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IRA-International Journal of Applied Sciences
ISSN 2455-4499; Vol.03, Issue 03 (2016)
Institute of Research Advances
http://research-advances.org/index.php/IRAJAS
Risk of Recurrent Miscarriage in India and the
Effect of Paternal Age and Maternal Age
Yamini Sharad Pokale1, 2, Prashant Khadke 1
1 Department of Biotechnology,
Shri Jagdishprasad Jhabarmal Tibrewal University,
Jhunjhunu, Rajasthan, India.
2 Department of Cytogenetics,
PreventiNe Life Care Pvt Ltd., Mumbai, India.
DOI: http://dx.doi.org/10.21013/jas.v3.n3.p16
How to cite this paper:
Pokale, Y., & Khadke, P. (2016). Risk of Recurrent Miscarriage in India and the Effect
of Paternal Age and Maternal Age. IRA-International Journal of Applied Sciences (ISSN
2455-4499), 3(3). doi:http://dx.doi.org/10.21013/jas.v3.n3.p16
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loss caused due to the published content to any party.
IRA-International Journal of Applied Sciences
460
ABSTRACT
Background: A risk of miscarriage increases with increase in parental age. However
many studies investigate only the effect of maternal age. This study focused on both the
maternal age and paternal age effect on miscarriage.
Method: Couples with the pregnancy loss issue were studied with the age range 19 to 50
years. Maternal age and paternal age were analyzed together. The couples composed of
a women and man both aged 20-29 years were used as reference group.
Results: Universally the risk of miscarriage was found to be higher if the women age was
35 years or more and man with age was 40 years or more. But due to small sample size
this has not been proved in this study.
Conclusions: The risk of pregnancy loss increases if male and female partners are
having advanced age.
Keywords: recurrent miscarriage, parental age, age effect
Introduction
Recurrent miscarriage was initially defined as the loss of three or more clinically
recognized pregnancies spontaneously during early gestation. However, the modern
definition refers to the spontaneous loss of two or more consecutive pregnancies before
twenty weeks of gestation (Vanilla et al, 2015).
The average life expectancy is increasing with availability of modern technology. In
recent decades, women have been increasingly delaying the start of motherhood and the
same trend is also seen for men because of changes in marriage patterns, lots of
competition and carrier opportunities, changes in contraception use, social support, and
possibly with other factors (e.g. stress, pollutants, and smoking) which are responsible for
the increase in miscarriage rate. This trend has been observed in the worldwide and
across all groups in the population. The association between parental age and fertility has
been of significant interest to both modern and ancient scientists.
The study of age effect on human reproduction is complicated as numerous physiological
changes occurring in male and females, also environmental and socioeconomic
conditions influence the reproductive outcome. The purpose of this investigation was to
determine whether pregnancy outcome influenced by parental age.
Most common difficult reproductive event is spontaneous abortion, with up to 10% of
clinically documented conceptus are miscarried during the pregnancy (Nybo Anderson et
al, 2000). Chromosomal anomalies in the zygote may result from errors during
gametogenesis in either parent, during fertilization, or during the first cellular divisions of
the zygote and there are many more pregnancies that fail prior to being clinically
recognized. Only 30% of all conceptions result in a live birth. The risk of miscarriage is
30% after two previous losses and 35% after the third one (Imam et al,2011).
Most studies have concluded that women aged more than equal to 35 years have a higher
frequency of various adverse reproductive measures such as infertility, spontaneous
IRA-International Journal of Applied Sciences
461
abortion, pregnancy complications, congenital abnormalities than do younger women
(Nybo Anderson et al, 2000; Rochebrochard et al, 2002; Homan et al, 2007; Garrisi et al,
2009; Spandorfer et al, 1998; Fretts et al, 1995). About 30-40% men in reproductive age
group have quantitative or qualitative defects in sperm production (Dada et al, 2008).
Similarly spontaneous abortion could be caused by paternally inherited genetic mutation,
it may be more frequent with increasing paternal agebecause of continuous replication of
stem cells after puberty (Slama et al, 2005).
The effect of paternal age on pregnancy outcome following natural conception has been
investigated in population- based studies. In a study conducted by Slama et al. found that
the spontaneous abortion rate was significantly higher in women with male partners older
than 45 years compared to those whose partners were less than 25 years of age (Slama et
al, 2005). Kleinhaus et al. reported that partners of women 40 years or older had an
almost three-fold increase in spontaneous abortion compared to those women with a
partners 25 years old or younger.
Error in gametogenesis results in the chromosomally abnormal conceptions most
frequently compared to the post fertilization event. This study focused on both the
maternal age and paternal age effect on miscarriage.
MATERIALS AND METHODS
The first group with 400 individuals of 200 couples (age range 19 to 50), with the
history of more than two miscarriages and no live birth and as control group 200
individuals of 100 couples with one or more than one normal child (age range 20 to
50), recruited simultaneously during the study.
There was no occupational or environmental exposure to radiation (electromagnetic
radiation), high temperature, toxic chemicals such as insecticides and pesticides in
the patients or the controls.
Studies by Osborn et al, 2000 and Nybo Anderson et al, 2000 have shown no effect
of maternal age on spontaneous abortion between the age group 20-29 years.
Therefore in the present study 20-29 years age group is used as a reference for male
and female. Maternal age was divided into groups such as 20-29 years, 30-34 years,
35 - 39 years and 40-50 years. Paternal age was divided into groups such as 20-29
years, 30-34 years, 35 - 39 years and 40-50 years.
RESULT:
The women had a mean age of 29.3 years, ranging between 19 and 45 years. In the
control group, the mean age of women was 29.5 with a range from 20 to 45 years.
The mean number of abortion cases was ranging from 3 to 6. It was observed higher
frequency of couples in the group with 3 abortions (83.5%), followed by the group with 4
abortions (10.5%) (Table 1).
Table 2 shows the distribution of paternal and maternal age of couples in case group. Out
of 200 couples, 145 couples had had three abortions where male age was 40 years and
above where as female age was 35 years or below.
Table 3 shows the distribution of paternal and maternal age of couples in Case and
Control groups. Maximum i.e. 61 (30%) couples had males in the age range of 30-34
years and females in the age range 20-29 years. This was followed by 33 (16.5%) couples
with males ranging between 35-39 years and females ranging between 30-34 years. There
were 27 couples with males and females in the age range of 20-29 years.
IRA-International Journal of Applied Sciences
462
In control groups also, maximum i.e. 32 (32%) couples had males in the range 30-34
years and females in the range 20-29 years; while 15 (15%) couples had males in the
range 35-39 years and females in the range 30-34 years. The difference in the distribution
of couples in two groups was statistically insignificant with p-value of 0.4154 as per
Kolmogorov-Smirnov test.
Table 4 provides the distribution of couples according to number of abortions and age of
males and females. Out of 200 abortions, 168 (84%) couples had three abortions, while
32 (16%) had more than 3 abortions. In the three abortions category, majority i.e. 52
(31%) couples had males in the age range of 30-34 years and females in the range of 20-
29 years. This was followed by 30 (18%) couples with males in the age category of 35-39
years and females in the category of 30-34 years. There were 25 (15%) couples with both
males and females in the age range of 20-29 years and having 3 abortions.
In the more than 3 abortions category, maximum i.e. 9 (28%) couples had males in the
age range 30-34 years and females in the range 20-29 years; followed by 7 (22%) couples
with both males and females in the age range of 30-34 years.
Table 5 gives the distribution of major chromosomal abnormalities according to gender
and age criteria. In Case group, out of 200 couples, 4 (2%) males and 6 (3%) females had
abnormalities. In Control group, none of the couples showed any type of abnormalities.
The distribution of polymorphic individuals according to gender and age in two groups
has been shown in Table 6. In Case group, 14 (7%) males and 11 (5.5%) females showed
polymorphism; while in Control group, in 100 couples, 5 (5%) males and 3 (3%) females
indicated polymorphism.
The difference in the proportion of males with polymorphism in two groups was
statistically insignificant with p-value of 0.6752 (p>0.05) using two-sample test for
equality of proportions. Similarly, the difference in the proportion of females with
polymorphism in two groups was statistically insignificant with p-value of 0.4981
(p>0.05).
DISCUSSION:
The purpose of this investigation was to determine if pregnancy outcome influenced by
parental age.
In females, the number of oocytes decreases naturally through the process of atresia.
According to American Society for Reproductive Medicine guidlines, the maximum
complement of oocytes is 6-7 million and exists at 20 weeks of gestation in the female
fetus. The number of oocytes decreases to approximately 1-2 million oocytes at birth;
300,000-500,000 at puberty; 25,000 at age 37 years and 1,000 at age 51 years (ASRM
2014).
Several studies have shown an increase in the risk of spontaneous abortion in women age
35years or more than 35 years (Osborn et al,2000; Nybo Anderson et al, 2000). Study by
Rochebrochard et al., 2002 suggested that, among women older than 35 years of age, the
risk of spontaneous abortion was higher when the partner was age 40 years or older than
when he was age 35–39 years. Multiple logistic regression analysis study done by
Dominguez et al, 1991 showed that the maternal age begins to have an effect on
pregnancy only after the 35 years of age.
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463
Nybo Andersen et al., 2000 studied the risk of pregnancy loss according to maternal age
at conception which followed a j shaped curve, with a steep increase in curve after age of
35 years. More than one fifth of all pregnancies in 35 year old women resulted in fetal
loss, and at 42 years of age more than half of the intended pregnancies resulted in fetal
loss.
A study by Sartorelli et al, 2001 compared men aged 23-39 years with men aged 59-74
years and found a higher frequency of sperm chromosome abnormalities in older male.
Slotter et al, 2000 concludes that advancing male age is associated with a gradual and
significant increase in the risk of fathering children with various chromosomal defects.
The sexual activity declines with age hence it is complex to separate the consequence of
sexual behavior from age.
Advanced paternal age has been shown to result in adverse pregnancy outcome such as
miscarriage, preterm delivery, low birth weight, fetal death, birth defects includes
congenital heart disease, cleft lip, cleft palate, Achondroplasia etc (Bray et al.,2006). The
possible causes could be structural abnormalities in sperm chromosomes (eg. Reciprocal
translocations) and multiple genetic or chromosomal defects, single gene mutations.
There is threefold increase in DNA damage in sperm was found in men aged 36-57 years
compared to age less than 35 years (Bray et al, 2006; Templado et al, 2011; Jaleel &
Khan, 2013).
Occupation, smoking, environmental exposure are the responsible factors other than age
in males which influence the sperm quality and hence affects the pregnancy outcome.
Stress, infection, alcohol consumption, competitive sports may result in sperm DNA
fragmentation.
It is been said that the relation between spontaneous abortion is not only depend upon
maternal age and the gravidity of the pregnant women but also the interval between the
successive pregnancies. Therefore it is said that, couples who wish for a baby having a
challenge to maintain the relative safety of having a baby with 35 years age of mother
and to maintain the proper intervals between successive pregnancies.
It shows that couples who wish to reduce the risk of recurrent pregnancy loss must avoid
not to wait too long to start a family and must use various contraceptive methods to
enable the gaps between the successive pregnancies for a healthy reproductive life.
CONCLUSION:
This study showed a negative correlation between parental age and fertility in couples
experiencing recurrent miscarriages.
Controlling for parental age effect on pregnancy outcome, we were unable to show
significant effects of paternal age. So far no clear picture of the role of parental age effect
on pregnancy has emerged from this study. Our sample size was insufficient to reveal
effects of parental age, but our results can be understood as providing an upper boundary
of any adverse pregnancy outcome.
More research in large populations and converging evidence may enable us to find out
more about the mechanisms of parental age effect and their association between the
pregnancy losses.
IRA-International Journal of Applied Sciences
464
Hence older couples i.e. couples with female aged 35years or more and male aged 40
years or above should be informed that they have a high risk of miscarriage.
Couples who are planning for pregnancy need to counsel to increase the awareness about
the effect of age on fertility. Women older than 35 years who failed to conceive after 6
months of attempts should receive immediate evaluation and treatment to conceive.
Detection of genetic causes helps to inform the couples with the recurrent miscarriages
about the risk of transmitting genetic abnormalities that may affect the chance for
successful treatment, may affect the health of offspring and can help to guide treatment
options.
. Acknowledgment
The author thanks Mr. Abhimanyu Kumar and Mr. Sushil Singh of Preventi Ne Life Care
Pvt Ltd. for their involvement and support for the study.
References
1. Bulletti C, Flamigni C, et al. Reproductive failure due to spontaneous abortion
and recurrent miscarriage. Hum Reprod Update 1996;2:118–136
2. Nybo Andersen A, Wohlfahrt J, Christens P, Olsen J, Melbye M. Maternal age
and fetal loss: population based register linkage study.BMJ 2000;320;1708-1712.
3. Rochebrochard E, Thonneau P. Paternal age and maternal age are risk factors for
miscarriage; results of a multicentric European study. Human Reprod 2002.
17(6); 1649-1656.
4. Garrisi J, Colls P, Ferry K, Zheng X, Garrisi M, Munne S. Effect of infertility,
maternal age, and number of previous miscarriages on the outcome of
preimplantation genetic diagnosis for idiopathic recurrent pregnancy loss.
Fertility and Sterility.2009. 92(1):288-295
5. Spandorfer S, Avrech O, Colombero L, Palermo G, Rosenwaks Z. Effect of
parental age on fertilization and pregnancy characteristics in couples treated by
intracytoplasmic sperm injection. Hum Reprod. 1998. 13(2); 334-338.
6. Fretts RC, Schmittdiei J, McLean FH, Usher RH, Goldman MB. Increased
maternal age and the risk of fetal death. The New England Journal of
Medicine.1995. 333(15):953-957
7. Vanilla S, Dayanand C, Kotur P, Kutty M, Vegi P. Evidence of Paternal N5, N10
- Methylenetetrahydrofolate Reductase (MTHFR) C677T Gene Polymorphism in
Couples with Recurrent Spontaneous Abortions (RSAs) in Kolar District- A
South West of India.Journal of Clinical and Diagnostic Research 2015; 9(2): 15-
18
8. Slama R, Bouyer J, Windham G, Fenster L, Werwatz A, Swan S. Influence of
Paternal Age on the Risk of Spontaneous Abortion. Am J Epidemiol
2005;161:816–823
9. Homan G, Davies M, Norman R. The impact of lifestyle factors on reproductive
performance in the general population and those undergoing infertility treatment:
a review. Human Reproduction Update 2007, 13(3); 209–223.
10. Kleinhaus K, Perrin M, Friedlander Y,Paltiel O, Malaspina D, Harlap S. Paternal
Age and Spontaneous Abortion. Obstet Gynecol 2006;108:369–377
11. Osborn J, Cattaruzz M, Spinelli A. Risk of spontaneous abortion in Italy, 1978-
1995, and the effect of maternal age, gravidity, amrital status and education. Am
J Epidemoil.,2000. 151,98-105.
IRA-International Journal of Applied Sciences
465
12. V. Domìnguez, E. Calle, P. Ortega, P. Astasio, J. Valero De Bernabè, J. Rey
Calero Source: European Journal of Epidemiology, Vol. 7, No. 2 (Mar., 1991),
pp. 171-174
13. Sloter E, Marchetti F, Eskenazi B, Weldon R, Nath J, Cabreros D, Wyrobek A.
Frequency of human sperm carrying structural aberrations of chromosome 1
increases with advancing age. Fertil Steril 2007;87:1077–86.
14. Sartorelli E, Mazzucatto L, De Pina Neto J. Effect of paternal age on human
sperm chromosomes. Fertil Steril. 2001.76;1119-1123
15. American society for reproductive medicine committee opinion no 589., Female
age-related fertility decline. Fertil Steril, 101(3):633-634(2014)
16. Jaleel R, Khan A. Paternal factors in spontaneous first trimester miscarriage. Pak
J Med Sci 2013;29(3):748-752.
17. Bray I, Gunnell D, Smith G.Advanced paternal age: How old is too old?. J
Epidemiol Community Health 2006;60:851–853.
18. Templado C, Donate A, Giraldo J, Bosch M, Estop A. Advanced age increases
chromosome structural abnormalities in human spermatozoa. European Journal
of Human Genetics (2011) 19, 145–151
19. Imam SN, Shamsi MB, Kumar K, Deka D, Dada R. Idiopathic Recurrent
Pregnancy Loss Role of Paternal Factors; A Pilot Study. J Reprod
Infertil.2011;12(4):267-276.
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466
(Figures and Tables)
TABLE 1- Number of Abortions of Women’s With History of Recurrent Miscarriage.
No of Abortions
No. of Couples
Percentage
3
167
83.5
4
21
10.5
5
10
5
6
2
1
Total
200
100
TABLE 2- Distribution of Couples According To Number of Abortions and Age Criteria For Males And Females In Case Group
Cases (couples=200)
Variable
Age category
F <= 35
F > 35
Total
Abortions
3
M <= 40
145
8
153
M > 40
11
3
14
Total
156
11
167
>3
M <= 40
27
1
28
M > 40
2
3
5
Total
29
4
33
IRA-International Journal of Applied Sciences
467
TABLE 3- Distribution Of Couples According To Age Criteria For Males And Females In Two Groups
Case (couples=200)
Control (couples=100)
Maternal age (year)
→
20 - 29
30 - 34
35 - 39
>= 40
20 - 29
30 - 34
35 - 39
>= 40
Paternal age (year)
20 – 29
27
0
0
0
8
0
0
0
30 – 34
61
19
2
0
32
18
1
0
35 – 39
16
33
15
0
9
15
5
0
>= 40
3
11
11
2
0
4
5
3
TABLE 4-Distribution of Couples According To Number of Abortions and Age Criteria for Males and Females In Case Group (n=200)
Variable
Maternal age →
20 - 29
30 - 34
35 - 39
>= 40
Abortions
Paternal age
3
(n=168)
20 - 29
25
0
0
0
30 - 34
52
12
1
0
35 - 39
15
30
11
0
>= 40
3
10
8
1
> 3
(n=32)
20 - 29
2
0
0
0
30 - 34
9
7
1
0
35 - 39
1
3
4
0
>= 40
0
1
3
1
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468
TABLE 5-Distribution of Abnormalities According To Gender and Age Criteria In Two Groups
Abnormality
Age category
Cases
(n=200)
Control
(n=100)
Males
20 - 29
0
0
30 - 34
1 (0.5%)
0
35 - 39
1 (0.5%)
0
>= 40
2 (1%)
0
Total
4 (2%)
0
Females
20 - 29
4 (2%)
0
30 - 34
0
0
35 - 39
2 (1%)
0
>= 40
0
0
Total
6 (3%)
0
TABLE 6- Distribution Of Polymorphic Variation According To Gender And Age In Study Subjects.
Polymorphic
variation
Age category
Cases
(n=200)
Control
(n=100)
Males
20 – 29
1 (0.5%)
0
30 – 34
6 (3%)
4 (4%)
35 – 39
6 (3%)
1 (1%)
>= 40
1 (0.5%)
0
Total
14 (7%)
5 (5%)
Females
20 – 29
6 (3%)
0
30 – 34
2 (1%)
1 (1%)
35 – 39
2 (1%)
2 (2%)
>= 40
1 (0.5%)
0
Total
11 (5.5%)
3 (3%)