PRENATAL DIAGNOSISPrenat Diagn 2009; 29: 520–524.Published online 23 February 2009 in Wiley InterScience(www.interscience.wiley.com) DOI: 10.1002/pd.2236

Factors influencing the duration of pregnancy terminationwith vaginal misoprostol for fetal abnormality

Jan E. Dickinson1,2* and Dorota A. Doherty1,2

1School of Women’s and Infants’ Health, The University of Western Australia, Perth, Western Australia, Australia2Women and Infants Research Foundation, Perth, Western Australia, Australia

Objective Evaluation of factors influencing the duration of second-trimester pregnancy interruption withvaginal misoprostol for fetal abnormality.

Methods All medical terminations ≥13 weeks of gestation 1/1997 to 12/2007 were prospectively identified.Cases receiving vaginal misoprostol 400 µg 6-hourly were extracted from the database and outcomes reviewed.

Results This consecutive case series comprised 1066 women. Median maternal age was 31 years [interquartilerange (IQR) 26, 36] and 15.4% had at least one prior cesarean delivery. Principal indications for terminationwere aneuploidy (37.6%), neural tube defects (15.9%) and cardiac anomalies (9.4%). Median gestation attermination was 19.5 weeks (IQR 17.9, 21). Median abortion interval was 16.1 h (IQR 12, 23.5). Lowermaternal age (median duration 17.6 vs 15.2 vs 13.6 h, age < 30 vs 30–39 vs > 40 years, p < 0.001),nulliparity (median duration 19 vs 14.3 h, nulliparous vs parous, p < 0.001) and increasing gestation (medianduration 13 vs 17.8 h, <16 vs >20 weeks, p < 0.001) were associated with abortion prolongation. Controllingfor gestation, age and parity, apart from musculoskeletal abnormalities (associated with abortion prolongation,p = 0.03), the specific fetal anomaly did not influence duration.

Conclusions Three factors: nulliparity, younger maternal age and increasing gestation, were associated withabortion prolongation. Apart from musculoskeletal abnormalities, the fetal anomaly had no impact on abortionduration. Copyright 2009 John Wiley & Sons, Ltd.

KEY WORDS: abortion; duration; fetal abnormality; misoprostol

INTRODUCTION

The prenatal identification of a serious fetal anomalymay initiate the process of pregnancy interruption, fol-lowing appropriate parental counseling and deliberation.Whilst surgical techniques of abortion may be used, theuse of medical methods is common, particularly whenpathology review of the fetus is required to further refineor clarify the precise diagnosis. Prostaglandins are thecentral abortifacient agents in medical termination andtheir actions may be augmented by prior administrationof mifepristone, a progesterone receptor antagonist (Hin-shaw et al., 1995; Jannet et al., 1996). Misoprostol hasbecome the most frequent prostaglandin used in medi-cal termination of pregnancy, principally due to its easeof administration and low cost (Dickinson et al., 1998;Lalitkumar et al., 2007).

Since 1997, misoprostol has been the principal agentused for medical termination of pregnancy for fetalabnormality at our institution, and this has provided alarge volume of experience with this prostaglandin. Dur-ing this time period we have completed three random-ized controlled clinical studies with misoprostol (Dickin-son et al., 1998; Dickinson and Evans, 2002, 2003) andthese have assisted in the development of our current

*Correspondence to: Dr. Jan E. Dickinson, School of Women’sand Infants’ Health, The University of Western Australia, 374Bagot Road, Subiaco, Western Australia 6008, Australia.E-mail: jan.dickinson@uwa.edu.au

regimen for medical termination of pregnancy. Mifepri-stone was not available in Australia until 2008 andtherefore our standard regimen was misoprostol alone.We present our experience with our standard regimenof intravaginal misoprostol, administered 6-hourly at adose of 400 µg for prenatally diagnosed fetal anomaliesover a 11-year period. We hypothesize that the durationof medical termination is not uniform for all women, butis influenced by preexisting maternal and fetal factors.The aims of this study are two-fold, firstly to assess thefactors which influence the duration of the abortion pro-cedure and secondly, to review the complications of thistermination process.

MATERIALS AND METHODS

All women admitted to King Edward Memorial Hospi-tal, Perth, Western Australia for pregnancy interruptionfollowing a prenatally identified fetal abnormality inthe second trimester between 1/1997 and 12/2007 wereprospectively identified and their information enteredonto a database. The database was interrogated to iden-tify those women who received the standard terminationprotocol of 400 µg misoprostol administered vaginally ata 6-hourly interval. The Institutional Ethics Committeeapproved this investigational protocol.

Medical termination using prostaglandins is the first-line procedure for pregnancy interruption for gestations>13 completed weeks at our institution. The process

Copyright 2009 John Wiley & Sons, Ltd. Received: 21 May 2008Revised: 20 August 2008

Accepted: 17 January 2009Published online: 23 February 2009

MISOPROSTOL FOR FETAL ANOMALY TERMINATION 521

of medical termination was conducted as an inpatientprocedure using a specific clinical pathway. Previouscesarean delivery was not considered a contraindica-tion to medical termination with misoprostol. Feticideusing intracardiac potassium was used for all nonlethalanomalies beyond 24 weeks of gestation, prior to thecommencement of the abortion process. The duration ofabortion was defined as the time from the commence-ment of misoprostol until fetal expulsion. During thestudy period, women undelivered after 48 h of miso-prostol therapy received a transcervical Foley catheterwith 2-hourly extra-amniotic PGF2α instillation, or highconcentration intravenous oxytocin, depending on thecervical status and amniotic membrane integrity. Rou-tine placental curettage was not employed. Spontaneousexpulsion of the placenta within 60 min of delivery wasawaited, with digital exploration of the uterine cavity andblunt curettage reserved for those cases where expulsiondid not occur or was incomplete on the basis of clinicalsigns and symptoms.

Continuous data was summarized using medians andIQRs. Categorical data was summarized using frequencydistributions. Univariate comparisons of outcomes wereconducted using Kruskal-Wallis and Mann-Whitney testsfor continuous data, and Fisher exact or chi-square testfor categorical outcomes. Probability estimates of timerequired until abortion was completed were estimatedusing the Kaplan-Meier method. Univariate and multi-variable Cox proportional hazards regression modelingwas implemented to evaluate effects of specific typesof fetal abnormalities on duration of pregnancy termi-nation while simultaneously adjusting for other factorssuch as maternal age, parity and total misoprostol used.The abnormality type of the shortest duration of termi-nation was used as a reference type in the multivariableCox regression model, and other abnormality types withsimilar duration intervals were combined into a singlegroup of fetal anomalies. Hazard ratios (HR) and their95% confidence intervals (CIs) were used to summarizethe effects of types of abnormality on duration of ter-mination. SPSS statistical software (SPSS version 15.0,SPSS Inc., Chicago, IL) was used for data analysis. Allhypothesis tests were two-sided and conducted at 5%significance level.

RESULTS

During the study period, 1275 women underwent a med-ical termination of pregnancy for a prenatally recognizedfetal abnormality between 13 and 28 weeks of gestation.The termination process was conducted with the insti-tutional standard misoprostol regimen of 400 µg intrav-aginally 6-hourly in 1066 women, and these form thestudy population. An additional 209 women receivedalternate dosage routes and regimens, most usually aspart of the conduct of two randomized trials, and wereexcluded from this study cohort (Dickinson and Evans2002, 2003).

The maternal characteristics of the 1066 women inthis cohort included a median maternal age of 31 years

with a range of 14 to 47 years. The median graviditywas 2 (IQR 1, 3). The majority of women had experi-enced one prior delivery [median parity 1 (IQR 0, 2)],and 424 (39.8%) were nulliparous. The median gestationat termination was 19.5 weeks (IQR 17.9, 21) with 79(7.4%) of cases occurring at <16 weeks, 589 (55.2%)at 16 to 19 weeks and 398 (37.4%) at ≥20 weeks ofgestation. Consistent with contemporary obstetric prac-tice profiles, 164 (15.4%) of women had experienced atleast one prior cesarean delivery. Thirty-three (20.1%)had two prior cesarean deliveries, six (3.7%) three pre-vious cesarean deliveries and two (1.2%) four previouscesarean deliveries.

The median abortion duration (time interval fromthe first misoprostol dose to expulsion of the fetus)was 16.1 h (IQR 12, 23.5) with a median dosageof misoprostol required to effect delivery of 1200 µg(IQR 800, 1600) (3 doses). Delivery within 12 h ofcommencement occurred in 256 (24%) and within24 hours in 821 (77%) of cases. The majority ofwomen (96.3%) had delivered within 48 h of the initialmisoprostol insertion. A prolonged abortion duration of≥48 h occurred in 39 (3.7%) of women, with 18 (50%)requiring the insertion of a transcervical Foley catheterand extra-amniotic PGF2α administration. Failure ofmedical termination occurred in five cases (0.47%) withcompletion of the abortion by dilatation and evacuationin two cases, hysterotomy in two cases and one caseof uterine rupture with laparotomy and suture repair ofthe defect after removal of the fetus from the peritonealcavity.

There were three factors that significantly impactedupon the duration of abortion: gestation, maternal ageand parity. Increasing gestation was associated with pro-longation of the abortion process (Figure 1). The medianduration of abortion at <16 weeks of gestation was13 h (IQR 10, 17.3) increasing to 17.8 h (IQR 13.1,25.4) at gestations ≥20 weeks (p < 0.001) (Figure 1).Increasing maternal age was associated with a reduc-tion in the duration of abortion (Figure 2). The medianduration of abortion was 17.8 h (IQR 13.0, 25.0) forwomen aged <30 years, 15.7 h (IQR 11.7, 23.0) forwomen of age between 30 and 39 years, and decreasedto 13.6 h (IQR 10.3, 18) for women aged ≥40 years(p < 0.001) (Figure 2). Multiparity was also associatedwith a reduction in abortion duration. The median dura-tion of abortion for nulliparous women (n = 424) was19 h (IQR 14.2, 27.2) compared with 14.3 h (IQR 10.8,20.6) for multiparous women (n = 642) (p < 0.001).In concert with the shorter duration of abortion, multi-parous women required less misoprostol to effect deliv-ery than nulliparous women [median dose 1200 µg (IQR800, 1600) vs 1200 µg (IQR 1200, 2000), multipara vsnullipara respectively, p < 0.001].

Six main diagnostic groups of fetal anomalies formedthe basis of this study cohort, with a seventh createdfor the several smaller groups of abnormalities whichon their own did not account for a large enough sam-ple size for individual analysis (denoted as “other”; n =170, 15.9%). These diagnostic groups consisted of chro-mosomal abnormalities (n = 401, 37.6%), neural tubedefects (n = 170, 15.9%), cardiac abnormalities (n =

Copyright 2009 John Wiley & Sons, Ltd. Prenat Diagn 2009; 29: 520–524.DOI: 10.1002/pd

522 J. E. DICKINSON AND D. A. DOHERTY

Figure 1—Kaplan-Meier probability curves of time required untiltermination was completed demonstrate the significant impact of ges-tation upon the duration of abortion. Relative to gestation between 16and 19 weeks, gestation <16 weeks was associated with significantlyshorter abortion duration (HR = 1.50 95% CI 1.19–1.90, p = 0.001),and gestation ≥20 weeks was associated with duration of similarlength (HR = 0.90 95% CI 0.80–1.02, p = 0.093)

Figure 2—Kaplan-Meier probability curves of time required untiltermination was completed demonstrate the significant impact ofmaternal age upon the duration of abortion. Relative to agebetween 20 and 29 years, the duration of the termination pro-cess was significantly shorter for women aged between 30 and 39(HR = 1.1595% CI 1.01–1.31, p = 0.040), and for women aged>40 years (HR = 1.6595% CI 1.30–2.09, p < 0.001) while amongwomen under 20 years of age termination process was of similarduration (HR = 0.93 95% CI 0.69–1.26, p = 0.646)

100, 9.4%), cerebral anomalies (n = 94, 8.8%), muscu-loskeletal anomalies (n = 79, 7.4%) and renal anomalies(n = 52, 4.9%). The actual fetal abnormality promptingthe termination was analyzed to ascertain if the diagnosisimpacted upon the duration of abortion. On univariableanalysis of these diagnostic groups, the prenatal diag-nosis did not significantly impact upon the duration ofabortion (Table 1). Multivariable analysis controlling forthe potential confounding effects of maternal age (rela-tive to age <30: HR = 0.95, 95% CI 0.71–1.29; HR =1.19, 95% CI 1.04–1.35, p = 0.013; and HR = 1.77,95% CI 1.37–2.28, p < 0.001 for ages 30–39 years,and ≥40 years respectively), parity (HR = 1.30; 95%

Table 1—Fetal anomaly type and duration of termination

Fetal abnormality(N = 1066)

Median duration of termination(hours)

Chromosomal abnormality 15.4 (11.6,23.5)(n = 401)Neural tube defects 16.7 (12.3,23.5)(n = 170)Cardiac anomalies 16.1 (12.3,23.1)(n = 100)Cerebral anomalies 18.9 (13.5,25.1)(n = 94)Musculoskeletal anomalies 16.6 (12.3,26)(n = 79)Renal anomalies 17.7 (12,25.6)(n = 52)Other 15.8 (11.1,21)(n = 170)

Variables presented as median (interquartile range). p = 0.104.

CI 1.14–1.48, p < 0.001 for parous women), gesta-tion (relative to gestation 16–19 weeks: HR = 1.61;95% CI 1.26–2.04, p < 0.001; and HR = 1.10; 95%CI 1.02–1.43, p = 0.185 for gestations <16 weeks andgestations ≥20 weeks respectively) and total misopros-tol dose (HR = 0.68; 95% CI 0.66–0.70, p < 0.001 pereach 200 µg dose) showed that relative to chromoso-mal, cerebral, cardiac, neural tube and renal abnormal-ities combined, musculoskeletal anomalies were asso-ciated with a prolongation of the abortion procedure(HR = 0.77; 95% CI 0.61–0.98, p = 0.032) and thediverse combination of other anomalies were associatedwith a significant reduction in the duration of abortion(HR = 1.21; 95% CI 1.02–1.43, p = 0.029) (Figure 3).

One in eight women in this study population had atleast one prior cesarean delivery and in 25% of casesthere was more than one cesarean scar. All cesareanscars were lower segment in location in this series.

Figure 3—Kaplan-Meier probability curves of time required untiltermination was completed demonstrate the impact of the specificfetal anomaly type upon duration of abortion, controlled for maternalage, parity and gestation. Neural tube defects, chromosomal, cardiac,cerebral and renal anomalies were associated with similar durationsof abortion and have been combined into a single group (“groupedanomalies”). Musculoskeletal anomalies were associated with a sig-nificant prolongation and the heterogeneous “other” grouping a sig-nificant reduction of abortion duration

Copyright 2009 John Wiley & Sons, Ltd. Prenat Diagn 2009; 29: 520–524.DOI: 10.1002/pd

MISOPROSTOL FOR FETAL ANOMALY TERMINATION 523

The median maternal age was greater in those womenwith prior cesarean deliveries [34 years (IQR 29, 38)]compared with those without a prior cesarean delivery(31 years (IQR 26, 35) (p < 0.001). There was nodifference in the median abortion duration betweenwomen with a prior cesarean delivery and those withoutit [16.5 h (IQR 12.1, 23.5) vs 14.8 h (IQR 11.1, 22.8);cesarean vs no cesarean; p = 0.101] nor in the totalmisoprostol dosage used (median 1200 µg) (p = 0.13).The only uterine rupture in this series occurred ina woman with two previous cesarean deliveries whounderwent a pregnancy termination following a prenataldiagnosis of renal agenesis. Laparotomy and suturerepair occurred, with no postoperative complications.Thus, in this cohort the incidence of uterine ruptureoverall was 0.09% and for women with a prior cesareandelivery, 0.6%.

The most frequently observed abnormal feature duringthe termination process was maternal fever, a recognizedside-effect of misoprostol. A temperature ≥37.8 ◦C wasrecorded in 389 (36.5%) women. There was a signifi-cant association between maternal fever and duration ofabortion. Duration of abortion for women with a max-imum temperature ≥37.8 ◦C was significantly shorter(median 15 h (11,21.5) compared with those cases witha temperature ≥37.8 ◦C [median 18.3 h (IQR 13.5, 25.6)(p < 0.001)]. The median blood loss was 100 mL (IQR50, 200) and 100 women (9.4%) experienced a peri-partum blood loss of ≥500 mL. There was no impactof gestation upon the incidence of maternal blood loss≥500 mL (p = 0.17). Blood transfusion was requiredfor 25 women (2.3%).

Placental retention, requiring manual removal or suc-tion curettage in the operating room, occurred in 332(31.1%) of cases. Maternal age and gestation at termi-nation were significantly associated with the requirementfor surgical removal of the placenta (Table 2). The inci-dence of placental retention was significantly greaterat the lower gestational ages. Placental retention at<16 weeks was 53.2% (n = 42), 16 to 19 weeks 40.6%(n = 239) and ≥20 weeks 12.8% (n = 51) (p < 0.001).Overall blood loss and the need for blood transfusionwere significantly greater when the placenta was retained(Table 2).

DISCUSSION

Prenatal screening is a fundamental component of mod-ern obstetric practice and has enabled millions of womento progress through a pregnancy with confidence inregard to the structural integrity of their fetus. On occa-sions, however, a significant fetal abnormality will bediagnosed and some women will elect to interrupt thepregnancy following counseling about the potential out-comes of such conditions. The majority of pregnancyterminations for fetal abnormalities occur after the firsttrimester of pregnancy, and medical techniques of abor-tion are frequently employed, especially when autopsy toclarify the precise diagnosis is required. Prostaglandinsare the mainstay of medical terminations, either in iso-lation or following priming by mifepristone (Lalitkumar

Table 2—Characteristics of cases in which the placenta wasretained compared with those with spontaneous expulsion

Not retained(n = 734)

Retained(n = 332) p

Maternal age(years)

31 (26,35) 32 (27,36) 0.025

Parity 1 (0,2) 1 (0,2) 0.713Gestation(weeks)

19.8 (18.3,21.3) 18.6 (17,19.7) <0.001

Abortionduration(hours)

16.1 (11.8,23.4) 16.6 (12.2,23.8) 0.2

Blood loss(milliliters)

100 (50,150) 200 (100,425) <0.001

Bloodtransfusion

4 (0.5%) 21 (6.3%) <0.001

Variables are presented as n (%) or median (interquartile range) asappropriate.

et al., 2007). We have in general used a standard regimenof misoprostol administered vaginally since 1997 andthese data represent our experience with this medication.

There were three main factors which influenced theduration of abortion in our study: gestation, maternalage and parity. The median duration of abortion wasinfluenced significantly by the gestation at which themisoprostol was administered. Increasing gestation wasassociated with an increasing duration of the abortioninterval, presumably secondary to the need for greatercervical dilatation due to the larger fetal size. Multi-parous women responded to the vaginal misoprostol witha shorter induction–delivery interval than nulliparouswomen, a phenomenon also observed by prior stud-ies using pretreatment with mifepristone (Ashok et al.,2004; Goh and Thong, 2006). The median abortion dura-tion was reduced by 25% in multiparous women com-pared with nulliparous women. Differences in cervicalcompliance have been postulated to explain this phe-nomenon (Goh and Thong, 2006).

The majority of pregnancies in whom a medical ter-mination was commenced, the vaginal delivery of thefetus resulted. In five cases (0.47%) alternative meth-ods were required to achieve evacuation of the fetus,either due to failure of the misoprostol to achieve vaginaldelivery (four cases) or uterine rupture (one case). Thus,in 99.5% of cases a successful medical termination ofpregnancy was achieved, an important outcome for cen-ters where skills in surgical evacuation may be limited.In addition, with the increasing incidence of cesareandelivery in modern obstetric practice, one in six womenhad at least one prior cesarean delivery in our studypopulation. Although there is no method which is risk-free in this setting, we noted only one scar rupture withour protocol in which women were not excluded dueto prior cesarean deliveries. It is important to note thatthere was more than one prior cesarean delivery in 25%of cases with prior casarean birth. Our group and othershave previously reported outcomes for women with prioruterine surgery undergoing misoprostol termination ofpregnancy in the second trimester, and these additionalcases support our opinion that misoprostol termination

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524 J. E. DICKINSON AND D. A. DOHERTY

is a reasonable option in the context of fetal abnormal-ity with previous cesarean delivery (Daskalakis et al.,2005; Dickinson 2005; Daponte et al., 2006). There isan inherent risk of uterine rupture in any terminationprocedure. The available data supports no excess of thisbasal complication risk for women with prior cesareandeliveries using misoprostol in the second trimester.

Consistent with our prior experience in randomizedcontrolled trials (Dickinson et al., 1998; Dickinson andEvans, 2002, 2003) the need for surgical removal of theplacenta was high, with almost 1 : 3 women requiringintervention. Increasing gestation was associated with areduction in the risk of placental retention, in the pres-ence of a uniform third stage management protocol, per-haps secondary to maturation of the uterine response todelivery as gestation advances. Increasing maternal agewas associated with an increased requirement for surgi-cal intervention in our series and this feature has alsobeen reported with mifepristone priming (Ashok et al.,2004). Complications with placental retention and post-delivery blood loss were the two main maternal compli-cations of misoprostol in our series. The phenomenon ofplacental retention appears to be a characteristic of ter-mination with prostaglandins alone, being an even morefrequent occurrence with the use of cervagem. A meta-analysis of vaginal misoprostol and cervagem in medicaltermination reported a relative risk of 0.71 (95% CI0.53–0.95) for vaginal misoprostol compared with cer-vagem in the requirement for surgical evacuation of theplacenta (Dodd and Crowther, 2006).

The fetal abnormality prompting the termination ofpregnancy was analyzed to assess if this impacted on theinduction–delivery interval. It has been previously sug-gested that fetal neural tube defects and hydrocephalusmay prolong the duration of termination (Nesbitt andGiles, 1996). In the retrospective series of Nesbitt andGiles, the mean duration of termination was 31.7 hfor fetuses with hydrocephalus or neural tube defects(n = 88), compared with 19.7 h for other fetal anoma-lies (n = 75). The authors of this study used cervagem astheir primary abortifacient. Recently Lo et al. reviewedthe impact of trisomy 21, trisomy 18 and hemoglobinBarts on second-trimester abortion duration (Lo et al.,2008). No consistent relationship between these threediagnoses and abortion duration was found, althoughtrisomy 21 was associated with an increased risk ofplacental retention. We analyzed the indications for ter-mination in diagnostic groups of at least 50 cases, andcould demonstrate no consistent effect of the principalfetal abnormality impacting upon the induction–deliveryinterval. Recognizing the impact of gestation, maternalage and parity, we assessed the effect of fetal abnormal-ity on the abortion duration whilst controlling for thesepotential confounders. Apart from a prolongation of thedelivery interval for fetal musculoskeletal anomalies,there was no significant impact of the specific anomalyprompting the termination upon the duration of abortion.There was no evidence that fetal neural tube defects orcerebral abnormalities prolonged the abortion procedurewith misoprostol alone.

CONCLUSION

In this large series of second-trimester medical termi-nation of pregnancy for fetal abnormality with vaginalmisoprostol alone the successful completion of the abor-tion process was high and the duration of the procedurewas strongly related to gestation, maternal age and par-ity. Apart from musculoskeletal abnormalities, the fetalabnormality prompting the termination did not signifi-cantly impact upon the duration of abortion. The require-ment for surgical evacuation of the uterus was high, andfacilities for timely removal of the placenta should beavailable in units using this regimen. This informationis of value to clinicians in counseling women prior topregnancy interruption for fetal abnormality in regardto maternal expectations of the duration and potentialcomplications of this procedure.

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Copyright 2009 John Wiley & Sons, Ltd. Prenat Diagn 2009; 29: 520–524.DOI: 10.1002/pd