text book of medicine

7/27/2019 text book of medicine

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figures given I occurs from' ts inany One

t the sperm lealth status latozoa Were

4tHe (1999)

Dr more

~r ejaculate,ore prog~e- 1

notility

tore normal

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 isreluctant to be examined as may happen in quite ~od number of cases.

Nomenclature

Asptrmia-- Failure of formation or emission of semen. OligosperrnialOligo zoospermia -- 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 motion-

Iess.

Teratozoospermia -- > 70% spermatozoa with abnormal morphology.

Oligoasthenoteratozoospermia -- Disturbance ofail 3 variables.

Indepth evaluation

These are needed in cases o f -- (a) Azo~mia {b) Oligospermia (e) Low vo lume eia culate (d) Problems o~potency. Fhr'--~er diagnostic protocols has bee n appropriately designed (scheme 4).e Serum FS~stosterone, proiactin, and-TS.-HH: Testkulfff~[ysfunction causes r i~SH and Lid. Low level ot. FSH and LH suggest hypogonado~ophic hypo -g0nadism (see' Scheme 4). Leydig cell dysfu nction causes 10wtesto~terone andhigh Lid level. Elevated prolactin due to pituitary adenoma

may cause impotency.. Fructose Content in the seminal fluid -- Its absence sugg ests congenital absence of seminal vesicle or portion of the duct al 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 for moi 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 o bstruction. It is mostly replaced by Taus.

' Karyotyp'~/inalysis -- This is to be done in cases with azoo spermia 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 a bnormalities.

"Immunological tests -- Two types of a ntibodies have been described -- sperm agglutinating and sperm immobilizing; the latter is probably related to infertility. The antibodies are prod uced following infection (orchitis), trauma or vasec tomy. These antibodies can be detected from the serum bythe 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 ce lls requires prostatic massage. The collected fluid is to be examined by StaIning and culture t o detect the organisms and appropriate antibiotic sensitivity.

FEMALEHistory

i


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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 tubercu losis, sexually transmitted disease, features suggestive of pelvic inflammation or diabetes.The u-rgical hLstory should be directed specially towards abdo minal or pelvic surgery. This may be related to peritubal adhesions;

Menstrual history should be taken in detafis. Wide spectrum of abnor malities ranging from h o~a- oligomenorrh0ba to amenorrhoea are associated with ~mtJrbed hypo ala~ary ovarian axis which may be either primary oi: secondar y 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 '


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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 pr esence 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 suspe nded.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.

Detection of abnormality of One factor does not

negate investigation for another defectelsewhere. Multiple defects may be present in

ll~ the same case e.g. tubal defects may be asso-

ciated 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 maybe 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 ovulationThe 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 historyEvaluation of peripheral or endorgan changes BBT

Cervical mucus studyVaginal cytology'

Hormone estimation- Serum progesterone

- Serum LH- Serum oestradiol

Endometrlal biopsySonography

Direct'

Laparoscopy ConclusivePregnancy

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 historyThe 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 orexcessive mu------%okt va~'~al discharge.(Mittels-

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


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Chapter 15: INFERTILITY

I Menstruation Ovulation '~. "~

- ,,,. - ~.

,,~ .'s . ' 3~ ~ :,.c '4 :9 c

'2 '8 u

,. s~

'7 ~ ]

R 'B 's

.s .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 ~'2Days from start of the menstrual cycle

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 pr egnancy occurs, the rise of temperatur e sustains along with absence of the period In anovu latory cycle, there is no rise of temperature thro ughout the cycle.

Principle --(~he rise of temperature is secondar y to progesterone outputS. The primary reason for the rise is the increase in the product ion and secretion of norepinephrine which is thermogenic neural hormone.B~edt[~res --~e patient is instructed to take her oral te'r~perature da ily on waking in the morning before rising out of the bed. The tempera ture 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 su stains 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 r ise actually occurs about 2 days after the LH peak and with a peripheral level of progesterone to greate r 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~,


5/26

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 hFindings --'EvJendP-me '~-abgl'anl give g(~t~:iotd,y,:i;tk~ predict ~9"+.~bfiSubnuclear vac appearing 36-48 h,

Cause -- The s, action of progest{ endometrium.

SonographySerial sonograp]

megiu~


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Scram oestradiqJ attains the peak rise approxi-mately 24 hours prmr to LH' surge at--bout 24-36haurS.~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 caSeSwhere~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.

SonographySerial 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~copyI~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.

CONCLUSIVEPr~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, t he endometriai changes . observed correspond to the day 23). This lag phaseendometrium 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 t he 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~ insuffiation test. Instead of air or CO=, dye is instilled

/3"~a*~- ~b"~j~.~-, ~k~ Oa:d C'~D~ transcervically.~~-~ When to be done? As in D + I.

Insufflafion test (Rubin's test)Limitation -- As in D + L

Principle -- The underlying principle lies with Advantages -- It has got distinct advantages overthe fact that the cervical canal is in continuity with insufflation test. It can precisely detect the side and


7/26

the peritoneal cavity through the t ubes. 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}~d trans~cfi~fl~"'und~r pressure, -gives ~ like synechae, fibroid). As such insuffiation of theence of tubal pitenc~ ..................... ........................ ........tubes has largely been replaced by HSG.

223

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 t he 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 co mmonly done these

days.

Disadvantages-- it involves radiation risk. Laparoscopy and ehromopertubationThe 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 yearsProtocols -- 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 Fig. lB.3. Chromopertubation shows the patencyperitoneal spillage of the tribes (Courtesy Dr. Manoj Samanta)

224


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 shou ld be regarded as complenientary to each other and sho uld not be used as a substitute to the other procedure.When to be done? It is preferably done in the secretory phase. Rece nt corpus luteum may be visualised and endometrial biopsy can be taken in the same sitting.

Table 15.4


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Indications of laparoscopy in infertility Age > 35 years Abnormal HSGDiagnostic Failure to conceive after

reasonable period (6 months)with normal HSG

"Unexplained infertility

Operative GIFT and ZIFT procedures Ovarian diathermy (see ch. 33) Reconstructive tubal surgery

Fulguration of endometrioticimplants

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 theperitoneal 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 hystero scope.

Salpingoscopy -- Tubal lumen is studied introducing a rigid endoscope t hrough file fimbrial end of the tube. It is performed through the op erating 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 p rimary 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 secreto ry phase, hinders their penetration (Fig. 15.4). As such, d ysfunction at this level should be carefully evaluated. This is done

by:Post~ (PCT) -- Marion Sims (1866) and Max Huhner (1913)

Principle--PCTis 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


9/26

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 des cribed 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 ser um TSH, prolactin, FSH, LH, dehydroepiandrosterone su lphate, testosterone and progesterone in midluteal phase. In case s with

family history of diabetes, postprandial blood sugar is to be estimated.Immunological factor -- Human sperm has immunologic potential and in sus ceptible women, it can elicit antibodies against tile antigens producing a cer vical immune response and infertility. The antibodies against sperm may affe ct fertility by immobilizing sperm or caus ing 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 sper m antibodies in cervical mucus may be demonstrated by post coital test or by sper m 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, bod y), can be detected. In MAR test human red cells sensitised with human IgG are treated withsemen. .'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 bo th husband and wife. An antibody titre of I: 4 o r 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 expectantmanagement 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.ATMENTCouple 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 co uple in such cases should be tactfully handled to minimise psychologic upset.


10/26


11/26

may be helpful

Genera~ ,~

Improvement of general health, :re dugti0m.of ~jcf"~J~'?6 r~'~;~~~'' ~~~'" ~'~ ~.~-,, ~~~o.u-~e(i.

~f376q'~ '"'""~t'~''''~t~"~q,.in~.

228

ancl~f Z oh~,,i!t~t6~;improve spermatogenesis is pro'ba~ toimprove the general health. They may reduce the toxic freeradicals (H202), released by abnormal sperm and leukocytespresent in the 'semeiL

In k.Yl~ggpna~pphic,hypog0n';idi~m~: the disordersof sp~togenesls can be treated wikk the following therapywith varying success.

dazsw'th f 5~~3?yd~s; It increases 'e'~--l'es rum 'ye- ofFSH~ ,~'H~es tosterone.';~-C 5,0.p0~ intrg, m,,~'.-, l~l"Sl21~aa~rl~.once or

twice a week is given to stimulate endogenous testo-sterone production.

- ~G~ andhCG are used in cas~ado-trp-p-.hindeficienc-y or failed c!0m!,phene, cl~atecases.

- 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 gotdirect 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'withhypogonadotrophic hypogonadism may also respond withGnlLH 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 washedspermatozoa is the choice of treatment for such cases (see p234).

Genital tract irffection needs.prolonged course ofantibioticsl Generally :~o~c ci'~e~hroz

on the response. In retro~rade ejaculation --~phenLlb~a

(C~-adrenergic agonist) is used to improve the toneo'~T~temal urea-M-sphincter. Sperm m----m-~ayb~eco-vered from the neutralised urme. Processed sper-matozoa could be used for IUI (see p 234). -'

In teratospermia, asthenospermia specific causes areunknown. No treatment is available.~DOnorDonor~insemination (AID) is Lhe option n~(seep..235). '

In genetic abnormality-- artificial insemination withdonor sperm (AID) is th~-bpfion is no o--~er tre'~-~eent isavai 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, obstructionof 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~0ut80 percent of cases and pregnancy rate is about 50 percent.

The presence of varicocele is c6~reeted b hi 'hligatmT' ff.~qf ,$permatic ?e~and the~e~.Z

' Or~ chifd~de-seended testers should be done15etween 2-3-~years to have adequate sperma-togenesis inlater life.

ImpotencyPsychosexual treatment may be of help. Hyper-'~prolactinemia needs further investigation and treatment (see p426). For eree-~ile~dysfunetion sildenafil (~iagra) iscurrentl~-d?ised. A single dose ~f 25-100 m'g i~iepe--q~, onresponse).is ~ven orally one hou~-~ beforesexual activi-tz. In unresponsive cases,artificial insemination is to be thought of(see p 234).

Assisted reproductive technology (ART)for male infertilityProspect of male infertility' has

improved significantly with the'ac/vent ofART. IUI, TESE, PESA, MESA andintracytoplasmic sperm injection (ICSI) arenow the treatment available for infertilemales (see p 234).

FEM~EaNFERTi'~i~

For convenience, the treatment modalitles?in femaleinfertility are grouped as follows according to the disgrdersidentified.

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 menstrualChapter 15: INFERTILITY

cycle or may be associated with o ligomen0rrhoea oramenorrhoea.

To facilitate effective folliculogenesis andovulation, the following may be prescribed.

~1 Psychotherapy :to-impriJEe the

emotional causes, if any,

improvement oft'nutrigon and- weight g

ah3...]and so also reduction of weight in obesity as in PCOS

cases (see p.431) are essential to have a good response ofdrug therapy for induction. They may also facilitatespontaneous ovulation

The following drugs are of use either singly or incombination.

Table 15.6Drugs 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) - recombinantFSH (Gonal-F, Recagon)

hCG (Profasi, Pregnyl)- recombinant hCG

GnRH (see p 231)

GnRH analogues (see p 236)

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

Prolactin - Bromocriptine (see p 432)

Insulin - Metformin (see p 431)

! SubstitUtion therapy Hypothyroidism - Thyroxino Diabetes mellitus - Antidiabe~ie drags

Monitoring d..~uring ovulation inductionFor diagnosis,of ovulation, BBT recording is en

some therapies, dmgnosm of ovulation ~i-~-6b~-ained-Chart supplemented by cervical mucus study (clear, water

type). But when a complicated regimen is followed to a~f:::eT;p~

. .d.~lvanr ~, ra

pregnancy by time intercourse or by ART, a detailA I

monitoring is a must which is only possibb ~.al~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.~'Vrod ....which are nomnvamve, sunple and quite inforraa,

Further -confir-

mation

five, other parameters used are serial es.;;mat;on ofplasma El and ultrasonic measurement of growia~

folhcles (folhculometry). These last two are obi;. gatory inART.

Table 15,7

Objectives of monitoring for induction of ovulatior

To select time for preovulatory administration of.hCG

o To prevent, hyperstimulation syndrome To select time for intercourse or artificial insemi.

nation

To select time for ovum retrieval in 1VF


12/26

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 causesovulat.o.~ rrh0ea. Bromocript~ fseep 432) increase~

'domiphene. Patien] elevated prolactin wi and

domiphene amI nancy,

(e) Hyperinsulin~ ovarian disease (se~ domiphene.Correc rnalily (see p 431) al~ satisfactory result. 10und toreduce hyt genemia.

(f) hCG --'In cas of LH surge, hCG ! 7 days after thela~ Prior monitoring ultrasonic measm (18-20 mm)is prefi

(g) Growth horn resp0nders spec;all

Couple instruct The couple is ad as per following

Several times change in ur!

wed to aehiev~ART, a dehil~ dypossible h arecosilyconsuming, ilmucus studyqmte informa. des,timation 0[ent of growia,

: tWO--reohl~.

m ofovulatio]n

ninistrafion of

tificial inserai.

IVF

ene

omc as well/~s

ogen receptorscreased GnRI-I;onadotrophinrogenic effects nthe'cervical

.'.eada.chl/~n(rare). Incidenceof abortion and Result - ~?:x~:!!~:t~em/plf;rma,nons arenot mcreasea

buSU;;?/nf~a lnicydUCttiffnja:;;t;s 4~gh~ 80enPLr Th:

s~ daily for 10days starting onfirst day of cycle.

Chapter 15:

INFERTILITY

In cases of hypergonadotrophic

hypogonadism, high gonadotrophin levels arelowered with the use of combined oestrogenand progestogen preparations (oral pill). Whenthe levels reach normal, gona-dotrophintherapy may be employed to achieveovulation. The success rate is poor.

Side effects of gonadotrophin therapy(see p. 482) ResultsPregnancy rate after six courses of

treatments is 90 per cent. Incidence of multiple

pregnancy (10-40 per cent) and ectopicpregnancy are high.GnRH

Patient selection

When ovulatory dysfunction is due to: Hypotiaalamic amenorrhoea Hypogonadotrophic

hypogonadismGnRH is administered intravenously or

subcutaneously with an infusion pump in apulsatile fashion.

A pulse of 5 gg is used IV at every 90

minutes. Follicular growth is similar to anormal menstrual cycle. Follicular growth

monitoring, hCG administration and coupleinstructions are same as in hMG therapy.Results

Pregnancy rate is 80 per cent followingsix course of treatment. Multiple pregnancyrate is 5 per cent. The risk of ovarian hyperstimulation is Iow (see p. 482).

GnRH analogues (p 480)

Patient selection

Patients refractory to gonadotrophlns

Patients having elevated LH

Patients with normal gonadotrophins

Patients with premature follicular luteinisation or premature ovulation due to premature LH surge

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

GnRH agonist is used for down regulation of pituitary gland

by desansitisation of pituitary GnRH receptors (see chi 6).GnRH agonist initially produce stimulation ofgonadotrophin secretion known as 'flare'effect. Generallythis flare effect lasts for about 2-3 weeks. Adequate pituitarysuppression 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 andgrowth monitoring is similar as in hMG therapy, hCG is alsoadministered when criteria is fulfilled as discussed withhMG therapy (see p 230).

Results -- ovulation rate is about 75 per cent andpregnancy rate is about 25 per cent.

GnRH antagonists -- can block pituitary GnRHreceptors completely without any initial stimulation (flareeffect). Cetrorelix is currently being tried to prevent

premature LH surge. As with GnRH analoguegonado-trophln stimulation is done (see above).

When pregnancy occurs following supero-vulationwith GnRH agonist therapy, luteal phase support should bemaintained either by giving hCG or progesterone.

It should be emphasized that the gonadotrophins,GnRH and GnRH analogues are cosily drugs. Their uses

have to be monitored carefully with sophis

not only to control the regimen but also thazards (table 15.7). Thus, its use isrestricted in selected centres and iscommonly used in ART.

SurgeryWede:e resectipn -- Bilateral

wedge resection of e~s done inPGOS-cases~here c!omi-phene citratefails to induce ovulation. One-third ofthe ovarian mass of each side should beresected and meticulous haemostasis is achieadhesions; The success of the operation wilvaginal bleeding within 2:.'4 days .of operatio'~, Laparoscopic ovarian diathermy andan-alternative to wedge resectio9 'has e-'~-

useful to minimise adhesions

(see ch. 33 p 549).

Fig. 15.5. Tuboztubal anastomosis. Placeme

five interrupted sucres using 8-0 polyglact

magnificafiqn)

Clomiphene citratePatient selection:

N0rmogonadotrophic - normoprolac 'tmaemicpatients who are having normal cycles with absent orinfrequent ovulation.

o PCOS cases with oligomenorrhoea or amenorr-hoea. Theoestradi01 level should be > 40 pg per ml.

Hypothalamic amenorrhoea following stress or 'pill'use.

DoseClomiphene therapy is simple, safe and at the

same time cost effective. Most centres use an initialdose of 50 mg daily. Dose is increased in 50 mgs~eps to a maximum 250 mg daily, if ovulation is notinduced by the lower dose. The actual starting day ofits 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 daysafter the last day of therapy. Therapy for four to slxcycle is generally given.

Mechanism of action ofclomipheneClomiphene citrate is anti-oestrogenic as well asweakly oestrogenic. It blocks the oestrogen receptorsin the hypothalamus. This results in increased GnRHpulse amplitude causing increased gonadotrophinsecretion from the pituitary. Anti-oestrogerdc effectsare seen on the endometrium and on the cervicalmucus;

) pre-

2

ia

Because of its anti-oestrogenic effect or indu-(a)J ,-drogenS the cervical mucus becomes

levateu ~' '~x,d e j .,4scid and hinders sperm penetration. AsRick anu. ,,-ted oestrogen 1.25 mg may be

admini-, c0nJuga .

' Dai!~ or on alternate days beg'm~g 5-7 days

after the laat dose of clomiphene therapy.. Several times for 2448hours after the colour

change in urine when tested by LH kit.

cervical mucus hostility and other non ovulatory factors.The incidence of multiple pregrtaI!,gt is about 5 per cent.Gonadotrophins

Prerequisites for gonadotrophin therapy Ovarian reserve must be present

Other (non-ovulatory) factors for infertility must be

ruled out. hMG (human menopausal gona ~ dotr0phin) is a

mixture of FSH and LH [Pergonal = FSH (75 ILl) + LH (75IU)].

Patient selection Hypogonadotrophic-hypogonadism Failed clomiphene

Dose schedule hMG stimulates follicular growth.: with'a variable

dose schedule starting with a Iow dose (1 ampule I.M/day) Stimulation is started any time from D2 to Ds of the

cycle and is continued for 7-10 days depending on theresponse.

Follicular growth is monitored with serumoestradiol estimation and follicular number and size aremeasured by transvaginal sonography (TVS).

Serum oestradiol level of 1000-1500 pg/ml(150-300 pg/mature follicle) and maximum folliculardiameter of 18-20 mm are optimum.

When this optimum levels are obtained $000-10000IU of hCG is administered I.M to induce ovulation. .'~

Endometdal thickness of 8-10 mm (as measured byTVS) on the day of hCG administration favours successfulimplantation.

Ovulation is expected to occur, approximately 36hours after the hCG administration.

Couple instructionCouple is advised for the timing of intercourse

or- insemination (ART) accordingly (see above).Patients with PCOS are more sensitive to hMG

stimulation. Purified FSH (metrodin) or highlypurified FSH (metrodin HP) or recombinant FSH(Gonal F, Recegon) have been used successfullyWith minimal :side effects.


13/26

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

during ~e utu t'J.. ~,-~ra~, in obese vatients with s ubclinical

hypothyroidism. (d) Elevated prolactin level with or without gala-ctorrhoea indicates abnormal GnP, H pulse secretion.

lhis causes ovulatory dysfunction, LPD or ameno-

,h0ea. Bromoeriptine (dopamine agonist) therapyI (see ?' 432) increases the ovarian' responsiveness' to

[ domipheue. Patients with normal or minimallyelevated prolactin when treated with bromocriptinezed clomiphene are fodnd to have increased preg-

prolactinaemic nancy.al cycles with ts) Hyperinsulinemia -- Patients with polycystic

varian disease (see p 421) are poor responders to11, 1o

d0miphene. Correction of their metabolic abnor-ea or amenorr, reality (see p 431) along with weight reduction givesLld be > 40 pg [ satisfactory result. Treatment with metformin isi 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) ispreferred 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 I


Appropriate surgery for pituitary prolactinomas

(see 13 4~2) Surgical removal of virilising or other function-ing.ovari~-~ or adrenal tumour (see p 356).

//Luteal phase defect (LPD)~' "/ Treatment

The following treatment may be of help in .theidiopathic groups:

Natural progesterone as vaginal suppositories1000 m~dailDLstarting from the day of ovula-

tion is effective. It should be continued until mensbegins. If mens fails to appear after 14 days, preg-

nancy test is to be done. If the test is positive, itshould 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 may-

be tried. It increases FSH which may improvefolliculogenesis and normal corpus luteum

formation with adequate production of progeste-rone. In refractory cases, IVF may be tried but o f

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

discrepancy is due to premature luteinisation, LPD,

Pre.existing or induced elevated androgens(b!'L in pCOS) during therapy may beecially

~'P ed b" dexamethasone 0.5 mg daily for 10


14/26

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 factorsThe 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 a nd damage, perfect haemostasis and minimal adhesion formation. Laparoscopic surgery gives thebest result.

Nylon may be used as a temporary splint to facilitate suturing the ends. It should be re moved 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 o r hydrocortisone may be employed to m'mimise adhesion formation. ~I

Table: 15.8: Tuboplasty operationAdhesiolysis(Salpingoovariolysis)

Separation or division of adhesions

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 calledterminal or 'cuff' at the abdominalostium. The eversion of the neoostium is maintained by few stitchesof 6-0 vicryl.

Tubo-tubalanastomosis

When the segment of thediseased tube or following tubectomy operation is resected and endto end anastomosis is done (fig.15.5).

Tubo-comualanastomosis

When there is cornual block, theremaining healthy tube is anastomused to the patent interstitial partof the tube.


Cannulation of the tube is done for proximal tubal obstruction. Probe is passed carefully under hysteroscopic guidance to overcome any ob struction. Cannulation and balloon t uboplasty when successful can avoid ART procedures which are expensive.Adjuvant therapy

~-djunctive procedures to improve the result of tubal surgery includeprophylactic 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 t he tubal lumen by medicated fluids passed transcervically through a cannula. The fluid contains anti biotic and hydrocortisone (Gentamicin 80 mg and de xamethasone 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-surgicaltechniques.

Factors for poor outcome following tuboplasty Dense pelvic adhesions Loss of fimbriae


15/26

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. EndometriosisIt 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 pre vents progression of the disease(for details see chap. 20).

Cervical factorCervical 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- teasto 300 m[o~ater~pr~..-----~z-~con'u~gen 1.2~7c~orally in the 'follicular phase.In proved cases ofCl. trachomatis orM. 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 spermpenetration. 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 s ubmu-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 preb/icrosurgiqa

, ~,luorne~ Myo

UnexplainedUnexplained 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 TherapyBecause of spo wait for sometim reproductive tectu IVF or GIFT is eqm

Combined fa,The faults dete( be treated simulb other'.

ASSISTETECE

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


16/26

Artificial insert Different methc ' IUI -- Intra Fallopian tu

~om the hos~ ~o from Phage.

)e improved by

orM. hominis

iA d3y.~ is to b~

teated, is over. Z, IVF or GIFT

tibodies in the n~d t ime 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 abnor-

JCD in uterine

titus (Fenton's aginal septum aprovement of

utation of the 'or c~al

correct third

n~i


Table 15.9' Attempt forpregnancy after infertility surgery

Npe of surgemj""- r~cal tubal anastomosis I MtcrOSU ~L

'""T"7. - -,,m,,/Metroplasty I My0rnec,~ ]

Interval6 weeks

6 months

6-12 months

Soon following surgery

3-6 months

"~dhesiolysis Soon followingI surgery

Unexplained infertilityUnexplained 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


17/26

IUI : WF-ET : GIFT ; ZIFT : POST : SUZI : ICSI

Intrauterine inseminationIn vitro fertilization and embryo transfer Gamete intra-Fallopian transferZygote intra-Fallopian transfer Peritoneal oocyte and sperm t ransfer Subzonal inseminationIntra-cytoplasmic sperm injection

TESEMESA

PESA

Methods of sperm recoveryTesticular sperm extractionMicro surgical epididymal sperm aspirationPercutaneous 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 t he 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.

TherapyBecause 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 factorThe 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 15.11Indications 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

TechniqueWashing, 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 notmore, Ferfilising capacity for Spermatozoa is for 24-48 hours. The procedure may be repeated


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' tab le 15.6).


18/26

Timing of IUIIn 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 ofcontrolled ovarian hyperstimulation (CCH) is required (see table

15.12).

Table 15.12Timing of IUI

Spontaneous cyclesCervical mucus study and BBT chart

IUI x 2, likelyon day 12 and

14

Clomiphene induced cyclesIUI - 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 follicleIUI 2,.follOwing 18 and 42 hours of hCG adminiktration

ResultsThe ,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 rateis 25-30 per centper cycle.

ARTIFICIAL (THERAPEUTIC)INSEMINATION DONOR (AID) /

When the semen cfa donor is used for insemi-

235

nation it is called t herapeutic 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 Rhtyping. Either fresh or frozen semen is used. The legal, psychological and religious aspects should be counselled before, its application.

ResultsA total of 3-6 cycles may have to be ut ilised 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 ovu m

retrieval.

Indications

The indications are listed in the table 15.13.

Table 15.13Indications of IVF

Tubal disease Unexplained infertility Endometriosis Male factor infertility Cervicalhostility

Failed ovulation induction

Patient selection (ideal)


19/26

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


20/26

236

Principal steps of an ART cycle1. Down regulation using GnRH a gonist.

2. Controlled ovarian hyperstimulation (COH) 3. Monitoringof follieul~r growth4. Oocyte retrieval

5. Fertilization in vitro (IVF, ICSI, GIFT)6. Transfer of gametes or e mbryos7. Luted support with progesterone

GnRH analogues for down regulation

Currently most ART procedures involvethe use of GnRH agonists (see ch. 30).

GnRH agonist therapy used for downregulafi.o-n of ~ituitary, giveshigher pregnancy rates.

GnRI-I agordst therapy iscontinued either subcutaneouslyor intranasally during thegonadotrophin treatment phase(see p 480).

GnRH antagonist~ are currentlytried along with gonadotrophinstimulation to prevent prematureLH surge or premature ovulation.

Cetrorelix and Ganirelix are the availabledrugs.Different schedules for GnRH agonist are available:

Long Follicular down regulation -- Whentherapy is started in the follicular phase ofprevious cycle.

11.

Long Lutealdown regu!atian (most commonlyused)

therapy is begun on D-21 of the previous cycle.Gonadotrophin stimulation is started following themenses (see chapter 30). Short protocol -- therapy is started in the

follicular phase (D-l) along with gonadotrophinstimulation. Ti'ds is also called 'flare' protocol,as gonadotrophin can work over the stimulatoryeffect of GnRH agordst.

Controlled Ovarian HypersUmulation (COH)

In the first case, Steptoe and Edwards (1978) achievedthe success from collecting the oocyte from a natural cycle,36'hours after the onset of LH surge. But subsequently, it hasbeen found that the success rate is much higher whenmore embryos are transferred which is onlypossible by COld. The other advantages ofinduction of superovulation are improvedcmalitv of the oocyte, timing of ovulationcan be controlled, stated to the personnelrevolved a~ exten~------~-~ed to all ~Tes

of ovulatory dysfuncti-~n. T"~ drugregimens used differ in each centre.Following drugs or combination of drugs arecommonly used.


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 growthCThe follicular growth response is monitored by ceryicalmucus studs, sono..~-%gm.~e measurement of the folliclesand serum oestradiol estimatLOn, 'commencing on the-Sthday of treatment cycle. When three or more follicles aregreater than 18 mm in diameter and serum E2 levels > 250

pg/ml/pef follicle, 5,000-10,000 IU of hCG is givenintramuscularly (36 hours prior to oocyte retrieval), hCGinduces oocyte maturationS/F!owever, if'the E2 level rises >2500 pg/ml, to m-mirrdse hyperstlmulation syndrome (see p482), hCG administration should be withheld. Thecomplication is mostly eliminated by the introduction ofGnRH analogues (see above).

Oocyte retrievalOocyte l:etrieval is done through vaginal route under

ultrasound guidance.~ith the development of vaginal

transducers, vaginal needle aspiration is d ne~36 hours afterC--'-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 s urrounded by a mass of cumulus cells. After recovery, the oocytesare 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

to 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 secondpolar body).(~perm density and motility are~-~e two most important criteria for successful IVF.;)rhe semen is collectedjust 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 aboutChapter 15: INFERTILITY I ii

lOO-

0 ~ ~ ~ 7 9 1'1 1'3 15Day of the treatment cycle

Fig. 15.6. Example of stimulated cycle in ART

~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 GIFTprocedure is to havediagnosis of pregnancy by estimation of 0-hCG normal Uterine tubes The indications are the same

TEXTBOOK

OF GYb2AECOLOGYChapter 15: fNFERTILITY I 239

1000-

60~

E 5O0'

o 300 E

(,o200-

Follicular HCG3~aspiratin

Human menopausalgondorrophins 1

ollicles

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 ovulationstimulation as well as the risk of ovarian hyper

risk of congenital malformation of the baby remainsinconclusive.

GAMETE INTRA FALLOPIAN TRANSFER (GIFT)

GIFT was first described by Asch and colleagues in1984. It is a more invasive and expensive proce-

(quantitative value) is possible.Result

The overall delivered pregnancy rate variesfrom 25-38 per cent per oocyte retrieval.

There is increased risk of abortion (18 percent), multiple pregnancy (30 per cent), ectopic (0.9per cent), law birth weight baby and prematurity.The

as that of IVF except the tubal factor. Best result is obtainedin unexplained infertility and the result is poor in malefactor abnormality.

The superovulation is done as in ['CF. Two hoursprior to ovum retrieval, semen specimen is obtained. Thesemen is washed and by a technique called 'swim-up', themost motile fraction of the sperm is obtained and used fortransfer.

stimulation (see p 482). ' dure than IVF but the result seems better than WF.


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Fig.15.7.Teclmiqueofintracytoplasmicsper

minjection(ICSI).

Theoocytesarecollectedfrom:

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).

The recipients must iaave oestrogen and progesterone tlierapies to prime the endometrium prior to embryoreplacement.

Embryos of 4;8 cell stage are transferred on 17-19th day of the

recipient's menstrual cycle.In agonadal women, exogenous steroids must be

continued at least for 10 weeks tlntil adequate hormones areavailable fi'om placenta. Oocytes and embryos can be

cryopreserved (at -196 under liquid nitrogen) forrestoration of fertility in future. Survival of cryopreservedembryo 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-formationsor birth defects. ICSI is often done due to male factors for

infertility and it eliminates the natural process of spermselection. It is not yet certain whether ICSI is associatedwith increased chromosomal abnormalities of theoff-spring.

Increased number of pregnancy loss, multiplepregnancy and ectopic pregnancy have been observed. Perinatal mortality and morbidity are high.

Ovarian hyperstimulation syndrome (see p 482) is arare but known health risk.

Psychological stress and anxiety of the couple aresevere. It is specially so when there is failure in thetreatment or witli a pregnancy loss.

PROGNOSIS OF INFERTILITYThe pregnancy rate within two years after the start of

investigation, ranges between 30-40 per cent. The rate ishowever, increased to about 50-60 per cent, if AID casesare included.

However, if pregnancy occurs theincreased chance of abortion, 5 times of ecperinatal mortality rate doubles.Adoption

Inspite of excellent advances in the fielmanagement, expectations are not always fumust understand the infertility factors, cosmanagement. End point of managemerealistically understood. Adoption is an alterncouples.

aby remains

}lAN

l colleaguestsive proce-;rthan WF. tile

unfer-

; is to havere the same

~st result ishe result is

Two hours sobtained. quecalled tesperm is

Thistechnique lisa suitablealternative ofGIFT whendefect lies inthe malefactor or incases offailed GiFT.Results aresimilar to

that of IVF. GIFT or ZIFT is avoided when tubalfactors for infertility are present.

MICROMANIPULATION Intracytoplasmic sperminjection (ICSI)

ICSI was first described by van Steirteghem andcolleagues in. Belgium (1992).Indications Azoospermia, severe oligospermia Sperm antibodiesinsemination (SUZI). ICSI is veW effective to reduce the

need of AID.Results

Ferfilisation rate is about 60-70 per cent. Pregnancyrate is 20-40 per cent per embryo-tran-sfer.

EMBRYO OR OOCYTE DONATIONindications 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 within1 year of regular m~protected coitus.

10 per cent remain infertile by the end of 2nd year.

In fully lactating women, pregnancy is unlikely up to10 weeks postpartum.

Male factor is responsible in 30-40 per cent, thefemale in 40-50 per cent, both in 10 per cent andunexplained in 10 per cent.

Common causes of male infertility include defectivespermatogenesis, obstruction of efferent duct, failureto deposit sperm high in vagina and error in seminalfluid (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 withdisturbed hypothalamo-pituitary-ovarian axis eitherprimary or secondary from thyroid or adrenaldysfunction (scheme - 1).

Luteal phase defect is observed with older'women,drug induced ovulation, elevated prolaetin, patientswith repeated pregnancy wastage, pelvicendometriosis, DUB and subclinicalhypothyroidism.

~- Serum progesterone more than 10 rig/mi on 8th postovulatory day indicates adequate luteal function.

~wo collected oocytes along with approximately200,000-500,000 motile sperm for each Fallopian tubp.are~n.a plastic tube container. It is then pass'"7'8-F~oughIaparoscope and inserted 4 cm into tbe distal end of theFallopian tube where the combination is injected.

ResultThe oiterall delivered pregnancy rate is as high as

30-40 per cent. However, some centres could not 'find anysignificant difference between the success rate of IVF-ETand GIFT.

ZYGOTE INTRAFALLOPIAN TRANSFER(ZIFT)

Zygote intra-Fallopian transfer was first describedby Devroey et al (1986).

~,~e placement of the zygote (following one day

Obstruction of efferent duct system (male) Congenitalabsence of vas (bilateral)

Failure of fertilisation in IVFo Unexplained infertility

Sperm is recovered from the ejaculate.Otherwise sperm is retrieved by TESE (testicularsperm. extraction) or by MESA (microsurgicalepididymal sperm aspiration) procedures.

Technique

One single spermatozoon or even a spermatid isinjected directly into the cytoplasm of an oocyte bymieropuncture of the zona pellucida. This procedureis carried out under a high quality inverted operatingmicroscope. Micropipette is used to hold the oocytewhile the spermatozoon is deposited inside theooplasm by an injecting pipette (see fig. 15.7).


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be done either through the abdominal ostium b----~ other mieromanipulation methods like subzonalA~arl'r--FGff~pe or through the uterine ostium underultrasonic guidance~

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GENETICFACTORS: Majority(50%) ofearlymiscarriages are duetochromosomalabnormality in theconceptus.Autosomal

trisomy istilecommonest(50%)cytogenetic

abnormality. Trisomyfor everychromosome exceptchromsome 1 hasbeenreported.The mostcommon

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 ahaploid number of chromosome e.g. 3n = 69 4al = 92. Triploidy is more common than tetraploidy). Monsomy constitutes 20% of all abortuses. Commonest ismonosomy X (45X). Structural chromosomal rearrangements are observed in 2-4% of abortuses. These includes translocation, deletion, inversion and ringformation. 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 placentationare not supported adequatelyl Deficient progesterone secretion from corpus lu)teum or poor endometriai response to progesterone is the cause. Thyroidabnormalities: 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 oracquired is one of tiie commonest cause of midtrimester and recurrent aborfi-o~n~-(2)-C-ongeni~al malformation of the uterus in the form ofbicornuate 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 irritabilityand contractility. (3) Uterine (fibr-oic!) specially of the submucous variety might be responsible not only for infertility but also for abortion. Thisis due to distortion or partial obliteration of the uterine cavity Other causes are: decreased vascularly at the implantation site, red degeneration offibroid and increased uteirne irritability. (4) Intra uterine adhesions (synechiae) interfere with implantation, placentation and fetal growth.

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 andfetal 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 theplacenta. 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 (seep. 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 containingforeign paternal antigens are not rejected by ti~e mother. Paternal human leukocyte antigen (HLA) sharing with the mother leads to diminishedfetal-maternal immunologic interaction and ultimately fetal rejection (abortion).

Maternal medical illness (seep. 262): Cyanotic heart disease, haemoglobinopathies are associated with early abortion.Antifetal antibodies: T helpercells and Natural Killer (N.K.) ceils when activated by Th-1 pathway produce abc)rtogenic cytokines (IL-l, '/-interferon). But Th-2 ce lls 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 butRh 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 incidenceof abortion.

PREMATURE RUPTURE OF THE MEMBRANES inevitably leads to 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 coag

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 es tablish.Cigarette smoking -- increases file risk due to formation of carboxy haemoglobin and decreased oxygen trshould be avoided or minimised during pregnancy. X-Irradiation and antineoplastic drugs are known to cause ablittle risk. Contraceptive agents -- IUD in situ increases ti~e risk whereas oral pills do not. Drugs, chemicals, noxianiline, lead, formaldehyde increase the risk. Miscellaneous -- Exposure to electro-magnetic radiation from viincrease 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 pithe exact cause of abortion. Too often, more than one factor is present. However, risk of abortion increases with incrabortions 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.

wh

sta

fro

CLThof

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 s pontaneously.

of in vih'o fertilisation) into'the fallopian tube can ICSI is found to be very effective compared to

HAEMORRHAGE IN EARLY PREGNANCY m

Second trimester: (1) Anatomic abnormalities -- (a) Cervical incompetence (congenital oracquired). (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 mayhave signs of life but is too small to survive.

Before 8 weeks: The ovum, surrounded by the villi with the decidual coverings, is expelledout intact. Sometimes, the external os fails to dilate so that the entire mass is accommodatedin 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 themembranes. A part of it may be partially separated with brisk haemOrrhage or remains totallyattached to the uterine wall.

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


23/26

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GENETIC FACTORS: Majority (50%) of early miscarriages are due to chromosomal abnormality in the conceptus. Autosomal trisomy is tilecommonest (50%) cytogenetic abnormality. Trisomy for every chromosome except chromsome 1 has been reported. The most common t risomy 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 ofchromosome 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 placentationare not supported adequatelyl Deficient progesterone secretion from corpus lu)teum or poor endometriai response to progesterone is the cause. Thyroidabnormalities: Overt hypothyroidism or hyperthyroidism are associated with increased fetal loss. Thyroid auto antibodies are often increased. Diabetesmellitus 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 oracquired is one of tiie commonest cause of midtrimester and recurrent aborfi-o~n~-(2)-C-ongeni~al malformation of the uterus in the form ofbicornuate 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 irritabilityand contractility. (3) Uterine (fibr-oic!) specially of the submucous variety might be responsible not only for infertility but also for abortion. Thisis due to distortion or partial obliteration of the uterine cavity Other causes are: decreased vascularly at the implantation site, red degeneration offibroid and increased uteirne irritability. (4) Intra uterine adhesions (synechiae) interfere with implantation, placentation and fetal growth.

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 andfetal 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 e ffective 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 theplacenta. 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 fetalhypoxia is the ultimate pathology (p. 343) to cause abortion.

Alloimmune disease (seep. 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 containingforeign paternal antigens are not rejected by ti~e mother. Paternal human leukocyte antigen (HLA) sharing with the mother leads to diminishedfetal-maternal immunologic interaction and ultimately fetal rejection (abortion).

Maternal medical illness (seep. 262): Cyanotic heart disease, haemoglobinopathies are associated with early abortion.Antifetal antibodies: T helpercells and Natural Killer (N.K.) ceils when activated by Th-1 pathway produce abc)rtogenic cytokines (IL-l, '/-interferon). But Th-2 ce lls 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 prRh incompatibility is a rare cause of death of the fetus before 28th week. Couple with group 'A' husband and grof abortion.

PREMATURE RUPTURE OF THE MEMBRANES inevitably leads to 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 coag

common cause.Some women who abort habitually may have normal pregnancies following marriage with a different man. ENVIRrelating to environmental factors are difficult to es tablish.

Cigarette smoking -- increases file risk due to formation of carboxy haemoglobin and decreased oxygen trshould be avoided or minimised during pregnancy. X-Irradiation and antineoplastic drugs are known to cause ablittle risk. Contraceptive agents -- IUD in situ increases ti~e risk whereas oral pills do not. Drugs, chemicals, noxianiline, lead, formaldehyde increase the risk. Miscellaneous -- Exposure to electro-magnetic radiation from vi

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 pithe exact cause of abortion. Too often, more than one factor is present. However, risk of abortion increases with incrabortions 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 progressimpossible.

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HAEMORRHAGE IN EARLY PREGNANCY m

Second trimester: (1) Anatomic abnormalities -- (a) Cervical incompetence (congenital oracquired). (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 mayhave signs of life but is too small to survive.

Before 8 weeks: The ovum, surrounded by the villi with the decidual coverings, is expelledout intact. Sometimes, the external os fails to dilate so that the entire mass is accommodatedin 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 themembranes. A part of it may be partially separated with brisk haemOrrhage or remains totallyattached to the uterine wall.

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


24/26

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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 followinghaemorrhage.

Pelvic examination should be done as gently as possible. (a) Speculum examination reveals bleeding if any, escapes through theexternal os. Any local lesion in the cervix may co-exist. (b) Digital examination reveals the closed external os (Fig. 15.2). The uterine sizecorresponds to the period of amenorrhoea. The uterus and cervix feel soft. Pelvic examination is avoided when ultrasonography isavailable (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 forimmunological 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 healthyfetus (see p. 625). (2) Observation of.fetal cardiac motion. With this there is 98% chance of continuation of pregnancy. (3) A blightedovum 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 h as 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 tpregnancy is impossible.

CLINICAL FEATURES: The patient, having the features of threatened abortion, develIncreased 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 interproducts of conception are felt (Fig. 15.2). On occasion, the features may develop quickly withoabortion. In the second trimester, however, it may start with rupture of the membranes or intlabour).

MANAGEMENT: The principles in the management are: (1) To take appropriate measuresTo accelerate the process of expulsion. (3) To maintain strict asepsis as outlined in conduction o

Generat measures: Excessive bleeding should b.e promptly controlled by a dministering m

and the size of the uterus is less than 12 weeks. The shock is corrected by intravenous fluid thera

Active Treatment: Before 12 weeks: (1) Dilatation and evacuation followed by curettage of the uterine

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 50

minute. If the fetus is expelled and the placenta is retained, it is removed by ovum forceps, ifseparated, digital separation followed by its evacuation is to be done under general anaesthesia. (2closed (suggestive of low implantation of placenta) -- evacuation of the uterus may have to be do

a (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 increasedfrequency 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.

DEFINITION: When the products of conception are expelled en masse, it is called complete abortion.

CLINICAL FEATURES: There is history of expulsion of a f

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