JOURNAL READING

Recurrent Pregnancy Loss in Patients with Polycystic Ovary

Syndrome: A Case Control Study

Disusun oleh :

ISNI AYU LESTARI

1610221008

Diajukan kepada :

dr. HARY PURWOKO, Sp. OG, KFER

Kepaniteraan Klinik Bagian Obstetrik dan Ginekologi

RSUD AMBARAWA

FAKULTAS KEDOKTERAN

UNIVERSITAS PEMBANGUNAN NASIONAL “VETERAN” JAKARTA

2018
 LEMBAR PENGESAHAN

Journal reading ini diajukan oleh :

Nama : Isni Ayu Lestari

NRP : 1610221008

Program Studi : Kepaniteraan Klinik Obstetrik dan Ginekologi

Judul : Recurrent Pregnancy Loss in Patients with Polycystic Ovary

Syndrome: A Case Control Study

Disetujui,

dr. Hary Purwoko, Sp.OG, KFER

Ditetapkan di : Ambarawa, Departemen Obstetrik dan Ginekologi

Tanggal presentasi : Januari 2018

Kehilangan Kehamilan berulang pada Pasien dengan
Sindrom Ovarium Polikistik: Studi Kontrol Kasus
Lulwa Ashaq1, Yousef Al Mazer1, Nourah Al Qahtani2

1
Adan Hospital, Al Ahmadi, Kuwait
2
Feto-Maternal Medicine, Immam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia

Abstark
Tujuan: Mengidentifikasi faktor biofisik dan hormonal yang berbeda yang dapat
menyebabkan hilangnya kehamilan berulang pada wanita Saudi yang telah
mengalami sindrom ovarium polikistik. Desain Studi: Studi kasus-kontrol.
Setting: Klinik Infertilitas Rumah Sakit Bersalin dan Anak di Dammam.
Kasus: pasien PCOS dengan keguguran berulang.
Kontrol: Pasien PCOS tanpa keguguran berulang.
Hasil: Prevalensi keguguran berulang pada pasien PCOS adalah 31%. Tidak ada
perbedaan yang signifikan antara kasus dan kontrol di usia 33,1 tahun dibandingkan
31,9 tahun, BMI, 31,4 kg / m2 dibandingkan 31,6 kg / m2. Tidak ada perbedaan
yang signifikan dalam keberhasilan hasil kehamilan pada kasus dan kontrol,
kelahiran rata-rata 84% berbanding 90%, persalinan prematur 10% berbanding 5%,
kehamilan kembar 6% berbanding 5%. Tidak ada perbedaan yang signifikan dalam
rasio hormonal (rasio prolaktin, LH, FSH, LH / FSH, TSH, progesteron,
testosteron) antara kasus dan kontrol. Tingkat serum estradiol secara signifikan
lebih rendah pada kasus dibandingkan kontrol, 55,5 pg / mL terhadap 83,9 pg / mL
masing-masing (p <0,01).
Kesimpulan: Pasien PCOS dengan kegugura berulang tidak mengalami
peningkatan yang signifikan pada usia, BMI, kehamilan prematur, kehamilan
multipel dan kehamilan ektopik. Rasio hormonal (prolaktin, LH, FSH, LH / FSH,
TSH, progesteron, testosteron) sebanding antara kasus dan kontrol, kecuali kadar
serum estradiol, yang secara signifikan lebih rendah pada pasien PCOS dengan
aborsi berulang.
Kata kunci : Ovarium polikistik, Abortus berulang
Pendahuluan:
Kehilangan kehamilan berulang secara klasik mengacu pada terjadinya tiga atau
lebih kehilangan secara berturut-turut kehamilan yang diakui secara klinis sebelum
minggu ke 20 kehamilan. Kehamilan ektopik, molar, dan biokimia tidak termasuk
[1]. Sekitar 15 persen wanita hamil mengalami kehilangan sporadis dari kehamilan
yang diakui secara klinis. Sekitar 2 persen wanita hamil mengalami dua kehilangan
kehamilan berturut-turut dan hanya 0,4 sampai 1 persen di antaranya memiliki tiga
kehilangan kehamilan berturut-turut [2].
Faktor risiko yang teridentifikasi untuk kehilangan kehamilan berulang termasuk
kerugian kehamilan sebelumnya, usia ibu lanjut, anomali rahim dan perlengketan,
cervical insufficiency (ketidakmampuan serviks uterus untuk mempertahankan
kehamilan pada trimester kedua, karena tidak adanya kontraksi rahim), penyakit
imunologis seperti sindrom antifosfolipid dan penyakit tiroid autoimun, kelainan
endokrin seperti diabetes melitus, sindrom ovarium polikistik, dan
hiperprolaktinemia. Meskipun dalam hampir lima puluh persen kasus, patofisiologi
tetap tidak diketahui, asosiasi klinis kehilangan kehamilan berulang dan sindrom
ovarium polikistik lebih dari biasanya [2].
Sindrom ovarium polikistik adalah kelainan endokrin yang biasanya muncul
dengan spektrum fitur klinis yang beragam, mulai dari anovulasi kronis dan
hiperandrogenisme, hingga morfologi ovarium polikistik pada ultrasound tanpa
kelainan menstruasi dan biokimia.
Tingkat kejadian antara sindrom ovarium polikistik dan kehilangan kehamilan
berulang masih belum pasti, karena variasi yang luas dalam penelitian yang
berbeda, berkisar antara 10 persen dalam penelitian baru-baru ini [3], dan sampai
80 persen di lain [4].
Selain itu, beberapa penelitian telah melaporkan bahwa wanita dengan sindrom
ovarium polikistik yang merupakan hormon luteinizing hypersecrete (LH) atau
yang hiperandrogenemia, berisiko mengalami keguguran setelah konsepsi spontan
atau asuhan [5], sementara peneliti lain tidak setuju [6].
Tujuan dari penelitian ini adalah untuk mengidentifikasi faktor biofisik dan
hormonal yang berbeda yang dapat menyebabkan hilangnya kehamilan berulang
pada wanita Saudi yang didiagnosis dengan sindrom ovarium polikistik.

Metode
Metode pada penelitiani adalah studi kasus-kontrol. Dilakukan di the Maternity
and Children Hospital (MCH), Dammam, Provinsi Timur, Arab Saudi. Ini adalah
rumah sakit bersalin utama di Provinsi Timur Arab Saudi. Jumlah pengiriman
sekitar 14.000 kelahiran setiap tahunnya. Bagian administrasi dan etika rumah sakit
menyetujui penelitian ini.
Pasien Saudi yang didiagnosis dengan sindrom ovarium polikistik dan mereka yang
diobati untuk kehilangan kehamilan berulang dan juga memiliki sindrom polikistik
ovarium yang dievaluasi.
Pasien yang menghadiri klinik infertilitas di bagian rawat jalan dari persalinan yang
disebutkan di atas telah didaftarkan. Kriteria eksklusi adalah wanita non-Saudi,
wanita lajang dengan PCOS, wanita menikah dengan nulipara, wanita dengan
anomali rahim, sindrom antifosfolipid (APS), atau wanita dengan penyakit kronis
yang dapat menyebabkan hilangnya kehamilan.
Pasien diidentifikasi dengan mencari database rekam medis untuk diagnosis PCOS,
pengukuran tubuh, paritas dan hasil kehamilan, dan kadar hormonal.

Pengumpulan data
Data dikumpulkan dari catatan medis pada buku kerja Excel 2011 yang dirancang
khusus (Microsoft Inc.).
Informasi diambil untuk variabel berikut: usia, tinggi badan, berat badan, indeks
massa tubuh, hasil paritas dan kehamilan, riwayat kehamilan ektopik dan molar,
dan kadar hormonal termasuk prolaktin, hormon luteinizing (LH), hormon
perangsang folikel (FSH), tiroid stimulating hormone (TSH), estradiol (E2),
progesteron, dan testosteron.
Analisis data
Variabel ini untuk pasien yang didiagnosis dengan PCOS dengan kehilangan
kehamilan berulang dibandingkan dengan kelompok kontrol wanita dengan PCOS
tanpa kehilangan kehamilan berulang.
Analisis statistik dilakukan dengan menggunakan situs statistik Excel 2011 dan
statistik sosial. Mean, median, mode, standard deviation, dan range, diukur. Untuk
data kontinyu, study t-test digunakan untuk membandingkan mean. Nilai p kurang
dari 0,05 dianggap signifikan.

Hasil
Sebanyak 148 wanita diidentifikasi sebagai PCOS. Empat puluh enam wanita
(31%) memiliki riwayat aborsi berulang, dan 102 wanita (69%) didiagnosis
menderita PCOS namun tanpa riwayat aborsi berulang.
Tabel 1 menunjukkan data demografis 46 pasien dengan PCOS dengan aborsi
berulang dan 102 kontrol.
Wanita dengan PCOS dengan aborsi berulang sedikit lebih tua daripada kontrol,
dengan usia rata-rata 33,1 tahun (21 - 50) dibandingkan dengan 31,9 tahun (21 -
47), namun hasilnya tidak signifikan secara statistik (p-value> 0,05 ).
Tinggi dan berat diukur untuk menghitung indeks massa tubuh (BMI). Tinggi rata-
rata 1,57 cm untuk kasus ini, dan 1,56 cm untuk kontrol, dan berat rata-rata adalah
78,4 kg untuk kasus tersebut, dan 77,9 kg untuk kontrol. Tidak ada perbedaan yang
signifikan dalam BMI antara kasus dan kontrol, 31,4 kg / m2 (16,8 - 47,1) dan 31,6
kg / m2 (17,0 - 49,1) masing-masing (p-value> 0,05).
Tabel 2 (a) membandingkan hasil paritas dan kehamilan pada kedua kasus dan
kontrol. Sebanyak 211 kehamilan diidentifikasi dalam kasus tersebut, dan 198
kehamilan diidentifikasi dalam kontrol.
Sebanyak 26/211 pengiriman (12%) diidentifikasi dalam kasus tersebut,
dibandingkan dengan 102/198 pengiriman jangka panjang (51%) pada kontrol (p-
value <0,05).
Tabel 1. Rata-rata data demografis (Rentang).
Kasus Kontrol P-Value
Nomor (n) 46 102 -
Usia (tahun) 33,1 (21-50) 31,9 (21-47) NS
Tinggi (m) 1,57 1,56 -
Berat (kg) 78,4 77,9 -
BMI (kg/m2) 31,4 (16,8-47,1) 21,6 (17,0-49,1) NS

Tabel 2. (a) hasil Paritas dan angka (Persentase); (b) nomor kehamilan yang
berhasil (Persentase).
(a)
Kasus (n) % Kontrol (n) % p-value
Term 26 -12,3 102 -51,5 <0,05
Preterm 3 -1,4 6 -3 NS
Twin 2 -0,9 6 -3 NS
Abortus 174 -82,4 77 -38,8 <0,001
Ektopik 3 -1,4 7 -3,5 NS
Molar 3 -1,4 0 0 -
Total 211 100% 198 100% 409

(b)
Kasus (n) % Kontrol (n) %
Term 26 -84 102 -90
Preterm 3 -10 6 -5
Twin 2 -6 6 -5
Total 31 100% 114 100%

Tidak ada peningkatan yang signifikan dalam persalinan prematur dalam kedua
kasus atau kontrol, 1,4% (3/211) dan 3% (6/198), dan tidak ada perbedaan yang
signifikan baik (p-value> 0,05).
Tidak ada peningkatan yang signifikan dalam tingkat kehamilan kembar pada kasus
dan kontrol, masing-masing 0,9% (2/211) dan 3% (6/198). Tidak ada perbedaan
yang signifikan baik (p-value> 0,05).
Sebanyak 174/211 aborsi (82%) diidentifikasi dalam kasus ini, dibandingkan
dengan 77/198 aborsi (38%) pada kontrol, dan sangat signifikan (p-value <0,001)
Prevalensi keseluruhan kehamilan ektopik di antara kasus dan kontrol adalah 2,4%
(10/409). Tingkat kehamilan ektopik dalam kasus dan kontrolnya adalah 1,4%
(3/211) dan 3,5% (7/198) per paritas total masing-masing. Tidak ada perbedaan
signifikan (p-value> 0,05). Tiga episode kehamilan molar diidentifikasi pada satu
pasien dalam kelompok kasus saja.

Tabel 2 (b) adalah subdivisi Tabel 2 (a) untuk menilai hasil dari keberhasilan
kehamilan. 84% (26/31) kasus dan 90% (102/114) kontrol memiliki kehamilan
atermal. Insiden persalinan prematur dua kali lipat dalam kasus yang dikompres
untuk kontrol, masing-masing 10% (3/31) versus 5% (6/114). Tingkat kehamilan
kembar serupa antara kasus dan kontrol dimana 6% (2/31) versus 5% (6/114) dalam
kasus dibandingkan dengan kontrol.

Tabel 3 membandingkan tingkat hormonal rata-rata antara kasus dan kontrol.

Tidak ada perbedaan bermakna pada tingkat prolaktin rata-rata antara kasus dan
kontrol, 16,7 (4,68 - 75,4) dan 17,7 (0,76 - 297) masing-masing (p-value> 0,05).
Tingkat hormon luteinizing (LH) adalah 7,18 (1,06 - 75,4) pada kasus
dibandingkan dengan 6,93 (1,29 - 26,2) pada kontrol. Hasilnya tidak signifikan
secara statistik (p-value> 0,05).
Tingkat FSH (Follicle-stimulating hormone) adalah 6,54 (0,75 - 16,2) dalam kasus
ini, dibandingkan dengan 6,24 (2,7 - 23,5) pada kontrol. Hasilnya tidak signifikan
secara statistik (p-value> 0,05). Selain itu, tidak ada perbedaan yang signifikan
dalam rasio LH / FSH antara kasus dan kontrol masing-masing, 1,29 dan 1,17 (p-
value> 0,05).
Tidak ada perbedaan bermakna pada tingkat thyroid-stimulating hormone (TSH)
antara kasus 2,57 (0,86 - 6,25), dan kontrol 2,48 (0,46-14,4) (p-value> 0,05).
Tingkat rata-rata estradiol (E2) sedikit lebih rendah dalam kasus dibandingkan
dengan kontrol, 55,5 (13,1 - 224) dan 83,9 (0,83 - 482). Perbedaannya secara
statistik signifikan (p-value <0,01). Koefisien korelasi Pearson untuk estradiol (R-
value) adalah -0.188.
Tingkat progesteron rata-rata adalah 11,04 (0,1 - 25,3) dalam kasus ini,
dibandingkan dengan 9,50
(0,1 - 35,8) pada kontrol. Perbedaannya tidak signifikan secara statistik (p-value>
0,05).

Tabel 3 Hormonal level (rata-rata)

Kasus Kontrol P-value
(rata-rata) (rata-rata)
Prlaktin (ng/mL) 16,7 (4,68-75,4) 17,7 (0,76-297) NS
LH (IU/L) 7,18 (1,60-28,2) 6,93 (1,29-26,2) NS
FSH (IU/L) 6,54 (0,75-16,2) 6,24 (2,7-23,5) NS
LH/FSH Rasio 1,29 0,145-6,86) 1,17 (0,247-4,93) NS
TSH (μIU/L) 2,57 (0,86-6,25) 2,48 (0,46-14,4) NS
Estradiol (pg/mL) 55,5 (13,1-224) 83,9 (0,46-14,4) <0,01
Progesterone (ng/mL) 11,04 (0,1-25,3) 9,5 (0,1-33,8) NS
Testosterone (ng/mL) 6,22 (0,23-38,9) 8,5 (0,08-126,4) NS

Tingkat testosteron rata-rata sedikit lebih rendah dalam kasus dibandingkan dengan
kontrol, 6,22 (023 - 58,9) dan 8,50 (0,08 - 126,4), namun perbedaannya tidak
signifikan secara statistik (p-value> 0,05).

Diskusi
Hubungan antara PCOS dan kehilangan kehamilan berulang telah dipelajari dalam
banyak literatur sejak beberapa dekade. Sebagian besar peneliti mempelajari PCOS
dan membandingkannya dengan kontrol normal. Dalam penelitian kami, kami
membagi wanita yang telah didiagnosis dengan PCOS menjadi dua kelompok,
PCOS dengan aborsi ulang dan PCOS tanpa aborsi berulang. Prevalensi aborsi
berulang bervariasi dalam literatur yang berbeda. Dalam sebuah penelitian
bersejarah oleh Sagle dkk, mereka melaporkan bahwa 80% wanita PCOS
mengalami kehilangan kehamilan berulang [4], sementara studi yang lebih baru
melaporkan prevalensi 30 sampai 40 persen [6]. Homburg dkk. mempelajari
prevalensi kehilangan kehamilan berulang di antara pasien PCOS dan non-PCOS
yang menjalani induksi ovulasi. Dia melaporkan prevalensi 33% di antara pasien
PCOS, dibandingkan dengan 10% pada wanita non-PCOS [6]. Rai et al. dan Banu
dkk. juga melaporkan prevalensi aborsi berulang 40% di antara wanita dengan
PCOS dibandingkan dengan kontrol normal [7] [8].
Dalam penelitian kami, kami menemukan prevalensi kehilangan kehamilan
berulang di antara wanita yang didiagnosis dengan PCOS menjadi 31%, hampir
mendekati sebagian besar laporan.
Usia ibu merupakan faktor penting untuk prediksi kemungkinan kehilangan
kehamilan. Sayangnya, kami tidak dapat menemukan banyak laporan yang
membandingkan usia ibu dengan dua kelompok PCOS dengan dan tanpa
kehilangan kehamilan berulang. Sebagian besar laporan mempelajari prevalensi
kehilangan kehamilan sehubungan dengan usia ibu lanjut usia. Literatur
melaporkan bahwa risiko meningkat secara signifikan setelah usia 35 tahun. Dalam
sebuah penelitian Skandinavia yang besar oleh Andersen dkk, mereka menemukan
bahwa wanita berusia di atas 35 tahun memiliki 25 persen risiko aborsi spontan [9].
McClure dkk. mempelajari hubungan tingkat serum estradiol, usia ibu, dan hasil
kehamilan pada pasien PCOS. Mereka menemukan bahwa peningkatan usia ibu
dikaitkan dengan tingkat estradiol serum yang lebih rendah, yang pada gilirannya,
secara signifikan terkait dengan keguguran berulang [10]. Dalam penelitian kami,
rata-rata usia ibu di bawah 35 tahun untuk kedua kasus dan kontrol. Selain itu, kami
tidak menemukan perbedaan signifikan dalam usia rata-rata antara kasus dan
kontrol, masing-masing 33,1 tahun dibandingkan 31,9 tahun.
Obesitas secara konklusif dikaitkan dengan peningkatan prevalensi keguguran, dan
obesitas jelas lebih umum terjadi pada pasien PCOS daripada kontrol normal [6].
Wang et al. menemukan bahwa tingkat keguguran spontan yang lebih tinggi pada
pasien PCOS disebabkan oleh prevalensi obesitas yang lebih tinggi [11]. Selain itu,
Boots dkk. menemukan bahwa wanita gemuk lebih rentan mengalami keguguran
euploid dibandingkan dengan kontrol non-obesitas [12]. Obesitas adalah temuan
umum pada wanita Saudi karena kebiasaan makan dan gaya hidup pribadi. Saat
Fakhoury dkk. membandingkan pasien PCOS dengan kontrol normal pada wanita
Saudi; Mereka menemukan kedua kelompok memiliki BMI di atas 25 kg / m2 [13].
Mirip dengan Fakhoury et al., Kami menemukan bahwa kedua kelompok kasus
PCOS dan kontrol memiliki BMI di atas 30 kg / m2. Di sisi lain, tidak ada
perbedaan yang signifikan dalam BMI antara kedua kelompok dimana 31,4 kg / m2
di antara kasus, dan 31,6 kg / m2 di antara kontrol.
Banyak peneliti telah mempelajari hasil obstetrik yang merugikan pada pasien
PCOS, terlepas dari kehilangan kehamilan. Dalam sebuah meta-analisis baru-baru
ini oleh Qin et al., Mereka menemukan bahwa pasien PCOS memiliki insidensi
hipertensi yang diinduksi kehamilan, diabetes gestasional, persalinan prematur, dan
seksio sesarea yang lebih tinggi [14]. Selain itu, Naver et al. melaporkan kejadian
kelahiran prematur dan pre-eklampsia berlipat ganda pada wanita hiper androgenik
dengan PCOS dibandingkan dengan PCOS normo-androgenik [15]. Dalam
penelitian kami, sebagian besar kasus dan kontrol yang disampaikan, memiliki
kehamilan rata-rata, 84 persen dibandingkan 90 persen. Di sisi lain, serupa dengan
yang diamati oleh Naver dkk, tingkat persalinan prematur di antara kasus tersebut
dua kali lipat kontrol, 10 persen dibanding 5 persen, masing-masing. Multiple
gestation adalah kemungkinan komplikasi induksi ovulasi sebagai pengobatan
siklus anovulasi pada pasien PCOS. Nahuis dkk. melaporkan kejadian kehamilan
kembar pada pasien PCOS dalam uji coba secara acak sebagai 5 persen setelah
diobati dengan elektrokauter laparoskopi, dan 8 persen setelah menerima FSH
rekombinan [16]. Selain itu, Zhao dkk. mempelajari hasil kehamilan setelah
pematangan in vitro dari oosit yang belum matang, dan menemukan peningkatan
yang signifikan pada kehamilan multipel hingga 30 persen, berat lahir rendah, dan
persalinan prematur [17]. Dalam penelitian kami, kami tidak menemukan
peningkatan yang signifikan dalam tingkat kelahiran kembar di kedua kasus atau
kontrol. Serupa dengan apa yang diamati oleh Nahuis dkk, tingkat kehamilan
kembar, dari persalinan yang berhasil, adalah sebanding dua kasus dan kontrol, 6
banding 5 persen. Ada beberapa laporan yang meneliti kejadian kehamilan ektopik
pada pasien PCOS. Wang et al. mempelajari kejadian kehamilan ektopik setelah
fertilisasi in vitro pada pasien PCOS, dan melaporkan peningkatan tiga kali lipat
kejadian kehamilan ektopik pada pasien PCOS dibandingkan dengan kontrol
normal khususnya setelah transfer embrio segar [18]. Dalam penelitian kami,
prevalensi kehamilan ektopik secara keseluruhan di antara kasus dan kontrol adalah
2,4 persen, yang sedikit lebih tinggi dari populasi umum, dua puluh per seribu [19].
Selain itu, kasus tersebut memiliki kejadian kehamilan ektopik yang sedikit lebih
tinggi daripada kontrol, 8 persen berbanding 6 persen. Ada 3 insiden kehamilan
mola pada satu pasien pada kelompok kasus.
Seperti diketahui sebelumnya, sindrom ovarium polikistik adalah kelainan endokrin
yang biasanya hadir dengan spektrum fitur klinis yang luas. Banyak literatur telah
mempelajari hubungan antara endokrinopati yang berbeda dan keguguran berulang
yang ada pada pasien PCOS dan non-PCOS. Sebagian besar peneliti mempelajari
efek hiperprolaktinemia, hipotiroidisme subklinis, hormon luteisasi dan hormon
perangsang folikel, tingkat progesteron abnormal, dan hiperandrogenisme. Dalam
penelitian kami, kami mengukur hormon ini, dan membandingkannya antara kasus
dan kontrol.
Banyak peneliti telah memperhatikan hubungan antara hiperprolaktinemia dan awal
kehamilan. Dalam percobaan terkontrol secara acak oleh Hirahara dkk, mereka
mengevaluasi efek hiperprolaktinemia terisolasi dalam patogenesis aborsi spontan
berulang. Mereka menemukan bahwa pemulihan tingkat prolaktin normal dengan
bromokriptin dikaitkan dengan peningkatan yang signifikan dalam hasil kehamilan,
dan menyimpulkan bahwa kadar timbal prolac yang sesuai dapat memainkan peran
penting dalam mempertahankan kehamilan dini, terutama pada kasus keguguran
berulang hiperprolaktinemia [20]. Di sisi lain, Li et al. menemukan bahwa tingkat
prolaktin serum basal yang rendah dikaitkan dengan hilangnya kehamilan dini [21].
Dalam penelitian kami, tingkat prolaktin serum rata-rata adalah antara kasus dan
kontrol, 16,7 ng / mL versus 17,7 ng / mL masing-masing, dan berada dalam batas
normal.
Luteinizing hormone (LH) dan follicle-stimulating hormone (FSH) memainkan
peran penting dalam sekresi hormonal, ovulasi, dan integritas endometrium. Ada
kontroversi antara literatur mengenai hubungan antara kadar gonadotropin yang
abnormal dan hasil kehamilan.
Sebelumnya diperkirakan bahwa peningkatan kadar hormon luteinizing pada pasien
PCOS dikaitkan dengan keguguran berulang [5]. Namun, banyak penelitian tidak
menemukan hubungan yang signifikan antara konsentrasi LH serum dan keguguran
ulang saat ini [10] [22] [23]. Dalam percobaan kontrol acak oleh Clifford dkk,
mereka menekan pelepasan LH pituitari dan mengamati pengaruhnya pada pasien
dengan kehilangan kehamilan berulang. Mereka menyimpulkan bahwa penekanan
hormon pre-pregnancy terhadap hormon hormon luteinizing tinggi pada wanita
ovulasi dengan keguguran berulang dan hipersekstensi hormon luteinizing tidak
memperbaiki hasil kehamilan [24]. Di sisi lain, beberapa literatur menemukan
hubungan yang signifikan antara peningkatan tingkat FSH hari ke 3 pada wanita
dengan keguguran berulang yang tidak jelas [25] [26]. Selain itu, Fakhoury dkk.
melaporkan peningkatan rasio LH / FSH pada pasien PCOS dibandingkan dengan
kontrol normal [13]. Dalam penelitian kami, kami tidak menemukan perbedaan
yang signifikan antara kasus dan kontrol mengenai rasio LH, FSH, dan rasio LH /
FSH, 7.18 IU / L versus 6,93 IU / L, 6,54 IU / L terhadap 6,24 IU / L, 1,29 versus
1,17 masing-masing.
Hormon tiroid sangat penting untuk metabolisme dan pertumbuhan janin normal.
Hipotiroidisme dianggap terkait dengan hilangnya kehamilan dini berulang. Dalam
sebuah penelitian oleh Jacob melibatkan seribu wanita, dia melaporkan bahwa
bahkan disfungsi tiroid ringan dapat sangat meningkatkan risiko masalah serius.
Wanita dengan disfungsi tiroid ringan memiliki dua kali lipat risiko keguguran,
persalinan pra-matang, dan berat lahir rendah dibandingkan dengan kontrol normal
[27]. Dalam penelitian kami, tidak ada perbedaan yang signifikan dalam tingkat
hormon tiroid-stimulating hormone (TSH) antara kasus dan kontrol, dan tidak ada
dugaan hipotiroidisme subclini-kal. Ada kontroversi dalam literatur mengenai
asosiasinya kadar serum estradiol dan kehilangan kehamilan saat ini. Gurbuz dkk.
dan Trout & Seifer melaporkan peningkatan kadar estradiol serum pada wanita
dengan kehilangan kehamilan berulang [25] [26]. Di sisi lain, McClure dkk.
menemukan bahwa pasien PCOS dengan kehilangan kehamilan berulang memiliki
tingkat estradiol serum yang lebih rendah [10]. Evrim dkk. ketika mempelajari
hubungan tingkat LH dan volume tiroid pada pasien PCOS, juga melaporkan
tingkat estradiol serum normal rendah pada pasien PCOS dibandingkan dengan
kontrol normal [28]. Mirip dengan McClure dkk. dan Evrim dkk., dalam penelitian
kami, kami menemukan bahwa pasien PCOS dengan aborsi berulang memiliki
tingkat estradiol serum normal yang lebih rendah dibandingkan PCOS tanpa aborsi
berulang, dan secara statistik signifikan. Selain itu, kadar serum estradiol
berkorelasi negatif dengan kejadian kehilangan kehamilan.
Hubungan antara progesteron serum dan kehilangan kehamilan berulang dipelajari
pada beberapa literatur, terakhir oleh Yan et al. yang menemukan pengukuran
progesteron serum midluteal tidak memprediksi hasil kehamilan berikutnya pada
wanita dengan keguguran berulang yang tidak dapat dijelaskan [29].
Beberapa literatur menemukan korelasi positif antara hiperandrogenemia dan aborsi
rekuren. Banu et al., Tulppala dkk., Dan Okon dkk, telah menemukan bahwa
peningkatan testosteron serum dan tingkat androgen lainnya dikaitkan dengan
hilangnya kehamilan rekursi pada pasien PCOS dan non-PCOS [8] [23] [30] . Di
sisi lain, Nardo dkk. dan Lathi dkk. tidak menemukan hubungan antara kadar
testosteron serum dan keguguran berulang pada pasien PCOS dan non-PCOS [22]
[31]. Dalam penelitian kami, kadar testosteron serum lebih tinggi pada kelompok
kontrol dibandingkan dengan kasus, dan perbedaannya tidak signifikan secara
statistik.
Beberapa peneliti mempelajari efek serum estradiol dan hasil kehamilan pada kasus
non-PCOS seperti wanita normal, kasus fertilisasi in-vitro (IVF), dan wanita yang
menjalani injeksi sperma intra-sitoplasma (ICSI). Dalam tiga penelitian yang
berbeda oleh Check et al., Takeuchi et al., Dan Aksoy dkk, tingkat serum estradiol
diukur pada wanita dengan riwayat aborsi yang tidak terjawab atau preg-nancy
embrio dan dibandingkan dengan kontrol normal. Semua penelitian ini menemukan
bahwa wanita dengan riwayat aborsi yang tidak terjawab memiliki tingkat estradiol
serum yang lebih rendah dibandingkan dengan kontrol normal [32] [33] [34].
Peneliti lain menemukan bahwa wanita dengan aborsi berulang memiliki tingkat
progesteron serum yang jauh lebih rendah dibandingkan dengan kontrol normal
[33] [34]. Dalam penelitian kami, kami tidak menemukan perbedaan yang
signifikan dalam kadar progesteron serum menjadi dua kasus dan kontrol.
Salah satu manifestasi terpenting PCOS adalah hiperandrogenisme, dan banyak
literatur mempelajari hubungan peningkatan androgen pada pasien PCOS dan hasil
kehamilan. Fujimoto dkk. dan Joo dkk. difokuskan pada efek kadar serum estradiol
dan hasil kehamilan pada kasus IVF. Fujimoto dkk. menemukan bahwa kadar
estradiol serum yang lebih tinggi dikaitkan dengan hasil kehamilan yang lebih baik,
sementara Joo et al. menemukan efek yang bergantung pada konsentrasi antara
serum estradiol dan hasil kehamilan [35] [36]. Ada dua penelitian oleh Rehman
dkk. mempelajari hubungan antara obesitas, kadar serum estradiol, dan hasil
kehamilan pada kasus ICSI. Mereka menemukan bahwa kadar estradiol serum yang
lebih rendah memiliki efek buruk pada hasil kehamilan, dan estradiol puncak tinggi
dengan pemeliharaan tingkat op-timal pada fase pertengahan luteal diperlukan
untuk implantasi sel telur yang telah dibuahi dan pencapaian kehamilan klinis [37]
[38]. Carranza-Lira dkk. dan Sa-lazar dan Calzada mengukur kadar serum estradiol
dan progesteron pada wanita dengan keguguran berulang disamping reseptor
endometrium untuk estrogen dan progesteron. Mereka menemukan bahwa reseptor
estrogen dan progesteron berada pada tingkat terendah di sitosol dan kompartemen
nuklir pada wanita dengan keguguran berulang dibandingkan dengan kontrol
normal [39] [40].
Keterbatasan dalam penelitian kami adalah ukuran sampel, dimana kami memiliki
46 kasus dan 102 kontrol selama periode yang diteliti. Selain itu,
dehydroepiandrosterone (DHEA) tidak diukur secara rutin dalam kasus atau
kontrol.

5. Kesimpulan
Pasien PCOS dengan aborsi berulang tidak mengalami peningkatan yang signifikan
dalam usia, BMI, kehamilan prematur, kehamilan multipel dan kehamilan ektopik.
Rasio hormonal (prolaktin, LH, FSH, LH / FSH, TSH, progesteron, testoste-rone)
dapat dibandingkan antara kasus dan kontrol, kecuali kadar estradiol serum, yang
secara signifikan lebih rendah pada pasien PCOS dengan aborsi berulang.

Recurrent Pregnancy Loss in Patients with
Polycystic Ovary Syndrome: A Case
Control Study
Lulwa Ashaq1, Yousef Al Mazer1, Nourah Al Qahtani2
1
Adan Hospital, Al Ahmadi, Kuwait
2
Feto-Maternal Medicine, Immam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
How to cite this paper: Ashaq, L., Al
Mazer, Y. and Al Qahtani, N. (2017) Re-
current Pregnancy Loss in Patients with
Polycystic Ovary Syndrome: A Case Con-
trol Study. Open Journal of Obstetrics and
Gynecology, 7, 1073-1085.
https://doi.org/10.4236/ojog.2017.711108
Received: August 27, 2017
Accepted: October 15, 2017
Published: October 18, 2017
Copyright © 2017 by authors and
Scientific Research Publishing Inc.
This work is licensed under the Creative
Commons Attribution International
License (CC BY 4.0).
http://creativecommons.org/licenses/by/4.0/
Open Access
DOI: 10.4236/ojog.2017.711108 Oct. 18, 2017
Open Journal of Obstetrics and Gynecology, 2017, 7, 1073-1085
http://www.scirp.org/journal/ojog
ISSN Online: 2160-8806
ISSN Print: 2160-8792
Abstract
Objectives: To identify different biophysical and hormonal factors that could
contribute to recurrent pregnancy loss in Saudi women who have been diag-
nosed with polycystic ovary syndrome. Study Design: Case-control study.
Settings: Infertility clinic in Dammam Maternity and Children Hospital. Cases:
PCOS patients with recurrent pregnancy loss. Controls: PCOS patients without
recurrent pregnancy loss. Results: The prevalence of recurrent abor-tion in
PCOS patients was 31%. There was no significant difference between the cases
2
and the controls in the age, 33.1 years versus 31.9 years, BMI, 31.4 kg/m
2
versus 31.6 kg/m respectively. There was no significant difference in the
successful pregnancies outcome in cases and controls, term deliveries 84%
versus 90%, preterm deliveries 10% versus 5%, twin pregnancy 6% versus 5%
respectively. There was no significant difference in the hormonal profile (pro-
lactin, LH, FSH, LH/FSH ratio, TSH, progesterone, testosterone) between cases
and controls. Serum estradiol level was significantly lower in the cases
compared to the controls, 55.5 pg/mL versus 83.9 pg/mL respectively (p <
0.01). Conclusion: PCOS patients with recurrent abortions had no significant
increase in the age, BMI, preterm pregnancy, multiple gestation and ectopic
pregnancy. The hormonal profile (prolactin, LH, FSH, LH/FSH ratio, TSH,
progesterone, testosterone) was comparable between the cases and the con-trols,
except for serum estradiol level, which was significantly lower in PCOS
patients with recurrent abortions.
Keywords
Polycystic Ovary, Recurrent Abortion
1073 Open Journal of Obstetrics and Gynecology
L. Ashaq et al.

1. Introduction
Recurrent pregnancy loss classically refers to the occurrence of three or more
consecutive losses of clinically recognised pregnancies prior to the 20th week of
gestation. Ectopic, molar, and biochemical pregnancies are not included [1].
Approximately 15 percent of pregnant women experience sporadic loss of a
clinically recognized pregnancy. About 2 percent of pregnant women experience
two consecutive pregnancy losses and only 0.4 to 1 percent of them have three
consecutive pregnancy losses [2].
Identified risk factors for recurrent pregnancy loss include previous pregnan-cy
loss, advanced maternal age, uterine anomalies and adhesions, cervical insuf-
ficiency, immunological diseases such as antiphospholipid syndrome and au-
toimmune thyroid disease, endocrine disorders such as diabetes mellitus, poly-
cystic ovary syndrome, and hyperprolactinemia. Although in almost fifty percent
of the cases the pathophysiology remains unknown, the clinical association of
recurrent pregnancy loss and polycystic ovary syndrome is more than common
[2].
Polycystic ovary syndrome is an endocrine disorder that typically presents with
a wide spectrum of clinical features, ranging from chronic anovulation and
hyperandrogenism, to polycystic ovaries morphology on ultrasound with no
menstrual or biochemical abnormality.
The incidence rate between polycystic ovary syndrome and recurrent preg-
nancy loss remains uncertain, due to a wide variation in different studies, ranged
from 10 percent in a recent study [3], and up to 80 percent in another [4].
In addition, some studies have reported that women with polycystic ovary
syndrome who either hypersecrete luteinizing hormone (LH) or who are hyper-
androgenemic, are at increased risk of miscarriage following spontaneous or as-
sisted conception [5], while other researchers disagreed [6].
The objective of this study was to identify different biophysical and hormonal
factors that could contribute to recurrent pregnancy loss in Saudi women diag-
nosed with polycystic ovary syndrome.

2. Methods
This was a case-control study. It was conducted in the Maternity and Children
Hospital (MCH), Dammam, Eastern Province, Saudi Arabia. This is the main
maternity hospital in the Eastern Province of Saudi Arabia. The total number of
deliveries is around 14,000 births each year. The hospital administration and ethics
and board committee approved this study.
Saudi patients diagnosed with polycystic ovary syndrome and those who were
being managed for recurrent pregnancy loss and also have polycystic ovary syn-
drome were evaluated.
Patients attending the infertility clinic in the outpatient department of the afore-
mentioned maternity were enrolled. The exclusion criteria were non-Saudi
women, single women with PCOS, married nulliparous women, women with

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 L. Ashaq et al.

uterine anomalies, antiphospholipid syndrome (APS), or women with chronic

diseases that could contribute to pregnancy loss.
The patients were identified by searching the medical records database for the
diagnosis of PCOS, body measurements, parity and pregnancy outcome, and
hormonal levels.

2.1. Data Collection

Data was collected from the medical records on a specifically designed Excel
2011 workbook (Microsoft Inc.).
Information was retrieved for the following variables: age, height, weight, body
mass index, parity and pregnancy outcome, history of ectopic and molar
pregnancy, and hormonal levels including prolactin, luteinizing hormone (LH),
follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), estra-diol
(E2), progesterone, and testosterone.

2.2. Data Analysis

These variables for patients diagnosed with PCOS with recurrent pregnancy loss
were compared with a control group of women with PCOS without recurrent
pregnancy loss.
Statistical analysis was carried out using Excel 2011 and social science statis-
tics website. The mean, median, mode, standard deviation, and range, were
measured. For the continuous data, student t-test was used to compare the means.
A p-value of less than 0.05 was considered significant.

3. Results
A total of 148 women were identified as PCOS. Forty-six women (31%) had a
history of recurrent abortions, and 102 women (69%) were diagnosed as PCOS
but without history of recurrent abortion.
Table 1 shows the demographic data of 46 patients with PCOS with recurrent
abortions and 102 controls.
Women with PCOS with recurrent abortions were slightly older than the con-
trols, with a mean age of 33.1 years (21 - 50) compared to 31.9 years (21 - 47),
but the result was not statistically significant (p-value > 0.05).
Height and weight were measured to calculate the body mass index (BMI).
Mean height was 1.57 cm for the cases, and 1.56 cm for the controls, and the mean
weight was 78.4 kg for the cases, and 77.9 kg for the controls. There was no
2
significant difference in the BMI between the cases and the controls, 31.4 kg/m
2
(16.8 - 47.1) and 31.6 kg/m (17.0 - 49.1) respectively (p-value > 0.05).
Table 2(a) compares the parity and pregnancy outcome in both cases and
controls. A total number of 211 pregnancies were identified in the cases, and 198
pregnancies were identified in the controls.
A total 26/211 term deliveries (12%) were identified in the cases, compared to
102/198 term deliveries (51%) in the control (p-value < 0.05).

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L. Ashaq et al.

Table 1. Demographic data mean (Range).

CASES CONTROL p-value

Number (n) 46 102 -

Age (years) 33.1 (21 - 50) 31.9 (21 - 47) NS

Height (m) 1.57 1.56 -

Weight (kg) 78.4 77.9 -

2
BMI (kg/m ) 31.4 (16.8 - 47.1) 31.6 (17.0 - 49.1) NS

Table 2. (a) Parity and outcome number (Percentage); (b) Successful pregnancy number
(Percentage).
(a)

CASES (n) % CONTROL (n) % p-value

Term 26 −12.3 102 −51.5 <0.05

Preterm 3 −1.4 6 −3 NS

Twin 2 −0.9 6 −3 NS

Abortion 174 −82.4 77 −38.8 <0.001

Ectopic 3 −1.4 7 −3.5 NS

Molar 3 −1.4 0 0 -

Total 211 100% 198 100% 409

(b)

CASES (n) % CONTROL (n) %

Term 26 −84 102 -90

Preterm 3 −10 6 -5

Twin 2 −6 6 -5

Total 31 100% 114 100%

There was no significant increase in preterm deliveries in either cases or con-

trols, 1.4% (3/211) and 3% (6/198) respectively, and there was no significant dif-
ference either (p-value > 0.05).
There was no significant increase in the rate of twin pregnancy in cases and
controls, 0.9% (2/211) and 3% (6/198) respectively. There was no significant dif-
ference either (p-value > 0.05).
A total of 174/211 abortions (82%) were identified in the cases, compared to
77/198 abortions (38%) in the controls, and it was very highly significant (p-value
< 0.001).
The overall prevalence of ectopic pregnancy among cases and controls was
2.4% (10/409). The rate of ectopic pregnancies in the cases and the controls was
1.4% (3/211) and 3.5% (7/198) per total parity respectively. There was no signif-
icant difference (p-value > 0.05). Three episodes of molar pregnancy were iden-

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 L. Ashaq et al.

tified in a single patient in the cases group only.

Table 2(b) is a subdivision of Table 2(a) to assess the outcome of successful
pregnancy. 84% (26/31) of the cases and 90% (102/114) of the controls had term
pregnancies. The incidence of preterm delivery was double in the cases com-pared
to control, 10% (3/31) versus 5% (6/114) respectively. The rate of twin pregnancy
was similar between the cases and the controls where it was 6% (2/31) versus 5%
(6/114) in the cases compared to the controls.
Table 3 compares the mean hormonal level between the cases and the con-trols.

There was no significant difference in the mean prolactin level between the
cases and the controls, 16.7 (4.68 - 75.4) and 17.7 (0.76 - 297) respectively (p-
value > 0.05).
Luteinizing hormone (LH) level was 7.18 (1.06 - 75.4) in the cases compared to
6.93 (1.29 - 26.2) in the controls. The result was not statistically significant (p-
value > 0.05).
Follicle-stimulating hormone (FSH) level was 6.54 (0.75 - 16.2) in the cases,
compared to 6.24 (2.7 - 23.5) in the controls. The result was no statistically sig-
nificant (p-value > 0.05). In addition, there was no significant difference in the
LH/FSH ratio between the cases and the controls, 1.29 and 1.17 respectively (p-
value > 0.05).
There was no significant difference in the mean thyroid-stimulating hormone
(TSH) level between the cases 2.57 (0.86 - 6.25), and the controls 2.48 (0.46 -
14.4) (p-value > 0.05).
The mean estradiol (E2) level was slightly lower in the cases compared to the
controls, 55.5 (13.1 - 224) and 83.9 (0.83 - 482) respectively. The difference was
statistically significant (p-value < 0.01). Pearson correlation coefficient for estra-
diol (R-value) was –0.188.
Mean progesterone level was 11.04 (0.1 - 25.3) in the cases, compared to 9.50
(0.1 - 35.8) in the controls. The difference was not statistically significant (p-value
> 0.05).

Table 3. Hormonal levels mean (Range).

CASES CONTROL
p-value
(mean) (mean)

Prolactin (ng/mL) 16.7 (4.68 - 75.4) 17.7 (0.76 - 297) NS

LH (IU/L) 7.18 (1.06 - 28.2) 6.93 (1.29 - 26.2) NS

FSH (IU/L) 6.54 (0.75 - 16.2) 6.24 (2.7 - 23.5) NS

LH/FSH Ratio 1.29 (0.145 - 6.86) 1.17 (0.247 - 4.93) NS

TSH (μIU/L) 2.57 (0.86 - 6.25) 2.48 (0.46 - 14.4) NS

Estradiol (pg/mL) 55.5 (13.1 - 224) 83.9 (0.83 - 482) <0.01

Progesterone (ng/mL) 11.04 (0.1 - 25.3) 9.5 (0.1 - 35.8) NS

Testosterone (ng/dL) 6.22 (0.23 - 58.9) 8.5 (0.08 - 126.4) NS

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L. Ashaq et al.

The mean testosterone level was slightly lower in the cases compared to the
controls, 6.22 (023 - 58.9) and 8.50 (0.08 - 126.4), but the difference was not sta-
tistically significant (p-value > 0.05).

4. Discussion
The association between PCOS and recurrent pregnancy loss has been studied in
many literatures since a couple of decades. Most researchers studied PCOS pa-
tients and compared them to normal controls. In our study, we divided the women
who have been diagnosed with PCOS into two groups, PCOS with re-current
abortions and PCOS without recurrent abortions. The prevalence of re-current
abortions varied widely in different literatures. In an old historic study by Sagle et
al., they reported that 80% of PCOS women had recurrent pregnancy loss [4],
whereas more recent studies reported a prevalence of 30 to 40 percent [6].
Homburg et al. studied the prevalence of recurrent pregnancy loss among PCOS
and non-PCOS patients who underwent ovulation induction. He reported a
prevalence of 33% among PCOS patients, compared to 10% in non-PCOS women
[6]. Rai et al. and Banu et al. also reported a prevalence of recurrent abortion of
40% among women with PCOS compared to normal controls [7] [8].
In our study, we found the prevalence of recurrent pregnancy loss among
women diagnosed with PCOS to be 31%, which is close to most reports.
Maternal age is an important factor for the prediction of possible pregnancy
loss. Unfortunately, we could not find many reports comparing maternal age in
two groups of PCOS with and without recurrent pregnancy loss. Most reports
studied the prevalence of pregnancy loss in association with advanced maternal
age. Literatures reported that the risk increases significantly after 35 years of age.
In a large Scandinavian study by Andersen et al., they found that women older
than 35 years of age had 25 percent risk of spontaneous abortion [9]. McClure et
al. studied the association of serum estradiol level, maternal age, and pregnancy
outcome in PCOS patients. They found that increased maternal age was asso-
ciated with lower serum estradiol level, which in turn, was significantly asso-
ciated with recurrent miscarriage [10]. In our study, the mean maternal age was
below 35 years for both cases and controls. In addition, we did not find any sig-
nificant difference in the mean age between cases and controls, 33.1 years versus
31.9 years respectively.
Obesity has been conclusively associated with an increased prevalence of mis-
carriage, and obesity is obviously more common in PCOS patients than in nor-mal
controls [6]. Wang et al. found that a higher rate of spontaneous miscarriage in
PCOS patients was due to higher prevalence of obesity [11]. In addition, Boots et
al. found that obese women are more prone to have euploid miscarriage com-
pared to non-obese controls [12]. Obesity is a common finding in Saudi women
due to dietary habits and personal lifestyle. When Fakhoury et al. compared PCOS
patients to normal controls in Saudi women; they found both groups to have BMI
2
above 25 kg/m [13]. Similar to Fakhoury et al., we found that both groups of
2
PCOS cases and controls having a BMI above 30 kg/m . On the other

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 L. Ashaq et al.

hand, there was no significant difference in the BMI between both groups where it
2 2
was 31.4 kg/m among cases, and 31.6 kg/m among controls.
Many researchers have studied adverse obstetric outcome in PCOS patients,
apart from pregnancy loss. In a recent meta-analysis by Qin et al., they found that
PCOS patients had higher incidence of pregnancy induced hypertension,
gestational diabetes, preterm delivery, and Caesarean section [14]. In addition,
Naver et al. reported a doubled incidence of preterm delivery and pre-eclampsia in
hyper-androgenic women with PCOS compared to normo-androgenic PCOS [15].
In our study, most of the cases and controls who delivered, had a term pregnancy,
84 percent versus 90 percent, respectively. On the other hand, similar to what was
observed by Naver et al., the rate of preterm deliveries among the cases was twice
as much as the controls, 10 percent versus 5 percent, respective-ly. Multiple
gestation is a possible complication of induction of ovulation as a treatment of the
anovulatory cycles in PCOS patients. Nahuis et al. reported an incidence of twin
pregnancy in PCOS patients in a randomised trial as 5 percent after being treated
by laparoscopic electrocautery, and 8 percent after receiving recombinant-FSH
[16]. In addition, Zhao et al. studied the pregnancy outcome after in vitro
maturation of immature oocytes, and found a significant increase in multiple
gestation up to 30 percent, low birth weight, and preterm deliveries [17]. In our
study, we did not find a significant increase in the rate of twin preg-nancy in either
cases or controls. Similar to what was observed by Nahuis et al., the rate of twin
pregnancy, out of the successful deliveries, was comparable be-tween cases and
controls, 6 versus 5 percent respectively. There are few reports studied the
incidence of ectopic pregnancy in PCOS patients. Wang et al. studied the
incidence of ectopic pregnancy after in vitro fertilization in PCOS patients, and
reported a threefold increase in the incidence of ectopic pregnancy in PCOS
patients compared to normal controls specially after fresh embryo transfer [18]. In
our study, the overall prevalence of ectopic pregnancy among cases and con-trols
was 2.4 percent, which is slightly higher than general population, twenty per
thousand [19]. In addition, the cases had slightly higher incidence of ectopic
pregnancy than the controls, 8 percent versus 6 percent. There were 3 incidents of
molar pregnancy in a single patient in the cases group.
As previously known, polycystic ovary syndrome is an endocrine disorder that
typically present with a wide spectrum of clinical features. Many literatures have
studied the association between different endocrinopathies and recurrent mis-
carriage that present in PCOS and non-PCOS patient. Most researchers studied the
effect of hyperprolactinemia, subclinical hypothyroidism, abnormal lutei-nizing
and follicle stimulating hormones, abnormal progesterone level, and
hyperandrogenism. In our study we measured these hormones, and compared them
between the cases and the controls.
Many researchers have noticed the association between hyperprolactinemia and
early pregnancy loss. In a randomized controlled trial by Hirahara et al., they
evaluated the effect of isolated hyperprolactinemia in the pathogenesis of recurrent
spontaneous abortion. They found that restoration of normal prolactin

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L. Ashaq et al.

level with bromocriptine was associated with a significant improvement in the

pregnancy outcome, and concluded that appropriate circulating levels of prolac-tin
may play an important role in maintaining early pregnancy, especially in cases of
hyperprolactinemic recurrent miscarriage [20]. On the other hand, Li et al. found
that even low basal serum prolactin level was associated with early pregnancy loss
[21]. In our study, the mean serum prolactin level was compara-ble between the
cases and the control, 16.7 ng/mL versus 17.7 ng/mL respective-ly, and it was
within normal limits.
Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) plays a
critical role in the hormonal secretion, ovulation, and endometrial integrity. There
is a controversy between literatures regarding the association between abnormal
gonadotropin levels and pregnancy outcome.
It was previously thought that elevated level of luteinizing hormone in PCOS
patient was associated with recurrent miscarriage [5]. However, many research-ers
found no significant association between serum LH concentration and re-current
miscarriage [10] [22] [23]. In a randomized control trial by Clifford et al., they
suppressed pituitary LH release and observed its effect on patients with recurrent
pregnancy loss. They concluded that pre-pregnancy suppression of high
luteinizing hormoneconcentrations in ovulatory women with recurrent miscarriage
and hypersecretion of luteinizing hormone does not improve the outcome of
pregnancy [24]. On the other hand, some literatures found a signifi-cant
association between elevated day 3 FSH level in women with recurrent un-
explained miscarriage [25] [26]. In addition, Fakhoury et al. reported an elevated
level of LH/FSH ratio in PCOS patients compared to normal controls [13]. In our
study, we found no significant difference between the cases and the controls
regarding mean LH, FSH levels, and LH/FSH ratio, 7.18 IU/L versus 6.93 IU/L,
6.54 IU/L versus 6.24 IU/L, 1.29 versus 1.17 respectively.
Thyroid hormones are essential for the normal fetal metabolism and growth.
Hypothyroidism was thought to be associated with recurrent early pregnancy loss.
In a study by Jacob involved one thousand women, he reported that even mild
thyroid dysfunction could greatly increase the risk of serious problems. Women
with mild thyroid dysfunction had double the risk of miscarriage, pre-mature
labor, and low birth weight as compared to normal controls [27]. In our study,
there was no significant difference in the thyroid-stimulating hormone (TSH) level
between cases and controls, and there was no suspicion of subclini-cal
hypothyroidism. There was a controversy in literatures regarding the associa-tion
of serum estradiol level and current pregnancy loss. Gurbuz et al. and Trout
&Seifer reported an elevation of serum estradiol level in women with recurrent
pregnancy loss [25] [26]. On the other hand, McClure et al. found that PCOS
patients with recurrent pregnancy loss had lower serum estradiol level [10]. Evrim
et al. when studied the association of LH level and thyroid volume in PCOS
patients, also reported a low normal serum estradiol level in PCOS pa-tients in
comparison to normal controls [28]. Similar to McClure et al. and Evrim et al., in
our study we found that PCOS patients with recurrent abortion

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 L. Ashaq et al.

having lower normal serum estradiol level compared to PCOS without recurrent
abortion, and it was statistically significant. In addition, serum estradiol level was
negatively correlated with the incidence of pregnancy loss.
The association between serum progesterone and recurrent pregnancy loss was
studied in few literatures, last was by Yan et al. who found mid-luteal serum
progesterone measurement does not predict the outcome of a subsequent preg-
nancy in women with unexplained recurrent miscarriage [29].
Some literatures found positive correlation between hyperandrogenemia and
recurrent abortion. Banu et al., Tulppala et al., and Okon et al., have found that
elevated serum testosterone and other androgen level was associated with recur-
rent pregnancy loss in PCOS and non-PCOS patients [8] [23] [30]. On the other
hand, Nardo et al. and Lathi et al. found no relation between serum testosterone
level and recurrent miscarriage in PCOS and non-PCOS patients [22] [31]. In our
study, serum testosterone level was higher in the control group compared to the
cases, and the difference was not statistically significant.
Some researchers studied the effect of serum estradiol and pregnancy outcome
in non-PCOS cases such as normal women, in-vitro fertilisation cases (IVF), and
women undergoing intra-cytoplasmic sperm injection (ICSI). In three different
studies by Check et al., Takeuchi et al., and Aksoy et al., serum estradiol level
was measured in women with history of missed abortion or an embryonic preg-
nancy and compared to normal controls. All of these studies found that women
with history of missed abortion had lower serum estradiol level compared to
normal controls [32] [33] [34].
Other researchers found that women with recurrent abortion had significantly
lower serum progesterone level compared to normal controls [33] [34]. In our
study, we found no significant difference in the serum progesterone level be-
tween cases and controls.
One of the most important manifestations of PCOS is hyperandrogenism, and
many literatures studied the relationship of increased androgens in PCOS pa-tients
and pregnancy outcome. Fujimoto et al. and Joo et al. focused on the effect of
serum estradiol level and pregnancy outcome in IVF cases. Fujimoto et al. found
that higher serum estradiol level was associated with better pregnancy outcome,
while Joo et al. found a concentration-dependent effect between serum estradiol
and pregnancy outcome [35] [36]. There are two studies by Rehman et al. studied
the relationship between obesity, serum estradiol level, and pregnancy outcome in
ICSI cases. They found that lower serum estradiol level had adverse effect on
pregnancy outcome, and high peak estradiol with maintenance of op-timal levels
in mid-luteal phase is required for implantation of fertilized ovum and
accomplishment of clinical pregnancy [37] [38]. Carranza-Lira et al. and Sa-lazar
and Calzada measured serum estradiol and progesterone levels in women with
recurrent miscarriages in addition to endometrial receptors for estrogen and
progesterone. They found that both estrogen and progesterone receptors were at
their lowest level in the cytosol and nuclear compartment in women with recurrent
miscarriage compared to normal controls [39] [40].

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L. Ashaq et al.

The limitations in our study was the sample size, where we had 46 cases and
102 controls over the period studied. Also, dehydroepiandrosterone (DHEA) was
not routinely measured in either cases or controls.

5. Conclusion
PCOS patients with recurrent abortions had no significant increase in the age,
BMI, preterm pregnancy, multiple gestation and ectopic pregnancy. The hor-
monal profile (prolactin, LH, FSH, LH/FSH ratio, TSH, progesterone, testoste-
rone) was comparable between the cases and the controls, except for serum es-
tradiol level, which was significantly lower in PCOS patients with recurrent
abortions.

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