ULTRASOUND IN ART(Marvin). Master class series

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1. ULTRASOUND IN REPRODUCTION SERUWU MARVIN, MDU 2022

2. Objectives Define Infertility Role of ultrasound in screening Pelvic pathologies that affect fertility or early pregnancy Explain Assisted Reproductive Technology Explain the role of ultrasound in ART on ovarian monitoring

3. Infertility Infertility is the inability to conceive a pregnancy after one year of unprotected intercourse or after 6months in a woman over 35yeras old. Infertility affects about 15% of couples. This is the main reproductive concern among couples. Infertility may be due to male or female factors or a combination of both. Primary infertility is the inability to have any pregnancy. Secondary infertility is the inability to have a pregnancy after a previous successful conception. Ultrasound is usually the first investigation done. Assisted reproductive technology is considered for treatment in specific cases.

4. Role of ultrasound in screening Pelvic pathologies that affect fertility or Early Pregnancy Transvaginal Ultrasound is the gold standard in fertility assessment with ultrasound. Different types of ultrasound scanning for infertility include: Baseline or screening ultrasound to assess the pelvic anatomy of the uterine lining and bilateral ovaries. Abnormalities are detected, measured and characterized ie fibroids, uterine malformation. Follicular Monitoring ultrasounds are used to track follicles that are maturing and measure the endometrial thickness and also note endometrial consistency. Saline Infusion Sonograms (SIS) with or without 3D assessment are used to assess the uterine cavity for any abnormalities and can also be used for tubal patency assessment. Trans-Abdominal ultrasound may be used in cases where there is limitation to Transvaginal Ultrasound.

5. Ultrasound Indications Transvaginal Sonogram Baseline assessment of the uterus, ovaries, and adnexa to rule out any pathology like fibroids, polyps, uterine anomalies, hydrosalpinx , or PCOS Ovarian reserve assessment- antral follicular count Monitoring ovulation induction during clomiphene citrate, letrozole , or gonadotropin cycles with or without intrauterine insemination (IUI) and with in-vitro fertilization (IVF) cycles. For timing the ovulation trigger during IUI and IVF Assessment of endometrial thickness during IUI and IVF For performing oocyte retrievals and sometimes for embryo transfer or other uterine procedures, transabdominal scanning is ineffective. Transabdominal Sonogram Women with a large uterus caused by fibroids or adenomyosis , or both. When the uterus or ovaries closely adhered to the anterior abdominal wall secondary to scarring from prior surgery, infection or endometriosis. Saline Infusion Sonogram To assess the uterine cavity for pathologies such as polyps, submucosal fibroids, intrauterine synechiae or scarring, and uterine malformations. To assess tubal patency (instead of a traditional hysterosalpingogram (HSG)).

6. Assisted Reproductive technology(ART) Medical procedures used to address infertility. Also known as fertility treatment. Procedures include: In vitro fertilization(IVF), Intracytoplasmic sperm injection(ICSI), cryopreservationof gametes or embryos, Intra-uterine Insemination(IUI), Ovulation induction and others. Ultrasound is useful in timing the various treatments, predicting success and for guidance during maneuvering of ART devices.

7. Role of ultrasound in assessing complications with ART Ovarian assessment during ART : Evaluation of Antral Follicle Count(AFC) predicts the ovarian reserve and response to stimulation. Hence AFC can be used to adjust gonadotropin dosage. Ultrasound follicle growth monitoring is important for clinical decision making and early detection of complications such as ovarian hyperstimulation . Its important to identify maturing follicles. Diagnosis of PCOS. Diagnosis of the other ovarian cysts like tumors. Endometrial assessment during ART : Exponential endometrial growth is observed in women undergoing gonadotropin stimulated cycles, whereas reduction in the endometrial lining was noted with increasing age and use of clomiphene citrate. Higher clinical pregnancy rates are noted when grade 3 endometrial vascularity was observed on color flow power Doppler.

8. The presence of polyps, endometrial fluid, adenomyosis , and leiomyomas is associated with abnormal endometrial molecular expressions, in turn altering endometrial receptivity and negatively impacting implantation and early embryo development. Uterine assessment during ART : Submucosal fibroids can reduce implantation, live birth rates, and their surgical resection has improved clinical pregnancy rates, live birth rates in some studies. Adenomyosis has an overall negative impact on fertility due to its effect on endometrial receptivity and decidualization . Congenital anomalies of the uterus or Mullerian duct anomalies significantly affect preterm delivery, pregnancy losses, malpresentation , and possibly infertility. Tubal assessment during ART : The presence of hydrosalpinges reduced live birth rates by 30% due to the reflux of toxic fluid into the endometrium. Evaluation of tubal patency plays a key role in counseling infertility patients considering IUI or IVF therapies.

9. Transabdominal ultrasound is usually used to guide the embryo transfer catheter during embryo transfer. An increase in pregnancy rate from 30.1% to 36.8% was noted when embryo transfer was performed using ultrasound versus clinical touch method.

10. OVULATION Release of ovum from woman’s ovary. Ovulation is key for conception. Stages of Ovulation: Early follicular phase(day 5-7) Late follicular phase(day 11-130 Early Luteal phase(day 15-17) Late Luteal Phase(day 26-28) Hormonal control: Hypothalamus GnRH Pituitary LH Ovary ovulation

11. Day 1-5: Follicular selection : 5-10mm sized follicles Day 5-7: Dominance : 10mm sized follicle, growth rate of 2-3mm/day Day 12-16: LH surge : Ovulation

12. Ovulation was initially monitored by conventional methods like BBT, mid luteal serum progesterone level at day 21-22 and Urinary LH. Current practice, ultrasound is preferred for follicular monitoring for both natural cycles and stimulated cycles. Simple technique of assessing ovarian follicles on regular intervals and help in documenting the pathway of ovulation to assess morphological growth of follicles and its functional activity. Useful in those women who are not conceiving due to ovarian factors and taking fertility medication. Follicular monitoring is a vital component of ART(Assisted Reproductive Technology). FOLLICULAR MONITORING

13. Monitoring gives a view of the functional maturity of follicle. It assists in prediction of impending ovulation. Its necessary for: HCG administration and dose optimization. Intra-Uterine Insemination(IUI) Ovum Pickup (Egg collection) in IVF cycles If not ovulating can be treated with ovulation induction agents Random HCG administration should be avoided to prevent a risk of Ovarian Hyperstimulation Syndrome (OHSS). Ultrasound monitoring is done with 2D, Color Doppler, Power Doppler, Pulse Doppler and 3D in Trans-Vaginal Ultrasound scanning. Its suited for monitoring induced cycles and predicting success of Infertility treatment.

14. PROTOCOL Three scans are done: Baseline scan, Preovulatory scan and Secretory scan Baseline scan done on day 2 or 3. Starting from day 7 or 8 of the cycle, serial follicular monitoring Baseline scan Done on the 2 nd or 3 rd day of the cycle. Absolute baseline status of ovaries: Ovaries have no active follicles, oestrogen and progesterone are both at lowest levels. Scan consists of gray scale, color Doppler and pulsed Doppler TVS. 2D ultrasound assessment of ovaries: Ovarian diameters and volume Counting of antral follicles(AFC) Quantitative and qualitative assessment of stromal abundance

15. Color and Pulse Doppler: presence of vessels in stroma. 3D and 3D Power Doppler: Ovarian volume, stromal volume and counting AFC. Normal sized ovaries have follicles of 3-5mm in diameter. Follicle size is measured by taking mean of the longest two diameters perpendicular toeach follicle. Baseline scan classifies ovaries into four categories: Normal Ovaries Polycystic ovaries Low reserve ovaries Poorly responding ovaries Predicting ovarian reserve and response which can guide to decide the stimulation protocols for ART.

16. Ovarian Volume Easily measured in three dimensions. Normal Ovarian volume: 3.3-6.6cc Polycystic Ovaries: >6.6cc Low reserve ovary: <3cc Poorly responding ovaries can have any volume AFC is the marker of ovarian reserve. Precise counting of AFC is the best predictor of ovarian response to stimulation. AFC: 5-12per ovary=normal, >15 = PCO, <5=Inactive ovaries and <3=usually signify possible failure of ART. Antral Follicular count

17. Role of 3D Ultrasound 3D rendering is very important for showing all antral follicles. Correlation in 3D ovarian stromal flow index(FI) and number of mature oocytes retrived in IVF cycles and pregnancy rates. Global vascular indices: VI(Vascularity index), FI(Flow Index), VFI(Vascularity flow index) calculated by volume histogram.

18. Ovarian Stromal blood flow A good predictor of ART success Ovarian PSV and RI Increased PSV >10cm/sec is one of the major parameters. Normal reserve Ovaries Diameter=2-3.5cm Volume=3-6.6cc AFC=5-12per ovary Low reserve Ovaries Small sized ovaries Diameter=<2cm Volume=<3cc AFC=<3per ovary Polycystic Ovaries Diameter=>3.5cm Volume=>6.6cc AFC=12-15per ovary Hyperechoic stroma

19. Preovulatory scan: assess the follicular maturity Follicle that grows to 12mm = Dominant Follicle It grows at rate of 2-3mm/day Usually ovulation occurs at 18-24mm in size. Follicular flow can be first detected when follicular size is 10mm Its resistance starts falling 2days prior to ovulation.

20. Features of mature Follicle( Preovulatory ) On 2D: Rounded 18-20mm sized follicle Thin walled anechoic Cumulus oophorus develops: 24-36hrs before ovulation Sonolucent halo appears around the follicle: 24hrs prior to ovulation Separation and infolding of inner layers 6-10hrs before ovulation.

21. For Anovulatory cycles Clincians stimulate ovulation with medications such as clomiphene or injectable gonadotropins such as hCG - Ovulation Induction. Also use the above medications alone or in conjunction with procedures such as IUI or In vitro fertilization(IVF). The end point of any ovulation induction protocol is to identify the best time for triggering ovulation ( ie in hCG , dominant follicle is 18-20mm Vs in clomiphene, dominant follicle is 20-22mm). Follicular Doppler flow studies: Color Doppler: Perifollicular vascularity is surrounding 3/4 th of follicular circumference. Pulse Doppler: PSV>10cm/sec, RI=0.4-0.48

22. Doppler correlation with Physiology of ovulation PSV of follicle reaches 10cm/sec- LH surge starts Follicle is said to be functionally matured when PSV>10cm/sec, 36hrs prior to ovulation. Perifollicular PSV keeps on rising constantly under the effect of LH. PSV gradually increases from 10cm/sec and reaches upto 45cm/sec an hour before the rupture.

23. Timing of Intra-Uterine Insemination(IUI) If PSV>15cm/sec; Single IUI: IUI is done 36-38hrs after hCH injection Double IUI: IUI is done at 12-14hrs and 36-38hrs after hCG administration. IUI in 12-24hrs becomes very fruitful with higher pregnancy rates when PSV>20cm/sec and RI within normal range. Rising PSV with steady low RI suggest that follicle is close to rupture. Fertilization of follicle with PSV<10cm/sec at ovulationhave high chances of embryo with chromosomal abnormality. Decreasing PSV with rising RI suggests that follicle is processing towards LUF. On the day of hCG injection, if culumus like echo is not seen in the follicle, its less likely to become mature fertilizable oocyte. Ovulation: Disappearance of the follicle and presence of crenated follicle. Presence of free fluid in the cul-de-sac.

24. Poorly responding ovaries May be of any size. Low PSV: Ovarian PSV<5cm/sec High RI: more Ovarian stromal RI=>0.6 Have less vascularity Hyperresponsive ovaries: OHSS Complication of ovarian stimulation treatment for IVF. Rarely may occur as a spontaneous event in pregnancy. >4 follicles larger than 16mm or 8follicles larger than 12mm Its best not to give random doses of hCG so as to prevent OHSS and high order multiple births.

25. Secretary scan Luteal Phase defect: Corpus luteum is essential for conception to occur and for pregnancy to last. Corpus luteum defect = Luteal phase defect (short luteal phase): last for less than 10days – leads to Infertility/Early miscarriages. Color Doppler ultrasound helps in assessing corpus luteum- evaluation of luteal vascularity and can detect corpus luteum defect. RI of corpus luteum corresponds to Plasma progesterone levels. Healthy corpus luteum shows: Surrounding vascular ring. RI = 0.35-0.50 PSV = 10 – 15 cm/sec

26. Luteinized unruptured follicle (LUF) LUF syndrome: failure of ovulation despite of secondary changes Ultrasound findings: Persistent follicle with thick walls, progressive loss of cystic appearance and luminal echogenicity. No free fluid in the Pouche of Douglas. Spectral Doppler shows High resisitance flow. Decreasing PSV with rising RI suggests that follicle is progressing towards LUF

27. References Ultrasound Imaging in Reproductive Medicine: Advances in Infertility Work-up Treatmeant , and ART, Laurel A, Stadtmauer , 2014 Diagnostic Ultrasound 5 th edition, Carol M. Rumack , 2018 Textbook of Diagnostic sonography 8 th edition, Sandra L. Hagen- Ansert , 2018 Ultrasound follicle monitoring, lecture series by Dr. Tejashree Patekar .