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Myomectomy is the gold standard to preserve fertility with the best pregnancy outcome
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Fibroid ablation may be offered to women where there are contraindications to surgery
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Uterine artery embolisation is associated with poor pregnancy outcomes.
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There are too few reported pregnancies after ulipristal acetate to assess.
Abstract
The aim of this study was to compare pregnancy outcomes after medical (ulipristal acetate [UPA]), surgical (myomectomy) and radiological (uterine artery embolization [UAE] or thermal ablation) therapy for fibroids in women. A systematic review was conducted and ScienceDirect, PubMed, Web of Science and Cochrane Library databases were thoroughly searched from 2000 to 2018. Only primary research was included with independent extraction of articles by two reviewers, using a standardized form. Data were available on 12 pregnancies after treatment with UPA, 1575 after myomectomy, 424 after UAE and 420 after fibroid ablation. Results after UPA therapy were not included in the statistical analysis owing to the limited number of cases; most were ongoing pregnancies. High rates of successful pregnancy were seen after myomectomy (75.6%) and fibroid ablation (70.5%), whereas pregnancies after UAE had the lowest live birth rates (60.6%) and highest miscarriage rates (27.4%) (both P < 0.001 versus other treatments). In conclusion, myomectomy is associated with better pregnancy outcomes than other fertility-preserving treatments for fibroids. At present, UPA is the only medical treatment for fibroids; however, the evidence on pregnancy outcome is limited. In the absence of randomized controlled trials, these data may be of benefit in advising patients about future pregnancy.
Fibroids (leiomyomata) are the most common benign tumours of the pelvis in women of reproductive age group and are more commonly seen in African–American women (
). In addition to pain and abnormal uterine bleeding, fibroids have been associated with infertility and a higher risk of miscarriage, placenta praevia, fetal malpresentation, preterm labour, the need for caesarean section and peripartum haemorrhage (
). Present evidence indicates that submucosal fibroids of any size and intramural fibroids wider than 4 cm in diameter significantly impair fertility and results of assisted reproductive therapy (
The appropriate approach for the treatment of fibroids depends on multiple factors, including age, fertility wishes, the severity of symptoms and clinical presentation, the type and size of the fibroids, and the woman's overall health, with an emphasis on medical and surgical history or ongoing treatments (
Abdominal myomectomy: A retrospective review of determinants and outcomes of complications at the University of Ilorin Teaching Hospital, Ilorin, Nigeria.
Alternative medical treatment with ulipristal acetate (UPA) and radiological procedures, including uterine artery embolization (UAE) and fibroid thermal ablation, have been evaluated. Ulipristal acetate is a selective progesterone receptor modulator that has antiproliferative effects on the leiomyoma and endometrium (
Progesterone receptor modulator CDB-2914 down-regulates vascular endothelial growth factor, adrenomedullin and their receptors and modulates progesterone receptor content in cultured human uterine leiomyoma cells.
). It is, however, associated with potential complications, such as premature ovarian insufficiency and pelvic infection, and has a high re-intervention rate (
). Fibroid thermal ablation techniques include radiofrequency volumetric thermal ablation and high-intensity focused ultrasound, magnetic resonance imaging or laparoscopy (
); these induce targeted necrosis in the fibroid. These treatment methods are primarily indicated for women who are unable to undergo surgery for symptomatic fibroids (
Women who undergo myomectomy or UAE seem to be at higher risk during pregnancy as complications with abnormal placentation and a higher risk of the fetus being small for gestational age have been recorded (
A UK multicentre retrospective cohort study comparing hysterectomy and uterine artery embolisation for the treatment of symptomatic uterine fibroids (HOPEFUL study): main results on medium-term safety and efficacy.
It is unclear whether the risks to a subsequent pregnancy from conservative approaches to treatment of fibroids differ from surgical myomectomy. Hence, the purpose of this review is to evaluate and compare pregnancy outcomes resulting from currently used therapeutic modalities.
Materials and methods
The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) approach was used for this study. ScienceDirect, PubMed, Web of Science and Cochrane Library databases were thoroughly searched using the following key words: ulipristal acetate, myomectomy, uterine artery embolism, ablation, reduction, fibroid, leiomyoma, leiomyomata, pregnancy, infertility, pregnancy loss and IVF. The articles reviewed were inclusive of primary research, such as randomized controlled trials, cohort studies, prospective studies, retrospective studies, case control studies, case reports and case series from year 2000 to 2018. Additional studies were searched for in the references of all identified publications, including previous narrative reviews and meta-analyses.
Selection criteria
Only studies published as full-length articles were included. Pregnancy outcomes were assessed by rates of live birth, miscarriage, stillbirth, ectopic pregnancy, premature delivery and cases of uterine rupture. The exclusion criteria were women treated for indications other than fibroids and studies that used more than one treatment method.
Data extraction
All identified publications were then independently reviewed by two reviewers (SCK and ZZW). The data were independently extracted using a standardized form, and study design, patient demographics, intervention, time taken to conceive, number of pregnancies, pregnancy outcomes and complications were recorded. Discrepancies were subsequently resolved through consensus. The selection process according to PRISMA is presented in Figure 1.
Figure 1Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Flowchart.
Pregnancy outcomes after UPA, myomectomy, UAE or thermal ablation were compared. Statistical software SPSS Version 24.0.0.2 (IBM Corp., USA) was used to analyse the dataset. A chi-squared test of independence was conducted to examine the relationship between treatment modality and pregnancy outcomes. The time taken to conceive was expressed as mean and range. P < 0.05 was regarded as statistically significant.
Ethics Review Board approval was not required as all data were abstracted from previously published studies. No funding was received for this study.
Results
The initial literature search retrieved 1805 articles after duplicates were removed. One study was removed from the analysis as it only presented post-hysteroscopic myomectomy data, and therefore has significant differences in techniques used and post-myomectomy risks compared with other studies (
). Some articles were excluded for more than one criterion, in which case the first criterion according to the order methodology, intervention and insufficient results is reported. After exclusion, four randomized controlled trials, three cohort studies, 15 prospective studies, 19 retrospective studies, 11 case series and 16 case reports were included; the PRISMA flowchart is presented in Figure 1. Details of the study type included for each treatment modality is presented in Figure 2. Overall, data were available from 12 pregnancies after treatment with UPA, 1575 after myomectomy, 424 after UAE and 420 after ablation (Figure 2).
Figure 2Studies included by conservative treatment modality.
Case report: successful pregnancy after combined preoperative pretreatment with ulipristal acetate and laparoscopic myoma enucleation in deep-seated cervical posterior wall myoma and desire to have children.
). Of the 12 pregnancies (Table 1), six (50.0%) resulted in live birth, four (33.3%) were ongoing and two (17.7%) ended in miscarriage. Of the six livebirths, two babies were delivered prematurely at 34 and 36 weeks, respectively (
), whereas the others were delivered at term. No cases of intrauterine growth retardation or congenital malformation were recorded. The time to conception after UPA was reported in seven cases, and ranged from 1–3.5 months (
Case report: successful pregnancy after combined preoperative pretreatment with ulipristal acetate and laparoscopic myoma enucleation in deep-seated cervical posterior wall myoma and desire to have children.
A total of 1575 pregnancies after myomectomy were identified. The surgical approach was reported in 1449 women: 1047 women underwent laparoscopic myomectomy, 107 operations were robotic assisted, 51 were open surgeries or laparotomies, 26 were mini-laparotomies, whereas 218 cases were not clearly stated (Table 2). These pregnancies resulted in 1191 live births (75.6%), 42 ongoing pregnancies (2.7%), 299 miscarriages (19.0%), 24 ectopic pregnancies (1.5%) and two stillbirths. Of the 17 pregnancies that were terminated (1.1%), three were caused by fetal anomaly, one was caused by chromosomal abnormalities, whereas the remaining terminations were for either social or maternal medical reasons (
). Sixty-three preterm deliveries (5.3%) were reported, in which eight were of extreme prematurity of less than 34 weeks with one case at 24 weeks. Overall, 60.8% were delivered by caesarean section versus 39.2% delivered vaginally.
Includes those who did not intend pregnancy. CS, caesarean section; HM, hysteroscopic myomectomy; LM, laparoscopic myomectomy; LSCS, lower segment caesarean section; ML, mini-laparotomy; NR, not reported; OM, open/laparotomic myomectomy; RM, robot-assisted myomectomy; VD, vaginal delivery.
Includes those who did not intend pregnancy. CS, caesarean section; HM, hysteroscopic myomectomy; LM, laparoscopic myomectomy; LSCS, lower segment caesarean section; ML, mini-laparotomy; NR, not reported; OM, open/laparotomic myomectomy; RM, robot-assisted myomectomy; VD, vaginal delivery.
Includes those who did not intend pregnancy. CS, caesarean section; HM, hysteroscopic myomectomy; LM, laparoscopic myomectomy; LSCS, lower segment caesarean section; ML, mini-laparotomy; NR, not reported; OM, open/laparotomic myomectomy; RM, robot-assisted myomectomy; VD, vaginal delivery.
Includes those who did not intend pregnancy. CS, caesarean section; HM, hysteroscopic myomectomy; LM, laparoscopic myomectomy; LSCS, lower segment caesarean section; ML, mini-laparotomy; NR, not reported; OM, open/laparotomic myomectomy; RM, robot-assisted myomectomy; VD, vaginal delivery.
a Twenty-four ectopic pregnancies, 17 terminations and two stillbirths.
b Includes those who did not intend pregnancy.CS, caesarean section; HM, hysteroscopic myomectomy; LM, laparoscopic myomectomy; LSCS, lower segment caesarean section; ML, mini-laparotomy; NR, not reported; OM, open/laparotomic myomectomy; RM, robot-assisted myomectomy; VD, vaginal delivery.
). One out of 10 woman had undergone open myomectomy, one had undergone robotic-assisted myomectomy and the remaining eight had undergone laparoscopic myomectomy. Two of the women treated with laparoscopic myomectomy had undergone an additional laparotomy for myomectomy and for corneal reanastomosis afterwards. One uterine rupture occurred after a road traffic accident at 24 weeks in a twin pregnancy. Three cases occurred at term, whereas six cases occurred before 35 weeks (range 24–34). The myomectomy-to-conception interval was only reported in four cases, with one patient conceiving 18 weeks after surgery. The other three women conceived more than 12 months from surgery, at 14, 18 and 36 months (
). Uterine rupture occurred in two women in whom the uterine cavity had been breached and five women in whom the uterine cavity was not entered, although two of them had undergone repeat laparotomy. The remaining three cases did not indicate whether the uterine cavity was breached (
Overall, the average time from surgery to pregnancy was 13.0 months (range 5–24 months). This contrasts with the only case series of pregnancy after hysteroscopic myomectomy, the time to pregnancy was shorter in women with no intramural fibroids at 3.1 months (range 2–5 months) compared with 4.8 months in those with intramural fibroids (P = 0.05) (
From the 19 studies of 424 pregnancies (Table 3), the overall live birth rate, ongoing pregnancy rate and miscarriage rate were 60.6% (257/424), 4.0% (17/424) and 27.4% (116/424), respectively. Ten (2.4%) ectopic pregnancies and three (0.7%) stillbirths were reported, whereas the remaining 21 (5%) pregnancies were terminated (
A UK multicentre retrospective cohort study comparing hysterectomy and uterine artery embolisation for the treatment of symptomatic uterine fibroids (HOPEFUL study): main results on medium-term safety and efficacy.
). Overall, 27 premature deliveries were reported, whereas the rest were at term. Most deliveries were by caesarean section (63.5%) compared with 36.5% by vaginal delivery. In 17 reports of placenta abnormalities in 424 pregnancies after UAE, five cases of placenta praevia were reported, four placenta accreta, one placenta membranacea, one placental abruption, and the others were uncategorized (
). No cases of uterine rupture or intrauterine growth restriction were reported. The average time taken for women to conceive after UAE was 15 months (range 9–36 months) (
A UK multicentre retrospective cohort study comparing hysterectomy and uterine artery embolisation for the treatment of symptomatic uterine fibroids (HOPEFUL study): main results on medium-term safety and efficacy.
A UK multicentre retrospective cohort study comparing hysterectomy and uterine artery embolisation for the treatment of symptomatic uterine fibroids (HOPEFUL study): main results on medium-term safety and efficacy.
A total of 420 pregnancies were reported after fibroid ablation, resulting in 296 live births (70.5%), 50 miscarriages (11.9%), 39 terminations (9.3%) and 35 ongoing pregnancies (8.3%) (Table 4). All terminations were elective and none were stated to be caused by fetal abnormality (
). Eight successful cases of placental abnormalities were reported (seven placenta praevia and one placental insufficiency) and no cases of stillbirth or ectopic pregnancy (
). A total of 15 preterm deliveries were reported. Most pregnancies were delivered vaginally (61.6%), with the remaining 38.4% by caesarean section. No cases of uterine rupture were reported (
Magnetic resonance imaging-guided focused ultrasound surgery for symptomatic uterine fibroids: estimation of treatment efficacy using thermal dose calculations.
Eur. J. Obstet. Gynecol. Reprod. Biol.2013; 169: 304-308
Comparing focused ultrasound and uterine artery embolization for uterine fibroids-rationale and design of the Fibroid Interventions: reducing symptoms today and tomorrow (FIRSTT) trial.
Magnetic resonance imaging-guided focused ultrasound surgery for symptomatic uterine fibroids: estimation of treatment efficacy using thermal dose calculations.
Eur. J. Obstet. Gynecol. Reprod. Biol.2013; 169: 304-308
Magnetic resonance imaging-guided focused ultrasound surgery for symptomatic uterine fibroids: estimation of treatment efficacy using thermal dose calculations.
Eur. J. Obstet. Gynecol. Reprod. Biol.2013; 169: 304-308
As only 12 pregnancies after UPA treatment were reported, it was not included in the statistical analysis. No significant difference was observed in the percentage of live birth in women who received myomectomy or ablation (75.6% versus 70.5%; P > 0.05). After UAE, however, the live birth rate was significantly lower at 60.6% (P < 0.001) compared with both myomectomy and ablation groups. Pregnancies after UAE also showed the highest rate of miscarriage (27.4%), followed by myomectomy (19.9%) and ablation (11.9%) (P < 0.001).
Five cases of stillbirth were reported, three after UAE and two after myomectomy (
). Abnormal placentation was more common after UAE at 4% (n = 17) than after myomectomy (0.38%; n = 6) or after ablation (1.9%; n = 8; P < 0.001). No placental abnormalities were reported in women who underwent UPA therapy. Ten cases of uterine rupture were recorded after myomectomy and none after UPA, UAE or ablation therapy (
This is the first review of pregnancy outcomes comparing medical, radiological and surgical conservative treatment of uterine fibroids, and is limited by the quality of the evidence available, with significant risk of bias. It seems, however, that the live birth rate is highest after myomectomy (75.6%) and ablation (70.5%). Pregnancies after UAE had the lowest live birth rate of 60.6% and the highest rate of miscarriage, at 27.4%, compared with the general population rate of 10–20% (
). Live birth rates after UPA were excluded from the statistical analysis owing to the limited number of cases. The stillbirth rates were low (range: 0–3%) with all treatments and are similar to the global average stillbirth rate of 2% (
Lancet Stillbirth Epidemiology Investigator G National, regional, and worldwide estimates of stillbirth rates in 2015, with trends from 2000: a systematic analysis.
At present, myomectomy is the gold-standard fertility preservation treatment for fibroids and seems to have an advantage over UPA, UAE or ablation for pregnancy outcomes. Surgical complications, such as major haemorrhage requiring transfusion and infections, do occur (
Practice Committee of American Society for Reproductive Medicine in collaboration with Society of Reproductive Surgeons Myomas and reproductive function.
Eunice Kennedy Shriver National Institute of Child HHuman Development Maternal-Fetal Medicine Units N Risk of uterine rupture and placenta accreta with prior uterine surgery outside of the lower segment.
). Myomectomy also contributes to postpartum complications by increasing the incidence of placenta praevia and placenta accreta, but the rate of placental abnormalities identified here was only 0.25% (
A UK multicentre retrospective cohort study comparing hysterectomy and uterine artery embolisation for the treatment of symptomatic uterine fibroids (HOPEFUL study): main results on medium-term safety and efficacy.
Eunice Kennedy Shriver National Institute of Child HHuman Development Maternal-Fetal Medicine Units N Risk of uterine rupture and placenta accreta with prior uterine surgery outside of the lower segment.
Maternal W.H.O.M.S.oNewborn Health Research N Postpartum haemorrhage management, risks, and maternal outcomes: findings from the World Health Organization Multicountry Survey on Maternal and Newborn Health.
). Although pregnancy outcomes after myomectomy seem to be better than with other conservative treatments for fibroids, it remains unclear whether myomectomy has a benefit for fertility (
Fibroid ablation using either ultrasonography or magnetic resonance guided focused ultrasound minimizes the damage to surrounding tissue by focusing on the area within the fibroid; however, cases of skin burns and bowel perforation have been reported (
Comparing focused ultrasound and uterine artery embolization for uterine fibroids-rationale and design of the Fibroid Interventions: reducing symptoms today and tomorrow (FIRSTT) trial.
). It is mostly limited to centrally situated fibroids, whereas fibroids usually grow peripherally. To maintain a certain safety margin, its use is limited to fibroids wider than 4 cm. Also, because of the long duration of the procedure, each treatment session is focused on a single fibroid only (
). Radiofrequency volumetric thermal ablation has shown great potential by allowing a higher number of fibroids to be treated, with less intraoperative blood loss and a faster recovery compared with laparoscopic myomectomy (
). In this analysis, fibroid ablation had comparable pregnancy outcomes to myomectomy, with similar live birth rates (70.5% versus 75.6%) and low miscarriage rates (11.9% versus 19.0%). No cases of uterine rupture were reported, and it was not associated with higher risk of placental abnormalities. Although promising, fibroid ablation through a focused energy delivery system is relatively new and more controlled trials are required to evaluate its potential for the treatment of fibroids in women who intend pregnancy (
After UAE treatment, the disruption of normal uterine blood supply to the endometrium and placental blood supply may explain the suboptimal pregnancy outcomes after UAE compared with myomectomy, UPA and ablation therapy (
), women who had fibroids and intended to conceive yet were unable to undergo myomectomy were offered UAE. Only one out of 31 women who were actively trying for pregnancy after UAE succeeded, but the pregnancy ended in miscarriage. This analysis confirms that UAE should not be considered as first-line conservative management of fibroids for women with fertility wishes. As for UPA and ablation therapy, no controlled trials were conducted on pregnancy outcomes. Therefore, more studies need to establish whether UPA or ablation therapy are indeed associated with a lower live birth rate compared with myomectomy. Both UPA and ablation therapy, however, seem promising in women with leiomyomata who intend to have a subsequent pregnancy.
This analysis is unable to assess pregnancy rates and time taken to achieve pregnancy owing to the limited and potentially selective nature of the data, and the lack of a denominator of women who wished and tried to conceive. Research includes mostly cohort studies or cases series, and pregnancy was not a primary outcome of the randomized controlled trials that were included. In addition, women being advised to wait after surgery before conceiving may also have an effect (
), which may also apply to treatment with ablation or UAE. The lack of direct comparisons of different fibroid treatment within studies where pregnancy is desired by a significant proportion of women is, however, the most important limitation to this analysis, as systematic differences may exist in the characteristics of women offered the various treatments in the studies reported.
In conclusion, myomectomy seems to be the treatment modality of choice for women wishing conservative management of fibroids with a view to subsequent pregnancy, although infrequent but specific risks of uterine rupture and abnormal placentation occur. Pregnancy outcomes were similar after fibroid ablation but were worse after UAE, and too few pregnancies have been reported after UPA treatment to allow analysis. In view of this, UAE is perhaps limited to women who have contraindications for other conservative approaches. Until large comparative randomized controlled trials or prospective cohort studies focusing on pregnancy outcomes are carried out, these data may allow more accurate counselling and decision making.
Acknowledgements
We would like to express our utmost gratitude to Mr Zhen Zhe Wong for taking up the role of the second reviewer and Ms Donna Watson for analytical resources and research methodology advice.
References
Adesina K.T.
Owolabi B.O.
Raji H.O.
Olarinoye A.O.
Abdominal myomectomy: A retrospective review of determinants and outcomes of complications at the University of Ilorin Teaching Hospital, Ilorin, Nigeria.
Comparing focused ultrasound and uterine artery embolization for uterine fibroids-rationale and design of the Fibroid Interventions: reducing symptoms today and tomorrow (FIRSTT) trial.
A UK multicentre retrospective cohort study comparing hysterectomy and uterine artery embolisation for the treatment of symptomatic uterine fibroids (HOPEFUL study): main results on medium-term safety and efficacy.
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