Sunday, November 30, 2008

Monitoring in IVF cycles - details


E. Tawfik, A. Mastrorilli and A. Campana
Infertility and Gynecologic Endocrinology Clinic,
Department of Obstetrics and Gynecology,
University Cantonal Hospital, 1211 Geneva 14, Switzerland

The term " monitoring " means " close continuous observation ", so when we refer to monitoring an in vitro fertilization and embryo transfer (IVF-ET) cycle we mean close observation not only of a patient’s initial parameters and her own ovarian response to ovulation induction, but also events after completion of the therapy.

Why monitor the patient? Monitoring serves two purposes. On the one hand, it helps the physician to choose the most suitable protocol, or to modify the dose and/or the approach for the protocol being applied in an attempt to obtain the best possible outcome and avoid complications of therapy or of the procedure as a whole. On the other hand, monitoring our patients adds to the common pool of information which increases our knowledge and understanding of human reproduction.

In our opinion, monitoring IVF patients begins with the initial infertility work-up, and continues until after delivery. This chapter is concerned, however, with the time period of an IVF cycle which starts just before induction therapy and ends either by the establishment of a biochemical pregnancy, or failure of implantation. Before discussing different methods of monitoring, it is better to divide monitoring into three stages: before starting induction therapy, the period of induction and the period that follows completion of therapy.

Before induction therapy

During this period, one has to think about which protocol should be offered to the patient. This depends on many factors such as the patient’s endocrine profile and general health, her age and financial situation, and the physician’s previous experience.

Clomiphene citrate

Before prescribing clomiphene citrate (CC), the physician should be sure that the follicle stimulating hormone (FSH) is not abnormally elevated and that the patient is not hypoestrogenic. One should rule out disorders of the pituitary, adrenal and thyroid which require specific treatment. Liver function evaluation should precede CC therapy if history and physical examination findings suggest liver disease. Ultrasonography (US) should be done just before starting the therapy to exclude ovarian cysts.

Gonadotropin therapy

If gonadotropin therapy is chosen, it is of utmost importance to exclude ovarian incompetence because this type of treatment is very expensive and is not free of complications. Abnormally high serum levels of gonadotropins with low estrogen levels indicate ovarian failure which precludes induction of ovulation except in a few special cases. Non gynecological endocrine problems should be treated before starting the therapy. Hypogonadotropic function with galactorrhea requires evaluation for an intracranial lesion. It is important to know that hyperprolactinemia has no adverse effect on ovarian response to exogenous gonadotropin therapy (8). Ultrasonography should be done to exclude the presence of ovarian cysts and/or polycystic ovary disease (PCO) which require special care.

Gonadotropin releasing hormone analogue (GnRHa) combined with exogenous gonadotropin therapy

This approach is especially effective for women who either show no response to exogenous gonadotropins, or who develop premature spontaneous luteinizing hormone (LH) and progesterone rise. Indeed the major effect appears to be the prevention of premature luteinization which is a major reason for decreased success with other therapies. Patients with significant estrogen and gonadotropin levels, especially anovulatory women with PCO do not respond well to gonadotropins but the response can improve after GnRHa desensitization. Some protocols call for GnRHa use during the luteal phase of the preceding IVF cycle, others advocate its use during the follicular phase concomitantly with human menopausal gonadotropin (hMG) and/or pure FSH. At present there is no agreement as to which protocol is best, and the information available is rather conflicting.

If it is decided to prescribe the long term GnRHa protocol, the patient should be monitored for the criteria of pituitary and ovarian suppression. Complete suppression is verified by the onset of menstruation associated with a serum LH <2>10 mm in diameter. If all these criteria are not met on day 12, GnRHa should be continued and the patient assessed at weekly intervals until suppression is complete, then induction can be started.

Monitoring ovarian response to induction therapy

Monitoring ovarian response to induction therapy depends mainly on the biophysical parameters of follicular growth, and hormonal parameters, principally E2 levels.

Monitoring follicular growth

Sonography can depict developing follicles, beginning at the time they measure between 3 and 5 mm. As follicles spontaneously reach maturity in the natural cycle their inner dimensions range from 17 to 25 mm (9). Within the same individual however, the size of a mature follicle is relatively constant. Intrafollicular echoes may be observed within mature follicles probably arising from clusters of granulosa cells that shear off the wall near the time of ovulation. After ovulation, the follicular wall becomes irregular. The fresh corpus luteum usually appears as an echogenic structure with a small hypoechoic center. Patients undergoing ovulation induction are usually examined every other day beginning at day 10, but those undergoing IVF–ET are examined earlier, usually starting between day 5 and 8 of their cycles, and daily thereafter.

In CC-treated cycles, each follicle seems to develop at an individual rate, and at times may be accelerated or slowed down. Therefore the largest follicle on a given day may not be the same one that is the largest two days later, and it may not even be the one that is most mature. Furthermore, correlation of E2 and follicle size is poor and the maximum preovulatory diameter can range from 19 to 24 mm. However, the largest diameter in these cases estimated by Fossum et al. (12) ranged between 22 and 31 mm.

In hMG-treated patients, there seem to be two distinct patterns of follicular development (35). In amenorrheic women with dormant ovaries, a small number of large follicles develops. The growth rate and E2 production are linear, correlate well and are of equal predictive value. A high pregnancy rate is achieved in this group. In contrast, stimulation of patients with estrogenic activity requires less hMG and usually results in the rapid recruitment of many follicles with different growth rates and E2 secretory capacity. The rate at which E2 increases is exponential, increasing the risk of hyperstimulation. The growth rate and functional maturity are asynchronous. In this group of women, both E2 and sonographic follicular monitoring are essential.

The biophysical indicators that correlate best with the day of LH surge (12) have been found to be the follicular volume in spontaneous cycles (range: 3.4-5.6 ml), the cross-sectional area in GnRH stimulated cycles (range 1074-1382 mm2) and the largest diameter in CC-treated cycles (range: 22-31 mm). Because no significant difference was seen in the correlation among the various biophysical variables and the mid cycle LH peak however, it could be concluded that in women ovulating spontaneously, or in those induced to ovulate with CC or GnRH, any available biophysical index will have the same predictive value. In contrast, correlation analysis in cycles treated with hMG indicates that both the follicular diameter and E2 are required for optimal timing of human chorionic gonadotropin (hCG) administration.

Sonographic delineation of follicle size is crucial because hCG is best administered once follicles reach 15 to 18 mm in size even in non-IVF cycles when ovulation is allowed to occur, as the LH surge is less frequent when hMG is used for stimulation. For IVF, follicles are typically aspirated when they reach 15 to 18 mm in average diameter and when the E2 level is approximately 400 pg/ml per large follicle (20). Another sonographic sign of mature follicles is the presence of low level intrafollicular echoes, as mentioned earlier. When follicles >15 mm are aspirated, oocytes are at all stages of maturity (23). Therefore one can rely on follicular diameters alone if the patient’s previous cycles and her E2 response are known.

There is no difference in E2 production between follicles measuring 14 mm and those that are smaller, nor between follicles measuring 17 mm and those which are larger (32). The authors devised an equation to determine expected serum E2 levels depending on number and size of follicles in both ovaries. Thus the serum E2 level on the day of hCG injection is:

E2 = 291 pg/ml + 180 (x) + 64 (y) + 18.7 (z)

where x, y and z represent follicles measuring >17 mm, 15 to 16 mm and <14>9 mm thick) and group B (<9>300 pg/ml by day 8 of stimulation. Fast responders had their E2 levels >300 pg/ml by day 5 of stimulation. However because E2 levels can be augmented to comparable levels by increasing the dose of gonadotropins, a correlation between E2 levels and gonadotropin dose is needed. Ibrahim and co-workers (16) defined poor response in desensitization protocols as the need for 4 or more ampoules of hMG/day to induce ovulation.

The dose of gonadotropin should not be changed as long as serial E2 levels rise between 50 and 100% every other day (32). Dirnfeld et al. (6), showed that very slow or very rapid estrogen growth rates (EGRs), calculated from the 4 days preceding oocyte aspiration in CC/hMG stimulated cycles, were associated with a reduced pregnancy rate. EGRs of 0.31 to 0.41 were associated with optimal pregnancy rates. EGR is calculated by the formula:

EGR = e-B -1

where B is the slope of the least square line corresponding to the semilogarithmic plot of E2 values versus time and e = 2.718.

Using GnRHa and gonadotropin in a desensitization protocol, the ovarian response was evaluated in terms of E2 levels on the day of hCG injection, and 36 hours later at egg retrieval (23). Low responders, medium responders and high responders were those with E2 levels of <800>1500 pg/ml respectively on the day of hCG injection or <400>1000 pg/ml respectively at egg retrieval. There were no differences between the three groups in respect to development of mature oocytes and rapidly cleaving embryos. The pregnancy rate in the low responding group, however, was significantly lower than in the other two groups, despite replacement of an equivalent number of oocytes and cleaving embryos. Thus it seems that the receptivity of the endometrium depends at least partially on adequate E2 levels. It also seems that E2 levels do not directly correlate with oocyte maturity and embryonic growth.

An upper limit of estradiol of 3800 pg/ml for anovulatory women (with polycystic ovaries) and 2400 for women with hypothalamic amenorrhea produces a risk of severe hyperstimulation of 5% in pregnant cycles and 1% in non conceptional cycles (14).

Paltieli and colleagues (28) found that in hMG cycles in which ovulation was triggered by using hCG injections, at least 80% of pregnancies were achieved when the E2 rise (active phase) was 6±1 days, whereas only 15% of pregnancies were achieved when the active phase was >7 days. They attributed the high incidence of early abortion, when the active phase was >7 days, to be an expression of oocyte overexposure to hMG prior to hCG injection. Such overexposure may result in postmature oocytes and end in early abortion. The same group of investigators noted also that in good outcome cycles, E2 continued to rise until hCG was administered, but in nonpregnant cycles, E2 plateaued on the day before hCG administration, which suggests that luteinization or atresia of the more advanced follicles had commenced spontaneously.

Monitoring special situations

CC/hMG protocols

Although adequate follicular development occurs with CC and hMG combination regimen, it is thought that one problem with that regimen is premature luteinization (13). In general, it is believed that the rise in serum progesterone occurs 12 hours before or on the day of the onset of a spontaneous LH surge in a natural cycle, or in a controlled ovarian hyperstimulation for IVF-ET program (36). Fleming and Coutts (10) defined the criteria for premature luteinization to be: serum progesterone >1.5 ng/ml associated with a rise in serum LH concentration before maturation of the developing follicles, together with a decline or plateauing of the serum E2 concentration despite continued hMG administration. However, there were reports that a significant rise in serum progesterone occurs in advance of the onset of the LH surge in regimens using a combination of CC and hMG (30).

In 1992, Mio and colleagues (24) defined " subtle progesterone rise " as a fluctuation in the serum progesterone concentration of between 1 and 2 ng/ml from day 7 of the cycle until 24 hours before the hCG administration, or the onset of the LH surge. This is not coupled with a significant increase in the serum LH concentration, defined as an increase of <100%>17-18 mm in diameter. Patients with poor follicular development or with only one developing follicle are not given hCG. It is inadvisable to give hCG to patients in whom the serum estradiol level is seen to increase rapidly (i.e. doubling in 24 hours) in order to minimize the risk of the OHSS.

Just prior to hCG injection, a serum LH can be drawn and compared to values earlier in the cycle. This helps to identify women who have initiated a premature LH surge (LH value 2.5 times baseline). However, without frequent sampling of LH (every 3 hours), the onset of the surge cannot be identified with precision (33). LH sampling is not required in patients who are treated with GnRHa. If a spontaneous LH surge occurs in a stimulated cycle, some centres cancel the treatment cycle, whereas others give hCG if there is a satisfactory estradiol response and adequate follicular growth has taken place (37). In these cases, it is necessary to adjust the timing of oocyte recovery.

As a general rule, hyperstimulation is associated with the presence of many follicles. It is advisable that hCG not be administered if there are more than 3-4 follicles of 14 mm or more in diameter (33). Mild hyperstimulation has been associated with an increased number of intermediate size follicles and severe hyperstimulation with an increase in small follicles (2). A large number (11 or more) of small follicles should also preclude hCG administration.

Check and colleagues (4) used hCG to trigger ovulation in their patients in whom ovulation was induced by hMG. The timing of injection of hCG was influenced by the serum progesterone level as follows: if the serum progesterone was >1.8 ng/ml, then 10,000 units of hCG would be given as long as there was at least one dominant follicle with serum estradiol >200 pg/ml, even if multiple follicles were present and the serum estradiol was <200>25 mIU/ml is diagnostic and is confirmed by a rising titre 3 days later. When pregnancy is diagnosed, it may be necessary to support it by exogenous hCG administration until 12 weeks gestation. The diagnosis of a clinical pregnancy is made when one or more gestational sacs can be identified by ultrasound image 4 to 6 weeks after oocyte retrieval. Embryonic viability is diagnosed when the heart beats can be detected on the screen.

This is not the whole story. Pregnant patients still need close follow-up and special care in relation to an expensive precious pregnancy until after labour and delivery.


Belaisch-Allart, J., Testart, J., and Frydman, R. (1989): Hum. Reprod., 4:33-34.
Blankstein, J., Shalev, J., Saadon, T., Kukia, E.E., Rabinovici, J., Pariente, C., Lunenfeld, B., Serr, D.M., and Mashiach, S. (1987): Fertil. Steril., 47:597-602.
Channing, C.P., Kammerman, S. (1974): Biol. Reprod.,10:179-198.
Check, J.H., Adelson, H.G., Stern, J., and Lauer, C. (1992): Int. J. Fertil., 37:103-105.
deCrespigny, L., Cooper, D., and McKenna, M. (1988): J. Ultrasound Med., 7:7-10.
Dirnfeld, M., Lejeune, B., Camus, M., Vekemans, M., and Leroy, F. (1985): Fertil. Steril., 43:379-384.
Fakih, H., and Bello, S. (1992): Fertil. Steril., 58:829-832.
Farine, D., Dor, J., Lupovici, N., Lunenfeld, B., and Mashiach, S. (1985): Obstet. Gynecol., 65:658-660.
Fleischer, A.C., Daniell, J.F., Rodier, J., Lindsay, A.M., and James, A.E. (1981): J. Clin. Ultrasound, 9:275-280.
Fleming, R., and Coutts, J.R.T. (1986): Fertil. Steril., 45:226-230.
Forrest, T.S., Elyadereni, M.K., Muilenburg, M.I., Bewtra, C., Koble, W.T., and Sullivan, P. (1988): Radiology, 167:233-237.
Fossum, G.T., Vermesh, M., and Kletzky, O.A. (1990):Obstet. Gynecol., 75:407-411.
Hamori, M., Stuckensen, J.A., Rumpf, D., Kniewald, T., Kniewald, A., and Kurz, C.S. (1987): Hum. Reprod., 2:639-643.
Haning, R.V. Jr., Boehnlein, L.M., Carlson, I.H., Kuzma, D.L., and Zweibel, W.J. (1984): Fertil. Steril., 42:882-889.
Hodgen, G.D. (1989): Hum. Reprod., 4:37-46.
Ibrahim, Z.H., Matson, P.L., Puck, P., and Lieberman, B.A. (1991): Fertil. Steril., 55:202-204.
Kamrava, M.M., Seibel, M.M., Berger, M.J., Thompson, I., and Taymor, M.L. (1982): Fertil. Steril., 37:520-523.
Laufer, N., Reich, R., Braw, R., Shenker, J.G., and Tsafriri, A. (1982): Biol. Reprod., 27:463-470.
Leeton, J., Trounson, A., and Jessup, D. (1985): J. In Vitro Fert. Embryo Transf., 2:166-169.
Marrs, R.P., Vargyas, J.M., and March, C.M. (1983): Am. J. Obstet. Gynecol., 145:417-421.
Marut, E.L., and Hodgen, G.D. (1982): Fertil. Steril., 38:100-104.
McFaul, P.B., Traub, A.I., and Thompson, W. (1989): Acta Eur. Fertil., 20:157-161.
Mettler, L., and Tavmergen, E.N. (1989): Hum. Reprod., 4:59-64.
Mio, Y., Sekijima, A., Iwabe, T., Onohara, Y., Harada, T., and Terakawa, N. (1992): Fertil. Steril., 58:159-166.
Mizunuma, H., Andoh, K., Yamada, K., Takagi, T., Kamijo, T., and Ibuki, Y. (1992): Fertil. Steril., 58:46-50.
Muasher, S., Oehninger, S., Simonetti, S., Matta, J., Ellis, L.M., Liu, H.C., Jones, G.S., and Rosenwaks, Z. (1988): Fertil. Steril., 50:298-307.
Navot, D., Rosenwaks, Z., and Margalioth, E.J. (1987): Lancet, 2:645-647.
Paltieli, Y., Tal, J., Porat, N., Tesler, B., Abramovici, D., and Sharf, M. (1991): Int. J. Fertil., 36:94-98.
Schenken, R.S., and Hodgen, G.D. (1983): J. Clin. Endocrinol. Metab., 57:50-55.
Serafini, P., Stone, B., Kerin, J., Batzofin, J., Quinn, P., and Marrs, R.P. (1988): Fertil. Steril., 49:86-89.
Sher, G., Herbert, C., Maassarani, G., and Jacobs, M.H. (1991): Hum. Reprod., 6:232-237.
Silverberg, K.M., Olive, D.L., Burns, W.N., Johnson, J.V., Groff, T.R., and Schenken, R.S. (1991): Fertil. Steril., 56:296-300.
Speroff, L, Glass, R.H., and Kase, N.G. (1989): Clinical Gynecologic Endocrinology and Infertility, 4th ed. Williams & Wilkins, Baltimore.
Tanbo, T., Dale, P.O., Abyholm, T., and Stokke, K.T. (1989): Hum. Reprod., 4:647-650.
Tarlatizis, B.C., Laufer, N., and DeCherney, A.H. (1984): J. In Vitro Fert. Embryo Transf., 1:226-232.
Trounson, A.O., and Calabrese, R. (1984): J . Clin. Endocrinol . Metab., 59:1075-1080.
WHO, editor (1992): Recent advances in medically assisted conception. Geneva.

Measuring estradiol levels before HCG to predict success of IVF treatment

Found this article the other day while surfing the net - interesting read for those who are looking for quantitative methods to predict success rate of IVF treatment.

Association of estradiol levels on the day of hCG administration and pregnancy achievement in IVF: a systematic review Ioannis P. Kosmas, Efstratios M. Kolibianakis1 and Paul Devroey
Center for Reproductive Medicine, Dutch-speaking Brussels Free University, Laarbeeklaan 101, 1090 Brussels, Belgium
1 To whom correspondence should be addressed. Email:

BACKGROUND: Evaluation of the association between estradiol (E2) levels on the day of hCG administration and pregnancy achievement in IVF has so far yielded conflicting results. The purpose of the present study was to systematically review the above association in cycles down-regulated with GnRH analogues. METHODS: Literature search was performed using Medline, Embase (1978–2004) and the Cochrane Library. Additionally, references of retrieved articles were hand-searched. Only full articles published in peer-reviewed medical journals were considered for analysis. RESULTS: All the eligible studies (n=9) involved the use of GnRH agonists and were retrospective. Two studies (including 191 patients) suggested that the higher the E2 levels on the day of hCG administration, the higher the probability of pregnancy. However, five studies (including 1875 patients), did not support an association between E2 levels on the day of hCG administration and pregnancy rates. Moreover, two of the studies including (1286 patients) suggested that high E2 levels on the day of hCG administration are associated with a decreased probability of pregnancy. If we consider only studies in which criteria used for administering hCG include follicular development but not E2 levels (including 2687 patients), there is no study suggesting a positive association between E2 levels on the day of hCG administration and pregnancy achievement. CONCLUSIONS: Currently there is no high-quality evidence to support or deny the value of E2 determination on the day of hCG administration for pregnancy achievement in IVF cycles, where pituitary down-regulation is performed with GnRH agonists. Existing retrospective studies suggest that there is no positive association. However, in order to arrive at recommendations for clinical practice, there is a need to perform well-designed prospective studies in both agonist and antagonist cycles.
Key words: estradiol/GnRH agonist/IVF/pregnancy rate

Thursday, November 13, 2008

Extension of lucin jabs

Wed 12 Nov 2008
Did a estradiol bloodtest and scan today at 8am and was told to call back between 3pm and 4pm for the results.

The results will determine whether i can start on puregon the next day or the lucrin jabs have to be extended.

Time flew by as i was busy with reading up for my exams on Friday, before you know it, my mobile rang with Nurse Phua on the line.

She said that i have to collect the puregon meds on Sat 22 Nov and continue with the lucrin jabs as "hormones are not properly suppressed". I ask her how did they know that by 22 Nov, hormones will bor perhaps i am just being sensitive...but .. but.. my questions still left hanging in my mind.

I'm puzzled. there was no baseline test before i started on lucrin, so how did they know the hormones level is not suppressed properly? is there a fixed number that all women have to meet or is it subjective to indiv level?

there is no planned bloodtest 11 days later - so how do they know that 11 days later, the hormones will be sufficiently suppressed?

and how did they come up with 11 days, why not 7 days, 9 days or 12 days, it seems random to me since there is no blood test to test the level of estradoil again, how do they know that hormones will be suppressed by then?

another question, does the extension of the lucrin mean that the lining of the womb will be thicker and hence reduce the success of implantation?

so many questions and no answers.

Wednesday, November 05, 2008

Re start blogging again

It has been quite some time since i last posted anything in here. In between Jan to Nov 2008, many things have occured.

Feb: Quit FP after another failed FET cycle
Mar: Join BMC as their centre manager
May : Quit to start another FET cycle, decided to concentrate on IVF and continue my studies
Jun : Accepted into 3 yr degree program, classes to start in July.
Jul : FET Cycle 2 failed, started classes
Aug : decide to close down online business and reconsider other options
Sep : offered a couple of part time & freelance positions, but decided to re start IVF cycle
Oct : started IVF Cycle 2, lucrin jabs end of Oct and accupunture @ raffles medical hospital
Nov: prepare for exams, and 2nd stage of IVF: puregon

Sunday, January 06, 2008

Life Cycle of an embroyo - From the start

Early Hours
Fertilization begins when a sperm penetrates an oocyte (an egg) and it ends with the creation of the zygote. The fertilization process takes about 24 hours. A sperm can survive for up to 48 hours. It takes about ten hours to navigate the female productive track, moving up the vaginal canal, through the cervix, and into the fallopian tube where fertilization begins. Though 300 million sperm may enter the upper part of the vagina, only 1%, 3 million, enter the uterus.

At 6 hours
The sperm must make the penetration of the zona pellucida, a tough membrane surrounding the oocyte. Only one sperm needs to bind with the protein receptors in the zona pellucida to trigger an enzyme reaction allowing the zona to be pierced. Penetration of the zona pellucida takes about twenty minutes.

At 1 - 5 days
Within 11 hours following fertilization, the oocyte has extruded a polar body with its excess chromosomes. The fusion of the oocyte and sperm nuclei marks the creation of the zygote and the end of fertilization. The zygote now begins to cleave, with each division occurring into two cells called blastomeres. The zygote's first cell division begins a series of divisions, with each division occurring approximately every twenty hours. Each blastomere within the zona pellucida becomes smaller and smaller with each subsequent division. When cell division ungenerated about sixteen cells, the zygote becomes a morula (mulberry shaped). It leaves the fallopian tube and enters the uterine cavity three to four days after fertilization.

At 6 days
The blastocyst hatches from the zona pellucida around the sixth day after fertilization, as the blastocyst enters the uterus. The trophoblast cells secretes an enzyme which erodes the epithelial uterine lining and creates an implantation site for the blastocyst.In a cyclical process of hormonal stimulation, the ovary is induced to continue producing progesterone while human chorionic gonadotropin (hCG) is released by the trophoblast cells of the implanting blastocyst. Endometrial glands in the uterus enlarge in response to the blastocyst and the implantation site becomes swollen with new capillaries. Circulation begins - a process needed for the continuation of pregnancy.

At 12 days
Trophoblast cells engulf and destroy cells of the uterine lining creating blood pools, both stimulating new capillaries to grow and foretelling the growth of the placenta. The inner cell mass divides, rapidly forming a two-layered disc. The top layer of cells will become the embryo and amniotic cavity, while the lower cells will become the yolk sac. Ectopic pregnancies can occur at this time and sometimes continue for up to 16 weeks of pregnancy before being noticed. Diagnosed quickly, ectopic pregnancies can be treated pharmacologically without surgery, reducing danger to the mother, and preserving the site of the ectopic pregnancy.

At 15 - 18 days
The formation of blood and blood vessels of the embryo begins. The blood system appears first in the area of the placenta surrounding the embryo, while the yolk sac begins to produce hematopoietic or non-nucleated blood cells. The embryo is attached by a connecting stalk (which will later become part of the umbilical cord), to the developing placenta. A narrow line of cells appears on the surface of the embryonic disc. This primitive streak is the future axis of the embryo and it marks the beginning of gastrulation, a process that gives rise to all three layers of the embryo: ectoderm, mesoderm and endoderm.

At 19 - days
The embryonic area is now shaped like a pear, and the head region is broader than the tail end. The ectoderm has thickened to form the neural plate. The edges of this plate rise and form a concave area known as the neural groove. This groove is the precursor of the embryo's nervous system and it is one of the first organs to develop. The blood cells of the embryo are already developed and they begin to form channels along the epithelial cells which form consecutively with the blood cells

at 21 days
If you could look at the embryo from a top view, it would resemble the sole of a shoe with the head end wider than the tail end, and a slightly narrowed middle. Somites, which are condensations composed of mesoderm, appear on either side of the neural groove. The first pair of somites appear at the tail and progress to the middle. One to three pairs of somites are present. Every ridge, bump and recess now indicates cellular differentiation. A head fold rises on either side of the primitive streak. The primitive streak now runs between one-fourth to one-third of the length of the embryo. Secondary blood vessels now appear in the chorion/placenta. Hematopoietic cells appear on the yolk sac simultaneously with endothelial cells that will form blood vessels for the newly emerging blood cells. Endocardial (muscle) cells begin to fuse and form into the early embryo's two heart tubes.

at 23 - 26 days
Rapid growth and change as the embryo becomes longer and the yolk sac expands. On each side of the neural tube, between four and twelve pairs of somites can exist by the end of this stage. The cells which become the eyes appear as thickened circles just off of the neural folds. The cells of the ears are also present. Neural folds are rising and fusing at several points along the length of the neural tube concomitant with the budding somites which appear to zipper the neural tube closed. Neural crest cells will eventually contribute to the skull and face of the embryo. The two endocardial tubes formed in before fuse here to form one single tube derived from the roof of the nueral tube, which becomes S-shaped and makes the primitive heart asymmetric. As the S-shape forms, cardiac muscle contraction begins.

at 28 - 31 days
Thirteen to twenty pairs of somites are present and the embryo is shaped in a modified S curve. The embryo has a bulb-like tail and a connecting stalk to the developing placenta. A primitive S-shaped tubal heart is beating and peristalsis, the rhythmic flow propelling fluids throughout the body, begins. However, this is not true circulation because blood vesel development is still incomplete. At this stage, the neural tube determines the form of the embryo. Although the primary blood vessels along the central nervous system are connecting, the central nervous system appears to be the most developed system. If twenty somites are present in the embryo, the forebrain is completely closed.

at 32 days
The brain differentiates into the three main parts: the forebrain, midbrain and hindbrain. The forebrain consists of lobes that translate input from the senses, and will be responsible for memory formation, thinking, reasoning, problem solving. The midbrain will serve as a relay station, coordinating messages to their final destination. The hindbrain will be responsible for regulating the heart, breathing and muscle movements.Thyroid continues to develop and the lymphatic system, which filters out bacteria, starts to form. Otic placode invaginates and forms the otic vesicle, which will develop into the structures needed for hearing and maintenance of equilibrium. Retinal disc presses outward and touches the surface ectoderm. In response the ectoderm proliferates forming the lens disc. Specific parts of the eye, such as the retina, the future pigment of the retina and the optic stalk are identifiable. Primitive mouth with a tongue is recognizable. Thyroid continues to develop and the lymphatic system, which filters out bacteria, starts to form. Heart chambers are filled with plasma and blood cells making the heart seem distended and prominent. The heart and liver combined are equal in volume to the head by this stage. Blood circulation is well established, though true valves are not yet present.. The villous network is in place to accommodate the exchange of blood between the woman and the embryo. Aortic arches 4 and 6 develop and 5 may appear. Lung buds continue to form. Gall bladder, stomach, intestines, pancreas continue to form and the metanephric bud appears in the chest cavity. The stomach is in the shape of a spindle and the pancreas may be detected at the intestinal tube. The developing liver receives blood from the placenta via the umbilical cord. The amnion encloses the connecting stalk helping to fuse it with the longer and more slender umbilical vesicle (the remnant of the yolk sac). Upper limb buds are visible as ridges and the lower limb buds begin to develop. Folding is complete and the embryo is now three-dimensional and is completely enclosed in the amniotic sac. The somites will be involved in building bones and muscles. The first thin surface layer of skin appears covering the embryo.

at 35 days
The brain and head grow rapidly. The mandibular and hyoid arches are noticeable. Ridges demarcate the three sections of the brain (midbrain, forebrain and hindbrain). The spinal cord wall at this stage contains three zones: the ventricular, the mantle and the marginal. The ventricular zone will form neurons, glial cells and ependymal cells, the intermediate mantle will form neuron clusters and the marginal zone will contain processes of neurons. Adenohypophyseal pouch, which will develop into the anterior pituitary, is defined. Lens vesicle opens to the surface and is nestled within the otptic cup. Otic vesicle increases its size by approximately one-fourth and its endolymphatic appendage is more defined. Nasal plate can be detected by thickened ectoderm. Esophagus, the tube through which food is swallowed, forms from a groove of tissue that separates from the trachea, which is also visible. Semilunar valves begin to form in the heart. Four major subdivisions of the heart (the trabeculated left and right ventricles, the conus cords and the truncus arteriosus) are clearly defined. Two sprouts, a ventral one from the aortic sac and a dorsal one from the aorta, form the pulmonary (sixth aortic) arch. Right and left lung sacs lie on either side of the esophagus. Ureteric bud appear. Metanephros, which will eventually form the permanent kidney, is developing. Upper limbs elongate into cylindrically-shaped buds, tapering at tip to eventually form hand plate. Nerve distribution process, innervation, begins in the upper limbs.

at 42 days
s the brain has increased in size by one-third since the last stage, it is still larger than the trunk. Rostral neuropore is closed and four pairs of pharyngeal arches are visible now, though the fourth one is still quite small. The maxillary and mandibular prominence of the first arch are clearly delineated. The stomodeum, the depression in the ectoderm which will develop into the mouth and oral cavity, appears between the prominent forebrain and the fused mandibular prominence.Swellings of the external ear begin to appear on both sides of the head, formed by the mandibular arch. Lens pit has closed, retinal pigment may appear in the external layer of the optic cup and lens fibers form the lens body. Two symmetrical and separate nasal pits may appear as depressions in the nasal disc. Esophagus lengthens. Blood flow through the atrioventricular canal is divided into left and right streams, which continue through the outflow tract and aortic sac. The left ventricle is larger than the right and has a thicker wall. Lobar buds appear in the bronchial tree. The intestine lengthens. Ureteric bud lengthens and its tip expands, thus beginning the formation of the final and permanent set of kidneys. Distinct regions of the handplate, forearm, arm and shoulder may be discerned in the upper limb bud. Lower limb bud begins to round at top and tip of its tapering end will eventually form the foot. Innervation, the distribution of nerves, begins in the lower limb buds. The relative width of the trunk increases from the growth of the spinal ganglia, the muscular plate and the corresponding mesenchymal tissues.

at 44 days
Brain is well marked by its cerebral hemispheres. The hindbrain, which is responsible for heart regulation, breathing and muscle movements, begins to develop. Future lower jaw, the first part of face to be established, is now visible while future upper jaw is present, but not demarcated. Mesenchymal cells originating in the primitive streak, the neural crest and the prechordal plate, continue to form the skull and the face. External retina pigment is visible and the lens pit has grown into a D shape. Nasal pits are still two separate plates, but they rotate to face ventrally as head widens. Primary cardiac tube separates into aortic and pulmonary channels and the ventricular pouches deepen and enlarge, forming a common wall with their myocardial shells. Mammary gland tissue begins to mature. The mesentery, which attaches the intestines to the rear abdominal wall, holds them in position and supplies them with blood, nerves and lymphatics, is now clearly defined. Ureter, the tube that will convey urine from the kidney to the bladder, continues to lengthen. Proliferation of the coelomic epithelium indicates the gonadal primordium. Hand region of upper limb bud differentiates further to form a central carpal part and a digital plate. The thigh (rostrolateral part), leg (the caudomedial part) and foot areas can be distinguished in the lower limb buds.

at 46 days
Jaw and facial muscles are now developing. The nasofrontal groove becomes distinct and an olfactory bulb (sense of smell) forms in the brain. Auricular (ear) hillocks become recognizable. The dental laminae or teeth buds begin to form. The pituitary, which is the master gland responsible for growth of hormones that regulate other glands, such as the thyroid, adrenal glands, gonad) begins to form.Trachea, the larynx and the bronchi begin to form. The heart begins to separate into four chambers. The diaphragm, the tissue that separates the chest cavity from the abdomen, forms. Intestines begin to develop within the umbilical cord and will later migrate into the abdomen when the embryo's body is large enough to accommodate them. Primitive germ cells arrive at the genital area and will respond to genetic instructions to develop into either female or male genitals. Digital rays in appear in the foot plates and finger rays are more distinct. Trunk becomes straighter.

at 51 days
Nerve plexuses begin to develop in the region of the scalp. Eyes are pigmented and eyelids begin to develop and may fold. Within the heart, the trunk of the pulmonary artery separates from the trunk of the aorta. Nipples appear on the chest. Body appears more like a cube. Kidneys begin to produce urine for the first time. Genital tubercle, urogenital membrane and anal membrane appear. The critical period of arm development ends, and the arms are at their proper location, roughly proportional to the embryo. However, the hand plates are not finished, but develop further in the next two days. The wrist is clearly visible and the hands already have ridges or notches indicating the future separation of the fingers and the thumbs. Ossification of the skeleton begins.

FET day 3

After what it seems like months on OCP and progynova (oestradiol), finally got the go ahead for FET on last friday.

It took only one scan on wed to reveal that the lining is primed sufficiently at 8mm to proceed with FET in 2 days time. - a lot less hassle than a fresh cycle.

was put on cylogest suppositories but had very bad bloatededness, and some nausea. switched to im progesterone instead for luteal support. the jabs are really painful. somehow though having gone thru the same jabs for a fresh cycle, this time round, the oil based jabs are less tolerable. :(

got to just grin and bear! perhaps it's the oestradiol acting as well, cause every pain seem to be magnified and am really super short fused. husband got the brunt of that..

what we did different this time - we did accupunture 3 days continuously before the FET (inluding on the day of the FET itself). and am taking 14 days of twice a day sachets of some TCM powder.

also avoiding all cold water and raw food. and taking chicken essence once or twice a day. trying to drink lots of warm water.

I have good feelign about this cycle, the law of averages should be on my side this time.

Saturday, October 13, 2007

one month later

i am just so tired..tired of living, tired of life. it's not as if there is no laughter and light hearted moments...but just that life is a trial. maybe i just need a holiday and break from work.

even thinking about planning a exhaustive..i wonder what is wrong with me.

Monday, September 10, 2007

Post IVF

It has been 2 weeks since the results are out. AF is already over and i am back at work, throwing myself into work which happens to be a busy period, enrolled in a gym and am going regularly *cross fingers* made plans to do more about the online shop and in fact met some pple over it. learning to write a biz plan, and figuring out the legal registration of the company.

i thought i was coping well with the failure.

on Sat, went for dinner at Yv, met a pregnant S and the whole bunch of kids and all of it came crashing back to me. looking at Yv younger boy and it came crashing to me that if my baby survive, he/she would be exactly that age.

Just why not me?

the pain is excrutiating. i wish i could cry and get rid of it once and forever, but comes and goes..this empty feeling.

Thursday, August 23, 2007

negative - THE END

been testing since 7DPET and gotten negative all along. Decided to bring forward the beta hcg blood test to Monday, got the results at 1pm, it's a very miserable 2.4. the nurse was still saying that it's early, and it may rise..but who the hell is she kidding?

all articles and all ivf centres in the world will concur that 2.4 is very NON PREGNANT. in fact any level below 5 is NON PREGNANT. I must admit that i am pretty annoyed at being 'entertained'

tried contact SF loh but was unable to get through to him as he was in OT all day. emailed him but didnlt get a reply either. it's frustrating, frustrating frustrating.

called kkh ivf again and was told to continue the progesterone jabs till thursday and then take another blood test on Friday. what the '1 quarter fish, 3 quarter duck' for?

hubby was optimistic, said why we end up trudging to KKH early on tuesday. I then asked another the nurse manager if it's really necessary to continue on the progesterone jabs - she took a look at the chart and said ' let sf loh see you later and he will let you know'

that answers everything.

we waited 30 min to see as he's in OT (again). sf loh explained the figures and went through the egg retrival process, how many eggs retrieved (22), how many fertlised through IVF (final figure ?) and how many fertlised through ICSI. roughly half of the eggs retrieved was via IVF and ICSI.

total of 7 fertlised embroyos with 3 at grade 4 and treated with ICSI which was transferred this cycle.

The balance of 4 embroyos are frozen and mostly grade 3.

we discuss about the next cycle FET. And he still works on the premise that if so long the embroyo survives the thaw overnight, it should be transferrred, rather than waste it trying to grow it to blastocyst stage.

he said the chances that the embroyo will grow to blastocyst stage in the culture medium is so much lower than the chances that it will grow in the womb, that it is considered like wasting the embroyos.

i mentioned about the fact that if the embroyo doesn't survive till blastocysts stage after thawing , what makes him think that it will survive in the womb? he replied with some analogy about SAF men in camp training in the desert (which i so didn;t get) but anyways.....the idea is that the culture medium though the best that KKH uses is still not the real womb environment.

why did this cycle fail?
there is no specific reason. we can do only so much, the rest is still unexplained medically.

will the next cycle work?
no one can answer that question. FET has been known to have at least 10% chances lower than a fresh IVF cycle. But then there are also women who didn't get pregnant via a fresh cycle but gotten pregnant with FET. There's always hope!

Article in ST

Fertility clinics must disclose success rates by Andy HoThe Straits Times31 July 2007
A LOWER court had awarded a middle-age couple $32,000 for in-vitro fertilisation (IVF) treatment, but the High Court reversed this recently. The couple had lost both their teenage sons in a car accident and were asking for, among other things, IVF costs as replacement expenses in their effort to have a child.
The couple may appeal, so one may not comment on the case which involved, quite unusually, a motor vehicle insurer. But this tragic case does bring into focus the need for an IVF-specific law, which must address, if nothing else, two big issues.
First, given that Singapore needs more babies, it seems odd that there isn’t a law that requires (health) insurers to cover IVF treatment - or at least to offer coverage for it.
Insurers have argued that infertility is not an illness. Even if it were, they say, IVF does not treat the illness since it does not cure the underlying infertility. And, even if it did, coverage should be left to the market. After all, most plans here do not cover dental or psychiatric services.
Mandates to provide or offer coverage would distort markets, they say. That is, people who do not need IVF would have to bear part of the costs in higher premiums.
But I am pooled together with smokers anyway, so my insurance premium is already higher than it would be if my pool was smoker-free. After all, the essence of insurance is to socialise, or share out, risks.
Moreover, the lack of coverage means that health insurers are not helping to rein in IVF fees. It also means that IVF utilisation is probably less than that which would give Singapore more babies.
If so, instead of leaving it to the courts to decide piecemeal - someone must actually bring a suit for them to even consider the issue - Parliament should debate the question of coverage thoroughly.
And while Parliament is at it, it might also consider another issue, that is, how to regulate the sector.
Comprising mainly fee-forservice procedures, the sector is currently largely unregulated. Specifically, patients have no access to reliable information to help them choose service providers optimally, so they depend on word of mouth.
Most couples go through much pain for many years before they attain success, but many do not get that far.
IVF involves using drugs to urge a woman’s ovaries to produce eggs at each menstrual cycle, surgically retrieving the eggs, fertilising them with sperm in the lab to produce embryos, and then implanting the embryos into the woman’s womb. Women endure physical pain and couples are buffeted emotionally by the trials and tribulations the process puts people through. Moreover, each cycle of IVF treatment costs about $10,000.
Also, it is risky. Unlike most medical technologies, fertility treatments were introduced with little rigorous testing, except on animals. Most governments have simply left oversight of the sector to the medical profession’s self-regulation - and the courts.
Unsurprisingly then, it was merely five years ago that scientists were able to pin down the fact that IVF babies are six times more likely to have low or very low birth weights, and twice more likely to have major birth defects. Although clearer information has surfaced in the last dozen years, much is still unknown about the technology’s risks.
True, there is always some reluctance to regulate sectors where technology is rapidly evolving, since any law enacted today will have a hard time keeping up with the science tomorrow. But perhaps regulation can be targeted specifically to help with what customers really care about: results.
So whether we eventually pass a law to mandate insurance coverage or not, a law could be passed to mandate that providers report their individual success rates.
This is important because the infertile are very vulnerable and may persist in trying even when success is very unlikely. What they need is reliable data to make informed decisions that optimise their chances of getting a healthy baby.
However, providers in Singapore do not publicly report such statistics, so patients just go by word of mouth. And in jurisdictions where clinics do report their success rates, providers have been known to manipulate their data.
For example, some clinics count pregnancies rather than live births in their ’success’ rates, but some of those pregnancies end in miscarriages. Or, clinics may compare the number of live births to the number of embryos transferred, but this leaves out those cycles that are cancelled when eggs are harvested but cannot be fertilised.
However, the number of egg retrievals done does matter because the invasive procedure involved is painful and not risk-free. Any statistic that excludes failed cycles underplays the number of painful procedures (and risks) a woman might have to bear.
What to do?
We should pass a law to require service providers to disclose their success rates, specifying also how success-rate statistics are to be presented.
An unusually good model is that found in the American state of Virginia, where the law requires that before IVF treatment can commence, the clinic must give the patient a signed disclosure form detailing its success rates in specific ways. (This law specifies three statistics: First, the total number of live births, which is what couples care about most; second, the proportion of live births per menstrual cycle of retrieving eggs - which measures the true rate of success per attempt; and lastly, the numbers of both pregnancies and live births per retrieval cycle - which indicates the woman’s risk of miscarriage.)
The provider must also break down its data by age groups, since success rates drop as women age.
I urge Parliament to consider enacting a similar law. With uniform statistics among clinics, consumers can comparison shop and optimise the quest to make babies. And while Parliament is at it, mandate coverage of IVF services as well.