Infertility, infertility treatment, and fetal growth restriction

OBJECTIVE: To examine the association between infertility, with or without treatment, and fetal growth, as well as perinatal and infant mortality. METHODS: From the Danish National Birth Cohort (1997-2003), we identified 51,041 singletons born of fertile couples (time to pregnancy 12 months or less), 5,787 born of infertile couples conceiving naturally (time to pregnancy more than 12 months), and 4,317 born after treatment. We defined small for gestational age (SGA) as the lowest 5% of birth weight by sex and gestational age. RESULTS: Crude estimates suggested an increased risk of perinatal mortality and SGA among infertile couples (treated and untreated), but the odds ratios (ORs) of perinatal mortality among infertile couples were attenuated after adjustment for maternal age and body mass index (1.32, 95% confidence interval [CI] 0.95-1.84 among untreated and 1.26, 95% CI 0.86-1.85 among treated couples). The elevated risk of SGA among infertile couples persisted after adjustment for maternal age, parity, and smoking (OR 1.24, 95% CI 1.10-1.40 among untreated, and OR 1.40, 95% CI 1.23-1.60 among treated). The risk of SGA increased with time to pregnancy, and a longer time to pregnancy was associated with a small reduction in birth weight across the whole distribution. CONCLUSION: The increased risk of SGA observed among infertile couples with or without infertility treatment suggests that infertility may be a risk factor for intrauterine growth restriction. Treatment per se may have little effect on fetal growth. A small-to-moderate increased risk of perinatal mortality in infertile couples cannot be ruled out due to the small number of cases. LEVEL OF EVIDENCE: II.     

Intrauterine insemination with controlled ovarian stimulation for treatment of infertility: an audit of a new IUI programme in a low resource setting.

This study is an audit of a new intrauterine insemination (IUI) programme in a low resource private fertility practice in southeast Nigeria. IUI was performed using a Wallace flexible catheter 1 day before or on the day of ovulation after ovarian stimulation with clomiphene citrate. The 18 couples treated had either male (16) or unexplained (2) infertility. The women were between 25 and 49 years and 13 (72.2%) of the couples had primary infertility while the duration of infertility ranged from 3 to 15 years. All the women had tubal patency confirmed by laparoscopy and dye test before undergoing IUI. The pregnancy rates per couple and per insemination cycle and the effect of maternal age and source of semen (partner or donor) were determined. The 18 couples had a total of 48 treatment cycles and five became pregnant (confirmed by early ultrasound scan) giving a pregnancy rate of 27.8% per couple or 10.4% per treatment cycle. The pregnancy rate was 41.7% per couple, 15.6% per treatment cycle for the donor group and 0% for the partner group (p<0.01). Poor sperm quality was responsible for the poor pregnancy outcome in the partner group. The pregnancy rate per couple was 36.5% in women<35 years compared with 14.3% in those>or=35 years (p=0.02). Similarly, the cycle pregnancy rate was significantly higher in women<35 years (16.0% vs 4.4%; p<0.02). There was one (20%) case of twin pregnancy and no miscarriage. Four of the women had a live birth (80%) at term and one had an intrauterine death following severe pre-eclampsia at 29 weeks' gestation. In conclusion, the overall couple and cycle pregnancy rates at our centre is comparable with the rates in many centres. Younger age and good quality semen are good indicators of a successful outcome. Infertile couples should therefore be evaluated early and recommended for this treatment option before advanced female age.     

Gamete intrafallopian transfer: A treatment for long-standing infertility

Gamete intrafallopian transfer (GIFT) has been described by Asch et al. (1,2) as an alternative technique in the treatment of infertile couples. At the University of the Orange Free State, the GIFT technique was introduced in July 1985, and during phase I, 31 patients were treated by means of GIFT. All patients had had at least six cycles of ovulation induction with human menopausal gonadotropin (hMG) and human chorionic gonadotropin (hCG). Their diagnoses were anovulation (3 patients), mild endometriosis (17 patients), and unexplained infertility (11 patients). All husbands' semen analyses were normal. Of the 31 patients, 3 failed, due to spontaneous ovulation before laparoscopy (1 patient) and unsuccessful follicle aspiration at laparoscopy with no oocytes found (2 patients). Four ongoing pregnancies resulted from the remaining 28 patients. This represents a pregnancy rate of 14.29% per laparoscopy (including the failures). The patients who became pregnant had had infertility treatment for 5, 6, 8, and 8 years, respectively. GIFT therefore appears to be a promising method of treatment for long-standing infertility.     

Laparoscopy for the treatment of unexplained infertility

Aim:  To determine the best treatment for unexplained infertility.
Methods:  A retrospective study was used to examine Japanese women with unexplained infertility that had undergone laparoscopy. The main outcome measure of the study was the rate of pregnancy after laparoscopy.
Results:  One hundred and thirty-eight women diagnosed with unexplained infertility received laparoscopy and as a result 55 women had their diagnosis of unexplained infertility confirmed. There were no statistically significant differences between the women who became pregnant after laparoscopy in terms of duration of infertility, duration of treatment or age. The pregnancy rate of women with unexplained infertility was 56.4%, with 90% of these pregnancies achieved within the first 6 months. There were 64 women with minor endometriosis considered to be suffering from unexplained infertility before laparoscopy. The characteristics of the patients in the unexplained infertility group and in the minor endometriosis group were similar, but patients with minor endometriosis were found to have a lower pregnancy rate compared to those with unexplained infertility (35.9% vs 56.4%; P  = 0.02).
Conclusions:  The effective period after laparoscopy appears to be 6 months. Assisted reproductive technology should be considered after that time. Pregnancy rates were low in women with minor endometriosis compared with unexplained infertility. It is important to clarify the cause of infertility using laparoscopy. (Reprod Med Biol 2006; 5 : 59–64)     

The better prognosis in secondary infertility is associated with a higher proportion of ovulation disorders

To determine the reason for the higher pregnancy rate in couples with secondary infertility, the authors compared 237 infertile couples who had a previous pregnancy in the current partnership (secondary infertility) with 135 infertile couples in whom the woman had been pregnant only in a previous partnership and 925 couples with primary infertility. Couples with secondary infertility had the highest proportion of ovulation disorders (36%); these couples with secondary infertility and an ovulation disorder had the shortest duration of infertility (26 months). Cumulative pregnancy rates at 36 months were 56% in secondary fertility, 44% in primary infertility, and 42% in pregnancy in a previous partnership (P = 0.001). In this study, the better prognosis in secondary infertility may be related to the higher proportion of couples with ovulation disorders, who had a shorter duration of infertility. Abortion rates in the earlier pregnancies with current or previous partners were 37% and 30%, respectively; after the period of infertility, the abortion rates were 14% and 12%, respectively.     

Ⅰ～Ⅱ期子宫内膜异位症伴不孕腹腔镜术后应用GnRHa对妊娠的影响

目的：探讨Ⅰ～Ⅱ期子宫内膜异位症（endometriosis,EMs）伴不孕腹腔镜术后应用促性腺素释放激素激动剂（GnRHa）治疗对妊娠的影响。方法：对60例在清远市人民医院经腹腔镜确诊为Ⅰ～Ⅱ期EMs并排除其他不孕因素的不孕患者,按患者意愿分为GnRHa组（30例,A组）和人绝经期促性腺激素（HMG）组（30例,B组）。A组于术后第1次月经第1～3天给予GnRHa（达菲林3.75 mg）肌内注射,每28 d 1次,共3次,第3次GnRHa后40 d+HMG 37.5～112.5 IU肌内注射诱发排卵共6周期;B组于术后第1次月经第3～5天给予HMG37.5～112.5 IU肌内注射诱发排卵6周期。观察两组患者治疗1,3,6和12个月时妊娠情况以及两组患者腹腔镜术后3,6和12个月血清CA125水平和痛经情况及复发率。结果：①A组和B组1,3,6及12个月累积临床妊娠率分别为36.6%（11/30）、56.6%（17/30）、66.7%（20/30）、76.7%（23/30）和16.7%（5/30）、30%（9/30）、36.7%（11/30）、50.0%（15/30）;两组比较,A组3,6及12个月妊娠率均显著高于B组（P＜0.05）。②A组术后3,6个月血清CA125水平明显低于同期B组水平,A组患者术后6,12个月痛经复发率明显低于B组。结论：Ⅰ～Ⅱ期EMs伴不孕患者经腹腔镜治疗后应用GnRHa治疗可延缓EMs的复发、提高术后妊娠率;对EMs伴不孕患者的促排卵治疗不宜超过6周期。     

Laparoscopic ovarian drilling as first line of treatment in infertile women with polycystic ovary syndrome.

Laparoscopic ovarian drilling (LOD) is used as a first line of treatment, as a second line of treatment after patients have proved resistant to clomiphene or as a third line of treatment after failed ovulation induction with gonadotropins. We present the postoperative pregnancy rates of 57 women to evaluate a potential optimal time of LOD together with the other treatment regimens of infertile women with polycystic ovary syndrome (PCOS). Data on the preoperative and operative treatment, and background data were evaluated for their influence on pregnancy rates. The pregnancy rate was 61% among women with PCOS who had LOD. No difference was found in the clinical data between the women who became pregnant and those who did not. Likewise, no difference was found between the women who had pre- and/or postoperative medical ovulation treatment and those who had none. The median time to pregnancy after LOD was 135 days. LOD alone resolves infertility within 4-6 months in 50-60% of couples. A strategy with diagnostic laparoscopy and LOD as the first line of treatment of infertility in women with PCOS will shorten the time to pregnancy for many women, reduce the need for medical ovulation induction and enable diagnosis of those women with anatomic infertility, who can achieve pregnancy only by in vitro fertilization treatment.     

Early conception in patients with untreated mild endometriosis

The purpose of this paper is to report the reproductive experience in 31 infertile patients with mild endometriosis who were not treated by surgery or medication. A series of 31 cases of laparoscopically diagnosed mild endometriosis were followed up without therapy for a period of 36 months. Ten patients received artificial insemination by donor (AID) because of male-related infertility; 21 patients had well-timed postcoital tests and monitored ovulation cycles. Life-table analysis of conceptions was used for presentation of the pregnancy rate. The group of patients whose husbands were azoospermic had a 90% pregnancy rate within 18 months, with a mean of 3.5 treatment cycles for pregnancy. The nonazoospermic couples had a 47.6% pregnancy rate within 18 months, with a mean of 7.2 monitored cycles for pregnancy. The calculated median delays for the series of patients who conceived were 1.9 cycles. The whole series (n = 31) of patients with mild endometriosis had an 8.3% monthly pregnancy rate within 18 months and a 61.2% cumulative pregnancy rate within 18 months. We have come to the conclusion that mild endometriosis does not interfere with female fertility, and patients with this extent of disease should not be treated for a trial period of at least 18 months as an alternative to more aggressive therapy.     

Unilateral versus bilateral adnexal disease in stage III and stage IV endometriosis does not affect pregnancy outcome after operative laparoscopy

To study the effect of unilateral versus bilateral adnexal involvement on the pregnancy rate after operative laparoscopy. Historic cohort study. A total of 143 patients with advanced stages of endometriosis (stage III and IV) who underwent operative laparoscopy for infertility treatment were categorized into those with unilateral versus bilateral adnexal disease. Forty-three patients had primarily unilateral (group 1) and 100 had bilateral disease (group 2). Follow-up was up to 2 years. There was no significant difference between group 1 and group 2 with respect to pregnancy rates (28% vs 31%), delivery rates (21% vs 23%), miscarriage rates (25% vs 13%), and ectopic rates (0% vs 13%). Cumulative conception rates after up to 24 cycles of natural intercourse and up to three IUI cycles were 59% and 49% for group 1 and group 2, respectively. Operative laparoscopy for advanced stages of endometriosis appears to be an effective treatment modality for establishing a pregnancy in infertile patients. Pregnancy and delivery rates are not different in patients with unilateral or bilateral adnexal involvement. Support: None     

Laser vaporization of endometriosis in an infertile population: the role of complicating infertility factors

One hundred twenty-two infertility patients with endometriosis were evaluated and treated using laparoscopy and laser vaporization to provide immediate elimination of all intraperitoneal disease. Ninety-five couples (77.8%) had one or more infertility factors (other than endometriosis) contributing to their infertility. Cervical factors, male factors, and luteal defects were associated with significantly decreased pregnancy rates, despite the use of laser vaporization. The number of contributing factors seemed to be unrelated to the likelihood of success in achieving pregnancy. The authors emphasize the need for total evaluation of other infertility factors in these patients. Such factors should be corrected prior to the use of laser laparoscopy, if possible, and dealt with on a continuing basis following use of this technique.     

Follow up of infertile patients after failed ART cycles: a preliminary report from Iran and Turkey

Objectives

Assisted reproductive technology (ART) has become an established and increasingly successful form of treatment for infertility. However, significant numbers of cycles fail after embryo transfer (ET) and it becomes necessary to follow up the infertile couples after failed ART treatments. The main goal was to follow up the infertile patients after failed IVF/ICSI+ET treatments in Iran and Turkey.

Study design

198 infertile couples from Iran and 355 infertile couples from Turkey were followed up after IVF/ICSI failures. The patients’ demographic data, the couples’ decisions about continuation of treatment and the spontaneous pregnancy rates were compared in the two countries.

Results

The drop-out rate was higher in Iran (28.3%) than in Turkey (23.4%). The reasons for treatment discontinuation in Iran and Turkey were: financial problem (33.9% vs. 41%), hopeless (10.7% vs. 22.9%), fear of drug side-effects (7.1% vs. 12%), achieving pregnancy (37.5% vs. 19.6%), child adoption (5.4% vs. 2.4%), lack of spouse cooperation (5.4% vs. 2.4%), and divorce (0% vs. 2.4%). Spontaneous pregnancy was significantly higher in Iran (10.1%) than in Turkey (3.9%). There was correlation between duration of infertility and female factor infertility with spontaneous pregnancy.

Conclusions

Since the majority of couples that discontinued treatment had financial problems, it is essential for health professionals to support infertile couples during their childlessness crisis.     

The expectancy of pregnancy for "normal" infertile couples

The prognosis of unexplained infertility was studied for 47 couples. The cumulative rate of pregnancy was 65%, with 81% achieving a full-term pregnancy. The type and duration of infertility, the age of the woman, and the previous use of contraceptives did not significantly modify the results. This study indicates that a complete investigative protocol should include laparoscopy. It also suggests caution in the application of untried empirical treatments to normal infertile couples.     

Zygote intrafallopian transfer or in vitro fertilization and embryo transfer for the treatment of male-factor infertility: a prospective randomized trial.

OBJECTIVE: To compare zygote intrafallopian transfer (ZIFT) and in vitro fertilization and embryo transfer (IVF-ET) as treatments of male-factor infertility. DESIGN: Patients were prospectively randomized to ZIFT or IVF-ET. SETTING: In vitro fertilization program of the Centre for Reproductive Medicine of the Dutch-speaking Brussels Free University, Belgium, which is a tertiary referral institution. PATIENTS: One hundred fifty-seven couples were enrolled in the study. Inclusion criteria allowed only first trials of couples with long-standing infertility caused by a male factor. Female factors were excluded. INTERVENTIONS: In ZIFT, up to three fertilized oocytes were transferred into one single patient fallopian tube by means of laparoscopy 18 hours after insemination. In IVF-ET, cleaving embryos were replaced into the uterine cavity about 48 hours after insemination. MAIN OUTCOME MEASURES: Fertilization and transfer rates, implantation and pregnancy rates, pregnancy outcome, and cost per procedure were evaluated. RESULTS: Implantation rates of 12.3% and 10% per replaced conceptus were achieved for ZIFT and IVF-ET, respectively. CONCLUSIONS: This study demonstrates no therapeutic advantage of ZIFT over IVF-ET in male-factor infertility in terms of reproductive outcome or economic benefit.     

A proportional hazards analysis of the clinical characteristics of infertile couples

Evaluated were methods of ordering the many possible predictors of infertility outcome. The clinical characteristics of infertile couples were studied with respect to the occurrence of pregnancy during follow-up, by means of the methods of survival analysis. Among 1,297 couples who were infertile for 12 months or more, the cumulative pregnancy rate at 36 months with 95% confidence limits was 49% ± 4%. The proportional hazards analysis identified three independent predictors of the occurrence of pregnancy from the couple's history (with P values in brackets); a history of pregnancy in the partnership (0.0001); shorter duration of infertility (0.0001); and shorter length of marriage (0.005). The predictors arising from the diagnostic process (with P values in brackets) were: fewer infertility diagnoses (0.0001); a favorable primary clinical diagnosis (0.001); and the presence of any tubal disease, regardless of the primary clinical diagnosis (0.001). The analysis selected an economical set of significant predictor variables and demonstrated that a longer period of contraception was associated with a lower pregnancy rate among infertile couples. Also, three simple questions from the history were nearly equivalent to the entire diagnostic process as predictors of the outcome.     

Accuracy of diagnostic laparoscopy in the infertility work-up before intrauterine insemination

OBJECTIVE:To evaluate the accuracy of diagnostic laparoscopy after normal hysterosalpingography (HSG) and before intrauterine insemination (IUI) with respect to laparoscopic findings leading to a change of treatment decisions in couples with male subfertility, cervical hostility, or idiopathic infertility. DESIGN: Retrospective chart review. SETTING: University medical centre. PATIENT(S): Infertility patients who had undergone diagnostic laparoscopy after a normal HSG and before IUI in a period of 5 years. INTERVENTION(S): Diagnostic laparoscopy in infertility work-up before IUI. MAIN OUTCOME MEASURE(S): Prevalence of laparoscopic findings leading to change in treatment decision. RESULT(S): Of 495 patients, 21 (4%) had severe abnormalities that resulted in a change of treatment to in vitro fertilization or open surgery. In 103 patients (21%) abnormalities, endometriosis (stages I and II), and adhesions were directly treated by laparoscopic intervention, followed by IUI treatment. If surgery to remove early stage endometriosis does not improve pregnancy rates, then the laparoscopic yield would be 40 out of 495 (8.1%). CONCLUSION(S): Diagnostic laparoscopy altered treatment decisions in an unexpectedly high number of patients before IUI. This suggests that laparoscopy may be of considerable value, provided the change in treatment is effective. Further prospective studies are required to assess whether the diagnostic use of laparoscopy is cost effective and whether interventions as result of laparoscopic findings are effective in improving pregnancy rates.     

Efficacy of danazol treatment for minimal endometriosis in infertile women. A prospective, randomized study

We compared pregnancy rates between a danazol-treated and an untreated group of infertile women with minimal endometriosis. After completion of a basic infertility workup and laparoscopy, women with minimal endometriosis were entered into the study and randomly selected to receive either a six-month course of danazol or no treatment at all. Those patients with other infertility factors were included in the study only if the factors were correctable and ultimately determined to be noncontributory. Life-table analysis was used to compare pregnancy rates between the two groups over a 12-month period that started immediately after laparoscopy in the untreated group and after completion of danazol therapy in the treated group. The cumulative pregnancy rate (+/- SEM) was 37.2 +/- 8.4% in the danazol group (n = 37) and 57.4 +/- 10.4% in the untreated group (n = 36) (NS, P greater than .10). This prospective, randomized study showed danazol to be ineffective in improving pregnancy rates over doing nothing at all in patients with minimal endometriosis.     

Pregnancies following use of metformin for ovulation induction in patients with polycystic ovary syndrome

OBJECTIVE: To assess pregnancy outcome in anovulatory infertility patients diagnosed with polycystic ovary syndrome (PCOS) who were treated with metformin. DESIGN: Case series. SETTING: Outpatient. PATIENT(S): Anovulatory patients (n = 48) with a diagnosis of PCOS based on clinical, diagnostic, and laboratory evaluations were enrolled in the study over a 15-month period. INTERVENTION(S): Metformin was started at 500 mg b.i.d. for 6 weeks and then increased to 500 mg t.i.d. if no ovulation occurred. Clomiphene citrate (CC; 50 mg) was added if no ovulatory response occurred after 6 weeks. MAIN OUTCOME MEASURE(S): Resumption of menses, presumptive ovulation, and pregnancy. RESULT(S): Nineteen of 48 (40%) patients resumed spontaneous menses following treatment and showed presumptive evidence of ovulation with metformin alone; 15/48 (31%) required CC (50 mg) in conjunction with metformin therapy, and 10 of these 15 (67%) had evidence of ovulation; 20/48 (42%) conceived with a median time to conception of 3 months, and 7 of these 20 (35%) had spontaneous abortions (SAB); 19/48 (40%) had gastrointestinal-related side effects, and 5 of 48 patients (10%) had to decrease the dosage of metformin. Only 1 patient discontinued therapy. CONCLUSION(S): Metformin alone in patients with PCOS results in a substantial number of pregnancies, with 69% (20/29) of those who ovulated conceiving in less than 6 months.     

Direct intraperitoneal or intrauterine insemination and superovulation in infertility treatment: a randomized study

Direct intraperitoneal or intrauterine insemination in combination with superovulation was used randomly as the treatment of infertility that was unexplained or due to male subfertility or mild endometriosis in 124 couples during 326 cycles. The pregnancy rate per couple was 24% in the direct intraperitoneal insemination group and 31% in the IUI group. The difference was not significant. The pregnancy rates with both treatments were significantly higher than those seen during the 326 control cycles of the same couples (1.1% and 0.6%).     

宫腹腔镜联合检查在原因不明不孕症诊断和治疗中的临床价值

目的探讨宫腹腔镜联合检查在原因不明不孕症诊断和治疗中的重要性。方法回顾性分析2012年5月至2015年12月因原因不明不孕症在北京协和医院行宫腹腔镜联合检查的患者519例,宫腹腔镜联合检查寻找"原因不明"不孕症的病因。结果在519例原因不明不孕症患者中,宫腹腔镜联合检查未发现异常者占10.2%(53/519),发现盆腔异常者占89.8%(466/519);盆腔异常患者分别为72.4%(376/519)盆腔粘连合并子宫内膜异位症、12.3%(64/519)盆腔粘连、3.7%(19/519)子宫肌瘤或卵巢囊肿以及1.3%(7/519)子宫内膜息肉。宫腹腔镜联合检查后随访12~36个月,最终纳入386例患者统计术后自然妊娠情况,术后总自然妊娠率为53.9%(208/386),年龄≥35岁患者的自然妊娠率为29.8%(31/104)。结论临床诊断为原因不明不孕症的患者,应行宫腹腔镜联合检查,在宫腹腔镜联合检查下能更直观地发现不孕症的病因,并且可进行针对性的治疗,提高妊娠率。高龄患者术后自然妊娠率明显下降,尝试自然妊娠的时间不宜过长。     

Mild and moderate endometriosis. Comparison of treatment modalities for infertile couples.

A series of 1,268 consecutive patients with stage I and II endometriosis (American Fertility Society classification) were treated for the disease. In 675, no other factors contributed to their infertility. Among these patients, with no problems other than mild endometriosis, 57% (16/28) became pregnant when treated expectantly, 54% (51/95) after being treated medically, 47% (9/19) after laparoscopic cautery treatment, 81% (147/181) after laparoscopic laser treatment and 84% (97/116) after conservative surgery (laparotomy). Statistical analysis of the pregnancy rates revealed no difference between expectant, medical and laparoscopic cautery treatment. No difference was noted between laparotomy and laser laparoscopy; however, there was a statistically significant difference between these treatments and expectant, medical and cautery treatment. Similar results were seen with stage II endometriosis in couples with no contributing factors other than endometriosis: 39% of patients (23/59) became pregnant after medical treatment, 70% (80/115) after laser laparoscopy and 74% (46/62) after undergoing major conservative treatment (laparotomy). A statistically significant difference between medical treatment and laparotomy as well as laser laparoscopy was noted. However, no such difference existed between laparotomy and laser laparoscopy. Therefore, it appears that in experienced hands the use of laser laparoscopy in stage I and II endometriosis is as successful as major surgery and statistically significantly better than expectant, medical and laparoscopic cautery treatment.