The prospective study was conducted between October 2016 to December 2018 in the Assisted Reproduction Unit at the Department of Obstetrics and Gynaecology, University of Hong Kong, Queen Mary Hospital, Hong Kong. It was approved by the Institutional Review Board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster and was registered under the University of Hong Kong Clinical Trials Registry (registration number: HKUCTR-2124).
Infertile women undergoing stimulated IVF and FET were screened and recruited following their first ultrasound scan at 6 weeks of gestation. We recruited women under the age of 42 years, with a viable singleton intrauterine pregnancy in IVF cycles or FET cycles and those who had multiple pregnancy, underlying thyroid or gastric problems, molar pregnancy or those currently on traditional Chinese medicine were excluded. Written consent forms were signed after counselling.
All patients underwent their IVF treatment with ovarian stimulation using either the long gonadotrophin releasing hormone (GnRH) agonist protocol or fixed GnRH antagonist protocol as previously described . During day 2–3 of the menstrual cycle, transvaginal ultrasound examination and serum oestradiol measurement were performed. Human menopausal gonadotrophin (hMG) (Menogon, Ferring GmbH, Kiel, Germany) or recombinant FSH (Puregon, Organon, Dublin, Ireland or Gonal F, Merck Serono S.p.A, Modugno, Italy) were started at a dose between 150 and 300 IU per day based on the antral follicle count and previous ovarian response, according to the standard operating procedures. Serial ultrasound scans with or without hormonal monitoring was performed to monitor ovarian response. Further dosage adjustments were based on the ovarian response. GnRH antagonist 0.25 mg/day (Orgalutran, Organon, Dublin, Ireland or Cetrotide®, Merck, Germany) was started on the sixth day of stimulation. When three leading follicles were ≥ 18 mm, 5000–10000IU human chorionic gonadotrophin (hCG) (Pregnyl®, Organon, Oss, the Netherlands) or 250 mg Ovidrel® (Merck Serono S.p.A, Modugno, Italy) was given to trigger final oocyte maturation. Oocyte retrievals under the guidance of transvaginal ultrasound were scheduled 34–36 h later. A maximum of two embryos or blastocysts were transferred 2 or 5 days respectively after oocyte retrieval. Single embryo transfer was advised in women less than 35 years old. Excess good quality embryos were frozen for subsequent transfer.
The details of the freezing and thawing protocols were reported previously . In ovulatory women, natural cycles were used for FET. Luteinizing hormone (LH) surge was defined as an elevation of the LH to 2 times the level of the average of the previous 3 days and the absolute level of the LH should be greater than 20 IU/L. It was determined by serial blood tests, and FET was performed on the third day after LH surge for day 2 embryos and on the sixth day for blastocysts. For anovulatory subjects, FET was carried out in either letrozole-induced or hormone replacement cycles. A maximum of two frozen embryos or blastocysts were allowed to be transferred in any one FET cycle.
Pregnancy test was performed 18 days after hCG trigger in stimulated IVF cycles, or LH surge or starting vaginal progesterone in FET cycles. All women with a positive pregnancy test were recruited following their first ultrasound scan at 6 weeks of gestation. They filled in a questionnaire to document whether they had any nausea and vomiting weekly till 12 weeks of gestation. The modified Pregnancy-Unique Quantification of Emesis and Nausea (PUQE) index was used to quantify the symptoms of nausea and vomiting  (Appendix). It included the amount of time the respondents felt nauseated or sick in a day, the number of times they vomited and the number of times they had retching or dry heaves without vomiting during a day. Women were referred for antenatal care after 12 weeks of gestation.
The primary outcome of this study was the prevalence of nausea and vomiting. The secondary outcomes included severity of nausea and vomiting which was shown by the frequency and number of times of nausea and vomiting, and whether seeing a doctor or hospitalization was necessary.
Other secondary outcomes were the miscarriage rate, complications of pregnancy, sex and weight of the baby Complications of pregnancy included small for gestational age, which was defined as fetal weight < 10th centile for gestation, low birth weight which was defined as birth weight < 2.5 kg; preterm delivery which was defined as delivery of fetus before 37 completed weeks of gestation, gestational hypertension which was defined as raised diastolic blood pressure (DBP) > = 90mmHg consecutively 4 h apart or DBP > = 110mmHg on any one occasion), pre-eclampsia which was defined by gestational hypertension and gestational proteinuria (urine protein > = 0.3 g/day or urine protein / creatine ratio > = 30) with onset after 20 completed weeks of gestation, with both returned normal by 3 months postpartum, gestational diabetes which was defined by a 75 g oral glucose tolerance test (OGTT) during pregnancy showing fasting glucose > = 5.1mmol/L, 1 h glucose > = 10.0mmol/L or 2 h glucose > = 8.5mmol/L, which returned normal 8 weeks postpartum, and perinatal death which was defined as stillbirth or early neonatal death.
Sample size calculation
It has been reported that the prevalence of nausea and vomiting in natural pregnancy was around 70% . We hypothesized that the prevalence of nausea and vomiting in pregnant women from stimulated IVF cycles was 85%. To achieve statistical comparison with 80% power and a two-sided 5% level of statistical significance, 242 women (121 in each arm) were needed to show the anticipated difference of 15% (70% versus 85%) between stimulated IVF and FET cycles. To account for 25% drop out rate, at least 150 women in each arm were aimed for.
Demographic and clinical characteristics were summarized with counts (percentages) for categorical variables, mean (standard deviation [SD]) for normally distributed continuous variables, or median (25th – 75th percentile) for non-normally distributed continuous variables. Demographic features and outcomes of the two study groups were compared. Chi-square test or Fisher’s exact test were used for categorical variables. Mann-Whitney U test was used to compare the continuous variables between the two groups where appropriate. Statistical analyses were carried out using IBM SPSS Statistics, version 25 (IBM Corporation, New York, USA). A two-sided P < 0.05 was taken as statistically significant.