Repeated or late miscarriage When to investigate and what to look

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					 Repeated or late miscarriage: When to investigate and what to look for
Miscarriage and chance               The chance of                                                                           Table 4: Tests used in miscarriage
THE chance of miscarriage
increases steadily and               miscarriage                          TEST                                                      WHY IT IS DONE OR WHAT IT IS LOOKING FOR
strongly with age (table 2).         recurring is                         1. Women, on presentation, at any time of the ovarian (or menstrual) cycle
Women using no contracep-            otherwise higher                     FBC, blood group and agglutinins, serum                   General medical health
tion seem to pass from
normal fertility through a
                                     if the woman has                     creatinine, LFTs
                                                                          Thyroid function tests                                    Mild hyperthyroidism is more prone to cause infertility and miscarriage than mild
phase when conceptions mis-          not previously                                                                                 hypothyroidism
carry, often with normal             had a live birth.                    Antinuclear antibody, anticardiolipin antibody,           Screening for the antiphospholipid syndrome, either primary or secondary to SLE
karyotypes, before physio-                                                lupus inhibitor
logical sterility sets in (for                                            Serum gliadin antibodies (IgG, IgA) and                   Asymptomatic coeliac disease is an occasional (though not unequivocal) cause of
most women about a decade                                                 transglutaminase (or endomysial) antibodies               unexplained infertility or recurrent miscarriage
before menopause).                                                        Fasting plasma glucose                                    Preclinical diabetes; if raised, check fasting plasma insulin and test for PCOS
   The chance of miscarriage                                              Serum free testosterone, or free androgen index           Screen for PCOS; confirm with day 7-8 vaginal ultrasound (see below)
recurring is otherwise higher                                             Anti-TjA antibody (anti-PP1Pk)                            Uncommon but well-described cause of up to 13 first trimester miscarriages; a
if the woman has not previ-                                                                                                         haemolysin, and not necessarily revealed by a blood group and agglutinin screen
ously had a live birth (table                                             Serum copper and caeruloplasmin                           Wilson’s disease, a rare copper storage disorder, can present this way in young
3). It is also higher after a        products of conception               with recurrent miscarriage                                women
chromosomally normal mis-            (preferably all recovered            Thrombophilia screen (haematological)                     Test for protein S, protein C and activated protein C resistance. Not Medicare
carriage than after an aneu-         tissue should be sent in                                                                       rebateable without a history of a thrombotic event
ploid or polyploid miscar-           normal saline to the specialist      Thrombophilia PCR panel                                   Test for factor V Leiden, MTHFR C677T and A1298C, prothrombin G20210A
riage. Many causes of                pathology lab for dissection         Karyotype, peripheral blood, both partners                Balanced chromosomal translocation in either partner
subfertility also increase the       under magnification to
risk of miscarriage when             recover trophoblast from             Male partner
pregnancy does occur.                what will be abundant mater-         Karyotype, peripheral blood                               As above
   Most miscarriages happen          nal decidua). A specialist lab-      Sperm count, preferably with morphology                   Brings the male partner into the management. Look for a high rate of head or
before 12 weeks. Miscar-             oratory can also perform his-        assessment using "strict criteria"                        mid-piece defects. May be necessary to repeat test in acknowledged infertility lab
riages should therefore be           tological examination of the         Sperm chromatin structure assay                           Index of sperm head DNA damage (double stranded breaks)
investigated if:                     placental site, including lym-
■ Two or more miscarriages           phocyte immunocytochem-              2. Woman, day 2 of menstrual period or cycle
  occur without a live birth         istry to identify T cell and         Serum FSH, LH, oestradiol (E2)                            Reduced egg numbers: serum FSH >11 U/L
  in a woman younger than            NK cell subtypes.                                                                              PCOS: possible if LH:FSH (U/L) >2:1
  30 (recurrent miscar-                                                                                                             In either case, E2 >200pmol/L = more severe
  riage).                            Causes of miscarriage                                                                          In either case, correlate with day 7-8 ultrasound
■ Miscarriage complicates            and the tests that can be
  infertility, especially in         done before the next                 3. Woman, day 7-8 of menstrual cycle (or estimated one week before ovulation)
  older women.                       pregnancy                            Transvaginal ultrasound for uterine abnormalities …       Normal endometrium is >5mm thick and echolucent (thick echogenic endometrium
■ A late miscarriage occurs          Some tests can be done at                                                                      means hyperplasia or polyp; thin echogenic, maybe endometritis)
  (>14 weeks’ gestation).            any time of the ovarian or                                                                     Look for fibroids distorting the cavity, for uterine septum or bicornuate uterus
   If a miscarriage is               menstrual cycle, while others        … and to characterise the ovaries                         Follicles present in the ovary indicate the typical egg number achievable: many
inevitable in one of these           should be timed carefully.                                                                     peripheral follicles indicate PCOS; few follicles may indicate premenopause
patients, a karyotype should         Table 4 details available            Vaginal culture                                           Vaginosis — either Gardnerella vaginalis or other organismal overgrowth with loss
be performed on the fresh            tests.                                                                                         of lactobacillus
                                                                          Hysterosalpingogram                                       Unilateral hydrosalpinx or intrauterine adhesions. Consider test if
                                                                                                                                    ■ Previous difficult appendicectomy, other pelvic surgery or presence of
       Table 2: Percentage of women experiencing
              miscarriage at increasing age                                                                                           antichlamydial antibodies in serum
                                                                                                                                    ■ History of diminished periods after an intrauterine procedure
        Age               Average chance of clinical miscarriage
        <20                             12%
                                                                          4. Mid-luteal phase (day 21 of 28-day cycle)
        20-24                           13%
        25-29                           14%                               Serum progesterone                                        Screen for adequacy of ovulation
        30-34                           16%
                                                                          5. Premenstrual phase (12 days after ovulation)
        35-39                           19%
        40-42                           25%                               Premenstrual endometrial biopsy                           Check integrated action of almost two weeks of progesterone on decidualising the
        43 plus                         50%                                                                                         endometrium
                                                     3                    Premenstrual endometrial biopsy for                       Relative prevalence of cytotoxic T cells, uterine NK cells and peripheral NK cells on
 Data predominantly from Warburton and Fraser, 1964.
                                                                          lymphocyte subsets                                        immunocytochemistry

   Table 3: Effect of previous miscarriages and births                      CD = cluster of differentiation                                                         KEY
                                                                            MTHFR C677T and A1298C =
                   on miscarriage rate                                                                                 Entry level                                  Family practitioners with an interest in miscarriage
                                                                            loss-of-function polymorphisms of
 Chance of next pregnancy                 Previous       No                 5,10-methylenetetrahydrofolate
 miscarrying                              baby           previous           reductase                                  General obstetricians and                    Reproductive endocrinology and infertility
 (average across all ages)                               baby               NK = natural killer cell                   gynaecologists                               gynaecologists
 After one previous miscarriage           23%            20%                PCOS = polycystic ovary
                                                                                                                       Research interest in miscarriage
 After two previous miscarriages          28%            44%
                                                                            Prothrombin G20210A = a gain-of-
 After three previous miscarriages        33%            58%                function mutation that increases            The table is not intended to discourage the interested practitioner from moving deeper into the
 Source: Jansen (2003).                                                     prothrombin production                                                    spectrum of testing or interpretation.

 Author’s case study
WITH a menstrual cycle that could           frustrated her efforts to predict ovu-      becoming increasingly painful, her               Sophie’s mother had been one of              19.2, which might account for the
vary from 30 to 38 days, it was a           lation), Sophie’s partner, Max, read-       doctor referred her to a gynaecologist        eight children; her father had died             cycle irregularity, particularly as
few weeks before Sophie became              ily agreed to have a sperm count,           for a laparoscopy. The tubes were             of a heart attack at 48. They’d had             she exercised frequently and inten-
concerned about her missed period.          which showed reduced sperm motil-           open, the ovaries looked normal and           a miscarriage before Sophie’s older             sively. There was no tachycardia,
She was just 20. The positive preg-         ity but otherwise appeared reason-          some endometriosis on the uterosacral         sister was born; Sophie’s sister had            tremor or lid-lag to suggest thyro-
nancy test caused her and her partner       able.                                       ligaments was ablated by diathermy.           not put her own fertility to the test           toxicosis.
a great deal of anguish but, to their          During the next six months,                 Sophie was prescribed clomiphene,          yet.                                               Polycystic ovary syndrome was
relief, she miscarried.                     Sophie used a saliva-based micro-           although earlier measurements of                 After toying with the notion that            excluded as an alternative explana-
   The pill not only provided a more        scopic “ferning” test she had bought        serum progesterone a week after ovu-          clomiphene in some circumstances                tion for the long cycle (a day-2 serum
planned future as they married, it also     at the chemist to detect her preovu-        lation on home testing had shown              can make miscarriage more likely and            FSH was 4U/L, with no increase in
regulated her menstrual cycle and pro-      latory oestrogen rise. A visible ferning    levels above 35nmol/L, indicative of          that ovulatory irregularity itself also         the LH:FSH ratio, and the free
vided welcome respite from increas-         pattern of her dried saliva alerted her     positive, if irregular, ovulation. In the     can sometimes produce metabolically             androgen index was low). A day-8
ingly troublesome dysmenorrhoea.            to start testing for her LH peak with       second month after the laparoscopy,           or chromosomally defective oocytes, I           ultrasound showed abundant folli-
   By 24 Sophie’s thoughts had              a urine-based kit she bought at the         she conceived. However, seven weeks           felt these were possible but not con-           cles but not in the peripherally dis-
turned to children. When after a year       supermarket.                                from her last menstrual period she            vincing explanations and agreed with            tributed and similar-sized pattern
nothing had happened (other than a             When their efforts continued to be       miscarried before an ultrasound had           them to do a full workup.                       typical of PCOS. However, it did
return to irregular periods that again      thwarted and her periods were again         been scheduled.                                  Clinically Sophie had a BMI of                                        cont’d next page

                                                                                                                                                  22 August 2003 | Australian Doctor |   33

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Description: Repeated or late miscarriage When to investigate and what to look