IVF versus IUI with ovarian stimulation for unexplained infertility: a collaborative individual participant data meta-analysis.

BACKGROUND: IVF and IUI with ovarian stimulation (IUI-OS) are widely used in managing unexplained infertility. IUI-OS is generally considered first-line therapy, followed by IVF only if IUI-OS is unsuccessful after several attempts. However, there is a growing interest in using IVF for immediate treatment because it is believed to lead to higher live birth rates and shorter time to pregnancy. OBJECTIVE AND RATIONALE: Randomized controlled trials (RCTs) comparing IVF versus IUI-OS had varied study designs and findings. Some RCTs used complex algorithms to combine IVF and IUI-OS, while others had unequal follow-up time between arms or compared treatments on a per-cycle basis, which introduced biases. Comparing cumulative live birth rates of IVF and IUI-OS within a consistent time frame is necessary for a fair head-to-head comparison. Previous meta-analyses of RCTs did not consider the time it takes to achieve pregnancy, which is not possible using aggregate data. Individual participant data meta-analysis (IPD-MA) allows standardization of follow-up time in different trials and time-to-event analysis methods. We performed this IPD-MA to investigate if IVF increases cumulative live birth rate considering the time leading to pregnancy and reduces multiple pregnancy rate compared to IUI-OS in couples with unexplained infertility. SEARCH METHODS: We searched MEDLINE, EMBASE, CENTRAL, PsycINFO, CINAHL, and the Cochrane Gynaecology and Fertility Group Specialised Register to identify RCTs that completed data collection before June 2021. A search update was carried out in January 2023. RCTs that compared IVF/ICSI to IUI-OS in couples with unexplained infertility were eligible. We invited author groups of eligible studies to join the IPD-MA and share the deidentified IPD of their RCTs. IPD were checked and standardized before synthesis. The quality of evidence was assessed using the Risk of Bias 2 tool. OUTCOMES: Of eight potentially eligible RCTs, two were considered awaiting classification. In the other six trials, four shared IPD of 934 women, of which 550 were allocated to IVF and 383 to IUI-OS. Because the interventions were unable to blind, two RCTs had a high risk of bias, one had some concerns, and one had a low risk of bias. Considering the time to pregnancy leading to live birth, the cumulative live birth rate was not significantly higher in IVF compared to that in IUI-OS (4 RCTs, 908 women, 50.3% versus 43.2%, hazard ratio 1.19, 95% CI 0.81-1.74, I2 = 42.4%). For the safety primary outcome, the rate of multiple pregnancy was not significantly lower in IVF than IUI-OS (3 RCTs, 890 women, 3.8% versus 5.2% of all couples randomized, odds ratio 0.78, 95% CI 0.41-1.50, I2 = 0.0%). WIDER IMPLICATIONS: There is no robust evidence that in couples with unexplained infertility IVF achieves pregnancy leading to live birth faster than IUI-OS. IVF and IUI-OS are both viable options in terms of effectiveness and safety for managing unexplained infertility. The associated costs of interventions and the preference of couples need to be weighed in clinical decision-making.

A revised prediction model for natural conception.

One of the aims in reproductive medicine is to differentiate between couples that have favourable chances of conceiving naturally and those that do not. Since the development of the prediction model of Hunault, characteristics of the subfertile population have changed. The objective of this analysis was to assess whether additional predictors can refine the Hunault model and extend its applicability. Consecutive subfertile couples with unexplained and mild male subfertility presenting in fertility clinics were asked to participate in a prospective cohort study. We constructed a multivariable prediction model with the predictors from the Hunault model and new potential predictors. The primary outcome, natural conception leading to an ongoing pregnancy, was observed in 1053 women of the 5184 included couples (20%). All predictors of the Hunault model were selected into the revised model plus an additional seven (woman's body mass index, cycle length, basal FSH levels, tubal status,history of previous pregnancies in the current relationship (ongoing pregnancies after natural conception, fertility treatment or miscarriages), semen volume, and semen morphology. Predictions from the revised model seem to concur better with observed pregnancy rates compared with the Hunault model; c-statistic of 0.71 (95% CI 0.69 to 0.73) compared with 0.59 (95% CI 0.57 to 0.61).

Dropout rates in couples undergoing in vitro fertilization and intrauterine insemination.

OBJECTIVE: To compare dropout rates in couples undergoing conventional in vitro fertilization with single embryo transfer (IVF-SET), in vitro fertilization in a modified natural cycle (IVF-MNC) or intrauterine insemination with ovarian stimulation (IUI-OS). STUDY DESIGN: Secondary analysis of a multicentre randomized controlled trial between January 2009 and February 2012. 602 couples with unexplained or mild male subfertility, allocated to IVF-SET (N=201), IVF-MNC (N=194) and IUI-OS (N=207). MAIN OUTCOME MEASURES: Dropouts, defined as couples who discontinued their allocated three cycles of IVF-SET, six cycles of IVF-MNC or IUI-OS, without having achieved a pregnancy. We classified dropouts as "following medical advice" or "patient initiated". RESULT(S): Thirty couples (15%) allocated to IVF-SET dropped out and 45 couples (23%) allocated to IVF-MNC, compared to 26 couples (13%) allocated to IUI-OS; relative risk (RR) 1.2 (95%CI; 0.73-1.9) for IVF-SET and 1.9 (95%CI; 1.2-2.9) for IVF-MNC, both compared to IUI-OS. Nine couples (4.5%) allocated to IVF-SET, 14 (7.2%) allocated to IVF-MNC and 14 (6.8%) allocated to IUI-OS dropped out following medical advice; RR of 0.51 (95%CI; 0.21-1.2) for IVF-SET and 0.84 (95%CI; 0.39-1.80) for IVF-MNC, both versus IUI-OS. Twenty-one couples (10%) allocated to IVF-SET were patient initiated dropouts, as were 31 (16%) allocated to IVF-MNC and 12 (5.8%) allocated to IUI-COS; RR 1.8 (95%CI; 0.91-3.6) for IVF-SET and 2.8 (95%CI; 1.5-5.2) for IVF-MNC both versus IUI-OS. CONCLUSION(S): IVF-SET and IUI-OS result in comparable drop-out rates, while drop-out rates after IVF-MNC are almost twice as high, mainly driven by patient preferences.

Dizygotic twin pregnancies after medically assisted reproduction and after natural conception: maternal and perinatal outcomes.

OBJECTIVE: To compare maternal and perinatal outcomes in dizygotic twin pregnancies conceived after medically assisted reproduction (MAR) with outcomes after natural conception (NC). DESIGN: Nationwide registry based study. SETTING: Academic medical center. PATIENT(S): Primiparous women who delivered opposite sex twins between January 2000 and December 2012 in the Netherlands, comprising dizygotic twin pregnancies: 6,694 women, 470 after ovulation induction (OI), 511 after intrauterine insemination with controlled ovarian hyperstimulation (IUI-COH), 2,437 after in vitro fertilization (IVF) with intracytoplasmic sperm injection (ICSI), and 3,276 after NC. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Multivariable logistic regression and generalized linear mixed models to evaluate differences in outcomes: maternal outcomes of hypertension, preeclampsia, preterm delivery, hemorrhage, and delivery mode, perinatal outcomes including small for gestational age (SGA) with birth weight <10th percentile, birth weight <1,500 g, 5-minute Apgar score <7, admission to neonatal intensive care unit, congenital anomalies, and perinatal mortality. RESULT(S): We found no statistically significant differences in maternal or perinatal outcomes after OI compared with NC. Women pregnant after IVF-ICSI had a lower risk for hypertension (adjusted odds ratio [aOR] 0.74; 95% confidence interval [CI], 0.66-0.83) compared with women pregnant after NC. After IUI-COH more children had Apgar scores <7 (adjusted odds ratio (aOR) 1.38; 95% confidence interval (CI) 1.05-1.81) and perinatal mortality rates were higher (aOR 1.56; 95% CI, 1.04-2.33) compared with NC. We found no differences in perinatal outcomes after IVF-ICSI compared with NC. CONCLUSION(S): Overall, maternal and perinatal risks other than those due to multiplicity are similar for twin pregnancies conceived after MAR and after NC.

Significantly increased pregnancy rates after laparoscopic restorative proctocolectomy: a cross-sectional study.

OBJECTIVE: To assess the impact of a laparoscopic approach on female fecundity in ileoanal pouch surgery. BACKGROUND: Restorative proctocolectomy with ileal pouch anal anastomosis (IPAA) is associated with tubal factor infertility in female patients. Different studies showed less adhesion formation after laparoscopic colectomy. The relation between laparoscopic pouch surgery and fertility, however, has not been studied so far. METHODS: This cross-sectional study was carried out in 3 university hospitals in the Netherlands and in Belgium. Female patients older than 18 years that had IPAA under the age of 41 were eligible for inclusion (n = 179). We sent them a questionnaire addressing medical and fertility history. The primary endpoint was time to first spontaneous pregnancy after IPAA. This study has been registered with ISRCTN.org (ISRCTN85421386). RESULTS: Of 179 eligible patients, 160 (89%) returned the questionnaire. After IPAA, 50 (31%) patients attempted to conceive. Of these, 23 (46%) had undergone open and 27 (54%) had undergone laparoscopic IPAA. Patient characteristics were similar in both groups. Indications for surgery were ulcerative colitis (UC) in 37 patients, familial adenomatous polyposis (FAP) in 12 patients, and colonic ischemia in 1 patient. A Kaplan-Meier survival function was plotted for time to first spontaneous pregnancy and showed a higher pregnancy rate after laparoscopic IPAA (log-rank, P = 0.023). Similarly, subsequent survival analysis for all patients with UC showed an increased pregnancy rate for the laparoscopic group (log-rank, P = 0.033). CONCLUSIONS: Pregnancy rates are significantly higher after laparoscopic IPAA. This makes the laparoscopic approach the method of choice in young women.

The INeS study: prevention of multiple pregnancies: a randomised controlled trial comparing IUI COH versus IVF e SET versus MNC IVF in couples with unexplained or mild male subfertility.

BACKGROUND: Multiple pregnancies are high risk pregnancies with higher chances of maternal and neonatal mortality and morbidity. In the past decades the number of multiple pregnancies has increased. This trend is partly due to the fact that women start family planning at an increased age, but also due to the increased use of ART.Couples with unexplained or mild male subfertility generally receive intrauterine insemination IUI with controlled hormonal stimulation (IUI COH). The cumulative pregnancy rate is 40%, with a 10% multiple pregnancy rate.This study aims to reveal whether alternative treatments such as IVF elective Single Embryo Transfer (IVF e SET) or Modified Natural Cycle IVF (MNC IVF) can reduce the number of multiple pregnancy rates, but uphold similar pregnancy rates as IUI COH in couples with mild male or unexplained subfertility. Secondly, the aim is to perform a cost effective analyses and assess treatment preference of these couples. METHODS/DESIGN: We plan a multicentre randomised controlled clinical trial in the Netherlands comparing six cycles of intra-uterine insemination with controlled ovarian hyperstimulation or six cycles of Modified Natural Cycle (MNC) IVF or three cycles with IVF-elective Single Embryo Transfer (eSET) plus cryo-cycles within a time frame of 12 months.Couples with unexplained subfertility or mild male subfertility and a poor prognosis for treatment independent pregnancy will be included. Women with anovulatory cycles, severe endometriosis, double sided tubal pathology or serious endocrine illness will be excluded.Our primary outcome is the birth of a healthy singleton. Secondary outcomes are multiple pregnancy, treatment costs, and patient experiences in each treatment arm. The analysis will be performed according tot the intention to treat principle. We will test for non-inferiority of the three arms with respect to live birth. As we accept a 12.5% loss in pregnancy rate in one of the two IVF arms to prevent multiple pregnancies, we need 200 couples per arm (600 couples in total). DISCUSSION: Determining the safest and most cost-effective treatment will ensure optimal chances of pregnancy for subfertile couples with substantially diminished perinatal and maternal complications. Should patients find the most cost-effective treatment acceptable or even preferable, this could imply the need for a world wide shift in the primary treatment. TRIAL REGISTRATION: Current Controlled Trials ISRCTN 52843371.