Recurrent Spontaneous Abortions ( RSA )
Dr. Anil B. Jalan
MD DCH MCPS
Here I would like to discuss in brief , few aspects related to RSA. It is impossible to cover all the aspects . Interesed readers are requested to consult specialized textbooks and monographs.
Definition and Incidence :- Abortion is defined as the termination of pregnancy before 20 weeks of gestation.
15 - 20 % of all pregnancies will endup as early prenancy losses. These losses however, are those recognised pregnancies which are confirmed usually 4 to 5 weeks after conception. There is now evidence that the pregnancy loss rate before this period i.e., during the 2 to 3 weeks following conception, may be as high as 50 % .
Habitual abortion is traditionally classified as three or more consecutive abortions.
Clinical studies have shown that the risk of pregnancy loss after three previous losses is only 30 to 40 %.
A successful outcome after three consequent abortions can be expected to be 55 to 60 %. With a previous live birth, this rate can be as high as 70 % .
Clinical Facts :-
1. Spontaneous salvage rate in recurrent first trimester pregnancy loss is 55 to 70 percent.
2. Fifty percent of fertilised ova do not progress to a viable pregnancy.
3. Seventy percent of abortions in early pregnancy are due to chromosomal anomalies.
4. The frequency of both euploid ( normal ) and aneuploid ( abnormal ) abortuses increases with maternal age.
5. In normal women, the detection of fetal cardiac activity by ultrasonography assures a 95 percent chance of term delivery. This does not hold true in women with reurrent spontaneous abortion. The rate of loss in these women even after the detection of fetal cardiac activity is 4.5 times higher than the normal population .
Risk of recurrent early pregnancy loss :-
1. Women who have had at least one liveborn infant :-
a. with no prior fetal losses - recurrence risk is 12 % for the next pregnancy
b. With atleast 1 prior fetal loss - recurrence risk is 24 % for the next pregnancy
c. With two prior fetal losses - recurrence risk is 26 % for the next pregnancy
d. With three prior fetal losses - recurrence risk is 32 % for the next pregnancy
2. Women who have not had atleast one liveborn infant with 2 or more fetal losses - recurenece risk for the next pregnancy is 40 - 45 % .
FACTORS INVOLVED IN RECURRENT EARLY PREGNANCY LOSS :-
1. Genetic factors
2. Endocrine factors
3. Anatomic factors
4. Immunologic factors
5. Infectious factors
6. Environmental factors
Genetic Factors :- In these days of small planned families and late pregnancies because of career pressures, repetitive pregnancy losses leave the couple frustrated and looking for answers. In the quest of finding some nswer to the causation of repeated abortions , couple will run from piller to post. However it is important to realise that many a times etiology is difficult to ascertain in a particlar couple. A clear understanding and systematic approach only will solve the problem. Most of the times we come across some chromosomal anomaly in a couple. It must be borne in mind that there is practically no treatment for chromosomal anomalies. Is it important for the prenatal diagnosis.
It appears likely that the large number of chromosomally abnormal pregnancies will not be reduced for some time to come. Patients and physicians must be aware that some degree of reproductive loss is to be expected.
1. Balanced chromosome rearrangements have been found with an increased frequency in couple with recurrent early pregnancy wastage. Major chromosome abnormalities have been found in 4.8 to 5.5 percent of investigated couples ( see the Indian data given below ) .
Other abnormalities usually encountered include
2. sex chromosome mosaicism,
3. chromosome inversions, and
4. ring chromosomes.
Besides spontaeous abortions, these abnormalities are associated with a high risk of malformations and mental retardation.
The birth of a normal child before or in between the spontaneous abortions is not a reason to cancel this investigation. Portnoi et al found the highest rate of chromosome rearrangement in couples who have had abortions and a normal child.
While investigating infertile women, Wramsby et al found a high proportion ( nearly 50 % ) of oocytes recovered from preovulatory follicles, with an abmnormal karyotype. Extrapolation of this fact to normal fertile women may give a false high rate of abnormal karyotypes as a cause of abortions.
If a couple has had a malformed infant or fetus in addition to abortions, karyotyping takes on more significance. Undetectabe single gene defects. Patients who fall into the category of unexplained repetitive pregnancy loss probably have this sort of single gene defect. Karyotyping of the abortus can give some direction to further treatment ( McDonough ). When the abortus has a normal complement of chromosomes ( euploid ), anatomical and endocrine causes must be looked for. If aneuploidy is documented, then timed insemination can be considered. This can be facilitated with documentation of ovulation with ultrasound ( follicular maturation studies ). Animal studies have shown that aged ovum and sperm have an increased risk of abnormal karyotype. In this situation, artificial donor insemination can also be offered as an alternative.
Karyotyping of the couple should be done when there is a history of two or more consecutive early pregnancy losses, or if there has been a history of an abnormal feotus or infant in addition to abortion.
Chromosomal abnormalities considered to be significant and contributing to RSA are as follows :- ( following data is a pooled data from various studies on spontaneous abortions ) :-
1. Normal 46 XY or 46 XX. 54.1 %
2. Triploidy 7.7 %
a. 69 , XXX ( 2.7 % )
b. 69 , XYX ( 0.2 % )
c. 69 , XXY ( 4.0 % )
d. Other ( 0.8 % )
3. Tetraploidy 2.6 %
a. 92 , XXXX ( 1.5 % )
b. 92 , XXYY ( 0.55 % )
c. Others ( 0.55 % )
4. Monosomy X 8.6 %
5. Structural abnormalities 1.5 %
6. Sex Chromosal polysomy 0.2 %
a. 47 , XXX ( 0.05 % )
b. 47 , XXY ( 0.15 % )
7. Autosomal monosomy ( G ) 0.1 %
8. Autosomal Trisomy 22.3 %
a. Chromosome no. 1 0 %
b. Chromosome no. 2 1.11 %
c. Chromosome no. 3 0.25 %
d. Chromosome no. 4 0.64 %
e. Chromosome no. 5 0.04 %
f. Chromosome no. 6 0.14 %
g. Chromosome no. 7 0.89 %
h. Chromosome no. 8 0.79 %
i. Chromosome no. 9 0.72 %
j. Chromosome no. 10 0.36 %
k. Chromosome no. 11 0.04 %
l. Chromosome no. 12 0.18 %
m. Chromosome no. 13 1.07 %
n. Chromosome no. 14 0.82 %
o. Chromosome no. 15 1.68 %
p. Chromosome no. 16 7.27 %
q. Chromosome no. 17 0.18 %
r. Chromosome no. 18 1.15 %
s. Chromosome no. 19 0.01 %
t. Chromosome no. 20 0.61 %
u. Chromosome no. 21 2.11 %
v. Chromosome no. 22 2.26 %
9. Double Trisomy 0.7 %
10. Mosaic Trisomy 1.3 %
11. Other abnormalities 0.9 %
Above picture is from karyotyping of abortuses. However most ofthe times in Indian situation we still do not have the abortus material available for chromosomal studies . Aortus studies would pickup chromosomal abnormalities in approximately 40 - 50 % of cases as against this we have parental karyotyping , where the pickup rate is not above 6 % in a couple.
Ideally we must do chromosomal studies on abortus , and both husband and wife. Abortus study is more likely to be contributory as far as cause for that abortion is concerned , howevere in recurrent abortions , the recurrence risk may me more realistically assessed if we do the chromosomal studies of both husband and wife.
There are certain chromosomal abnormalities seen in couple which are considered to be significant cause of RSA.
1. Numerical abnormalities
a. 45 , X / 46 , XX
b. 45 , X / 46 , XY
c. 46 , XX / 47, XXX
d. 46 , XY / 47 , XY + fragment
2. Structural abnormalities ( there are many structural anomalies , which are beyond the scope of this article ) .
3. Variants ( doubtful as far as the causation of RSA is concerned )
a. Inversion 9
b. 1 qh +
c. 9 qh +
d. 9 qh + & Y q +
e. 16 qh + inversion 9
f. 14 p +
g. 15 p +
h. markers
i. 14 ss
j. 15 ss
k. 22 p +
l. Y q +
m. Y q - ( pat )
n. Y q + & 15 ss
o. Inversion Y
p. fragile sites 3 p 14 & 6 q
4. Translocation
a. Robertsonian translocation
b. Reciprocal translocation
c. Multiple translocation
There are many Indian studies on karyopyte of couple with RSA. Here I would like to quote a few :-
1. Z. M. Patel et.al. 1996 :- reported 874 cytogenic studies performed on 437 couples experiencing 2 or more spontaneous abortions in first trimester .The overall abnormality rate was 5.8%. However exclusion of those variants , not generally accepted as being casual in spontaneous abortions leaves an abnormality rate of only 1.72 %. Balanced translocation was detected in only 10 cases out of 874 (0.9%) ; of these 8 were reciprocal and commonly found amongst women. Chromosomal variants were frequently seen in males.
2. Manorama Thomas et.al. 1998 :- described cytogenetic studies in 1725 individuals ( Couples + Individuals ) .
Total no. of chromosomal abnormalities 69 ( 4.0 % )
i. numerical abnormalities were 11 ( 15.94 % )
ii. structural abnormalities were 22 ( 31.88 % )
iii. invesrsions were 6 ( 8.70 % )
iv. Total 39 ( 2.26 % )
v. Y q + 13 ( 18.84 %)
vi. Other Variants 17 ( 24.64 %)
3. M.H.Panthaki et.al. 1999 :- described the cytogenetic findings in 174 couples & 6 single female patients , who were habitual aborters. The numerical abnormalities observed were 46, XY / 47, XXY ( 98 % : 2.0 % ) and 47, XXX. The structural abnormalities observed were 46, XY,t (1;16) (p22;p13), 46 , XY , t (2 ;13) ( p 21 ; q 34) , 46 , XX , t (4 ; 6) ( q 31 ; q 21). Among the chromosomal variations, an interesting finding was a fragile chromosome 16 present in 15% of the metaphases along with normal 46, XX cell line.
RSA and Y q + :- Patil and Lubs ( 1977 ) and Nielson ( 1978 ) studied the ??hromosome in 4,400 and 5,761 individuals respectively and suggested that : Yq+ in the father carried an increased risk of abortion . Dewald ( 1986 ) and De Braekleer (1990) in their studies of over 22,000 individuals found ???t siginificant (4, 13). Present study showed 13 individuals with Yq+ among 870 males. It is difficult to infer that these give increased risk of abortion or not. There are a few reports on premature condensation of chromosomes in RSA . Other variations like Heterochromatin polymorphism , Fragile sites, Markers , Fragmens , Satellites and p+ have not been found significant. Also single cell aberrations were found t o be of no consequence. ( 2 ) .
Translocation carriers males and females :- In males translocations may lead to spermatogenetic arrest therefore they could be sterile. If the male is a balanced carrier potential aneuploid viability is rare. This leads to a lower detection of translocation in male. Females even with multiple translocation have children with normal and abnormal chromosomes. However, the risk of having an abnormal child if the female is a carrier is much higher than if a male is a carrier. ( 17, 18, 19, 20 ). Study of sperm chromosome showed no significant difference between the effected and controlled groups for the total rates of aneuploidy and structural anomaly. However, the level of chromosome breaks and acentric fragments were significantly higher in the abortion group. ( 21 ).
Suggested investigations for Recurrent early foetal losses. :-
Karyotype of the abortus if available .
1. Hysterosalpingogram - to rule out anatomic causes.
2. Karyotyping of both parents - to rule out genetic factors.
3. Activated partial thrombolastin time ( aPPT ) and anticardiolipin antibody titer - to rule out immunological factors.
4. T 3 , T 4 & TSH screen for thyoid disease - in suspected cases of hypothyroidism. Thyroid antibodies ATA , AMA in certain cases.
5. Metabolic screening of mother for certain clinically unrecognosed metabolic disorders disorders like -
a. Diabetes mellitus
b. Phenylketonuria
c. Tyrosinemia
d. Homocystinuria
e. Galactosemia
f. Biotinidase deficiency
Conclusions :- Genetic causes of RSA is over 90 % , other causes of RSA should be ruled out before genetic investigations . As far as possible test couples not individuals. Couples with 2 or more abortions, couples with one abortion, with a still born child or with a malformed child should be investi-gated. Prenatal diagnosis is indicated whenever there is a chromosomal ano-maly in the parent. Only major Chromosomal abnormality i.e, translocations, sex chromosomal mosaicism and, inversions, should be taken as abnormality causing abortions. Prenatal diagnosis in chromosomally normal couples is cont-roversial. Molecular studies should be done to find minute rearrangements. Preimplantation molecular studies in the future, could be used as a screening method , so far only one gene has been located , responsible for recurrent abortions at Xq 28. Role of Inborn erors of metabolism , especially Galactosemia , Phenylketonuria , Tyrosinemia and Homocystinuria , Biotinidase deficiency should always be kept in mind. If we have an index case ( one affected child in the family ) , the diagnosis becomes easier other wise a systematic approach to IEM may be useful in certain cases with high index of suspicion.
Counselling and advise :- The obstetrician faced with a couple experiencing spontaneous abortion has several responsibilities . He or she must inform the couple ceoncerning the frequency of fetal wastage ( 12 - 20 % ) of recognised pregnancies , and its usual cause ( at least 50 % cytogenetic ) , provide recurrence risks , determine whether evaluation for repetitative abortion is necesary , and if so either perform the necessary evaluations or refer the patient to an appropriate centre. Those first trimester abortuses that do not show chromosomal abnormalities could still have undergone fetal demise from other genetic causes , either mendelian or polygenic / multifactorial .
The first obligation , education , can be fullfilled by summarizing the salient facts about RSA described above. Of relevance is the fact that spontaneous abption rates are positively correlated with advancing maternal age. Women over age 40 have twice the likelyhood of experiencing a fetal loss than women 2 decades younger. This increase is due to following reasons :-
1. Increase in embryos with trisomies
2. Cumulative exposure to toxins
3. Greater opportunity to acquire chronic infections
4. Diminished leutel response
5. Poorly vascualried endometrium
This fact of advancing age should also be discussed with couple and prenatal testing for chromosomal abnormalities ( trisomies etc. ) should be suggested.
References :-
1. Gita arjun , Recurrent Early Pregnancy Loss, An Introduction to Genetics and Fetal Medicine , editor Kamini Rao , pg. 27 - 30 .
2. Manorama Thomas , Cytogenetic basis of Recurrent abortions , Perinatology 1999, Vol. 1 ( 4 ) : 181 - 187.
3. Simpson and Golbus , Genetics of Pregnancy Losses , Genetics in Obstetric and Gynecology ; pg 181 - 200.
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