 wk 8-122 wk 12-166 wk Uncertain n Viable e pregnancy y ( ( / / 56 6 25 5 15 5 54 4 28 8 14 4 1 1 35 5 37 7 12 2 12 2 nn = 96) 29.3 3 (58.3) ) (26.0) ) (15.6) ) (56.3) ) (29.2) ) (14.6) ) (1.0) ) (36.5) ) (38.5) ) (12.5) ) (12.5) ) Complete e miscarriage e (nn = 51) 30.9 9 300 (58.8) 144 (27.5) 7(13.7) ) 388 (74.5) 77 (13.7) 66 (11.8) --211 (41.2) 211 (41.2) 55 (9.8) 44 (7.8) Ectopic c pregnancy y (nn = 8) 34.0 0 33 (37.5) 44 (50.0) 11 (12.5) 33 (37.5) 22 (25.0) 33 (37.5) --66 (75.0) 11 (12.5) --11 (12.5) No o n-viable e pregnancy0 0 ( ( n = 4 9 ) ) 31.4 4 25 5 14 4 10 0 33 3 10 0 6 6 10 0 23 3 8 8 8 8 (51.0) ) (28.6) ) (20.4) ) (67.3) ) (20.4) ) (12.2) ) --(20.4) ) (46.9) ) (16.3) ) (16.3) ) NativeNative country Western-Europe e andd USA 48(50.0) 29(56.9) 3(37.5) 2 7 ( 5 5 . 1 ) Africann country 11 (11.5) 5 (9.8) 1 (12.5) 5 (10.2) Surinamm and Antilles 26(27.1) 11(21.6) 2(25.0) 9 ( 1 8 . 4 ) Otherr and unknown 11(11.5) 6(11.8) 2(25.0) 8 ( 1 6 . 3 )
aa
Values are numbers with percentages in parentheses.
bb
Non-viable pregnancies; two hydatidiform mole pregnancies included.
withh a conventional correlation analysis (threshold 0.4). In case of multi-collinearityy the variable with the highest clinical face validity and/or ease of determinationn in primary care was selected. The level of significance for the multivariatee model was set at 0.05. With the variables, identified with multi-variatee regression analyses as independent predictors, Receiver-Operating-Characteristicc (ROC) curves were made, describing the relationship between sensitivityy and specificity for each model. We regarded the point with the
ThreatenedThreatened miscarriage in general practice
lowestt sum of false-positives plus false-negatives (highest accuracy) as the best thresholdd in the ROC curve.
Inn addition, the diagnostic performance of model 2 was compared with the GPs'' estimation of the probability of a viable pregnancy being present. Thee Statistical Package of the Social Sciences (SPSS, version 9.0) was used forr all analyses.
Results s
Outt of 225 women referred by GPs for an early pregnancy assessment, 217 weree eligible for the study; eight women with a negative hCG pregnancy test weree excluded. Of these 217 women 13 were excluded; two were lost to fol-low-upp before a final diagnosis was made and 11 because of an unacceptably highh number of missing data. Of the remaining 204 women, 96 (47%) had a viablee pregnancy, 51 (25%) a complete miscarriage, 47 (23%) a non-viable pregnancy,, two (1%) a hydatidiform mole, while eight women (4%) had an ectopicc pregnancy.
Noo significant differences in patient characteristics were observed between womenn with viable pregnancies, complete miscarriages and non-viable preg-nanciess (Table 3.1). The number of women with ectopic pregnancies was too smalll for a meaningful comparison.
Inn Table 3.2 the univariate analysis according to the three specified pre-dictivee models are presented. For gynaecological examination the possibility wass given to fill out 'not performed'. Vaginal examination was performed in 57.4%% and speculum examination in 61.3% of the cases. Performed or not performedd was not different between the diagnosis groups.
Tablee 3.3 shows the results of the multivariate regression analyses.
Forr model 1, we found both stable bleeding (OR: 0.3) and increasing bleeding (OR:: 0.4) to be independent predictors of the group of viable pregnancies and completee miscarriages.
Inn model 2, independent predictors of a viable pregnancy were stable and increasingg bleeding (OR: 0.4 and OR: 0.1 respectively). The absence of blood att speculum examination was also negatively associated with a viable preg-nancyy (OR: 0.4). A negative history of passing blood clots was a predictor of a viablee pregnancy (OR: 2.2).
Forr model 3, independent predictors of a complete miscarriage were stable or increasingg bleeding (positively associated) and a negative history of passing bloodd clots (negatively associated).
Inn Figure 3.1, the ROC curves of the three models and the ROC curve for the predictionn of the GPs are shown.
CHAPTERCHAPTER 3
Tablee 3.2. Univariate logistic regression analyses in three models3. Onlyy Odds ratios with p-values < 0.10 are reported.0
AgeAge (per year) PriorPrior miscarriage 0 0 1 1 >1 1 Bleeding Bleeding decreasing g stable e increasing g Bleeding Bleeding
lesss than period similarr to period moree than period HistoryHistory of passing
yes s no o
BloodBlood colour brown n
redd and brown
Modell 1 0.99 (0.9-1 NS S NS S NS S 0) ) 1 1 0.33 (0.1-0.7) 0.44 (0.2-1.0) NS S NS S NS S bloodblood clots NS S NS S NS S NS S Modell 2 0.99 (0.9-1.0) 1 1 2.00 (1.0-4.0) 1.33 (0.6-2.9) 1 1 0.33 (0.2-0.6) 0.11 (0.0-0.2) 1 1 0.22 (0.1-0.5) 0.6(0.3-1.5) ) 1 1 3.33 (1.7-6.3) NS S NS S Modell 3 NSC C 1 1 0.44 (0.2-1.0) 0.66 (0.2-1.6) 1 1 1.77 (0.7-4.1) 7.11 (2.3-17.3) 1 1 6.22 (2.6-14.4) 3.66 (1.4-8.9) 1 1 0.22 (0.1-0.5) 1 1 2.44 (1.0-5.5) HistoryHistory of passing tissue mass
yess NS noo NS AbdominalAbdominal pain
yes s no o
CourseCourse of abdominal pain noo pain decreasing g stable e increasing g NS S NS S 1 1 2.55 (0.9-7.1) 1.00 (0.5-2.2) 2.55 (0.7-9.4) 11 1 4 . 3 ( 1 . 4 - 1 3 . 3 )) 0 . 2 ( 0 . 1 - 0 . 6 ) NS S NS S NS S NS S NS S NS S 1 1 0.5(0.3-1.0) ) 1 1 1.55 (0.6-3.8) 2.11 (1.0-4.5) 1.99 (0.7-5.8) 3 0 0
ThreatenedThreatened miscarriage in general practice
LocationLocation of abdominal pain noo pain
nott in the middle (unilateral) ) middle e difficultt to say SpeculumSpeculum examination done e nott done Modell 1 NS S NS S NS S NS S NS S NS S Modell 2 NS S NS S NS S NS S 1 1 1.66 (0.9-2.9) Modell 3 1 1 2.9(1.1-7.8) ) 1.66 (0.8-3.4) 1.4(0.4-4.8) ) NS S NS S SpeculumSpeculum examination nott done done,, no blood done,, blood SpeculumSpeculum examination nott done 1 1 0.88 (0.3-2.0) 0.55 (0.3-1.1) 1 1 2.00 (0.8-4.8) 0.44 (0.2-0.8) 1 1 0.11 (0.0-0.9) 1.66 (0.8-3.0) done,, no clots done,, clots SpeculumSpeculum examination nott done
done,, no erosion of the cervi> done,, erosion of the cervix
VaginalVaginal digital examination done e
nott done
VaginalVaginal digital examination nott done
done,, cervix open done,, cervix closed
0.66 (0.3-1.1) 0.44 (0.1-1.6) 1 1 [0.55 (0.2-1.0) 0.88 (0.3-2.3) 1 1 1.77 (0.9-3.3) 1 1 0.66 (0.2-2.3) 0.55 (0.3-1.0) 0.7(0.4-1.2) ) 0.11 (0.0-0.8) 1 1 0.66 (0.3-1.1) 1.11 (0.4-2.8) NS S NS S 1 1 0.66 (0.2-1.8) 0.66 (0.3-1.1) 0.99 (0.5-1.9) 3.2 2 (0.8-12.1) ) NS S NS S NS S NS S NS S NS S NS S NS S aa 95% CI in parentheses. bb
Model 1: viable pregnancy and complete miscarriage versus ectopic and non-viable pregnancy.. Model 2: viable pregnancy versus all other diagnoses. Model 3: complete miscarriagee versus all other diagnoses. The three models included all characteristics (Tablee 3.1) as well as the variables feeling pregnant and period of pain and bleeding untill consultation of the GP.
CHAPTERCHAPTER 3
Tablee 3.3. Multivariate logistic regression analyses in three models. a'b
Modell 1 Model 2 Model 3
Bleeding Bleeding
decreasingg 1 1 1 stablee 0.3(0.2-0.7) 0.4(0.2-0.8) 1.5(0.6-3.8) increasingg 0.4(0.2-1.0) 0.1(0.0-0.3) 4.9(1.9-12.7) HistoryHistory of passing blood clots
yes s 11 1 noo 2.2(1.0-4.6) 0.4(0.2-0.8) SpeculumSpeculum examination nott done 1 done,, no blood 1.0(0.4-2.9) done,, blood 0.4 (0.2-0.8) aa
Results expressed in Odds ratio (95% CI).
bb
Model 1: viable pregnancy and complete miscarriage versus ectopic and non-viable pregnancy.. Univariately significant variables used as input were: age, amount of bleeding,, course of abdominal pain, and blood at speculum examination. Model 2: viablee pregnancy versus all other diagnoses. As input were used the variables age, priorr miscarriage, amount of bleeding, history of passing blood clots, and blood at speculumm examination. Model 3: complete miscarriage versus all other diagnoses. Variabless used as input were prior miscarriage, amount of bleeding, history of pass-ingg blood clots, blood colour, abdominal pain, and blood at speculum examination. Duee to multicollinearity we removed four, six and six variables, respectively, from the variabless selected with univariate analyses.
Modell 1: The optimal point in the ROC curve of this model, which tried to distinguishh between viable pregnancies together with complete miscarriages andd other diagnoses, is the point with a sensitivity of 80% and a specificity of 40%,, which resulted in a positive likelihood ratio (LR + ) of 1.3. The pre-test probabilityy of 72% (percentage of viable pregnancies and complete miscar-riagess in the study) changed to a post-test probability of 77%.
Modell 2: The optimal point in the ROC curve of this model, which predicted thee presence of viable pregnancies, showed a sensitivity of 68% and a speci-ficityy of 74% (LR+ 2.6). By using this model, the pre-test probability of a viablee pregnancy changed from 47% to a post-test value of 70%.
Modell 3: The best threshold in the ROC curve of this model, separating com-pletee miscarriage from all other diagnoses, has a sensitivity of 78% and a specificityy of 65% (LR 2.2 + ). The probability of a complete miscarriage increasess from 25% pre-test to a post-test value of 4 1 % .
Inn the ROC curve describing the prediction by GPs of a viable pregnancy
ThreatenedThreatened miscarriage in general practice in in 100-1 1
s o
--ar r
££ 6 0 -"55 5 4 0 2 0--// i; /
// / / / // ^ / "" / / Modell 1 Modell 2 Modell 3 Gp p T T T T 200 40 60 11 -specificity 80 0 i i 100 0Figuree 3 . 1 . ROC curves of the pre-specified models and of the GP prediction. Model 1 aimss to distinguish between viable pregnancies and complete miscarriages on the onee hand and all other diagnoses on the other, model 2 tries to predict viable preg-nanciess and model 3 distinguishes complete miscarriages from all other diagnoses. Thee GP model shows the prediction of a viable pregnancy by GPs.
beingg present, the best point, with a sensitivity of 89% and a specificity of 42%,, gives an LR+ of 1.5. This changes the pre-test probability of 47% to a post-testt probability of 58%, which is worse than the post-test probability of 70%% in model 2.
Thee weak relation between the prediction by model 2 and by the GPs' esti-matess on a viable pregnancy being present, is illustrated in a scatter plot (Figuree 3.2).
Discussion n
Inn this prospective study of pregnant women with first-trimester bleeding we triedd to develop diagnostic rules based on the patient's history and physical examinationn to enhance the efficiency of referral for ultrasonographic assess-ment.. ROC curve analysis showed that even the best of the pre-specified
CHAPTERCHAPTER 3 a. a. Ü Ü c c o o u u T5 5 0) ) i --Q. . 0.88 O—A-0 . 6 1 . 0 O A O
nr®
A A DDok n no
A A * > -A -A -A-A O 22 - A - A k - A - A A AA Gk--a>---CSO O
--m----CQO O
-m----CDD D --A --A --A --AO O
--a --a
-a--a-a -a--a-a
o o
-o--AA 1 0.22 0.4 0.6 0.8 1.0 Predictionn model 2 OO viable pregnancies other diagnoses
Figuree 3.2. Scatter plot of the prediction of a viable pregnancy by GPs versus pre-dictionn of a viable pregnancy by model 2.
modelss had insufficient discriminative power to be of any use in clinical practice. T h ee possibility t h a t GPs might be able to discriminate between viable pregnan-ciess and other diagnoses in early pregnancy on clinical grounds, was rejected. Inn model 1, which aims to identify p a t i e n t s for whom no referral is n e e d e d ( t h o s ee with c o m p l e t e miscarriages a n d viable p r e g n a n c i e s ) , s y m p t o m s r e l a t e d too t h e course and a m o u n t of bleeding have opposite significance for t h e two d i a g n o s e s ,, which most likely explains t h e insufficient d i s c r i m i n a t i o n . So a f u r t h e rr e x p l o r a t i o n of this model to distinguish b e t w e e n viable p r e g n a n c y and c o m p l e t ee m i s c a r r i a g e was not possible. H o w e v e r , models 2 and 3 , designed to identifyy e i t h e r viable pregnancies or complete m i s c a r r i a g e s , also t u r n e d out too b e of little v a l u e .
A l t h o u g hh t h e c o u r s e of b l e e d i n g was an i n d e p e n d e n t p r e d i c t o r in all t h r e e m o d e l s ,, t h e p r e d i c t i v e p o w e r was low and not discriminative enough to rely u p o nn in clinical decisions.
A n o t h e rr r e m a r k a b l e finding in our s t u d y was t h e very limited i m p a c t of t h e
ThreatenedThreatened miscarriage in general practice
gynaecologicall examination in our models. Apparently this examination is of noo diagnostic significance in first-trimester bleeding. However, we still regard thiss examination as important for evaluating the degree of bleeding (to rule outt emergency situations) and for finding products of conception in the vagi-naa and the cervical os. In our study, in which GPs were asked to perform as theyy did in normal practice, vaginal examination was only performed in 57.4%% and speculum examination in 61.3% of the cases. In a survey in Wessexx about management of bleeding in early pregnancy 24% of the GPs reportedd that they never performed a vaginal examination. A speculum examinationn was never done by 38%.2
Iff in our study gynaecological examination was performed in all cases, we can nott exclude that the multivariate analysis had given more support for this examination. .
AA potential drawback of our study was the delay between the measurements off classifying variables and the ultrasonographic verification with a median timee of two days (25-75 percentiles: 1-3 days), according to normal clinical practicee in the Netherlands. Perhaps a better diagnostic performance could bee achieved, especially in case of a complete miscarriage (model 3), without delayy between GP consultation and sonographic assessment. However, it is nott likely that the very low post-test probability of model 3 will increase in suchh a way that clinical relevance might be reached. Also such a procedure settingg may be feasible for research purposes, but has little relevance for practicess without direct access to ultrasonographic facilities.
Wee were unable to pay specific attention to ectopic pregnancies, because of thee limited number of cases. Earlier studies showed that a physical examina-tionn is insufficient too for diagnosing an ectopic pregnancy in the majority of cases.6 77 Highly suspect cases were usually referred directly to the gynaecolo-gyy department and thus not included in our study. Of the eight ectopic preg-nanciess diagnosed at our unit, only two were referred for suspected ectopic pregnancy.. Three ectopic pregnancies were treated surgically (including the twoo suspected cases), four self-limiting cases with declining serum hCG con-centrationss were managed expectantly, and one ectopic pregnancy was treat-edd with a single dose of methotrexate. The question as to whether it is accep-tablee to withhold an immediate ultrasonographic assessment from patients withh first-trimester bleeding, thereby postponing the diagnosis of ectopic pregnancy,, can not be answered from our data.
Chungg found discrepancy in uterine size to be the most significant predictor off non-viable pregnancies.8 We also included this item in our Case Record Form,, but could not confirm its prognostic value. In our study GPs did not carryy out a vaginal examination in 37% of the cases. In the remaining 63% of thee cases, GPs reported the uterine size to be according to gestational age in 32%,, indeterminate in 23%, while a discrepancy in uterine size was reported inn only 8%. Our study differs from Chung's in both its setting (primary care
CHAPTERCHAPTER 3
versuss secondary care) and in its analyses. We analysed all cases, including ectopicc and molar pregnancies in order to resemble as much as possible the situationn in which the physician has to make a decision in daily practice. The variabless analysed in our study all derive from the standard management of womenn with first-trimester bleeding and can easily be obtained.
Wee conclude that in a primary care setting clinical symptoms and physical examinationn are not useful in predicting a diagnosis in first-trimester bleed-ing.. To establish a certain diagnosis, sonographic assessment is required.
References s
1.. Everett C. Incidence and outcome of bleeding before the 20th week of pregnancy: prospectivee study from general practice. BMJ 1997;315:32-4.
2.. Everett C, Ashurst H, Chalmers I. Reported management of threatened miscarriage by generall practitioners in Wessex. BMJ 1987;295:583-6.
3.. Coulam CB, Goodman C, Dorfmann A. Comparison of ultrasonographic findings in spontaneouss abortions with normal and abnormal karyotypes. Hum Reprod 1997;12:823-6. .
4.. Deaton JL, Honore GM, Huffman CS, Bauguess P. Early transvaginal ultrasound followingg an accurately dated pregnancy: the importance of finding a yolk sac or fetal
heartt motion. Hum Reprod 1997;12:2820-3.
5.. Mol BW, Hajenius PJ, Engelsbel S, et al. Serum human chorionic gonadotropin measurementt in the diagnosis of ectopic pregnancy when transvaginal sonogra-phyy is inconclusive. Fertil Steril 1998;70:972-81.
6.. Buckley RG, King KJ, Disney JD, Gorman JD, Klausen JH. History and physical examinationn to estimate the risk of ectopic pregnancy: validation of a clinical pre-dictionn model. Ann Emerg Med 1999;34:589-94.
7.. Mol BW, Hajenius PJ, Engelsbel S, et al. Should patients who are suspected of hav-ingg an ectopic pregnancy undergo physical examination? Fertil Steril 1999;71:155-7. 8.. Chung TK, Sahota DS, Lau TK, Mongelli JM, Spencer JA, Haines CJ. Threatened
abor-tion:: prediction of viability based on signs and symptoms. Aust NZ J Obstet Gynaecol 1999;39:443-7. .
CHAPTERR 4
Managementt of miscarriage
aa randomised controlled trial of expectant
managementmanagement versus surgical evacuation
Margreett Wieringa-de Waard, Jeroen Vos, Gouke J. Bonsel, Patrickk J. E. Bindels, Willem M. Ankum
Submittedd for publication
Abstract t
OBJECTIVESS To determine safety and efficacy of either expectant management or surgicall evacuation for miscarriages.
DESIGNN Randomised controlled trial. SETTINGG Two Amsterdam hospitals.
PARTICIPANTSS Patients with a non-viable pregnancy or incomplete miscarriage at a gestationall age of less than 16 completed weeks.
INTERVENTIONN Allocation to either expectant management or surgical evacuation. Patientss who refused randomisation were managed according to their own preference. MAINN OUTCOME MEASURES Safety, complications, efficacy, success of intended treatment,, duration of clinical symptoms.
RESULTSS One hundred and twenty-two patients were randomised and 305 were managedd according to their choice. No differences were found in the number of emergencyy curettages and complications between expectant management and sur-gicall evacuation between the randomised groups. Intention-to-treat analysis showedd similar efficacy (92% versus 100%) for the randomised groups after six weeks.. The success rate of intended treatment at six weeks was 30/64 (47%) in womenn allocated to expectant management with a median time to evacuation after inclusionn of 19 days. After seven days, 37% of women in this group had a sponta-neouss complete miscarriage. Results in the preference groups were comparable withh the randomised groups.
CONCLUSIONSS In randomised patients the efficacy of expectant management and surgicall evacuation is similar. A waiting period of seven days after diagnosis may preventt about 40% of surgical procedures without loss of safety.
CHAPTERCHAPTER 4
Introduction n
Inn many countries surgical uterine evacuation is the standard treatment for womenn with a miscarriage. Expectant management has been advocated as an alternativee in several observational studies in a primary care setting.1 2 Just onee randomised clinical trial compared both management options in a hospi-tall setting, suggesting the outcomes to be similar.3 However, the duration of expectantt management in this study was restricted to only three days. From aa clinical and health policy point of view we regard this information as impor-tantt but insufficient to base guidelines and individual decisions upon. A longer periodd of expectant management and more information on the preference of patientss are necessary. Patients' preferences might even play a decisive role iff no substantial differences exist in the effectiveness, costs and availability of bothh treatment modalities.
Wee conducted a randomised controlled trial comparing expectant management withh surgical evacuation. Eligible women who refused randomisation because off a strong preference for either surgery or expectant management were man-agedd according to their choice, and evaluated similarly to randomised patients. Byy using this particular study design, we aimed to enhance the generalisability off our findings.
Methods s
Protocol Protocol
Thee study was conducted between April 1998 and September 2000 in two Am-sterdamm hospitals: the Academic Medical Center and the Onze Lieve Vrouwe Gasthuis.. General practitioners working in the health district covered by these twoo hospitals were asked to refer women with first-trimester vaginal bleeding forr an ultrasound assessment. In addition, all women attending the emergen-cyy departments or the outpatient clinics of both hospitals because of first-trimesterr vaginal bleeding were also asked to participate.
Patientss with an established diagnosis of a non-viable pregnancy or incomplete miscarriagee at a gestational age of less than 16 completed weeks were includ-edd in the study. Transvaginal sonographic criteria for non-viability were: a meann gestational sac diameter > 15 mm without a measurable embryonic pole,, an embryo without cardiac activity, or a gestational sac diameter < 15 mm,, not showing any growth after a seven-days interval.4-5 An incomplete miscarriagee was diagnosed in case of ultrasound evidence of retained products off conception (RPOC) > 15 mm anteroposterior (AP) diameter. All transvaginal-scanss were performed by trained physicians using a transvaginal 6.5 MHz sonographicc probe (Hitachi Corporation, Tokyo, Japan).
