figures given I occurs from' ts inany One t the sperm lealth status latozoa Were 4tHe (1999) Dr more

~r ejaculate ,ore prog~enotility tore normal 1

dng ':i6n/mI date :cent sper-therent ie gauge of rte;mlalysis ewer than the test at interval, if zinc (pro-lal vesicle ted. Their 'ml ni it of over ogressive not rare 5 million [ the wife vagina, hale. The Lission of

I TEXTBOOK OF GYNAECOLOGY [he ptiysical examination of the husband, if he is reluctant to be examined as may happen in quite ~od number of cases. Nomenclature Asptrmia-- Failure of formation or emission of semen. OligosperrnialOligozoospermia -- Sperm count is less thah 20 million per mi. , Polyzoospermia--Count is more than 350 million/mi. Azoqspermia -- No spermatozoon in the semen; Asthtaozoospermia -- < 50% spermatozoa having forward progressive movement. Necrezoespermia -- Spermatozoa are dead or motionIess. Teratozoospermia -- > 70% spermatozoa with abnormal morphology. Oligoasthenoteratozoospermia -- Disturbance of ail 3 variables.

Indepth evaluation These are needed in cases of -- (a) Azo~mia {b) Oligospermia (e) Low volume eia culate (d) Problems o~potency. Fhr'--~er diagnostic protocols has been appropriately designed (scheme 4). e Serum FS~stosterone, proiactin, and-TS.-HH: Testkulfff~[ysfunction causes ri~SH and Lid. Low level ot. FSH and LH suggest hypogonado~ophic hypo-g0nadism (see' Scheme 4). Leydig cell dysfunction causes 10wtesto~terone andhigh Lid level. Elevated prolactin due to pituitary adenoma may cause impotency. . Fructose Content in the seminal fluid -- Its absence suggests congenital absence of seminal vesicle or portion of the ductal system or both. . Testicular bio o. E.sy -- is done to differentiate primary t~sticular failure from obstruction as a cause of azoosper-mia or severe olignspermia. The biopsy material is to be sent in Bouin's solution and not in formoi saline. Transrectal Ultrasound (TRUS) -- is.done to visualize iht seminal~rostate and ejaculatory ducts obstruction. Indications of TRUS are: 0) Azoospermia or severe o!igost~ermia with a normal testicular volume. iii) Abnormal digital rectal examInation. (iii) Ejaculatory duct abnormality (cysts, dilatation or calcification). (iv) Genital abnormality (hypospadius). Vasegram is a radiographic study done to evalufite the qaculatory duct obstruction. It is mostly replaced by Taus. ' Karyotyp'~/inalysis -- This is to be done in cases with azoospermia or severe oligospermia and raised FSH. Klinefelter's Syndrome (XXY) in the commonest. Micro deletions of the long arm of Y chromosome can also cause severe semInal abnormalities. "Immunological tests -- Two types of antibodies have been described -- sperm agglutinating and sperm immobilizing; the latter is probably related to infertility. The antibodies are produced following infection (orchitis), trauma or vasectomy. These antibodies can be detected from the serum by the sperm immobilizing testPresence of sperm antibodies in the cervical mucous is demonstrated by post coital test (see p. 106, 224). Presence Of plenty of pus cells requires prostatic massage. The collected fluid is to be examined by StaIning and culture to detect the organisms and appropriate antibiotic sensitivity.

FEMALE
History

Age, duration of marriage, history of previous marriage with proven fertility {t~dny, are to be noted. A general medical history should be taken with speqial reference to tuberculosis, sexually transmitted disease, features suggestive of pelvic inflammation or diabetes. The u-rgical hLstory should be directed specially towards abdominal or pelvic surgery. This may be related to peritubal adhesions; Menstrual history should be taken in detafis. Wide spectrum of abnormalities ranging from h o~a- oligomenorrh0ba to amenorrhoea are associated with ~mtJrbed hypo ala~ary ovarian axis which may be either primary oi: secondary to adrenal or thyroid dysfunction. Previous.obstetric history -- including number of pregnancies, the interval between them and pregnancy related complications are to be enquired. In the case of secondary infertility, the obstetric history is important. The history of premature rupture of the membranes or puerperal sepsis may be responsible for ascending infection and tubal damage. Contraceptive practice should be elicited. Apart from IUCD '<v-~7--m--~ pTdduce HD, no other contraceptives have any adverse effect on fertility. Sexual problems such as dy sparetmia, and loss of libido are to~ed. It 's"-h-b"~h~e borne in mind that the femal~r~t essential for fertility and loss of semen from the vaginal orifice following coitus is normal. A psychosomatic evaluation should focus on general and infertility pr6blems.

-5
-- ['~~c7 '-2' tax3

Microscopic study Pus cells++

Prostatic massage Smear and culture appropriate antibiotics

Low/undetectable Hypogonado trophism Kallmarm's syndrome Spermatogenesis absent . Destruction of tubular epithelium Vasogram ~-.~ Examinations General, systemic.and gynaecological examinations are made to detect any abnormality which may hinder fertility. General examination must be thorough - special emphdsXK being given to obesity or marked reduction in weight. Abner -real dis~'-on.~jaairs or underdevelo ment of econdar -sex characters are to e~ Phial fe~-~taining to enddoo~cr' o~Eg-~..e,~s-~%.car~e~uU-y-evaluated to detect featuresof PCO-D~ hirsutism and inappropriate gaihct~6ea.---- ~' Systemic exam!ngtlon may accidentally detect such abno~ilitSes like .hyl~ertension, organic heart disease, chronic renal lesion, endocrinopathies and a e~ Gynaecological examination includes ad~y of hymenal 9e~gcevtde~gina/infe.~ons,

cerv~L!tar or c~?~ '~on, ~mdue elongation

of the~ cer----Vix-,, uterine size, position and mobility, presence of unilateral or bilateral adne'xa] masses -fixed or mobile with Or without tenderness and presence of n0t{ules in the pouch of Douglas. Spec~amination may reveal abnormal cervical discharge. The discharge is to 'be collected for Gram stain and culture. Cervical smear is taken as a screening procedure as a routine or in suspected cases.

220 TEXT BOOK OF GYNAECOLOGY Special Investigations Guidelines In the presence of major fault in male such as ~ - ~'-~ff~ azoosEerrma to testicular destruction at intersex, there is ve~ to proceed for investigation for female infertility. However, even in the presence of minor abnormality, not correctable with therapy,' female investigation should not be withheld. ' Similarly, when-.-~.~ defect is de~tected in female from the h/story and examination such as ~ agar in~ers x, ine f~ inve-'sh-~'flous should be suspended.Tt~wever, correctable abnormality should be rectified first prior to investigation e.g. narrow vaginal introitus, overt hypothyroidism or diabetes mellitus. Noninvasive or minimal invasive methods are to be employed prior to major invasive one. However, it is not uncommon to have pregnancy soon after the first visit.

ll~

Detection of abnormality of One factor does not negate investigation for another defect elsewhere. Multiple defects may be present in the same case e.g. tubal defects may be associated with anovulation. Pregnancy following laparosco~dye test or hy~arE?osalpingography is not unco~ff~iWn. It is presumed-tha-&smatt-flimsy adhesions or any mucus plug obstructing the tubal lumen is removed during such procedures. The cervical spasm may be relieved during dilatation. In' fact, this may be sufficient ground to withhold major invasive procedure for about 6 months following such a procedure with normal report.

G'e'~t~ktubereulos/s.as, a cause of infertility is to be kept in mind specially in the developing countries. The association is as high .as 10-15 per cent in contrast to a law figure of 0.5 per cent in the developed countries. Ovarian dysfimctions (dysovulatory) commonly associated with infertility are: Anovula----~jp-~or oligo-ov, lllag&~ (infrequent ovuiation) Luteal phase defect (LPD) Luteinised -~~Ilic!e (LUF)

Diagnosis of ovulation The various methods used in practic~ fo detect ovulation are grouped as follows (see table 15.3) Indirect Direct Conclusive Table 15,3 Diagnosis of ovulation Indirect Menstrual history Evaluation of peripheral or endorgan changes BBT Cervical mucus study Vaginal cytology' Hormone estimation - Serum progesterone - Serum LH - Serum oestradiol Endometrlal biopsy Sonography Direct'

Laparoscopy Conclusive Pregnancy The indirect or presumptive evidences of ovulation are commonly used in clLrdcal practice. These are inferred from: Menstrual history Evaluation of peripheral or end-organ changes due to oestrogen and progesterone Direct assays of gonadotrophins or steroid hormones preceeding, coinciding or succeeding the ovulatory process. ~Menstrual history The following features in relation to menstruation are strong evidnces of ovulation. Re l~ormal menstrual loss betw-.en the aAe .0( 20-3-,-5 Midmenstrual bleeding (spotting) or pain or excessive mu------%okt va~'~al discharge.(Mittels-

c er~m~)
Features suggestive o gL~rual syndrome or primary dysmenorrhoea

Chapter 15: INFERTILITY I Menstruation Ovulation '~. "~

,,~ .'s .c '4 '2 ,. s~ R 'B . '

,,,.

- ~.
3~ ~ :, :9 c '8 '7 's u ~ ]

.s
97 I 2 3 4 5 6 ? 8 9 10 a 12 13 14 15 16 17 18 19 20 21 ~ 23 24 25 2G 27 28 29 ao al ~'2 Days from start of the menstrual cycle

.s

Fig. 15.1. Biphasic BBT Chart Evaluatio,mo~:peri pheral?-or; .endorga~ changes {Tablle 15.5B) Observation -- There is "biphasie pattern" of temperature variation in ovulatory cyde. If pregnancy occurs, the rise of temperature sustains along with absence of the period In anovulatory cycle, there is no rise of temperature throughout the cycle. Principle --(~he rise of temperature is secondary to progesterone outputS. The primary reason for the rise is the increase in the production and secretion of norepinephrine which is thermogenic neural hormone. B~edt[~res --~e patient is instructed to take her oral te'r~perature daily on waking in the morning before rising out of the bed. The temperature is recorded on a special chart. Days when intercourse takes place should also be noted on"the'chart for better evaluation of coital frequency,. Int~rF?.e[ati2~: -- G~e body temperature ma~ini~in[n~'l~rofighout the first half of the cycle is raised to 0.5 to lE (0.2-0.5C) following ovulation. The rise sustains throughout the second l~hff of the cycle and falls about 2 d.a~s prior to the next period -called "biphasic pattern f~(fig. 15.1). There may be a drop in the temperature to about 0.5F befor%~the flsa and almost coincides with either LLI surge or ovulation. The demonstrable rise actually occurs about 2 days after the LH peak and with a peripheral level of progesterone to greater thark 4 ng/ml. :!~!!~ic~J i~t~gad:;tq'nce -- Mainter/ance of BBT chart o% during investigation is of h eI~j~] d~tZ~minlng m'ulation and timing.of po~t e~taLtest,~ e'nd/6~'~trial blop,~.y.;:,ce~al?muaus or vagmak:c)fE0~ggy~st~i~l~Tfqr '~,i~,<diafib~'ft'alsb' helps the C5'2:pf~"t~"~i%~%rmii{~ ttie ~sf f~rfile period, if the cycle is irregular. Limitations of BBT BBT indicates ovulation retrospectively. It cannot'predict ovulation precisely with time. Rarely ovulation has been observed though BBT is monophasic. How long to keep the record? It should not be continued for more than 3-4 months for investigation purpose. However, it has to be maintained for longer peri?ds during management of ovulation'ind~2ction. :Ce~mid~Amucus:: Stitdy :: 0estrogen and progesterone%

~isappearance of fernpat-'~ern beyond 22nd day

of the cycle which was present in the midcycle is suggestive of ovulation. Persistence of fern pattern even beyond 22nd day suggests anovulation~. Progesterone causes dissolution of the sodium chloride crystals. Following ovulation, there is loss of stretchability (spinbm'keit) which was presenbdh the midcycle (see ch. 8). z Maturation index shifts to the left from the midcycle to the-mid second half of cycle due to

r
the effect of pr single smcaE.! oCCUrSl Serum prol progeste{pne Js~1

mg ~n$4i:.,,:~,;

 Serum LH-midcyde can del about 3~ if'coincides abo~ Set.-r~ oesh merely 24 hours hours r~ The serum L} for in vitr9 ferti2 Endometrial tiI trial sampling) patient proced~ Sharman cu~rette Dilatation hxnd c cases where ~ulk in endometri~ tr When to do? day of the~ qy~l~ conception. How done within 24 h Findings --'EvJ endP-me '~-abgl'anl give g(~t~:iotd,y,:i;tk~ predict ~9"+.~bfi Subnuclear vac appearing 36-48 h, Cause -- The s, action of progest{ endometrium.

Sonography
Serial sonograp] megiu~<~.~e; Or earl (18-20 ~5: It iS pa: of'ovulation follow: h!semination and ! of recent 'oVulatioi in the pouch of D(

[rnunmg rmnE tl~e [y. ifil time. though ?, dan 3-4 :, it has lanagerties of fect of id day ycle is mttem ation~. ~dium is loss ;Out,ih TEXT BOOK OF GYNAECOLoGY affect of progesterone (see chap. 8). However, me ~ -- on:~da~v 25 or t26. o~ ~he~.cy421e=rev~ale
Ot'cultm ~lla,- ;~ 2.'n:~ ;' .......

Se

rum progesterone -- Estimation of serum ' ~-ne on:da .~'of~-:cy~. An

Serum LH ~ Daily estimation of serum LH at midcycle can detect the LH .surge. Ovulation occurs

,, t~e36 hou~~i~g or~ m aurge.

lV~'~bout I0-12 hours after t~

 Scram oestradiqJ attains the peak rise approximately 24 hours prmr to LH' surge at--bout 24-36 haurS.~to ovulation. The serum LH and oestradiol estimation is used f0r in vitr9 fertilization. Endometrial tissues to detect ovulation (endome-trial sampling) can easily be obtained as an out patient procedure using instruments such as Sharman cufette or PipelIe endometri~l sampler. Dilatation [nd curettage is however reserved in caSeS where~ulk endometrial study is required as in endometri~ tuberculosis. When to do? iB~bpsY.is to be done o'n 2t-23id day of :~:e.:.gydj& B'a~rier contracepfice shoulcl be pre~cri}Sed gii]?fhg the cycle to prevent accidental conception. However, if the cycle is irregular, it is done within 24 hours of the period. Findings -- 'gxdd~?xtggb. Qf ~e cr etory -5 ~~i.t -yT~f~. e endCmeetSaggFa~ m~the ~econtl 'h~alfl of~f~* :'~t~i~ give ~3otcgotgy.,~.~e .diagf3 'o7~. '~!!'pf g .vhlati6l~bEt~.n predict ~,..e,~,..,~tio]kaf:~t~'"~i~ of~[th~, corp".f0]"~-i~"rh. Subnuclear vacuolation is the earliest evidence appearing 36-48 hours following ovulation. Cause -- The secretory changes are due to the action of progesterone on the oestrogen primed endometrium. Sonography Serial sonography during midcycle dan precisely {18-20 mn'0. it is partiediarly helpful for confirmation of ovulation following ovdlation induction ar~eial msemmation,,and invit?o.'fertilizition. The fea 't02res of recent ovulation are collapsed fbllicle and fluid t in the pouch of Douglas.

DIRECT, ka~a,r~gs~copy
I~ar~r. oso'opie vig-uaIisafi'.cm ot5 recent..co~.us pgr~tpneak.:-~d~,from~.'!:t~::po, u.:c~:-o~- Oo'fi'glas is the only direct evidence of ovulation.

CONCLUSIVE
Pr~gtm'ncy ~is th'~-su~esbevide~- ce of cw.~.afi0n. Diagnosis is based on the following: ~,!},BT,c&~t -- (a) Slow rise of temperature taking 4-5 days following the fall in the'midcycle. (b) Rise of temperature sustains less than 10 days. Endometrial.biopsy -- Biopsy done on 25-27th day of the period reveals the endometrium at least 2 days out of phase (Example: If the biopsy is done on 25th day of cycle, the endometriai changes . observed correspond to the day 23). This lag phase endometrium must be proved in more than one cycle (see p' 86). ,,Serumcp.rogest~y(6ge estimated on 8th day following ovulation is less than 10 ng/ml. u~einised unrup~red follicle (LU'F) syndrome refer'~-io an infertile woman with regular menses and presumptive evidencemot vul~-, l~-...!~.inn.xv, ithout, zelease of the ovum from the follicle (trapped ovum). The features o-Wo~mn ~---formatmn ~'~6rpus luteum and its-~'ti'gma are absent Itis.gftein a~sgci~3~ed with pe l~vic endome![io~is:.. Diagnosis ~ In tha presence of biologic effects of progesterone in the early Iuteal phase: (i)?Sonogr.6pl~y -- P~rsistance of echofree o~ollicle beyond 36 hours after LH peak. (ii) L-apTly =-- Failure to Observe a stigma
':'.. t

(iii) varia.n bio=p..s -- Conclusive proof is determination of ovum amidst the structure of corpus Iuteum. Tu, b~[:,-.faet'6rs (Table 15.58) The anatomical patency and functional integrity of the tubes are assessed by the f611owing tests:

i-Chapter 15: INFERTILITY -"~ ,

-2-5p- eeI cbvonoo peM-u~a, hor~

7,:~ ,~'*v.:,~'~.'~,a ~D~O ~ LO~ g~ /3"~a*~- ~b"~j~.~-, ~k~ Oa:d C'~D~ ~~-~ Insufflafion test (Rubin's test) Principle -- The underlying principle lies with the fact that the cervical canal is in continuity with Limitation -- As in D + L Advantages -- It has got distinct advantages over insufflation test. It can precisely detect the side and insuffiation test. Instead of air or CO=, dye is instilled transcervically. When to be done? As in D + I.

the peritoneal cavity through the tubes. As such, entry of air or CO, into the peritoneal cavil wy~-~ site of block in the tube. It can reveal any abnormality in the uterus (congenital or acquired

- T
223

}~d trans~cfi~fl~"'und~r pressure, -gives ~ like synechae, fibroid). As such insuffiation of the

ence of tubal pitenc~ .....................................................tubes has largely been replaced by HSG.

Hysterosalpingography (HSG) PHnciple -- The principle is the same like that of When to be done? It should be done in the post-menstrual phase at least 2 qLavs after stoppage of menstrual bleedin .g:-Limitation -- It should not be done in the presence of pelvic infection. Observations -- The patency of the tube is confirmed by: (1) fail in the pressure when raised beyond 120 mm Hg, (2) hissing sound heard on auscultation on either lilac fossa and (3) shoulder pain experienced by the patient (irritation of the diaphragm by the air). Drawbacks -- tn about one-third of cases, it gives a false negahve findings due to cornual spasm. It also cannot identify the side and site of the block in the tube. As such, it is inferior to other methods of tubal study. This test is not commonly done these days. Disadvantages-- it involves radiation risk. Laparoscopy and ehromopertubation The scope of diagnostic laparoscopy in the investigation of infertility has been widened. As it is the most invasive irwestigation, it should be the final procedure performed in the basic infertility work up. The indications of its nse are: Abnormal HSG findings

Failure to conceive after reasonabie period (6 months) even with normal HSG Unexplained infertility Age > 35 years Protocols -- A double puncture technique is to be applied. All the pelvic organs are to be properly visualised, of particular importance is to note the

Fig, 15.2. Hysterosalpingogram showing bilateral peritoneal spillage

Fig. lB.3. Chromopertubation shows the patency of the tribes (Courtesy Dr. Manoj Samanta)

224 TEXT BOOK OF GYNAECOLOGY fimbrial end of the Fallopian tubes and their relation with the ovaries. Proper documentation with the aid of diagram is mandatory. Advantages over HSG -- It can precisely diagnose peritubal adhesions, pelvic endometriosis or evidences of ovulation. Chromopertubation with methylene blue cannot only reveal patency of tile tube but the nature of tubal motility. Drawbacks -- It is more invasive than HSG. It cannot detect abnormality in tile uterine cavity or tubal lumen. Thus, the two procedures should be regarded as complenientary to each other and should not be used as a substitute to the other procedure. When to be done? It is preferably done in the secretory phase. Recent corpus luteum may be visualised and endometrial biopsy can be taken in the same sitting. Table 15.4

Indications of laparoscopy in infertility Age > 35 years Abnormal HSG Diagnostic Failure to conceive after reasonable period (6 months) with normal HSG "Unexplained infertility GIFT and ZIFT procedures Operative Ovarian diathermy (see ch. 33) Reconstructive tubal surgery Fulguration of endometriotic implants Sonohysterosalpingography Principle -- Normal saline is pused within tile uterine cavity with a paediatric Foley Catheter. The catheter balloon is inflated at the level of the cervix to prevent fluid leak. Ultrasonography of the uterus and fallopian tubes are done. Ultrasound can follow the fluid through the tubes up to the peritoneal cavity and in the pouch of Douglas. Advantages -- It is a non-invasive procedure. It can detect uterine malformations, synechiae or polyps. Tubal pathology could be detected as that of HSG. There is no radiation 'exposure. Falloposcopy is to study the entire length of ~bal lumen with file help of a fine and flexible fibreoptic device. It is performed through the uterine cavity, using a hysteroscope. Salpingoscopy -- Tubal lumen is studied introducing a rigid endoscope through file fimbrial end of the tube. It is performed through the operating channel of a laparoscope. .Ute~'ine factor -- Uterine factors commonly associated with subfertility are submucous fibroids, (see p 258), congenital malformations (see ch. 4) and intrauterine adhesions (Asherman's syndrome). They are more likely to cause recurrent pregnancy loss rather than primary infertility. '~ Ultrasonographv, HSG, hysteroscopy and laparo-.~d~py'~re ne-"--eded in tile ev~ u~F~iH~a~-ol-for subfe~y. ~qJi~al facto~r (table 15.5B)- The cervix functions as a biological valve. This is in the sense that, in the proliferative phase, it permits the entry of sperm and in the secretory phase, hinders their penetration (Fig. 15.4). As such, dysfunction at this level should be carefully evaluated. This is done by: Post~ (PCT) -- Marion Sims (1866) and Max Huhner (1913) Principle--PCT is to assess the quality of cervical mucous and the ability of sperm to survive in it.

This has been described in chap. 8, p 106. Sperm cervical mucus contactjtt~ est (SCMCT) This in vitro cross over test is performed using midcycle cervical mucus of the wife and semen of the husband under question and compare with donor sperm and donor cervical mucus. Result is

ii A B' Fig. 15.4. (A) Oestrogenic effect on ceryical mucus facilitates sperm penetration (B) Progesterone effect hinders the penetration

) !r Chapter I5: INFERTILITY

[.

Table 15.5A i-)~' Sperm cervical mucus contact test ISCMCT) Penetration of sperm with shaking movements

Wife's cervical mucus + Fertile donor's semen Fertile Donor's cervical mucus + Husband's semen Inference

(+) (+)
Specific immunological problem in couple

(^) (-) (+)

Wife's mucus abnormal

(B) (+) (-)

Immunologic problem in male

(c) (-)
Problem in both

(D)
interpreted as in the table 15.5A. The test procedure has been described in ch. 8 p. 107. This is indicated, if consecutive 3 post coital tests become negative (Presence of immotile sperm with a normal sperm count in a good quality of cervical mucus). Endocrinopathy -- Indepth investigations in suspected or overt endocrinopathy with or without menstrual abnbrmality or ovarian dysfunction include estimation of serum TSH, prolactin, FSH, LH, dehydroepiandrosterone sulphate, testosterone and progesterone in midluteal phase. In cases with family history of diabetes, postprandial blood sugar is to be estimated. Immunological factor -- Human sperm has immunologic potential and in susceptible women, it can elicit antibodies against tile antigens producing a cervical immune response and infertility. The antibodies against sperm may affect fertility by immobilizing sperm or causing agglutination that prevent adequate penetration of cervical mucus. Male may also produce autoantibodies against seminal or sperm components. Sperm coated with these antibodies fail to migrate through the cervix. Most agglutinating antibodies to sperm are IgA immunoglobulins and are found in the cervical mucous and semen. Most immobilising antibodies are IgG or IgM immunoglobulins and are found in the serum. Diagnosis The presence of sperm antibodies in cervical mucus may be demonstrated by post coital test or by sperm cervical mucous contact test (SCMCT). 15 [TBOG] ' Currently mixed agglutination reaction (MAR) tests or immur/obead tests are used. Commercially available antibodies are used in immunobead tests. Antibody binding to specific sperm sites (head, body), can be detected. In MAR test human red cells sensitised with human IgG are treated with semen. .'These tests can detect presence of antisperm antibody and their specific type. Determination of specific antibody titres in the semen, cervical mucus or serum of both husband and wife. An antibody titre of I: 4 or above is very much suggestive. Unexplained infertility is defined When no obvious cause for infertility has been detected. following ali standard investigations. These include. semen analysis, ovulation detection, tribal and peritoneal factors, endocrinopathy and PCT. Overall incidence is 10-15 per cent. With expectant management about 60 per cent of couples with unexplained infertility will conceive witlfin a period of three years. IVF and ET (see p 235) may. be an option for those who fail to respond.

'TRE.ATMENT Couple instructions

The infertile couple remains psychologically disturbed right from the beginning, more so as the investigation progresses. Abnormality detected in anyone or both intensifies the disturbance. The couple in such cases should be tactfully handled to minimise psychologic upset.

Scheme - S ovuLATION TUBAL FACTOR CERVICAL Ovarian

Initial investig~ition protocol of an infertile couple [ Husband semen analysis -- normal

Endometrial ~

~',

Serum progesterone(Day 21) Cervical Tubal

FCT J

HSG

(-) (-)

0v1JLATION

Vaginal cytology

D 12-14 and D 21-23

I
:tion (MAR) >mmercially tobead tests. sites (head, mn red cells with semen. sperm antititres in ~ th husband )ove is very when no n detected. Lese include. tribal and CT. Overall expectant uples with Lin a period may- be an mlogically e so as the letected in ~ance. The handled to TEXT BOOK OF GYNAECOLOG Y

Serum progesterone Serial sonography i i / Insufflation test Laparoscopy

D 8 and D 21 D 12-14 Sdcretory phase Proliferative phase - 2 days after the bleeding stops As above Secretory phase

D 12-14 D 21-23 Discrete ceils Folded edges. Pyknotic nuclei, In clumps background background clear dirty D-8 < 1 ng/ml D-21 > 6ng/ml Follicular measurements -- approaching 20 mm Recent corpus luteum (i) Drop in pressure when raised to 120 mm Hg (ii) Hissing sound on iliac fossa (iii) Shoulder pain Spillage of dye into the peritoneal cavity Peritubal pathology Pelvic pathology (Endometriosis), Ovulation Tubal patency by dye spillage from both the tubes I As HSG Tubal luminal pathology Presence of progressive'motile sperm (10 per high power field) See table 15.5A Sperm antibodies (see p 225>

--J
Further evaluation for ovulation

TUBAL FACTOR

Hysterosalpingography Laparoscopy and dye test

WhtKgl~I- ' .~inom d,e,f~ts~.are~ d~te4;tcdci~,~th the husbanci~'an&th~.wff~g'each of which atone could not cause infertilityd~.~.~n?~eombirmtion, they significantly decrease the fertility potential: ~s such, the faults should be treated simultaneously and not one after the other Even when a gross abnormality is detected and the prospect of pregnancy is bleak, an optimistic discussion is worth rewarding. ~X3-verweight or underweight of any partner should be ade.-q-qale2y-deatt with to obtain an optimum m.-.wc!ght. Body mass index of 20-24 is op ti--.-~--m~ Sinokin a~t-al=~h~l Excess smoking or alcohol consumption is to be avoided. Coital problems The coital problems should be carefully evaluated by intelligent interrogation. The couple most often has got a misconception that the most fertile period is perimenstrual and they are utilising this period for years together, obviously without any effect. Advice to have intercourse during the midcycle too often gives the result early enough even prior Good Poor Normal Abnormal Repeat 2-3 cycles Poor ~ ~ Laparoseopy

to investigation. Using LH test kit, one can detect LH surge in urine by getting a deep blue colour of dipstick The test should be performed daily between day 12 to day 16 of a regular cycle. Timed intercourse over 24-36 hours after the colour change reasonably succeeds in conception l~inor psychosexual problems should be corrected accordingly. Male Female Combined

Sonohysterosalpingography Falloposcopy Post coital test (PCT) CERVICAL Sperm cervical mucus contact test (SCMCT) IvIAR test Immimobead test

Proliferative phase Proliferative phase Around ovulation (D 1244) As above As above

......... l

Chapter 15: INFERTILITY

227

[ 1'~ '~~ Table 15.5B Infertility work up calendar - - ,:~.~ Methods employed Day of cycle Biopsy (day 21-23) Observation BBT '" i ~:'tificati'~ I <6 ng/ml BBT i Throughout cycle Biphasic pattern Endometrial biopsy D 21-23 Secretory Further endometrium Cervical mucus D 12-14 and D 21-23 D 12-14 D 21-23 Biphasic Monophasic Nature Clear, watery Tldck, viscid NonIn phase Out of evaluation Threadability + ovulation secretory phase for Fern pattern +

Immunological factor

MAr E,: I N FERTI u;'r~'~.The treatment of male is indicated in(i), ex~eme ~9!igos9 e~d:(ii) az oos?,ermia, (iii)qow yolume ejaculate and,~(!v) 'imp To improve: spermatogenesis

may be helpful

Improvement of general health, :re dugti0m.of

~jcf"~J~'?6 r~'~;~~~'' ~~~'" ~'~ ~.~-,, ~~~o.u-~e(i. ~f376q'~ '"'""~t'~''' '~t~"~q,.in~.

Genera~ ,~

228 ancl~f Z oh~,,i!t~t6~;improve spermatogenesis is pro'ba~ to improve the general health. They may reduce the toxic free radicals (H202), released by abnormal sperm and leukocytes present in the 'semeiL In k.Yl~ggpna~pphic,hypog0n';idi~m~: the disorders of sp~togenesls can be treated wikk the following therapy with varying success. dazsw'th f 5~~3?yd~s; It increases 'e'~--l'es rum 'ye- of FSH~ ,~'H~es tosterone. ';~-C 5,0.p0~ intrg, m,,~'.-, l~l"Sl21~aa~rl~.once or twice a week is given to stimulate endogenous testosterone production. ~G~ andhCG are used in cas~ado-trp-p-.hin deficienc-y or failed c!0m!,phene, cl~ate cases.

In genetic abnormality-- artificial insemination with donor sperm (AID) is th~-bpfion is no o--~er tre'~-~eent is avai a' e.~-B'I-7--:~ TEX'T BOOK OF GYNAECOLOGY Surgical When the patient is found to be azoospermic and yet testicular biopsy shows normal sperma-togenesis, obstruction of vas must be suspected. This should be corrected by micr. o:st~zgery ~.;kaso-epidicl~p~s~my~?ol:, vasov~ostffn~.~yT'~r vasovaso:-' st'~'~f pat7 i's-~btaine~0ut 80 percent of cases and pregnancy rate is about 50 percent. The presence of varicocele is c6~reeted b hi 'h ligatmT' ff.~qf ,$permatic ?e~and the~e~. Z ' Or~ chifd~de-seended testers should be done 15etween 2-3-~years to have adequate sperma-togenesis in later life. Impotency Psychosexual treatment may be of help. Hyper-'~ prolactinemia needs further investigation and treatment (see p 426). For eree-~ile~dysfunetion sildenafil (~iagra) is currentl~-d?ised. A single dose ~f 25-100 m'g i~iepe--q~, on response).is ~ven orally one hou~-~ before sexual activi-tz. In unresponsive cases, artificial insemination is to be thought of (see p 234). Assisted reproductive technology (ART) for male infertility Prospect of male infertility' has improved significantly with the'ac/vent of ART. IUI, TESE, PESA, MESA and intracytoplasmic sperm injection (ICSI) are now the treatment available for infertile males (see p 234). FEM~EaNFERTi'~i~ For convenience, the treatment modalitles?in female infertility are grouped as follows according to the disgrders identified. Ovulatory Tubal Associated d'isorders like endometriosis, infections or endocrinopathy Cervical Immunological Unexplained infertility Uterovaginal canal Assisted reproductive tectmology (ART) . Ovulatory dysfunction Anovulation LPD LUF

For WHO classification see p. 241. ~no"vulafi6h .... Anovulation is the common ovular dysbanction. It may be present in otherwise normal menstrual Chapter 15: INFERTILITY cycle or may be associated with oligomen0rrhoea or amenorrhoea.

Insulin

- Metformin (see p 431)

! SubstitUtion therapy Hypothyroidism - Thyroxin o Diabetes mellitus - Antidiabe~ie drags

five, other parameters used are serial es.;;mat;on of plasma El and ultrasonic measurement of growia~ folhcles (folhculometry). These last two are obi;. gatory in

To facilitate effective folliculogenesis and ART. ovulation, the following may be prescribed. Table 15,7 Objectives of monitoring for induction of ovulatior ~1 Psychotherapy emotional causes, if any, :to-impriJEe
Further hCG confirthemation o To prevent, hyperstimulation syndrome

To select time for preovulatory administration of. To select time for intercourse or artificial insemi.
nation

improvement oft'nutrigon and- weight g

To select time for ovum retrieval in 1VF

T st~e:--~ 19~6,0:m. er. oral (P.O.)daily 'bor~oon'ths~ There win be ~fiai decrease ~owed by rebound rise of sperm count. It has got direct action in spermatogenesis. .-~ng~...L~e~ n{"a '-iiife~tile m.a~ seW;th hypo~q.~J~sfunctionK~~ann's syndrome) is effe-~-~--" I-'~~in~i~'ered by rain;pump infusion. Cases'with hypogonadotrophic hypogonadism may also respond with GnlLH therapy. ~l~e~.ce~pf:~emfi~ .~ tibo.~~e, male, deXamethas6~'e~ 0';5:/~gi, aa'ffy,~-~t :bed tLme may be tried-~y intrauterine insemination (IUD with washed spermatozoa is the choice of treatment for such cases (see p 234). Genital tract irffection needs.prolonged course of antibioticsl Generally :~o~c ci'~e~hroz on the response. In retro~rade ejaculation --~phenLlb~a (C~-adrenergic agonist) is used to improve the tone o'~T~temal urea-M-sphincter. Sperm m----m-~ay b~eco-vered from the neutralised urme. Processed spermatozoa could be used for IUI (see p 234). -' In teratospermia, asthenospermia specific causes are unknown. No treatment is available. ~DOnorDonor~insemination (AID) is Lhe option n~(see p..235). '

ah3...]and so also reduction of weight in obesity as in PCOS cases (see p.431) are essential to have a good response of drug therapy for induction. They may also facilitate spontaneous ovulation The following drugs are of use either singly or in combination. Table 15.6 Drugs u~ed in induction of ovulation Clomiphene citrate (CC)' k3o ~-oq ............. ~ ~O hMG (Humegon, Pergonal) (FSH 75 IU + LH 75 IU) FSH - purified urinary FSH - highly purified urinary FSH (Metrodin HP) - recombinant FSH (Gonal-F, Recagon) hCG (Profasi, Pregnyl) recombinant hCG GnRH (see p 231) GnRH analogues (see p 236)

Monitoring d..~uring ovulation induction For diagnosis,of ovulation, BBT recording is eno some therapies, dmgnosm of ovulation ~i-~-6b~-ainedChart supplemented by cervical mucus study (clear, watery

type). But when a complicated regimen is followed to a~ f:::eT;p~ .. w d.~lvanr ~, ra pregnancy by time intercourse or by ART, a detailAI monitoring is a must which is only possibb ~.a l~ecaUSe of xts selected centres. Not only the drugs are cost!y~,~ ,t~evated androge: regimens are complicated and time consumin'~ *re and viscid anti o. t~-" -;u~ated oesl A art from BBT chart and cervical mucus ss.~ conj o~ . ~n 4, P . ~-7.~'V rod .... which are nomnvamve, sunple and quite inforraa,

.Reductlon .of the raised levei of Androgen - Dexamethasone (see p 431) Prolactin - Bromocriptine (see p 432)

lly in PCO ?~pressed by dexm be stpPea (c) Eltroxin 0.1 n during the ~erapy ir hypothyroimsm'

(d) Elevated proh dorrhoea indicates a This causes ovulat.o.~ rrh0ea. Bromocript~ fseep 432) increase~ 'domiphene. Patien] elevated prolactin w i and

Because of its anti-oestrogenic effect or indu-(a) cervical mucus hostility and other non ovulatory factors. J ,-drogenS the cervical mucus becomes The incidence of multiple pregrtaI!,gt is about 5 per cent. levateu ~' ' ~x,d e j .,4scid and hinders sperm penetration. As Gonadotrophins Prerequisites for gonadotrophin therapy Rick anu. ,,-ted oestrogen 1.25 mg may be Ovarian reserve must be present admini Other (non-ovulatory) factors for infertility must be , c0nJuga . wed to aehiev~ INFERTILITY ruled out. hMG (human menopausal gona ~ dotr0phin) is a ART, a dehil~ dy mixture of FSH and LH [Pergonal = FSH (75 ILl) + LH (75 possible h are In cases of hypergonadotrophic IU)]. cosily hypogonadism, high gonadotrophin levels are Patient selection consuming, il lowered with the use of combined oestrogen Hypogonadotrophic-hypogonadism mucus study and progestogen preparations (oral pill). When Failed clomiphene qmte informa. d the levels reach normal, gona-dotrophin es,timation 0[ therapy may be employed to achieve Dose schedule ent of growia, ovulation. The success rate is poor. hMG stimulates follicular growth.: with'a variable : tWO--re Side effects of gonadotrophin therapydose schedule starting with a Iow dose (1 ampule I.M/day) ohl~. (see p. 482) Results Stimulation is started any time from D2 to Ds of the Pregnancy rate after six courses ofcycle and is continued for 7-10 days depending on the m of treatments is 90 per cent. Incidence of multiple response. ovulatio]n pregnancy (10-40 per cent) and ectopic Follicular growth is monitored with serum pregnancy are high. oestradiol estimation and follicular number and size are ninistrafion of GnRH measured by transvaginal sonography (TVS). Serum oestradiol level of 1000-1500 pg/ml Patient selection (150-300 pg/mature follicle) and maximum follicular diameter of 18-20 mm are optimum. tificial inserai. When ovulatory dysfunction is due to: When this optimum levels are obtained $000-10000 Hypotiaalamic amenorrhoea IU of hCG is administered I.M to induce ovulation. .'~ Hypogonadotrophic Endometdal thickness of 8-10 mm (as measured by IVF hypogonadism TVS) on the day of hCG administration favours successful GnRH is administered intravenously orimplantation. ene Ovulation is expected to occur, approximately 36 omc as well/~s subcutaneously with an infusion pump in a hours after the hCG administration. ogen receptors pulsatile fashion. Couple instruction creased GnRI-I A pulse of 5 gg is used IV at every 90 Couple is advised for the timing of intercourse ;onadotrophin or- insemination (ART) accordingly (see above). rogenic effects n minutes. Follicular growth is similar to a Patients with PCOS are more sensitive to hMG the'cervical normal menstrual cycle. Follicular growth stimulation. Purified FSH (metrodin) or highly .'.eada.chl/~n monitoring, hCG administration and couple purified FSH (metrodin HP) or recombinant FSH (rare). Incidence instructions are same as in hMG therapy. (Gonal F, Recegon) have been used successfully Results of abortion and Result ~? With minimal :side effects. Pregnancy rate is 80 per cent following :x~:!!~:t~em/plf; six course of treatment. Multiple pregnancy rma,nons are not mcreasea rate is 5 per cent. The risk of ovarian hyperstimulation is Iow (see p. 482). buSU;;?/nf~a lnicydUCttiffnja:;;t;s 4~gh~ 80enPLr Th: GnRH analogues (p 480) ' . Dai!~ or on alternate days beg'm~g 5-7 daysPatient selection after the laat dose of clomiphene therapy. Several times for 2448hours after the colour Patients refractory to gonadotrophlns change in urine when tested by LH kit. Patients having elevated LH Patients with normal gonadotrophins Patients with premature follicular luteinisation or premature ovulation due to premature LH surge

domiphene amI nancy,

(e) Hyperinsulin~ ovarian disease (se~ domiphene. Correc rnalily (see p 431) al~ satisfactory result. 10und to reduce hyt genemia. (f) hCG --'In cas of LH surge, hCG ! 7 days after the la~ Prior monitoring ultrasonic measm (18-20 mm)is prefi (g) Growth horn resp0nders spec;all

Couple instruct The couple is ad as per following g Several times change in ur!

GnRH agonist is used for down regulation of pituitary gland by desansitisation of pituitary GnRH receptors (see chi 6). GnRH agonist initially produce stimulation of gonadotrophin secretion known as 'flare' effect. Generally this flare effect lasts for about 2-3 weeks. Adequate pituitary suppression is achieved when serum oestradiol level is less than 10 pg/ml and FSH level is less than 10 mlU/ml. Follicular stimu!ation is achieved with highly purified or recombinant FSH. Follicular number and growth monitoring is similar as in hMG therapy, hCG is also administered when criteria is fulfilled as discussed with hMG therapy (see p 230). Results -- ovulation rate is about 75 per cent and pregnancy rate is about 25 per cent. GnRH antagonists -- can block pituitary GnRH receptors completely without any initial stimulation (flare effect). Cetrorelix is currently being tried to prevent

have to be monitored carefully with sophist not only to control the regimen but also to hazards (table 15.7). Thus, its use is ) pre-e restricted in selected centres and is commonly used in ART. Surgery Wede:e resectipn -- Bilateral wedge resection of e~s done in PGOS-cases~here c!omi-phene citrate fails to induce ovulation. One-third of the ovarian mass of each side should be resected and meticulous haemostasis is achiev adhesions; The success of the operation will vaginal bleeding within 2:.'4 days .of operatio '~, Laparoscopic ovarian diathermy and l an-alternative to wedge resectio9 'has e-'~-b

2 ia

useful to minimise adhesions

Clomiphene citrate Patient selection: N0rmogonadotrophic - normoprolac 'tmaemic patients who are having normal cycles with absent or infrequent ovulation. o PCOS cases with oligomenorrhoea or amenorr-hoea. The oestradi01 level should be > 40 pg per ml. Hypothalamic amenorrhoea following stress or 'pill' use. Dose Clomiphene therapy is simple, safe and at the same time cost effective. Most centres use an initial dose of 50 mg daily. Dose is increased in 50 mg s~eps to a maximum 250 mg daily, if ovulation is not induced by the lower dose. The actual starting day of its administration in the follicular phase varies between, day, 2 and day 5 and therapy is g~ven for 5 days. Ovulation !s expected to occur about 5-7 days after the last day of therapy. Therapy for four to slx cycle is generally given. Mechanism of action of clomiphene Clomiphene citrate is anti-oestrogenic as well as weakly oestrogenic. It blocks the oestrogen receptors in the hypothalamus. This results in increased GnRH pulse amplitude causing increased gonadotrophin secretion from the pituitary. Anti-oestrogerdc effects are seen on the endometrium and on the cervical mucus; premature LH surge. As with GnRH analogue gonado-trophln stimulation is done (see above). When pregnancy occurs following supero-vulation with GnRH agonist therapy, luteal phase support should be maintained either by giving hCG or progesterone. It should be emphasized that the gonadotrophins, GnRH and GnRH analogues are cosily drugs. Their uses (see ch. 33 p 549).

s~ daily for 10 days starting on first day of cycle. Chapter 15:

Fig. 15.5. Tuboztubal anastomosis. Placemen five interrupted sucres using 8-0 polyglacti magnificafiqn)

GnRH agonist (buserelin, nafarelin) is given subcutaneously or intranasally either maintaining a short or long protocol.

of esS

SUpr .-rtin~ from 1st day of cycle. The drug should jays, sm , -~n after ovulation. . be stOppea ~"~ '

ci Eltroxin 0.1 mg may be administered daily .. ~,-~ra~, in obese vatients with subclinicaldiscrepancy is due to premature luteinisation, LPD, hypothyroidism. ctorrhoea indicates abnormal GnP, H pulse secretion. lhis causes ovulatory dysfunction, LPD or ameno,h0ea. Bromoeriptine (dopamine agonist) therapy Pre.existing or induced elevated androgens (b!'L in pCOS) during therapy may be ecially ~'P ed b" dexamethasone 0.5 mg daily for 10 al cycles with ts) Hyperinsulinemia -- Patients with polycystic varian disease (see p 421) are poor responders to
11, 1o

during ~e utu t'J (d) Elevated prolactin level with or without gala-

I (see ?' 432) increases the ovarian' responsiveness' to [ domipheue. Patients with normal or minimally elevated prolactin when treated with bromocriptine zed clomiphene are fodnd to have increased pregprolactinaemic nancy.

d0miphene. Correction of their metabolic abnor-ea or amenorr, reality (see p 431) along with weight reduction gives Lld be > 40 pg [ satisfactory result. Treatment with metformin is i found to reduce hyperinsulinemia and hyperandro-~wing stress or ~ genemia. ! (0 hCG --'In cases of anovulation due to failure ]of LH surge, hCG 5000 IU is administered usually 3re and at the 17 days after the last dose of clomiphene therapy. s use an initial jPrior monitoring of serum oestradiol level and inS0 mg steps m ultrasonic measurement of follicular diameter ulation is not I(18-20 mm) is preferred to get a good result. al starting day ~ (g) Growth hormone - is combined to the poor r phase varies ~y is given for ?ponders specially, in the elderly group. about 5-7 days i Couple instruction for four to six The couple is advised to have sexual intercourse :as per following guidelines:

232

TEXT BOOK OF GYNAECOLOGY Appropriate surgery for pituitary prolactinomas

(see 13 4~2)

Surgical removal of virilising or other functioning.ovari~-~ or adrenal tumour (see p 356). // Luteal phase defect (LPD) ~' "/ Treatment The following treatment may be of help in .the idiopathic groups: Natural progesterone as vaginal suppositories 1000 m~dailDLstarting from the day of ovulation is effective. It should be continued until mens begins. If mens fails to appear after 14 days, pregnancy test is to be done. If the test is positive, it should be continued upto 10th week of pregnancy. Although, hCG is a potent luteotropic hormone, the response of LPD to hCG is unpredictable. In unresponsive cases, clo.-o~hene citrate maybe tried. It increases FSH which may improve folliculogenesis and normal corpus luteum formation with adequate production of progesterone. In refractory cases, IVF may be tried but of limited success.

/,/, ~ti:t~[O!~'~/~ B~@Jumd4ol!,o !e~t( L U F)

"~'/ 1~ Defective folliculogenesis or inadequate LH surge maybe corrected with: Ot~timally limed intxamuscular injectiorro[ hOG

 AdministratiOiVof.'o~ulati0'n if/ducing d'/tigs;in the fo'llicu at--lowed by" :'~wul~ato~y'h:'cG (5o004o000 rd). .Brom~.pcriptine theralfy; if associated with h~..?pr~tmfi~-~see p 432). Tubal and peritoneal factors The palpable tubal factors causing infertility include -- (1)daeri~.ba ! adh..e, sions-, (2) "mflammatory endosalpingea ! d a~,,.age and (3) tubal, occ!usion by infection or sterilisation. The following guidelines are prescribed: Pi:eroperatjze~s~assess.meAt:an.d p!a~g:~for surgery has to be- done by. HSG aft&: laparoscopy aided if possible, 'by falloposcopy to assess ~e tubal mucosa. Prior counselling of the couple about the hazards of surgery and prospect of future pregnancy should be done. The overall pregnancy rate is less than 50 per cent and the chance of ectopie pregnancy is about 10 per cent. Presence of hydrosalpinx or gross tubal da-ma agg re~ires their removal to prevent r ec~ j-~fe-ciion. IVF-ET sh~ be considered for such a situation. In tubercular salpingitis, surgery is to be withheld. Following antitubercular therapy, IVF-ET may be employed, when the endometrium becomes free from lesion. * IVF-ET is a better option for a failed case of tubo-comual anastomosis. Surggry TUboplasty is the name given to the finer surgery on the tubes to restore the anatomy and physiology as far as practicable (see Table 15.8). - The operation can be done by conventional methods , or by microsurgical techniques which may be employed following Iaparotomy or by laparoscopy (Fig. 34.5). Mierosurgica! techniques give better result due. to minimal tissue handling and damage, perfect haemostasis and minimal adhesion formation. Laparoscopic surgery gives the best result. Nylon may be used as a temporary splint to facilitate suturing the ends. It should be removed following anastomosis and if kept inside, should be removed after 48 hours to minimise mucosal damage. Intraoperative instillation of Ringer lactate mixed with hepa'rin or hydrocortisone may be employed to m'mimise adhesion formation. ~I Table: 15.8: Tuboplasty operation Adhesiolysis Separation or division of adhesions (Salpingo ovariolysis) Fimbrioplasty Separation of the fimbrial adhesions to open up the abdominal ostium. Salpingostomy That creates'a new opening in a completely occluded tube. It is called terminal or 'cuff' at the abdominal ostium. The eversion of the neo ostium is maintained by few stitches of 6-0 vicryl. Tubo-tubal When the segment of the diseased tube or following tube anastomosis ctomy operation is resected and end to end anastomosis is done (fig. 15.5). Tubo-comual When there is cornual block, the remaining healthy tube is anasto anastomosis mused to the patent interstitial part of the tube. Chapter 15: INFERTILITY

Cannulation of the tube is done for proximal tubal obstruction. Probe is passed carefully under hysteroscopic guidance to overcome any obstruction. Cannulation and balloon tuboplasty when successful can avoid ART procedures which are expensive. Adjuvant therapy ~-djunctive procedures to improve the result of tubal surgery include prophylactic antibiotics, use of adhesion prevention devices (interceed, seprafilm) a n d p o.9~sl~p-er -a tiv e hydrotuba~n) Hydrotubation -- Hydrotubation is a procedure to flush the tubal lumen by medicated fluids passed transcervically through a cannula. The fluid contains antibiotic and hydrocortisone (Gentamicin 80 mg and dexamethasone 4 mg in 10 ml distilled water). It should be done in postmenstrual phase. Results of tuboplastld --The result depends upon the nature of pathology, type of surgery and techniques employed -macro or microsurgery. Overall pregnancy rate (following laparoscopic sm:gery) is as follows: Salpldgo-ovariolysis 60%; Fimbrioplasty 32%;-Tubo-tubal 'anastomosis 75%; Tfibo-cornual anastomosis 55%: The result is better in microsur-gical ~echniques when done laparoscopically. The result is best in reversal tubal sterilisation by tubo-tgbal anastomosis using micro-surgical techniques. Factors for poor outcome following tuboplasty Dense pelvic adhesions Loss of fimbriae

Bilateral hydrosalpinx > 3 Cm (see. p. 162) Length of the reconstructed tube < 4 cm Reversal done after 5 years of sterillsation operation

Presence of other factors for infertility. Endometriosis It appears that minimal asymptomatic pelvic endometriosis is only an incidental finding and intensive medical or surgical therapy does not improve the infertility problem. However, the therapy should be instituted in minimal endome-triosis with otherwise unexplained 'tfffertility. Mild endometriosis With involvement of the ovary or moderate endometriosis should be treated with drugs or surgery ~of'both. Not only it has got a clinical effect on infertility but it also prevents progression of the disease (for details see chap. 20). Cervical factor Cervical mucus protects sperm from the hosm. environment of the vagina and also from 'phai~ cytosis. The cervical mucus quality can be improved By

weak

douchm X- teas

to 300 m[o~ater~pr~..-----~z-~con'u~gen 1.2~7c~ orally in the 'follicular phase. In proved cases of Cl. trachomatis or M. horninis, doxycycline 100 rog.twice dailjLf~ 14.days is to b, given to both the partners. Cervical factor when cannot be treated, is OVer. come by ART procedures like IUI, IVF or GIFT (see p 234).

immunological factor
~---the presence of antisperm antibodies in the cervical mucus, dexamethasone~ at bed time i-~t' the folli~ph,~e-m~y b~--~'~l~e drug should be suspended following ovulation. It may reduce antisperm antibodies and thereafter facilitate sperm penetration. Unprotected intercourse should however, be encouraged during the fertile period. If PCT shows no improvement, intraute.rine inse. ruination GUI) with washed sperm is an alternative. Utero-vaginal surgery The operations in the uterus to improve the fertility includes: M omy--q.-mg~omy-(see p 262) specially in submu-cous fibroid. Care should be taken to prevent or to mirdmise adhesions causing tubopathy. Me?-.~EEElasty (see ch. 4) either removal of septum or unification operation may be tried when no other cause is detected. This abnormality seldom causes infertility. Acihesiolysis with insertion of IUCD in uterine synechiae (see p 432). Enlargement of the va~mat introitus (Penton's op'e~tion p 539) or removal of vaginal septum causing dyspareunia results in improvement of fertility. Apart from cauterisation, amputation of the cervix may have to be done for don~al elongation of the cervix. Gilliam's type of operation to correct thir~l d-egree retroversion in unexplain~ty' (see p 550).

: Attempt for pre b/icrosurgiqa

~,luorne~ Myo

Unexplained Unexplained it couples who have ~q0rk up and in detected and still r extremely variabh magnitude of the extended to the c varies from 10-15 It is strange fha infertility become: having any specifi Therapy Because of spo wait for sometim reproductive tectu IVF or GIFT is eqm Combined fa, The faults dete( be treated simulb other'.

ASSISTE TECE
ART encompas! the process of rep from the ovary epididymis.

Artificial insert Different methc ' IUI -- Intra Fallopian tu ~om the hos~ ~o from Phage. )e improved by or M. hominis

iA d3y.~ is to b~
teated, is over. Z, IVF or GIFT tibodies in the n~d time t~m'- T h~ dru~ fiation. It may 'eafter facilita(e rcourse should fertile period. raute.rine inse-an altema~ve. ~ improve the ~:lly in submu-ken to prevent ng tub0Pathy. ~r removal of t may be tried d. This abnorJCD in uterine titus (Fenton's aginal septum aprovement of utation of the 'or c~al correct third

n~i
TEXT BOOK OF GYNAECOLOGY Table 15.9 ' Attempt for pregnancy after infertility surgery Npe of surgemj ""r~cal tubal anastomosis I MtcrOSU ~L '""T"7. - -,,m,,/Metroplasty I My0rnec,~ ]

Interval 6 weeks 6 months 6-12 months Soon following surgery 3-6 months "~dhesiolysis I Soon following surgery

Unexplained infertility Unexplained infertility is earmarked to those wuples who have undergone a complete infertility work up and in whom no abnormality has been detected and still remains infertile. The incidence is extremely variable and largely dependent on the Table 15.10: Different methods of ART

IUI : WF-ET : GIFT ; ZIFT : POST : SUZI : ICSI Intrauterine insemination In vitro fertilization and embryo transfer Gamete intra-Fallopian transfer Zygote intra-Fallopian transfer Peritoneal oocyte and sperm transfer Subzonal insemination Intra-cytoplasmic sperm injection TESE MESA PESA Methods of sperm recovery Testicular sperm extraction Micro surgical epididymal sperm aspiration Percutaneous epididymal sperm aspiration

!N~/RAuTERINE INSEMINATION (IUI)

IUI may be either AIH (artificial insemination husband) or AID (artificial insemination donor). Husband's semen is commonly used. Thg,; purpose magnitude of the indepth investigation protocol of IUI is t~4iypass ~e endocerx~icakcanal w~hich is b ....~ , Z.'~'2~' :': T"~ '~" '(~z ~- ,z~-:z~. , extended to the couple. The reported incidence :~. ~prn), G :,an~.to~l?cg:m.qreas~Rqnc~atio~,of varies from 10-15 per cent .....................................................................................................................,~ . ,,,:: -~:, ,motile~ sperm as~cl0se to/.the. F~Opm tubes. The It is strange that 40-80% patients of unexplained indications are tabulated'in the tab-ie-'i51]i.~' infertility become pregnant within 3 years without having any specific treatment.

Therapy
Because of spontaneous cure rate, one should wait for sometime till the complicated assisted reproductive technology (ART) is employed. IUI, [VF or GIFT is equally effective in appropriate cases. Combined factor The faults detected in both the partners should be treated simultaneously and not one after the other'. ASSISTED REPRODUCTIVE TECHNOLOGY (ART} ART encompasses all the procedures that assist the process of reproduction by retrieving oocytes [rom the ovary or sperm from the testis or epididymis. Artificial insemination (AI) Different methods are: IUI -- Intra uterine insemination Fallopian tube sperm perfusion Table 15.11 Indications of IUI * Hosffie~cer~cal 'mucus

Cervical stenos!s
' ~Oligope~a or asthenospermia~ Imm~e factQr:(male and female) Male factor- impotency or anatomical defect (hfpospadia~) but normal ejaculate can be obtained UnexRla~ed infertfiity Technique Washing, centrifugation and swim-up methods are commonly used. About 0.3 mi of washed and concentrated sperm is injected through a flexible polyethylene catheter within the uterine cavity around, the time of ovulation (see Table 15.12). Washing in culture media removes the proteins and prostaglandins from semen that may cause uterine cramps or anaphylactoid reactions. Swim.up method selects the motile spermatozpa. The processed motile sperm for insemination should be at least I million, if not more, Ferfilising capacity for Spermatozoa is for 24-48 hours. The procedure may be repeated Chapter 15: INFERTILITY 2-3 times over a period of 2-3 days. To increase sperm motility, pentoxyphylline (phosphodiesterase inhibitor) have been used. Generally 4-6 cycles of insemination with superovulation is advised (see' table 15.6).

Timing of IUI In cervical insemination, timing is not so much vital because the sperm can survive in the cervical canal for a day or two. As the reservoir function is not available in IUI, some form of controlled ovarian hyperstimulation (CCH) is required (see table 15.12). Table 15.12 Timing of IUI Spontaneous cycles Cervical mucus study and BBT chart IUI x 2, likely on day 12 and 14 Clomiphene induced cycles IUI - 5 and 7 days after completion of CC Urinary LH detection IUI - 24 hours after colour change Use of hCG and sonography - hCG at 18 mm diameter of the follicle IUI 2,.follOwing 18 and 42 hours of hCG adminiktration Results The ,result varies widely in different centres, ranging 20-40 per cenL The best results are obtained in the treatment of cervical' factor and unexplained infertility and in stimulated cycle. IUI along'with .-saperovu!ation (induction of ovulation with hMG/ hCG) gives higher result. FALLOPIAN TUBE SPERM PERFUSION Indications are same as that of IUI Technique Large volume of washed and processed sperm is injected within the uterine cavity ~round (he time of ovulation (see Table 15.12). This causes perfusion of the Fallopian tubes with spermatozoa. In conjunction wif. h ovulation induction pregnancy rate is 25-30 per centper cycle. ARTIFICIAL (THERAPEUTIC) INSEMINATION DONOR (AID) When the semen cfa donor is used for insemi235 nation it is called therapeutic insemination donor. The indications ar.e.-: ;-TUntreatable azoospermia, asthenospermia Genetic disease Rh-negative donor insemination -- for woman with Rh-sensitisation The donor should be healthy and of the same ethnic group as husband. He should be serologically and bacteriologically free from venereal diseases including AIDS and hepatitis. The recipient and donor must be matched for blood grouping and Rh typing. Either fresh or frozen semen is used. The legal, psychological and religious aspects should be counselled before, its application. Results A total of 3-6 cycles may have to be utilised to get a success. The success rate is about 50-60 per cent. Insemination when combined with supero-vulation, enhances success rate. Two inseminations, 18 and 42 hours after hCG administration give higher result when compared to single insemination after 36 hours. IN VITRO FERTILIZATION AND v~EMBRYO TRANSFER (IVF-E'r) The past decade has witnessed at least two dramatic changes in the technique protocol of IVF-ET. One such was change of natural cycle to super ovulation protocol and the other one was replacement of laparoscopy by vaginal sonography for ovum retrieval. Indications The indications are listed in the table 15.13. Table 15.13 Indications of IVF Tubal disease Unexplained infertility Endometriosis Male factor infertility Cervical Failed ovulation induction hostility Patient selection (ideal) /

 Age < 35 years Presence of at least one functioning ovary Husband -- normal seminogram Couple must be screen negative for HIV and' hepatitis.

236 Principal steps of an ART cycle 1. Down regulation using GnRH agonist. 2. Controlled ovarian hyperstimulation (COH) 3. Monitoring of follieul~r growth 4. Oocyte retrieval 5. Fertilization in vitro (IVF, ICSI, GIFT) 6. Transfer of gametes or embryos 7. Luted support with progesterone GnRH analogues for down regulation Currently most ART procedures involve the use of GnRH agonists (see ch. 30). GnRH agonist therapy used for down regulafi.o-n of ~ituitary, gives higher pregnancy rates. GnRI-I agordst therapy is continued either subcutaneously or intranasally during the gonadotrophin treatment phase (see p 480). GnRH antagonist~ are currently tried along with gonadotrophin stimulation to prevent premature LH surge or premature ovulation. Cetrorelix and Ganirelix are the available drugs. Different schedules for GnRH agonist are available: 11. Long Luteal down regu!atian (most commonly used) therapy is begun on D-21 of the previous cycle. Gonadotrophin stimulation is started following the menses (see chapter 30). Short protocol -- therapy is started in the follicular phase (D-l) along with gonadotrophin stimulation. Ti'ds is also called 'flare' protocol, as gonadotrophin can work over the stimulatory effect of GnRH agordst. Controlled Ovarian HypersUmulation (COH) Long Follicular down regulation -- When therapy is started in the follicular phase of previous cycle. In the first case, Steptoe and Edwards (1978) achieved the success from collecting the oocyte from a natural cycle, 36'hours after the onset of LH surge. But subsequently, it has been found that the success rate is much higher when more embryos are transferred which is only possible by COld. The other advantages of induction of superovulation are improved cmalitv of the oocyte, timing of ovulation can be controlled, stated to the personnel revolved a~ exten~------~-~ed to all ~Tes of ovulatory dysfuncti-~n. T"~ drug regimens used differ in each centre. Following drugs or combination of drugs are commonly used. TEXT BOOK OF GYNAECOLOGY Table 15.14: Drugs commonly used. Clomiphene citrate (CC) CC + human menopausal gonad0trophin (hMG) CC + Pure FSH hMG FSH (see Table 15.6) GnRH analogues + hMG or Pure FSH hCG is administered in each regimen fsee Table 15.6) Monitoring of follicular growth CThe follicular growth response is monitored by ceryical mucus studs, sono..~-%gm.~e measurement of the follicles and serum oestradiol estimatLOn, 'commencing on the-Sth day of treatment cycle. When three or more follicles are greater than 18 mm in diameter and serum E2 levels > 250 pg/ml/pef follicle, 5,000-10,000 IU of hCG is given intramuscularly (36 hours prior to oocyte retrieval), hCG induces oocyte maturationS/F!owever, if'the E2 level rises > 2500 pg/ml, to m-mirrdse hyperstlmulation syndrome (see p 482), hCG administration should be withheld. The complication is mostly eliminated by the introduction of GnRH analogues (see above). Oocyte retrieval Oocyte l:etrieval is done through vaginal route under ultrasound guidance.~ith the development of vaginal transducers, vaginal needle aspiration is d ne~36 hours after C--'-h aad~stration but be or~vulati0n occurs~Fig.15.6). Intravenous analgesia and sedationdg/adequate m most of the

cases. The oocyte is readily recognisable as a single cell surrounded by a mass of cumulus cells. After recovery, the oocytes are maintained in culture in vitro for 4-6 hours. Fertilization (in vitro) (~The sperm used for insemination in vitro is prepared by the wash and swim*up technique. Approximately 50,000 Follicular HCG 3~aspiratin Human menopausal gondorrophins 1 f ollicles E 5O0' o 300 E (,o 200to 100;000 sperm are placed into the culture media containing the oocyte within 4-6 hours or--he eggs may demonstrate ~ggns of fertilization when examined 12-24 hours after insemination (presence of two pronuclei in the presence of a second polar body).(~perm density and motility are~-~e two most important criteria for successful IVF.;)rhe semen is collected just prior to ovum retrieval. Embryo-transfer ~Qf~e fertilized ova at the 4-8 Cell stage ai*e placed into the uterine cavity close to the fundus about Chapter 15: INFERTILITY I ii

1000 60~

lOO0~ ~ ~7 9 1'1 1'3 15 Day of the treatment cycle risk of congenital malformation of the baby remains inconclusive. GAMETE INTRA FALLOPIAN TRANSFER (GIFT) GIFT was first described by Asch and colleagues in 1984. It is a more invasive and expensive procedure than IVF but the result seems better than WF.

Fig. 15.6. Example of stimulated cycle in ART 48-72 hours later through a fine flexible tube r cycle to minimise muitiple pregnancy. Excess oocytes and embryos can be cryopreserved for future use. This vail reduce the cost of ovulation stimulation as well as the risk of ovarian hyper stimulation (see p 482). ' ~wo collectec 200,000-500,000: p a%--k-e'a tl~rougn the distal end combination is

('~rl this procedure, both the sperm and the unfer LuteM phase support is maintained with proge- k. dtized oocvtes-~re transited into the~I~an sterone. Oral micronis, s.~-progesterone 200 m twg-,~-~ -' - ,'---------'~---~.. ' :" --~ tubes. Fertilization is -hr eTa~n v~x~ --t e'l~,~f 'd e~~lo~aSs0ti2g The prerequisite for GIFT procedure is to have diagnosis of pregnancy by estimation of 0-hCG normal Uterine tubes The indications are the same

TEXT BOOK

OF GYb2AECOLOGY Chapter 15: fNFERTILITY

(quantitative value) is possible. Result The overall delivered pregnancy rate varies from 25-38 per cent per oocyte retrieval. There is increased risk of abortion (18 per cent), multiple pregnancy (30 per cent), ectopic (0.9 per cent), law birth weight baby and prematurity. The I
239

as that of IVF except the tubal factor. Best result is obtained in unexplained infertility and the result is poor in male factor abnormality. The superovulation is done as in ['CF. Two hours prior to ovum retrieval, semen specimen is obtained. The semen is washed and by a technique called 'swim-up', the most motile fraction of the sperm is obtained and used for transfer.

Fig. 15.7 . Tecl miq ue of intra cyto plas mic sper m inje ctio n (ICS I). The ooc ytes are coll ecte d fro m: Sist

er or friend Those for IVF candidates, excess oocytes following retrieval and cryopreservation (see above). One undergoing laparoscopic'sterilisation (with financial compensation) The oocyte donor like the semen donor must be screened for infection and genetic diseases (see p 235).

recipient's menstrual cycle. In agonadal women, exogenous steroids must be continued at least for 10 weeks tlntil adequate hormones are available fi'om placenta. Oocytes and embryos can be cryopreserved (at -196 under liquid nitrogen) for restoration of fertility in future. Survival of cryopreserved embryo is more than that of oocytes. Health hazards of ART Most of the ART procedures are not associated with any increased risk of fetal congenital mai-formations or birth defects. ICSI is often done due to male factors for infertility and it eliminates the natural process of sperm selection. It is not yet certain whether ICSI is associated with increased chromosomal abnormalities of the off-spring. Increased number of pregnancy loss, multiple pregnancy and ectopic pregnancy have been observed. Perinatal mortality and morbidity are high. Ovarian hyperstimulation syndrome (see p 482) is a rare but known health risk. Psychological stress and anxiety of the couple are severe. It is specially so when there is failure in the treatment or witli a pregnancy loss. PROGNOSIS OF INFERTILITY The pregnancy rate within two years after the start of investigation, ranges between 30-40 per cent. The rate is however, increased to about 50-60 per cent, if AID cases are included.

However, if pregnancy occurs the increased chance of abortion, 5 times of ec perinatal mortality rate doubles. Adoption Inspite of excellent advances in the field management, expectations are not always ful must understand the infertility factors, cos management. End point of managemen realistically understood. Adoption is an alterna couples.

The recipients must iaave oestrogen and progesterone tlierapies to prime the endometrium prior to embryo replacement. Embryos of 4;8 cell stage are transferred on 17-19th day of the ~wo collected oocytes along with approximately 200,000-500,000 motile sperm for each Fallopian tubp. Obstruction of efferent duct system (male) Congenital are~n.a plastic tube container. It is then pass'"7'8-F~ough absence of vas (bilateral) Failure of fertilisation in IVF Iaparoscope and inserted 4 cm into tbe distal end of the o Unexplained infertility Fallopian tube where the combination is injected. Sperm is recovered from the ejaculate. Otherwise sperm is retrieved by TESE (testicular Result sperm. extraction) or by MESA (microsurgical The oiterall delivered pregnancy rate is as high as epididymal sperm aspiration) procedures. 30-40 per cent. However, some centres could not 'find any significant difference between the success rate of IVF-ET and GIFT. Technique One single spermatozoon or even a spermatid is injected directly into the cytoplasm of an oocyte by mieropuncture of the zona pellucida. This procedure is carried out under a high quality inverted operating microscope. Micropipette is used to hold the oocyte while the spermatozoon is deposited inside the ooplasm by an injecting pipette (see fig. 15.7). In fully lactating women, pregnancy is unlikely up to 10 weeks postpartum. Male factor is responsible in 30-40 per cent, the female in 40-50 per cent, both in 10 per cent and unexplained in 10 per cent. Common causes of male infertility include defective spermatogenesis, obstruction of efferent duct, failure to deposit sperm high in vagina and error in seminal fluid (table 15.1). Important causes of female infertility are tubal factor (30-40 per cent!, ovulatory factor (30-40 per cent) and endometriosis (1-10 per cent) (scheme - 3). Ovulatory dysfunction is likely to be linked with disturbed hypothalamo-pituitary-ovarian axis either primary or secondary from thyroid or adrenal dysfunction (scheme - 1). Luteal phase defect is observed with older'women, drug induced ovulation, elevated prolaetin, patients with repeated pregnancy wastage, pelvic endometriosis, DUB and subclinical hypothyroidism. ~- Serum progesterone more than 10 rig/mi on 8th post ovulatory day indicates adequate luteal function.

ZYGOTE INTRAFALLOPIAN TRANSFER (ZIFT) Zygote intra-Fallopian transfer was first described by Devroey et al (1986). ~,~e placement of the zygote (following one day aby remains that of IVF. GIFT or ZIFT is avoided when tubal factors for infertility are present. }lAN MICROMANIPULATION Intracytoplasmic sperm l colleagues injection (ICSI) tsive proce-;r ICSI was first described by van Steirteghem and than WF. tile colleagues in. Belgium (1992). unferIndications Azoospermia, severe oligospermia ; is to have Sperm antibodies re the same insemination (SUZI). ICSI is veW effective to reduce the ~st result is need of AID. he result is Results Two hours s obtained. que called te sperm is This technique lis a suitable alternative of GIFT when defect lies in the male factor or in cases of failed GiFT. Results are similar to

Ferfilisation rate is about 60-70 per cent. Pregnancy rate is 20-40 per cent per embryo-tran-sfer. EMBRYO OR OOCYTE DONATION indications Women with premature ovarian failure Women with removed ovaries Older women (POOr o0cyte quality) Failure to respond with super-ovulation regimen Genetic disease. KEY POINTS Infertility is defined as a failure to conceive within 1 year of regular m~protected coitus. 10 per cent remain infertile by the end of 2nd year.

HAEMORRHAGE IN EARLY PREGNANCY m

be done either through the abdominal ostium b----~ other mieromanipulation methods like subzonal A~arl'r--FGff~pe or through the uterine ostium under ultrasonic guidance~

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trisomy is trisomy 16 (30%). Polyploidy has been observed in about 22% of abortuses. (Polyploidy refers to the presence of three or more multiples of a haploid number of chromosome e.g. 3n = 69 4al = 92. Triploidy is more common than tetraploidy). Monsomy constitutes 20% of all abortuses. Commonest is monosomy X (45X). Structural chromosomal rearrangements are observed in 2-4% of abortuses. These includes translocation, deletion, inversion and ring formation. Other chromosomal abnormalities like mosaic, double trisomy etc, are found itl about 4% of abortuses. ENDOCRINE AND METABOLIC FACTORS (10-15%): Luteal Phase Defect (LPD) results in early miscarriage as implantation and placentation are not supported adequatelyl Deficient progesterone secretion from corpus lu)teum or poor endometriai response to progesterone is the cause. Thyroid abnormalities: Overt hypothyroidism or hyperthyroidism are associated with increased fetal loss. Thyroid auto antibodies are often increased. Diabetes mellitus when poorly controlled causes increased miscarriage. r-~ 7Xt BOO.xL L)F OkL~'FETRit-q ANATOMICAL ABNORMALITIES (10-15%) Cel~ico-uterine factors: These are related mostly to the second trimester abortions. (1) Cervical incompetence, either congenital or acquired is one of tiie commonest cause of midtrimester and recurrent aborfi-o~n~-(2)-C-ongeni~al malformation of the uterus in the form of bicornuate or septate uterus may be responsible for midtrimester recurrent abortion. Causes of fetal loss are: (i) Reduced intra uterine volume, (ii) Reduced expansile property of the nterus. (iii) Reduced placental vascularity when implanted on the septum, (iv) Increased uterine irritability and contractility. (3) Uterine (fibr-oic!) specially of the submucous variety might be responsible not only for infertility but also for abortion. This is due to distortion or partial obliteration of the uterine cavity Other causes are: decreased vascularly at the implantation site, red degeneration of fibroid and increased uteirne irritability. (4) Intra uterine adhesions (synechiae) interfere with implantation, placentation and fetal growth.

PREMATURE RUPTURE OF THE MEMBRANES inevitably leads to abortion.

j liqi I" GEN ETIC FACTORS : Majority (50%) of early miscarriag es are due to chromoso mal abnormalit y in the conceptus. Autosomal trisomy is tile commonest (50%) cytogenetic of in vih'o fertilisation) into'the fallopian tube can abnormalit y. Trisomy for every chromoso me except chromsom e 1 has been reported. The most common

Depending on the severity of adhesions e.g. total (AshermmYs syndrome), corporal or cervicoisthmic, patient suffers from amenorrhoea, hypomenorrhea, infertility or recto'rent abortion. INFECTIONS (5%) -- are the accepted causes of late as well as early abortions. Transplacental fetal infections occur with most micro organisms and fetal losses could be cause by any. Infections could be -- (i) Viral: Rubella, cytomegalo, variola, vaccinia or HIV. (ii) Parasitic: Toxoplasma, Malaria. (iii) Bacterial: Ureaplasma, chlamydia, brucella. Spirochaetes hardly cause abortion before 20th week because of effective thickness of placental barrier. IMMUNOLOGICAL DISORDERS (5-10%) --Both autoimmuno and alIoimmune factors can cause miscarriage (p. 634). Autoimmune disease -- can cause miscarriage usually in tile second trimester. These patients form antibodies against their own tissue and the placenta. These antibodies ultimately cause rejection of early pregnancy. Antibodies responsible are: (i) Anti-nuclear mltibodies (ANAs); (ii) Anti phospholipid antibodies includes lupus anticoagulant (LAC) and anticardiolipin antibodies (aCL). Placental thrombosis, infarction and fetal hypoxia is the ultimate pathology (p. 343) to cause abortion. ICSI is found to be very effective compared to Alloimmune disease (see p. 169, 343, 635). Paternal antigens which are foreign to tile mother invoke a protective blocking antibody response. These blocking antibodies prevent maternal immune cells from recognising the fetus as a foreign entity. Therefore, the fetal allograft containing foreign paternal antigens are not rejected by ti~e mother. Paternal human leukocyte antigen (HLA) sharing with the mother leads to diminished fetal-maternal immunologic interaction and ultimately fetal rejection (abortion). Maternal medical illness (see p. 262): Cyanotic heart disease, haemoglobinopathies are associated with early abortion. Antifetal antibodies: T helper cells and Natural Killer (N.K.) ceils when activated by Th-1 pathway produce abc)rtogenic cytokines (IL-l, '/-interferon). But Th-2 cells produce cytokines (IL-3, 4, 10) which promote antibody formation that blocks NK cells. Activated NK cells damage the placental trophoblast cells to course abortion. BLOOD GROUP INCOMPATIBILITY: Incompatible ABC group matings may be responsible for early pregnlancy wastage and often recurrent but Rh incompatibility is a rare cause of death of the fetus before 28th week. Couple with group 'A' husband and group 'O' wife have got higher incidence of abortion.

paternal factors: Sperm chromosomal anomaly (translocation) can cause abortion. inherited thrombophilia (see p. 277, 441) causes both early and late miscarriages due to intravascular coagu common cause. Some women who abort habitually may have normal pregnancies following marriage with a different man. ENVIR relating to environmental factors are difficult to establish. Cigarette smoking -- increases file risk due to formation of carboxy haemoglobin and decreased oxygen tra should be avoided or minimised during pregnancy. X-Irradiation and antineoplastic drugs are known to cause abo little risk. Contraceptive agents -- IUD in situ increases ti~e risk whereas oral pills do not. Drugs, chemicals, noxi aniline, lead, formaldehyde increase the risk. Miscellaneous -- Exposure to electro-magnetic radiation from vid increase the risk. Women can safely use hair dyes, watch television and fly in airlines during pregnancy. UNEXPLAINED (40-50%): Inspire of the numerous factors mentioned, it is indeed difficult, in the majority, to pin the exact cause of abortion. Too often, more than one factor is present. However, risk of abortion increases with incre abortions and the etiology are also important. cOMMON CAUSES OF ABORTION: First trimester: (1) Genetic factors (50%). (2) Endocrine disorders (LPD, thyroid abnormalities, diabetes). (3) and Alloimmune). (4) Infection and (5) Unexplained. Second trimester: (1) Anatomic abnormalities -- (a) Cervical incompetence (congenital or acquired). (b) Mullerian Fusion Defects (Bicornuate uterus, septate uterus). (c) Uterine synechiae. (d) Uterine fibroid. (2) Maternal medical illness and (3) Unexplained. MECHANISM OF ABORTION: In the early weeks, death of the ovum occurs first, followed by its expulsion. In the later weeks, maternal environmer~tal factors are involved leading to expulsion of the fetus which may have signs of life but is too small to survive. Before 8 weeks: The ovum, surrounded by the villi with the decidual coverings, is expelled out intact. Sometimes, the external os fails to dilate so that the entire mass is accommodated in the dilated cervical canal and is called cervical abortion (Fig. 15.1).

8-14 weeks: Expulsion of the fetus commonly occurs leaving behind the placenta and the wh membranes. A part of it may be partially separated with brisk haemOrrhage or remains totallysta attached to the uterine wall. fro

Beyond 14th week: The process of expulsion is similar to that of a "mini labour". The fetus is CL The expelled first followed by expulsion of the placenta after a varying interval. of p

The-bleeding is usually slight and bright red in colour. On rare occasion, the bleeding may be brisk and sharp, suggestive of low implantation of placenta. The bleeding usually stops spontaneously.

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BLOOD GROUP INCOMPATIBILITY: Incompatible ABC group matings may be responsible for early pre Rh incompatibility is a rare cause of death of the fetus before 28th week. Couple with group 'A' husband and gro of abortion. PREMATURE RUPTURE OF THE MEMBRANES inevitably leads to abortion. r-~ 7Xt BOO.xL L)F OkL~'FETRit-q

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GENETIC FACTORS: Majority (50%) of early miscarriages are due to chromosomal abnormality in the conceptus. Autosomal trisomy is tile commonest (50%) cytogenetic abnormality. Trisomy for every chromosome except chromsome 1 has been reported. The most common trisomy is trisomy 16 (30%). Polyploidy has been observed in about 22% of abortuses. (Polyploidy refers to the presence of three or more multiples of a haploid number of chromosome e.g. 3n = 69 4al = 92. Triploidy is more common than tetraploidy). Monsomy constitutes 20% of all abortuses. Commonest is monosomy X (45X). Structural chromosomal rearrangements are observed in 2-4% of abortuses. These includes translocation, deletion, inversion and ring formation. Other chromosomal abnormalities like mosaic, double trisomy etc, are found itl about 4% of abortuses. ENDOCRINE AND METABOLIC FACTORS (10-15%): Luteal Phase Defect (LPD) results in early miscarriage as implantation and placentation are not supported adequatelyl Deficient progesterone secretion from corpus lu)teum or poor endometriai response to progesterone is the cause. Thyroid abnormalities: Overt hypothyroidism or hyperthyroidism are associated with increased fetal loss. Thyroid auto antibodies are often increased. Diabetes mellitus when poorly controlled causes increased miscarriage. ANATOMICAL ABNORMALITIES (10-15%) Cel~ico-uterine factors: These are related mostly to the second trimester abortions. (1) Cervical incompetence, either congenital or acquired is one of tiie commonest cause of midtrimester and recurrent aborfi-o~n~-(2)-C-ongeni~al malformation of the uterus in the form of bicornuate or septate uterus may be responsible for midtrimester recurrent abortion. Causes of fetal loss are: (i) Reduced intra uterine volume, (ii) Reduced expansile property of the nterus. (iii) Reduced placental vascularity when implanted on the septum, (iv) Increased uterine irritability and contractility. (3) Uterine (fibr-oic!) specially of the submucous variety might be responsible not only for infertility but also for abortion. This is due to distortion or partial obliteration of the uterine cavity Other causes are: decreased vascularly at the implantation site, red degeneration of fibroid and increased uteirne irritability. (4) Intra uterine adhesions (synechiae) interfere with implantation, placentation and fetal growth.

paternal factors: Sperm chromosomal anomaly (translocation) can cause abortion. inherited thrombophilia (see p. 277, 441) causes both early and late miscarriages due to intravascular coagu common cause. Some women who abort habitually may have normal pregnancies following marriage with a different man. ENVIR relating to environmental factors are difficult to establish. Cigarette smoking -- increases file risk due to formation of carboxy haemoglobin and decreased oxygen tra should be avoided or minimised during pregnancy. X-Irradiation and antineoplastic drugs are known to cause abo little risk. Contraceptive agents -- IUD in situ increases ti~e risk whereas oral pills do not. Drugs, chemicals, noxi aniline, lead, formaldehyde increase the risk. Miscellaneous -- Exposure to electro-magnetic radiation from vid increase the risk. Women can safely use hair dyes, watch television and fly in airlines during pregnancy. UNEXPLAINED (40-50%): Inspire of the numerous factors mentioned, it is indeed difficult, in the majority, to pin the exact cause of abortion. Too often, more than one factor is present. However, risk of abortion increases with incre abortions and the etiology are also important. cOMMON CAUSES OF ABORTION: First trimester: (1) Genetic factors (50%). (2) Endocrine disorders (LPD, thyroid abnormalities, diabetes). (3) and Alloimmune). (4) Infection and (5) Unexplained.

DEFINITION: It is a clinica[entity where the process of abortion has started but has not progresse impossible.

Depending on the severity of adhesions e.g. total (AshermmYs syndrome), corporal or cervicoisthmic, patient suffers from amenorrhoea, hypomenorrhea, infertility or recto'rent abortion. INFECTIONS (5%) -- are the accepted causes of late as well as early abortions. Transplacental fetal infections occur with most micro organisms and fetal losses could be cause by any. Infections could be -- (i) Viral: Rubella, cytomegalo, variola, vaccinia or HIV. (ii) Parasitic: Toxoplasma, Malaria. (iii) Bacterial: Ureaplasma, chlamydia, brucella. Spirochaetes hardly cause abortion before 20th week because of effective thickness of placental barrier. IMMUNOLOGICAL DISORDERS (5-10%) --Both autoimmuno and alIoimmune factors can cause miscarriage (p. 634). Autoimmune disease -- can cause miscarriage usually in tile second trimester. These patients form antibodies against their own tissue and the placenta. These antibodies ultimately cause rejection of early pregnancy. Antibodies responsible are: (i) Anti-nuclear mltibodies (ANAs); (ii) Anti phospholipid antibodies includes lupus anticoagulant (LAC) and anticardiolipin antibodies (aCL). Placental thrombosis, infarction and fetal hypoxia is the ultimate pathology (p. 343) to cause abortion. Alloimmune disease (see p. 169, 343, 635). Paternal antigens which are foreign to tile mother invoke a protective blocking antibody response. These blocking antibodies prevent maternal immune cells from recognising the fetus as a foreign entity. Therefore, the fetal allograft containing foreign paternal antigens are not rejected by ti~e mother. Paternal human leukocyte antigen (HLA) sharing with the mother leads to diminished fetal-maternal immunologic interaction and ultimately fetal rejection (abortion).

CL Second trimester: (1) Anatomic abnormalities -- (a) Cervical incompetence (congenital or The acquired). (b) Mullerian Fusion Defects (Bicornuate uterus, septate uterus). (c) Uterine synechiae. (d) Uterine fibroid. (2) Maternal medical illness and (3) Unexplained. MECHANISM OF ABORTION: In the early weeks, death of the ovum occurs first, followed by its expulsion. In the later weeks, maternal environmer~tal factors are involved leading to expulsion of the fetus which may have signs of life but is too small to survive. Before 8 weeks: The ovum, surrounded by the villi with the decidual coverings, is expelled out intact. Sometimes, the external os fails to dilate so that the entire mass is accommodated in the dilated cervical canal and is called cervical abortion (Fig. 15.1).

Maternal medical illness (see p. 262): Cyanotic heart disease, haemoglobinopathies are associated with early abortion. Antifetal antibodies: T helper cells and Natural Killer (N.K.) ceils when activated by Th-1 pathway produce abc)rtogenic cytokines (IL-l, '/-interferon). But Th-2 cells produce cytokines (IL-3, 4, 10) which promote antibody formation that blocks NK cells. Activated NK cells damage the placental trophoblast cells to course abortion.

of p 8-14 weeks: Expulsion of the fetus commonly occurs leaving behind the placenta and the membranes. A part of it may be partially separated with brisk haemOrrhage or remains totallyThe red attached to the uterine wall. ble Beyond 14th week: The process of expulsion is similar to that of a "mini labour". The fetus is in t low expelled first followed by expulsion of the placenta after a varying interval. usu

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(2) Pain: Bleeding is usually painless but there may be mild backache or dull pain in lower abdomen. Pain appears usually following haemorrhage. Pelvic examination should be done as gently as possible. (a) Speculum examination reveals bleeding if any, escapes through the external os. Any local lesion in the cervix may co-exist. (b) Digital examination reveals the closed external os (Fig. 15.2). The uterine size corresponds to the period of amenorrhoea. The uterus and cervix feel soft. Pelvic examination is avoided when ultrasonography is available (see below). INVESTIGATIONS: Routine investigations include: (1) Blood for haemoglobin, haematocrit, ABO and Rh grouping. Blood transfusion may be required if abortion becomes inevitable and anti-D gamma globulin has to be given in RI~ negative non-immunized women. (2) Urine for immunological test of pregnancy is not helpful as the test remains positive for a variable period even after the fetal death. Ultrasonography (TVS) findings may be: (1) A well formed gestation ring with central echoes from the embryo indicating healthy fetus (see p. 625). (2) Observation of.fetal cardiac motion. With this there is 98% chance of continuation of pregnancy. (3) A blighted ovum is evidenced by loss of definition of the gestation sac, smaller mean gestational sac diametet, abgent fetal echoes and absent fetal cardiac movements. Serum progesterone value of 25 ng/m] or more generally indicates a viable pregnancy in about 95% of cases. Serial serum chorionic gonadotrophin (hCG) level is helpful to assess the fetal well being. Normally quantitative value of hCG should double by every 48 hours. TREATMENT: Rest: The patient should be in bed for few days until bleeding stops. Prolonged restriction of activity has got no therapeutic value. Drags: Sedation and relief of pain may be ensured by phenobarbitone 30 mg or diazepam 5 mg tablet twice daily. There is no evidence that treatment with natural progesterone or swlthetic progestilrs ilnproves the prognosm, on the

DEFINITION: It is the clinical type of abortion where the changes have progressed to pregnancy is impossible. CLINICAL FEATURES: The patient, having the features of threatened abortion, develo Increased vaginal bleeding. (2) Aggravation of pain in the lower abdomen which may be colicky

the patient is proportionate to the visible blood loss. (4) Internal examination reveals dilated inter products of conception are felt (Fig. 15.2). On occasion, the features may develop quickly withou abortion. In the second trimester, however, it may start with rupture of the membranes or inte labour). MANAGEMENT: The principles in the management are: (1) To take appropriate measures To accelerate the process of expulsion. (3) To maintain strict asepsis as outlined in conduction of Generat measures: Excessive bleeding should b.e promptly controlled by administering me and the size of the uterus is less than 12 weeks. The shock is corrected by intravenous fluid therap

Active Treatment: Before 12 weeks: (1) Dilatation and evacuation followed by curettage of the uterine c anaesthesia. (2) Alternatively, suction evacuation followed by curettage is done. After 12 zoeeks: (1) The uterine contraction is accelerated by oxytocin drip (10 units in 500 minute. If the fetus is expelled and the placenta is retained, it is removed by ovum forceps, if separated, digital separation followed by its evacuation is to be done under general anaesthesia. (2 closed (suggestive of low implantation of placenta) -- evacuation of the uterus may have to be do

(b)

Fig. 15.2: (a) T-t, reatened abortion (b) Inevitable abortion (c) Incomplete abortion (2) In the rest, it terminates either in inevitable or missed abortion. If the pregnancy continues, there is increased frequency of preterm labour, placenta praevia, intra-uterine growth retardation of the fetus and fetal anomalies. Blighted ovum (Fig. 15.la): It is a sonographic diagnosis. There is absence of fetal pole in a gestational sac with diameter of 3 cm or more. Uterus is to be evacuated once the diagnosis made. contrary, there is a probability of having a missed abortion. Even, some of the progestins structurally related to testosterone may result in viri]ization of the female fetus. Initial study suggests that use of HCG improves pregnancy outcome. General measures: (1) The patient is advised to preserve the vulval pads and anything expelled out per vaginam, for inspection. (2) To report if bleeding and/ or pain becolnes aggravated. (3) Routine note of pulse, temperature and vaginal bleeding. her ADVICE ON DISCHARGE: The patient should limit activities for at least two weeks an&avoid heavy work. Coitus is contraindicated during this period. She should be re-examined after one month tO assess the growth of the fetus. PROGNOSIS: The prognosis is very unpredictable whatever method of treatment is employed either in the hospital or at home. In isolated spontaneous threatened abortion, the following events may occur. (1) In about two-third, the pregnancy continues beyond 28 weeks. DEFINITION: When the products of conception are expelled en masse, it is called complete abortion.

CLINICAL FEATURES: There is history of expulsion of a fleshy mass per vaginam followed by: (1) Subsidence pain. (2) Vaginal bleeeding becomes trace or absent. (3) Internal examination

of T1 of is t
SOI USU

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Fig. 15.la: Ultrasonic picture of blighted ovum

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reve als: (a) Uter us is smal ler than the perio d of ame norr hoea and a little firm er. (b) Cerv ical os is close d. (c)

Bleeding is trace. (4) Examination of the expelled fleshy mass is found intact. ~ MANAGEMENT: The effect of blood loss, if any, should be assessed and treated. If there is doubt about complete expulsion of tile T products, uterine curettage should be done. Transvaginal sonography is useful to prevent umaecessary surgical procedure, Rh-NEGATIVE WOMEN: A Rh--negative patient without antibody in her E system should be protected by Anti-D gamma globulin-50 microgram or 100 microgram intramuscularly in cases of early abortion X or late abortion respectively within 72 hours. T weeks gestation where no instrumentation has been However, Anti-D may not be required in a case with complete miscarriage before 12 done. B O O DEFINITION: When the entire products of conception are not expelled, instead a part of it is left inside the uterine cavity, it is called incomplete abortion. This is the commonest type inet amongst women, hospitalised K for abortion complications. GLINIOAL FEATURES: History of expulsion of a fleshy mass per vaginam followed O by: (1) Continuation of pain lower abdomen, F of varying magnitude. (3) Internal examination colicky in nature, although in diminished magnitude. (2) Persistence of vaginal bleeding reveals -- (a) uterus smaller than the period of amenorrhoea, (b) patulous cervicalO os often admitting tip of the finger and (c) varying amount of bleeding. (4) on examination, tile expelled mass is found incomplete (Fig. B15.2). S TERMINATION: The products left behind may lead'to -- (a) profuse bleeding, (b) sepsis, (c) placental polyp and (d) rarely choriocarcinoma. I MANAGEMENT: In recent case~-- Tile same principles are to be followed like E that of tile inevitable abortion. It is emphasised, that the patient may be in a state of shock due to blood loss. She should be resuscitatedi before any active treatment is undertaken. Early abortion: Dilatation and evacuation under general anaesthesia is toRbe done. Late abortion: The uterus is evacuated under general anaesthesia and the i products are removed by ovum forceps or by blunt curette. c hz late cases, dilatation and curettage operation is to be done to remove the bits s of tissues left behind. The removed materials are subjected to a histological examination. ... [ 16>

--

Oxytocin -- To start with 10-20 units of oxytocin in 500 ml of normal saline at 30 drops per min oxytocin to the maximum of 200 mlU/rain, may be used with monitoring. -- Prostaglandins are more effective than oxytocin in such cases. The methods use (a) Prostaglandin E~ analogue (misoprostol) 200 gg tablet is inserted into the posterior vaginal maximum of 5 such. (b) Intramuscular administration of 15 methyl PGF2c~ (Carboprost tromethamine) 250 gg at th maximum of 10 such.

8.Nd ;PTIY ,&Be ~P~T~~

DEFINITION: Any abortion associated with clinical evidences of infection of the uterus and it abortion. Alth0ugf~"dinical -criteria vary, abortion is Usually considered-septic when there-are: (1) 100.4- F (38 C) for 24 hours or more; (2) offensive or Purulent vaginal discharge and (3) other evidenc

t ...::.l., lq: ttAEMORRHAGE IN EARLY PREGNANCY r

;: --

Gradually, the fluid portion of the blood surrounding the ovum gets absorbed and the wall becomes fleshy, hence the term fleshy or carneous mole (Fig. 15.3). GLINICAL FEATURES: The patient usually presents with features of threatened abortion followed by: (1) persistence of brownish vaginal discharge. (2) Subsidence of pregnancy symptoms. (3) Retrogression of breast changes. (4) Cessation of uterine growth which in fact becomes smaller in'size. (5) Non audibility of the fetal he'art sound even with Doppler cardioscope if it had been audible before (6) Cervix feels firm. (7) immunological test for pregnancy becomes negative. (8) Real time u!trasonography reveals an empty sac early in the pregnancy or the absence of fetal motion or fetal heart movement later in the pregnancy. COMPLICATIONS: The complications of the missed abortion are those mentioned in intrauterine fetal death (see Ch. 21). Blood coagulation disorders are less likely to occur in missed abortion: MANAGEMENT: Uterus is less than 12 weeks: Vaginal evacuation can be carried out without delay. This can be effectively done by suction evacuation or slow dilatation of the cervix by laminaria tent followed by dilatation and evacuation (D & E) of the uterus under general anaesthesia. The risk of damage to the uterine walls and brisk haemorrhage during the operation should be kept in mind. Uterus more than 12 weeks: The same principles of the management as advocated in the intrauterine fetal death are to be followed (see ch.21). Induction is done by the following methods: DEFINITION: When the fetus is dead and retained inside the uterus for a variable period, it is called missed abortion or silent miscarriage or early fetal demise. PATHOLOGY: The causes of prolonged retention of the dead fetus in the uterus is not clear. Beyond 12 weeks, the retained fetus becomes macerated or mummified. The liquor amnii gets absorbed and the placenta becomes pale, thin and may be adherent. Before 12 weeks, the pathological process differs when the ovum is more or less completely surrounded by tile chorionic villi. GARNEOUS MOLE ($yn: blood mole, fleshy mole): It is the pathological variant of missed.abortion affecting the'fetus before 12 weeks. Small repeated haemorrhages in the choriodecidual space disrupt the villi from its attachments. The bleeding is slight so it does not cause rupture of the decidua capsularis. The clotted blood with the contained ovum is known as a blood mole. By this time, the ovum becomes dead and i absorbed s as a rudimer structure.

lower abdominal pain and tenderness. INCIDENCE: It is difficult to work out the overall incidence of septic abortion. About 10% of abo hospital are septic. The majority of septic abortion are associated with incomplete abortion. While in the m occurs following illegal induced abortion but infection can occur even after spontaneous abortion. MODE OF INFEGTION: The micro-organisms involved in the sepsis are usually those nor (endogenous). The micro-organisms are: (a) Anaerobic -- Bacteroides group (fi'agilis), anaerobic Strepto bacillus. (b)Aerobic EscherMiia coli (E. coli)~ KlebsielIa, Stapl~Iococcus, Pseudomonas and haem exogenous).'7-Mixed fnfecti6fi is more common. The increased association of sepsis in illegal induce that: (1) proper antiseptic and asepsis are net taken; (2) in comp-lete-vacuation and (3) inadvertent inj adjacent structures, particularly the gut. PATHOLOGY: In the majority (80%), the organisms are of endogenous origin and the infection without any myometrial involvement. In about 15%, the infection either produces localised endomyometri leucocytic barrier, or spreads to the parametrium, tubes, ovaries or pelvic Eeritoneujn:In about 5%, there is end0toxic shock. GLINIGAL FEATURES: Depending upon the severity and the extent of infection, the clinical picture var an unauthorised '>erson is concealed.

Fig. 15.3 A carneous mole