What are the risks associated with lipiodol hysterosalpingography? A literature review.

INTRODUCTION: Hysterosalpingography is widely used as a first-line investigation for infertility, and may also be therapeutic, increasing pregnancy rates. Aqueous and oil-based contrast agents can be used. Some studies suggest Lipiodol hysterosalpingography has a greater therapeutic effect on fertility than aqueous contrast, though this is contentious. There are additionally safety concerns surrounding Lipiodol hysterosalpingography. This review summarises the adverse effects associated with Lipiodol hysterosalpingography, particularly on thyroid function. KEY FINDINGS: 331 articles were identified. Of these, 46 met inclusion criteria. 3 further articles were identified from reference lists. Complications typically cited in the literature include pain, intravasation, life-threatening oil embolism, and lipogranuloma formation. Emerging evidence suggests that Lipiodol hysterosalpingography may also impact maternal and neonatal thyroid function. Women may develop hypo- or hyperthyroidism. Thyroid dysfunction is clinically significant as even subclinical hypothyroidism reduces fertility, increases the risk of pregnancy complications including miscarriage, pre-eclampsia and perinatal mortality, and adversely impacts foetal neurodevelopment. One study suggested a possible link with neonatal congenital hypothyroidism. CONCLUSION: There is emerging evidence to suggest that Lipiodol hysterosalpingography can cause hypo- or hyperthyroidism, in addition to known adverse effects of pain, intravasation, oil embolism, and lipogranuloma formation. IMPLICATIONS FOR PRACTICE: Given the significance of these risks, and contention surrounding whether Lipiodol truly increases pregnancy rates compared to aqueous mediums, careful consideration is required in the selection of contrast agent. In particular, Lipiodol hysterosalpingography may not be suitable for women with pre-existing thyroid dysfunction.

Lipiodol flushing under ultrasound guidance at time of hystero-salpingo contrast sonography (HyCoSy): A retrospective observational study.

BACKGROUND: Up to 30% of female infertility can be attributed to tubal abnormalities. Assessment of fallopian tube patency forms a component of the basic assessment of infertility. Tubal patency can be checked through hysterosalpingogram (HSG) under radiologic guidance with oil- or water-based contrast medium (OBCM or WBCM), or hystero-salpingo contrast sonography (HyCoSy) under ultrasound guidance with WBCM. Tubal flushing with OBCM has been shown to improve fertility rates. OBJECTIVES: To study the feasibility and tolerability of performing Lipiodol (ethiodised oil) flush concurrently with HyCoSy. To examine the in vivo sonographic visibility of Lipiodol vs normal saline. MATERIALS AND METHODS: Retrospective observational study of patients with subfertility referred for Lipiodol flushing under ultrasound guidance between August 2017-September 2020 at six private ultrasound practices in Sydney, Australia. RESULTS: There were 412 patients who were referred for Lipiodol flushing. Of these, 86 patients did not have concurrent Lipiodol flush at HyCoSy performed due to strict exclusion criteria. Of the 326 patients who proceeded with Lipiodol flushing at HyCoSy, all cases were successful, with no cases of extravasation. There were no major complications. In vivo sonographic visualisation of Lipiodol was similar to that of the commonly used agitated 0.9% saline (n = 20; mean visibility score 4.3 ± 0.9 vs 4.0 ± 1.2). CONCLUSION: Our study has shown that Lipiodol flushing at time of HyCoSy as a single procedure is feasible and tolerable to patients. Flushing with Lipioidol during HyCoSy is likely as sonographically visible as 0.9% saline.

Treatment effect of oil-based contrast is related to experienced pain at HSG: a post-hoc analysis of the randomised H2Oil study.

STUDY QUESTION: Does pain or volume of used contrast medium impact the effectiveness of oil-based contrast during hysterosalpingography (HSG)? SUMMARY ANSWER: In women who report moderate to severe pain during HSG, the use of oil-based contrast resulted in more ongoing pregnancies compared to the use of water-based contrast, whereas in women who reported mild or no pain, no difference in ongoing pregnancies was found. WHAT IS KNOWN ALREADY: We recently showed that in infertile women undergoing HSG, the use of oil-based contrast results in more ongoing pregnancies within 6 months as compared to the use of water-based contrast. However, the underlying mechanism of this fertility-enhancing effect remains unclear. STUDY DESIGN, SIZE, DURATION: We performed a post-hoc analysis of the H2Oil study, a multicentre randomised controlled trial (RCT) evaluating the therapeutic effect of oil- and water-based contrast at HSG. Here, we evaluated the impact of pain experienced at HSG and volume of used contrast media during HSG on ongoing pregnancy. PARTICIPANTS/MATERIALS, SETTING, METHODS: In a subset of 400 participating women, pain during HSG by means of the Visual Analogue Scale (VAS) (range: 0.0-10.0 cm) was reported, while in 512 women, we registered the volume of used contrast (in millilitres). We used logistic regression analyses to assess whether pain and volume of used contrast media modified the effect of oil-based contrast on ongoing pregnancy rates. Data were analysed according to intention-to-treat principle. MAIN RESULTS AND THE ROLE OF CHANCE: In 400 women in whom pain scores were reported, the overall median pain score was 5.0 (Interquartile range (IQR) 3.0-6.8) (oil group (n = 199) 4.8 (IQR 3.0-6.4); water group (n = 201) 5.0 (IQR 3.0-6.7); P-value 0.28). There was a significant interaction between pain (VAS ≤5 versus VAS ≥6) and the primary outcome ongoing pregnancy (P-value 0.047). In women experiencing pain (VAS ≥6), HSG with oil-based contrast resulted in better 6-month ongoing pregnancy rates compared to HSG with water-based contrast (49.4% versus 29.6%; RR 1.7; 95% CI, 1.1-2.5), while in women with a pain score ≤5, 6-month ongoing pregnancy rates were not significantly different between the use of oil- (28.8%) versus water-based contrast (29.2%) (RR 0.99; 95% CI, 0.66-1.5). In the 512 women in whom we recorded contrast, median volume was 9.0 ml (IQR 5.7-15.0) in the oil group versus 8.0 ml (IQR 5.9-13.0) in the water group, respectively (P-value 0.72). Volume of used contrast was not found to modify the effect of oil-based contrast on ongoing pregnancy (P-value for interaction 0.23). LIMITATIONS, REASONS FOR CAUTION: This was a post-hoc analysis that should be considered as hypothesis generating. The RCT was restricted to infertile ovulatory women, younger than 39 years of age and with a low risk for tubal pathology. Therefore, our results should not be generalised to infertile women who do not share these features. WIDER IMPLICATIONS OF THE FINDINGS: The underlying mechanism of the fertility-enhancing effect induced by HSG with the use of oil-based contrast remains unclear. However, these findings suggest a possible mechanistic pathway, that is increasing intrauterine pressure occurring prior to dislodging pregnancy hindering debris or mucus plugs from the proximal part of otherwise normal fallopian tubes. This information might help in the search of the underlying fertility-enhancing mechanism found by using oil-based contrast during HSG. STUDY FUNDING/COMPETING INTEREST(S): The original H2Oil RCT was an investigator-initiated study that was funded by the two academic institutions (AMC and VUmc) of the Amsterdam UMC. The funders had no role in study design, collection, analysis and interpretation of the data. K.D. reports consultancy for Guerbet. H.V. reports consultancy fees from Ferring. C.B.L. reports speakers' fees from Ferring and research grants from Ferring, Merck and Guerbet. V.M. reports receiving travel and speakers fees as well as research grants from Guerbet. B.W.M. is supported by an NHMRC Practitioner Fellowship (GNT1082548). B.W.M. reports consultancy for ObsEva, Merck KGaA and Guerbet and travel and research grants from Merck KGaA and Guerbet. The other authors do not report conflict of interests. TRIAL REGISTRATION NUMBER: The H2Oil study was registered at the Netherlands Trial Registry (NTR 3270). TRIAL REGISTRATION DATE: 1 February 2012. DATE OF FIRST PATIENT'S ENROLMENT: 3 February 2012.

An investigation into the effect of evening primrose in dilatation of cervix and pain during and after hysterosalpingography.

Hysterosalpingography is one of the essential diagnostic methods for examining women who have difficulty becoming pregnant. This procedure is somehow invasive and is associated with numerous complications such as allergic sensitivity, pain, abdominal cramps and shock. Therefore, this study aimed to investigate the effect of evening primrose on cervical length and pain during and after hysterosalpingography. In this double-blind clinical trial, 66 candidates for hysterosalpingography were randomly divided into two groups. A group received 1000 mg of evening primrose orally for two days prior to hysterosalpingography, while the control group received a placebo drug similar in size to evening primrose three days prior to hysterosalpingography. The pain level was recorded based on the Visual Analogue Scale (VAS), during tenaculum placement but also immediately and four hours after hysterosalpingography. Finally, the data were analyzed using SPSS (version 20). There was a significant difference between the two groups in terms of pain during insertion of speculum and injection of the contrast medium (p <0.05). Less pain was reported in the evening primrose group compared to placebo. There was no significant difference between the two groups in terms of the length and diameter of the cervix (p <0.05). Given the fact that it is a medicinal plant with no complications and can reduce pain during speculum insertion and during contrast medium injection, evening primrose seems to be a good drug for managing pain during hysterosalpingography.

Examination of the antioxidant effects of pre-HSG melatonin use on ovarian surface epithelium in rats: An experimental study.

BACKGROUND: There is no study of whether the dysplastic changes in the ovarian surface epithelium of X-ray-exposed rats during hysterosalpingography (HSG) decrease or not with the use of Lipiodol and melatonin given both intraperitoneally (i.p.) and into the suspensorium ovarii. OBJECTIVES: We investigated the restorative effects of melatonin and Lipiodol administration during the HSG procedure on the dysplastic changes in the ovarian surface epithelium of X-ray-exposed rats. MATERIAL AND METHODS: A total of 50 Wistar rats with regular estrous cycles were randomly divided into 5 groups. Group 1 was the control group. In other groups, X-ray was applied (group 2), 0.1 mL Lipiodol was applied to each uterine horn (group 3), 20 mg/kg intraperitoneal melatonin application was followed by 0.1 mL Lipiodol administration to each uterine horn after 15 min (group 4), and 20 mg/kg melatonin was administered to the ligamentum suspensorium ovarii, followed by 0.1 mL Lipiodol application to each uterine horn after 15 min (group 5). The rats in groups 2-5 were exposed to whole body radiation 3 times. After 3 h, the abdomens of all rats were reopened and left oophorectomy was performed. RESULTS: The presence of nucleoli and mitosis values were found similar among the groups. All other parameters were significantly higher in group 2 compared to other groups, except for the presence of nucleoli and mitosis values (p < 0.05). The presence of hyperchromasia and the total score were found to be the highest in group 2, followed by group 3, when compared to other groups (p < 0.05). It was detected that the detrimental effects of X-ray exposure diminished with Lipiodol use, and were further reduced by the use of melatonin in combination. CONCLUSIONS: We suggest that the use of melatonin and Lipiodol during HSG may prevent the carcinogenic changes exerted by radiation on the ovarian surface epithelium.

Thyroid Dysfunction in Neonates Born to Mothers Who Have Undergone Hysterosalpingography Involving an Oil-Soluble Iodinated Contrast Medium.

BACKGROUND/AIMS: Patients developing neonatal thyroid dysfunction following maternal hysterosalpingography (HSG) involving the use of oil-soluble iodinated contrast medium (ethiodized oil) have been reported. The present study aimed to investigate the frequency and risk factors for neonatal thyroid dysfunction following HSG. METHODS: We studied 212 infants born to mothers who had become pregnant after undergoing HSG involving the use of ethiodized oil. RESULTS: Five of the 212 infants tested positive during congenital hypothyroidism screening; this frequency (2.4%) was higher than the recall rate among first congenital hypothyroidism screening results (0.7%) in Tokyo, Japan. Two of the 5 screening-positive infants showed hypothyroidism, and 3 showed hyperthyrotropinemia. The urinary iodine concentrations in 4 out of the 5 screening-positive infants were 1,150, 940, 1,570, and 319 µg/l. The subjects were divided into thyroid dysfunction (n = 5) and normal thyroid function (n = 207) groups. The median dosage of ethiodized oil in the thyroid dysfunction group was significantly higher than in the normal thyroid function group (20 vs. 8 ml, p = 0.033). CONCLUSION: When infertile women undergo HSG, the dosage of oil-soluble iodinated contrast medium should be as low as possible to minimize the risk of fetal or neonatal thyroid dysfunction.

The effect of valeric on anxiety severity in women undergoing hysterosalpingography.

AIM & SCOPE: Hysterosalpingography (HSG) is the radiographic evaluation of the uterine cavity and fallopian tubes, which is generally assumed as a stressful and painful procedure. This study aims to determine effect of oral Valeric capsules on anxiety severity in women under Hysterosalpingography. METHOD & EXAMINATION: This study, as a double-blind clinical trial, was conducted on 64 infertile women undergoing hysterosalpingography, who referred to radiology ward at Comprehensive Women's hospital. To measure anxiety, visual analog anxiety scale was used 90 minutes before starting procedure, individuals in intervention group (n=32) received a single dose (1,500 mg) of 3 Valeric capsules, together with routine prophylaxy, where routine prophylaxis contains Mefenamic acid 250mg capsules in 30 minutes before procedure, and the same capsules were prescribed to placebo group (n=32) with the same instruction. Anxiety severity before and once 90 minutes after intervention in both groups were measured and compared. RESULTS: There was no difference on anxiety severity before intervention in both groups (p=0.26), and the groups were homogeneous; after intervention, a significant difference on anxiety severity was reported in both groups (p<0/0001), and anxiety score in intervention group compared to placebo reduced statistically. CONCLUSION: Present study indicated that Valeric was effective on reducing anxiety in women undergoing hysterosalpingography.

Subsequent Cancer Risk of Women Receiving Hysterosalpingography: A Nationwide Population-Based Retrospective Cohort Study.

The objective of this study was to estimate the subsequent cancer risk of women after receiving hysterosalpingography (HSG) by conducting a nationwide retrospective cohort study. We identified a study cohort of 4,371 patients who had had a HSG examination and a comparison cohort of 17,484 women without HSG examination between 1998 and 2005. Both cohorts were followed up with until the end of 2010 to measure the incidence of cancer. The risk of developing cancer for patients with HSG was assessed using the Cox proportional hazard model. In the multivariate analyses, the HSG cohort did not have a significantly greater risk of cancer (Hazard Ratio [HR] = 1.02, 95% CI = 0.79-1.31) than the non-HSG cohort. The HR was highest for genital cancer (HR = 1.32, 95% CI = 0.77-2.25), followed by urinary system cancer (HR = 1.11, 95% CI = 0.23-5.40), and abdominal cancer not involving the GU system (HR = 1.04, 95% CI = 0.53-2.03), all of which were non-significant elevations. The cancer incidence rates, especially that for urinary system cancer, were increased in the HSG cohort, but the increase in cancer incidence was small and not statistically significant.

Lidocaine-prilocaine cream as analgesia for hysterosalpingography: a randomized, double blinded, controlled study.

OBJECTIVE: The efficacy of lidocaine-prilocaine cream (EMLA(®)) analgesia in the practice of hysterosalpingography is controversial. This study provides new drill results and a new method of application in terms of mode, time and place. The aim of the paper is to investigate the efficacy of 5% lidocaine 25 mg-prilocaine 25 mg/g cream applied to the uterine cervix for reducing pain during hysterosalpingography. STUDY DESIGN: A randomized, double blinded, controlled study set in the general gynaecology clinic of a university teaching hospital between September 2012 and June 2013. One hundred successive patients programmed to undergo hysterosalpingography were randomized to either 3 ml of EMLA (50) cream or 3 ml of placebo (50), placed endocervically and exocervically, 10 min before hysterosalpingography. Patients' intensity of pain was assessed in four steps: at baseline (speculum application), after application of Pozzi tenaculum and cannula on the uterine cervix, during cervical traction and after contrast medium injection, using a 10-cm Visual Analogue Scale (VAS) immediately after the procedure. The most painful step was also identified. VAS was administered again at one-month follow-up visit. TRIAL REGISTRATION: NCT01303614. RESULTS: The contrast medium injection was the most painful step of hysterosalpingography in both groups (EMLA 3.96, placebo 4.54, 95%CI: -0.481 to 1.641). No differences were found between the two groups (P=0.281) during this step. When comparing the VAS scale after the application of Pozzi tenaculum and cannula (EMLA 1.06, placebo 3.34, 95%CI: 1.495-3.065) and after cervical traction (EMLA 2.54, placebo 3.46, 95%CI: 0.034-1.806), significantly less pain was experienced by the EMLA group than the placebo group: P=0.000 and P=0.042, respectively. CONCLUSION: Endocervical and exocervical topical application of EMLA 10 min before performing hysterosalpingography significantly reduced pain during cervical manipulation with tenaculum and cannula and during cervical traction, but did not reduce pain during injection of contrast that was the most painful step.

Can the addition of a paracervical block to systemic or local analgesics improve the pain perceived by the patient during hysterosalpingography?

The aim of the present study was to investigate whether the addition of a paracervical block to local intrauterine anaesthesia or the use of an intramuscular non-steroidal anti-inflammatory drug was effective for pain control during and at 30 min after hysterosalpingography (HSG). A total of 120 patients undergoing hysterosalpingography were randomised into four groups. Patients received intramuscular dexketoprofen trometamol with or without a paracervical block or intracavitary lidocaine instillation with or without paracervical block. The primary outcome was the overall pain score from the four stages of the procedure. The lowest pain scores were observed in the patients receiving dexketoprofen trometamol with a paracervical block, whereas the highest pain scores were observed in patients with intracavitary lidocaine instillation without a paracervical block (p = 0.021). No beneficial effect was found when a paracervical block (PCB) was added to either systemic or local analgesics. The combination of intramuscular dexketoprofen and a paracervical block with plain lidocaine produced the best pain relief during the three specified steps and at up to 30 min after the HSG procedure.

Adverse reactions to lipiodol ultra fluid: report of an accidental case.

A 25-year-old Japanese woman experienced pulmonary edema, shock, encephalopathy and silent pancreatitis after hysterosalpingography using lipiodol ultra fluid, because the contrast media flowed directly into the blood stream from endometrium injured by several curettages for termination of pregnancy. Total iodine concentrations in plasma and urine decreased exponentially and their half-life was 16.12 and 13.04 days, respectively. Clear correlations were observed between the iodine concentration in plasma and the amelioration of both electroencephalogram and neuropsychic abnormalities. Adverse reactions of oil-soluble contrast media are also discussed.

Cerebral embolization and coma after hysterosalpingography with oil-soluble contrast medium.

A case of coma due to embolization after HSG, using oil-soluble contrast medium is presented. The patient was in a comatose state 11 days and then spontaneously regained full consciousness. The safety of oil-contrast medium for HSG is questionable.