risk of first trimester spontaneous miscarriage among singleton gestations following icsi and its...

Middle East Fertility Society Journal (2013) xxx, xxx–xxx

Middle East Fertility Society

Middle East Fertility Society Journal

www.mefsjournal.orgwww.sciencedirect.com

ORIGINAL ARTICLE

Risk of first trimester spontaneous miscarriage

among singleton gestations following ICSI and its

relation to underlying cause of infertility

Wessam Magdi Abuelghara,*, Osama Saleh Elkady

a, Tarek Fathi. Tamara

a,

Mona Hassan Khalil b

a Obstetrics and Gynaecology Department, Ain-shams University, Cairo, Egyptb Obstetrics and Gynaecology Department, El Khazendara MOH Hospital, Cairo, Egypt

Received 16 April 2013; accepted 12 June 2013

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KEYWORDS

Miscarriage;

ICSI;

Infertility

bbreviations: BMI, body ma

tradiol; ET, embryo transfe

nRH, gonadotropin-releasin

nadotropin; ICSI, intracyto

rtilization; LH, luteinizing h

R, odds ratio; SD, standard

Corresponding author. Tel.:

mail address: dr.awessam@g

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Abstract Study objective: To assess the association between the first trimester miscarriage rates

among women undergoing intracytoplasmic sperm injection (ICSI) and underlying etiology of

infertility.

Design: Prospective cohort study.

Setting: Ain Shams University maternity hospital.

Materials and methods: The study included women who became pregnant with singleton preg-

nancy following ICSI as a treatment for different causes of infertility. Women were followed up

throughout the first trimester of pregnancy up to 12 weeks’ gestation (10 weeks after the day of

embryo transfer).

Main outcome measure: First trimester miscarriage rate.

Results: Two hundred and thirty four pregnant young women were included in the study, 164

(70.9%) women miscarried. The causes of infertility among these women were as follows: 41

(25%) mild male factor infertility, 40 (24.4%) severe male factor infertility, 45 (27.44%) tubal fac-

tor, 7 (4.27%) polycystic ovarian syndrome, 3 (1.83%) endometriosis, 20 (12.19%) unexplained and

CI, confidence interval; E2,

follicle stimulating hormone;

ne; hCG, human chorionic

perm injection; IVF, in vitro

LMP, last menstrual period;

7460679.

(W.M. Abuelghar).

dle East Fertility Society.

g by Elsevier

ng by Elsevier B.V. on behalf of Middle East Fertility Society.

.005

ghar WM et al. Risk of first trimester spontaneous miscarriage among singleton gestations following ICSIinfertility, Middle East Fertil Soc J (2013), http://dx.doi.org/10.1016/j.mefs.2013.06.005

mailto:[email protected]

http://dx.doi.org/10.1016/j.mefs.2013.06.005


http://www.sciencedirect.com/science/journal/11105690



2 W.M. Abuelghar et al.

Please cite this article in press as: Abueland its relation to underlying cause of

8 (4.87%) multifactorial. Stepwise logistic multi-regression analysis showed that both maternal age

(>31 years) and tubal block were the most sensitive discriminators for the prediction of first trimes-

ter spontaneous miscarriage among the study population (P < 0.01).

Major conclusions: First trimester spontaneous miscarriage rates among pregnant women with

singleton pregnancy following ICSI were related to maternal age >31 years and/or the presence

of tubal block.

� 2013 Production and hosting by Elsevier B.V. on behalf of Middle East Fertility Society.

1. Introduction

Miscarriage is the most frequent complication of pregnancyand it is assumed that fetal viability is only achieved in 30%of all pregnancies, 50% of which are lost prior to the first

missed period (1). Gestational age, maternal age, previous his-tory of miscarriage and smoking are the major risk factors formiscarriage (2).

ICSI (intracytoplasmic sperm injection) is a microscopicmaneuver used to facilitate fertilization by injecting a singlesperm directly into the oocyte (3). Achievement of pregnancyin ICSI cycles is a real confrontation to physicians as it is

the last and most advanced track in the management of infer-tility till now. Although there was a great advancement in thesuccess rate in the last few years, a range between 30% and

40% is never pleasing to both physicians and patients (4).Moreover, miscarriage meaningfully reduces the initial successand capability of ICSI treatment, increasing the psychological

grievance of patients (5). Since chromosomal aberrations (fre-quently aneuploidy) have been accounted for 50–75% of mis-carriages during the first trimester of gestation, one measurable

outcome to authenticate the safety of ICSI can be the rate ofmiscarriage among ICSI pregnancies (6). The differences inmiscarriage rates in ICSI are not completely understood andmay emanate from predisposing factors that are more preva-

lent in patients suffering from infertility (5). The aim of thecurrent work was to assess the association between underlyingetiology of infertility and first trimester miscarriage rates

among women who underwent intracytoplasmic sperm injec-tion (ICSI).

2. Materials and methods

The current prospective study was conducted at the assistedreproduction unit of Ain Shams University maternity hospitalfrom January 2009 to December 2011 and included young

pregnant women with singleton pregnancy, proved by trans-vaginal ultrasound, following ICSI as a treatment for differentcauses of infertility. Women were followed up throughout the

first trimester of pregnancy up to 12 weeks’ gestation (10 weeksafter the day of embryo transfer). All couples were thoroughlyinformed about the treatment procedures, and written in-formed consent was obtained from all women. The treatment

protocols were approved by the Ethics Committee of AinShams University maternity Hospital, Cairo, Egypt in accor-dance with local institutional research governance require-

ments. Couples who had frozen–thawed embryo transfers, ahistory of recurrent pregnancy failure (3 or more miscarriages),structural or numerical chromosomal aberrations were ex-

cluded. Women with any medical disorders and/or having con-genital malformation of the uterus were also excluded.

ghar WM et al. Risk of first trimestinfertility, Middle East Fertil Soc J

According to the underlying cause of infertility, all women

were categorized. Tubal factor diagnosis was confirmed byhysterosalpingography, and or pelvic laparoscopy and malefactor infertility was diagnosed by semen criteria meeting theWorld Health Organization (1999) criteria (7,8). Mild oligozo-

ospermia (1–19 · 106 sperm/ml) was considered as mild malefactor and severe oligozoospermia (<106 sperm/ml) was con-sidered as severe male factor. Polycystic ovary syndrome

(PCOS) was diagnosed according to Rotterdam criteria [2out of 3 from the following: 1. Oligo- or anovulation, 2. Clin-ical and/or biochemical signs of hyperandrogenism, 3. Polycys-

tic ovaries by transvaginal sonography (presence of 12 or morefollicles in each ovary measuring 2–9 mm in diameter, and/orincreased ovarian volume >10 ml)] (9). Endometriosis was

diagnosed by either the presence of endometrioma(s) by trans-vaginal ultrasound and/or the laparoscopic criteria of theAmerican Fertility Society classification (10). Infertility wasdiagnosed as unexplained if all of the following were within

normal: mid-luteal serum progesterone level for the detectionof ovulation, hysterosalpingography and/or laparoscopy fortubal patency and semen analysis (11). According to our local

institutional protocol, long mid-luteal protocol was applied inall cycles. Down regulation was done using gonadotropin-releasing hormone (GnRH) agonist (Decapeptyl� 0.1 mg, Fer-

ring, Switzerland) starting from day 17 of the previous cycle.GnRH agonist was taken as a single subcutaneous injection tillday two of the treatment cycle when the dose was reduced to

half the dose till the day of human chorionic gonadotropin(hCG) injection.

The induction of ovulation was done using gonadotropinhormones, 75 IU FSH, 75 IU LH (Merional�, IBSA, Switzer-

land), starting from cycle day two calculated according to age,weight and antral follicle count, then the dose was fashionedaccording to each patient’s response as monitored by follicul-

ometry. Embryo transfer had been carried for all cases on the3rd day post ovum pick up. After embryo-transfer, 100 mgintramuscular daily progesterone was given to all women for

8 weeks as a luteal phase support (Prontogest�, EIPICO forMarcyrl Pharmaceutical Industries, Egypt). Quantitative hCGwas done 2 weeks later to diagnose chemical pregnancy, andonce more after 48 h to ensure the doubling pattern, then trans-

vaginal ultrasound (TVUS) was performed 2 weeks after posi-tive pregnancy tests to confirm the presence of gestational sacwith fetal echo and pulsation and to exclude ectopic pregnancy.

Once more TVUS was performed at 12 weeks gestation to deter-mine the main outcome measure, early pregnancy failure.

The diagnosis of early pregnancy failure was based on the

findings of obstetric ultrasound examination(s). First trimestermissed miscarriage was defined as an intact gestational saclacking any fetal cardiac pulsation [6 weeks after last men-

strual period (LMP)], intrauterine gestational sac with the larg-est diameter more than 10 mm in the absence of yolk sac or an

er spontaneous miscarriage among singleton gestations following ICSI(2013), http://dx.doi.org/10.1016/j.mefs.2013.06.005


Figure 1 Participants flowchart.

Spontaneous miscarriage among singleton gestations following ICSI 3

empty gestational sac with a sure confirmed gestational age ofnot less than 6 weeks (12).

2.1. Sample size justification

The calculation of sample size was done using EpiInfo� ver-sion 6.0, setting the power (b) at 80% and significance level

(a) at 0.05. Data from a previous study, indicated that the rateof first trimester pregnancy loss was 18.8%, of them, theunderlying causes of infertility were male factor in 18.9%,

unexplained in 18.1%, tubal factor in 17.5%, endometriosisin 23.9% and PCOS in 24% (13). Accordingly, a sample sizeof 78 women was selected.

2.2. Statistical methods

The collected data were coded, tabulated, and statistically ana-lyzed using SPSS program (Statistical Package for Social Sci-

Please cite this article in press as: Abuelghar WM et al. Risk of first trimestand its relation to underlying cause of infertility, Middle East Fertil Soc J

ences) software version 17.0. Descriptive statistics were donefor numerical parametric data as mean ± SD (standard devia-tion), and for categorical data as number and percentage.

Inferential analyses were done for quantitative variables usingindependent t-tests in cases of two independent groups withparametric data. Inferential analyses were done for qualitative

data using Chi square test for categorical data. Logistic regres-sion model was used to find out independent factors affectingcertain conditions. The level of significance was taken at P va-

lue <0.05.

3. Results

As shown in figure 1, a total of 234 pregnant women aged635 years old who underwent ICSI as a treatment for differentcauses of infertility were included in the study. By the end of 12

weeks, 70 (29.91%) women were continuing pregnancy, whilethe remaining 164 (70.9%) had miscarried. Out of these 164



Table 1 Distribution of infertility causes among all included

pregnant women.

Etiology Number Percentage (%)

Male (mild) 56 23.9

Male (severe)* 50 21.4

Tubal obstruction 60 25.6

PCOS 14 6.0

EØ 8 3.4

Multi-factorial 18 7.7

Unexplained 28 12.0

* Severe oligozoospermia (<106 sperm/ml); PCOS, polycystic

ovary syndrome; EØ, endometriosis.

Table 2 Distribution of infertility causes among the studied

groups.

Continuing

pregnancy

group n = 70

Miscarriage

group

n = 164

Mild male factor 15 (21.42%) 41 (25%)

Severe male factor 10 (14.28%) 40 (24.4%)

Tubal block 15(21.42%) 45 (27.44%)

PCOS 7 (10%) 7 (4.27%)

EØ 5 (7.14%) 3 (1.83%)

Multi-factorial 10 (14.28%) 8 (4.87%)

Unexplained 8 (11.42%) 20 (12.19%)

Data are expressed as number and percentage.

PCOS, polycystic ovary syndrome; EØ, endometriosis.

Table 4 Stepwise logistic multi-regression analysis for predic-

tion of first trimester spontaneous miscarriage among singleton

gestations following ICSI.

OR 95% CI Risk

Min. Max.

Endometriosis 1.2911 0.2541 6.5595 No

Mild male factor 0.7536 0.3668 1.5485 No

PCOS 0.4618 0.1959 1.0885 No

Severe male factor 0.7003 0.3617 1.3559 No

Tubal block 2.1534 1.1483 4.0385 Positive

Unexplained infertility 1.0764 0.4499 2.5752 No

Age >31 3.222 1.8028 5.7592 Positive

OR, odds ratio; CI, confidence interval; PCOS, polycystic ovary

syndrome; Min, minimum; Max, maximum; ICSI, intracytoplasmic

sperm injection.


women, 41 (25%) had mild male factor, 40 (24.4%) had severemale factor, 45 (27.44%) had tubal factor, 7 (4.27%) had

PCOS, 3 (1.83%) had endometriosis, 20 (12.19%) had unex-plained infertility, 8 (4.87%) had multiple factors. Stepwise lo-gistic multi-regression analysis showed that maternal age

>31 years and the presence of tubal block were the most sen-sitive discriminators for the prediction of first trimester spon-taneous miscarriage among singleton gestations following

ICSI (P < 0.01). The mean age of included women was30.7 ± 3.8 years, the mean body mass index (BMI) was29.5 ± 5.2 kg/m2, and the mean duration of infertility was6.9 ± 4.3 years. 178 (76.1%) out of 234 women had primary

infertility, while the remaining 56 (23.9%) had secondary infer-

Table 3 Comparison between fates at 12 weeks as regards demogr

Continuing pregnancy group n= 70

Age (years) 29.9 ± 3.9

BMI (kg/m2) 28.6 ± 4.8

Duration of Marriage (years) 6.5 ± 4.1

Primary infertility 62 (88.6%)

Secondary infertility 8 (11.4%)

Previous Abortions 7 (10.0%)

Duration of infertility (years) 6.5 ± 4.1

Previous ICSI failure 11 (15.7%)

– Analysis using independent t-tests.� Analysis Chi square test; OR, odds ratio; CI, confidence interval.


tility. 36 (15.4%) had a previous obstetric history of 1 or 2 mis-carriages. Distribution of infertility causes among the allincluded pregnant women who underwent ICSI is shown in Ta-

ble 1. Distribution of infertility causes is shown in Table 2. Acomparison between fates at 12 weeks as regards demographiccharacteristics is shown in Table 3. Stepwise logistic multi-regres-sion analysis showed that both maternal age >31 years and tu-

bal block were the most sensitive discriminators for theprediction of first trimester spontaneous miscarriage among sin-gleton gestations following ICSI (P< 0.01) (Table 4).

4. Discussion

To the best of our knowledge, the current study is the first pro-

spective study that authenticates the risk of first trimesterspontaneous miscarriage among singleton gestations followingICSI and its relation to the underlying cause of infertility. The

current study concluded that the first trimester spontaneousmiscarriage rates among singleton gestations following ICSIwere affected by maternal age >31 years and the presence of

tubal block as causes of infertility. It has been postulated thatpregnancy outcomes following ICSI carry an increased risk ofchromosomal abnormalities (14). Nevertheless, those abnor-

malities appear to be linked to underlying parental risk factorsthat are more prevalent in patients suffering from infertilityand not to the process of ICSI itself (5).

aphic characteristics.

Miscarriage group n= 164 P OR (95% CI)

31.1 ± 3.8 0.026– –

29.8 ± 5.3 0.097– –

7.1 ± 4.4 0.311– –

116 (70.7%) 0.003� 3.21

48 (29.3%) (1.43–7.21)

29 (17.7%) 0.136� 3.21

(1.43–7.21)

7.0 ± 4.3 0.397– –

39 (23.8%) 0.168� 3.21

(1.43–7.21)



Spontaneous miscarriage among singleton gestations following ICSI 5

We reported that age and BMI were higher in the miscar-riage group when compared to the continuing pregnancygroup, but the difference was statistically significant only

regarding age. In agreement with the current study, previousstudies showed that the miscarriage risk increases with in-creased maternal age in women undergoing ICSI (15–17).

Moreover, another study concluded that the first trimester mis-carriage rates in singleton gestations achieved by ICSI were af-fected by maternal age. This study was done on 1244 women;

the mean age of included women was 32.1 ± 4.3 years (13). Inaddition, Homan et al., found that other possible causes ofinfertility in older women can be higher BMI (BMI knownto be increased with age) (18). Tian et al. reported that in

IVF, insulin resistance alone increases the risk of miscarriageindependently of BMI (19). Collectively, Lintsen et al., foundthat the female age of >35 years and overweight had a strong

harmful effect on the live birth rate after IVF (20).In our study primary infertility was more frequent in the

continuing pregnancy group 62/70 (88.6%) than in the miscar-

riage group 116/164 (70.7%). No significant difference wasfound between the two groups regarding duration of marriage,duration of infertility, having previous ICSI failure and/or mis-

carriage. Other investigators found that ongoing pregnancychances were higher than average with shorter duration ofinfertility and secondary versus primary infertility in ICSI asinfertility treatment (21).

According to our study we reported the highest rate of mis-carriage among the group of women with tubal block 45/60(75%). Stepwise logistic multi-regression analysis showed that

both maternal age >31 years and tubal block were the mostsensitive discriminators for the prediction of first trimesterspontaneous miscarriage among singleton gestations following

ICSI. To the best of our knowledge, the current study is thefirst to conclude that tubal block is the most sensitive predictorfor miscarriage following ICSI. Other investigators authenti-

cated the inferior outcome of the tubal factor after IVF andICSI when compared to unexplained infertility and concludedthat the unexplained infertility group had a lower first trimes-ter miscarriage rate and a higher pregnancy rate in the first

treatment cycle compared to the minimal endometriosis andtubal factor infertility group. However, this study did not in-clude the other factors of infertility; moreover the inferior out-

come of the tubal factor was surprising as IVF is considered tobe the best treatment for this type of infertility but, their datawere incomplete regarding smoking and clinical variants of

hydrosalpinx, this bias in data collection could affect their re-sults (22). In addition Johnson et al. reported that the miscar-riage rate of tubal factor patients was significantly higheramong women with tubal factor type of infertility compared

to male subfertility. On the other hand other investigatorsfound that the first trimester miscarriage rates following ICSIare not influenced by the underlying infertility cause including

tubal factor (13). In the current study, the highest rate of mis-carriage among the group of women with tubal block may beexplained by clinically undiagnosed types of hydrosalpinx

associated with tubal block which did not affect the pregnancyrate but lead to first trimester miscarriage. However, largestudies with a bigger sample size are needed to negate or vali-

date this suggestion. Many studies which correlate the cause ofinfertility to miscarriage rate after ICSI concluded that severemale factor infertility increases the incidence of miscarriagerate in ICSI (21,23). Though in our work the percentage of se-


vere male factor group to tubal block group was almost thesame (24.4%, 27.44% respectively) yet the stepwise logisticmulti-regression analysis showed that both maternal age

>31 years and tubal block were the most sensitive discrimina-tors for the prediction of first trimester spontaneous miscar-riage among singleton gestations following ICSI. These

results may be as we choose our end point to be 12 weeks ges-tation and did not analyze miscarriage at earlier points whichtheoretically relates more to genetic defects believed to be the

most prevalent in severe male factor infertility. The strengthof the current study is its prospective design, in addition, thecurrent study is the first that endorsed the possible associationbetween tubal block and first trimester spontaneous miscar-

riage among singleton gestations following ICSI. Limitationof the current study included relatively small sample size,although the sample size was statistically calculated. Another

limitation of the current study was the inability to find a causalassociation between first trimester spontaneous miscarriageamong singleton gestations following ICSI and tubal block.

This small sample size may explain the high rate of miscarriagein our work together with the early diagnosis of pregnancy.

5. Conclusion

First trimester spontaneous miscarriage rates among singletongestations following ICSI were affected by maternal age

>31 years and only tubal block as causes of infertility.

6. Conflict of interest

All authors declare that they have no conflict of interest orcommercial obligations in connection with this paper.

Acknowledgment

Many thanks to Dr. Mohamed Ibrahem Ellaithy for his kind

scientific advice and his valuable assistance in manuscriptrevision.

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