PREGNANCY LOSS AND FETAL OUTCOME
A Dissertation Submitted to
THE TAMILNADU DR. M.G.R MEDICAL UNIVERSITY CHENNAI
In Partial fulfilments of the Regulations for the Award of the Degree of
M.S. (OBSTETRICS & GYNAECOLOGY) BRANCH – II
GOVERNMENT STANLEY MEDICAL COLLEGE, CHENNAI MAY 2019
CERTIFICATE BY THE INSTITUTION
This is to certify that dissertation entitled “EPIDEMIOLOGY AND ETIOLOGY OF RECURRENT PREGNANCY LOSS AND FETAL OUTCOME” is a bonafide work done by Dr.POORANI.V.G. at R.S.R.M Lying in Hospital, Stanley Medical College, Chennai. This dissertation is submitted to TamilnaduDr. M.G.R. Medical University in partial fulfilment of university rules and regulations for the award of M.S.
Degree in Obstetrics and Gynaecology.
Prof. Dr. PONNAMBALA NAMASIVAYAM, MD, DA, DNB.
Dean
Stanley Medical College & Hospital, Chennai – 600 001
Prof. Dr. K. KALAIVANI,
M.D., D.G.O., DNB.
Prof & Head of Department,
Dept. of Obstetrics and Gynaecology Government RSRM Lying In Hospital, Stanley Medical College, Chennai.
CERTIFICATE BY THE GUIDE
This is to certify that this dissertation entitled “EPIDEMIOLOGY AND ETIOLOGY OF RECURRENT PREGNANCY LOSS AND FETAL OUTCOME”submitted by Dr.POORANI.V.G, appearing for Part II MS, Branch II Obstetrics and Gynaecology Degree Examination in May 2019, is a Bonafide record of work done by her, under my direct guidance and supervision as per the rules and regulations of the Tamil Nadu Dr. MGR Medical university, Chennai, Tamil Nadu, India. I forward this dissertation to the Tamil Nadu Dr. MGR Medical University Chennai, India.
Dr.S.SUGANTHI,MD,DGO, Professor,
Dept. of Obstetrics and Gynaecology Government RSRM Lying In Hospital,
Stanley Medical College, Chennai.
DECLARATION
I, Dr.POORANI.V.G., solemnly declare that the dissertation titled,
“EPIDEMIOLOGY AND ETIOLOGY OF RECURRENT PREGNANCY LOSS AND FETAL OUTCOME” is a bonafide work done by me at R.S.R.M. Lying in Hospital. Stanley Medical College, Chennai – during October 2017–to October 2018 under the guidance and supervision of Prof.Dr. K. Kalaivani M.D., D.G.O., DNB., Professor and Head of the department , Obstetrics and Gynaecology. The dissertation is submitted to the Tamilnadu Dr. M.G.R. Medical University, in partial fulfilment of University rules and regulations for the award of M.S.
Degree in obstetrics and Gynaecology.
Place: Dr.POORANI.V.G.
Date :
I am grateful to Prof. Dr. PONNAMBALA NAMASIVAYAM, M.D.,D.A., D.N.B. Dean, Govt. Stanley Medical College for granting me permission to undertake this study. I take this opportunity to express my sincere and humble gratitude to Dr. K. KALAIVANI, M.D.,D.G.O., DNB., Superintendent, Govt. R.S.R.M. Lying in Hospital who not only gave me the opportunity and necessary facilities to carry out this work but also gave me encouragement and invaluable guidance to complete the task I had undertaken. I am deeply indebted to Prof.Dr.S.SUGANTHI, M.D,DGO the mover behind this study for her able guidance and inspiration and constant support without which this would not have been possible.
I am very grateful to RMO Dr.H.ANITHA VIRGIN KUMARI M.D.,D.G.O and Assistant Professor Dr.PREETHA, M.D.,D.G.O., for their invaluable advice, constant guidance and supervision during this study. I am extremely grateful to all our Assistant Professors, for their advice and support during this study. I sincerely thank my fellow postgraduates and friends for their support and co-operation. I owe a great many thanks to all my patients without whom this study would not have been possible. Finally I thank Lord Almighty, who gave me the will power and showered blessings to complete my dissertation work.
CONSENT FORM
I agree to participate in the study entitled "EPIDEMIOLOGY AND ETIOLOGY OF RECURRENT PREGNANCY LOSS AND FETAL OUTCOME"I confirm that I have been told about this study in my mother tongue and have had the opportunity to clarify my doubts. I understand that my participation is voluntary and I may refuse to participate at any time without giving any reasons and without affecting my benefits. I agree not to restrict the use of any data or results that arise from this study.
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PLAGIARISM CERTIFICATE
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I personally verified the urkund.com website for the purpose of plagiarism check. I found that the uploaded thesis file contains from introduction to conclusion pages and result shows 6 percentage of plagiarism in the dissertation.
GUIDE AND SUPERVISOR SIGN WITH SEAL
S.NO TITLE PAGE NO
1 INTRODUCTION 1
2
AIM OF THE STUDY AND
METHODOLOGY 2 - 3
3 REVIEW OF LITERATURE 4 - 36
4 RESULTS 37 - 69
5 DISCUSSION 70 - 73
6 SUMMARY 74
7 CONCLUSION 75
8
ANNEXURES PROFORMA MASTER CHART ABBREVIATIONS
ETHICAL COMMITTEE APPROVAL FORM
9 BIBLIOGRAPHY
Recurrent pregnancy loss is defined as two or more consecutive pregnancy losses prior to 20 weeks of gestation. It affects 2 to 5% of the couples. Primary RPL refers to multiple losses in a women with no previous viable infants whereas secondary RPL refers to multiple losses in a woman who has already had a pregnancy beyond 20 weeks of gestational age.
Most pregnancy losses result from chromosomal and genetic abnormalities and are random events. The abnormality may come from the egg, sperm or the embryo and it is estimated that about 12 to 15% of the clinically recognised pregnancies end up in miscarriage. Apart from the genetic reasons many other reasons contribute to the recurrent abortions and these include the uterine anatomical factors, hormonal factors, immunological and non-immunological mechanisms. Even environmental factors, stress and occupational factors do seem to be related in few cases though there is no strong evidence. Inspite of these known etiologies, recurrent pregnancy losses were found to be due to unknown reasons in majority of the patients.
The risk of miscarriage increases with increasing maternal age and the subsequent pregnancies and the loss of a pregnancy at any stage is a devastating experience to the woman as the chances of a next successful pregnancy outcome decrease. Hence early diagnosis and treatment should be initiated to provide a healthy baby to the mother.
AIM OF THE STUDY
To analyse the prevalence, etiology and perinatal outcome in patients with recurrent pregnancy loss in Govt RSRM Lying in Hospital, for a duration of one year.
STUDY DESIGN:
Cross sectional study METHODOLOGY:
This study was conducted in Govt.RSRM Lying in Hospital, Chennai during the period of October 2017 – October 2018 after getting approval from the Institutional Ethical Committee.
100 pregnant women with history of recurrent pregnancy losses are included in the study. Detailed history of previous pregnancy outcomes, physical examination , blood and radiological investigations along with karyotyping is done after obtaining consent from the patients and frequent periodical antenatal follow up of present pregnancy is carried out to monitor fetal outcome.
INCLUSION CRITERIA:
All pregnant women with history of recurrent pregnancy losses both primary and secondary,
* prior to 20 weeks of gestation
* singleton pregnancies EXCLUSION CRITERIA:
Patient with previous history of
* diabetes mellitus,
* cardiac disease,
* bleeding tendencies,
* ectopic pregnancy &
* multiple gestation.
REVIEW OF LITERATURE
DEFINITION(S) Historical Definition
Recurrent pregnancy loss (RPL), also referred to as recurrent miscarriage is historically defined as three consecutive pregnancy losses prior to 20 weeks from the last menstrual period.
Defined as the spontaneous demise of a pregnancy before the foetus reaches viability. The term includes all pregnancy losses from the time of conception until 20 weeks of gestation. From this, various distinctions between primary and secondary recurrent pregnancy loss can be made. Primary RPL is described as RPL without a previous ongoing pregnancy (viable pregnancy) , while secondary RPL is defined as an episode of RPL after one or more previous pregnancies progressing beyond 24 weeks’ gestation. By definition, “recurrent” pregnancy loss is defined as the loss of two or more pregnancies.
However according to Novaks and RCOG guidelines, it is defined as three or more clinically recognised pregnancy losses before 20 weeks from last menstrual period. Recently authors like Quenby and Fraquharson 1993 and Stephenson et al 1998 included two and more pregnancy losses in their studies. Also Van den Boogaard et al., 2013 concluded that there is no difference in the probability of carrier status (of a structural chromosomal abnormality) between couples that had two or
three consecutive pregnancy losses, compared to two or three non- consecutive losses.Egerup et al., 2016 concluded that only a minority of the RPL couples (estimated to be less than 10%) experience 2 or more non-consecutive pregnancy losses.
RECENT DEFINITION
According to the Practice committee of American Society for Reproductive Medicine 2008 RPL is defined as recurrent pregnancy loss of two or more failed pregnancies.
Hence a diagnosis of Recurrent Pregnancy Loss (RPL) could be considered after the loss of two or more pregnancies.
A pregnancy in the definition is confirmed at least by either serum or urine b-hCG, i.e. including non-visualized pregnancy losses (biochemical pregnancy losses and/or resolved and treated pregnancies of unknown location). In the non-visualized pregnancy loss group, pregnancy losses after gestational week 6 are included, where an ultrasound examination was only done after complete expulsion of the embryo and trophoblast or no ultrasound was done after heavy bleeding:
it includes pregnancies that would have been classified as clinical miscarriages in case an earlier ultrasound scan had been done. If identified as such, ectopic and molar pregnancies should not be included in the definition. Implantation failure is also excluded from the definition.
Pregnancy losses both after spontaneous conception and after ART treatments should be included in the definition.
IMPORTANCE OF THE STUDY
Ogasawara et al concluded that women who had miscarriage twice has a risk of about 43.7% of a subsequent failed pregnancy and the risk increases to 44.6% and 61.9% with a miscarriage thrice and fourth time respectively. This strongly suggests a role for evaluation even after two pregnancy losses in a women with no prior live births as it is distressing for the women and poses a significant emotional toll on women and their partners. Hence management of these patients in an organised multidisciplinary approach is recommended.
EPIDEMIOLOGY Global Prevalence
These data below are based on clinical losses, after the missed menstrual period, or a positive pregnancy test, excluding biochemical pregnancy losses. When other studies have shown a higher prevalence of pregnancy loss, ranging from 10 to 15%, a population based register study showed that 13.5% of the pregnancies intended to be carried to term ended with fetal loss (Nybo Andersen et al., 2000). It has been reported that RPL affects approximately 1% to 2% of women, when defined as three consecutive pregnancy losses prior to 20 weeks from the last menstrual period (Ford and Schust, 2009). Larsen reported a prevalence of 0.8% to 1.4% if only clinical miscarriages (confirmed by ultrasound and/ or histology) are included; adding biochemical losses
increases the prevalence to 2% to 3% (Larsen et al., 2013). However, these and other similar reviews often do not quote original sources of their data. The exact prevalence of RPL is very difficult to estimate, as both the numbers in the numerator (experienced RPL) and the denominator (women at risk of RPL, all women at fertile age, or all women who try to get pregnant), are difficult to obtain. In one study amongst female doctors who retrospectively reported about their previous pregnancies, 0.8% had experienced RPL among those who had attempted pregnancy 3 times (Alberman, 1988). In another study, 1.4% of women with 2 previous pregnancies had experienced RPL (Stray-Pedersen and Lorentzen-Styr, 1979) and in a Danish questionnaire-based study, 0.8%
had experienced RPL among women with 2 pregnancies (Fertility and employment). These studies, which all include a well-defined population in the denominator, thus find that the RPL prevalence is between 0.8%
and 1.4% among women with 2 pregnancies. In a more recent Japanese questionnaire-based study among an unselected group of women aged 35- 79 years, 0.88% reported a history of 3 consecutive miscarriages (Sugiura-Ogasawara et al., 2013b). Except for the latter, these studies are old (or include women being pregnant many years ago) and from a time where the methods for detection of very early pregnancy loss were uncertain. The RPL prevalence would probably be larger if these studies were repeated today.
Prevalence in Our Country
Spontaneous pregnancy loss is a shockingly and surprisingly common occurrence. Approximately 15% of clinically recognized pregnancies result in spontaneous loss, there are many more pregnancies that fail prior to being clinically recognized. Only 30% of all conceptions result in a live birth.1 Spontaneous pregnancy loss can be physically and emotionally a burn for couples, especially with recurrent losses. The incidence of pregnancy loss is generally between 12–15%. However, unrecognised pregnancy loss is considered to be much greater – there is suggestion that 15% of fertilised ova are lost before implantation, with an overall conception loss rate of up to 52%. Maternal age and number of previous miscarriages independently predict future miscarriage. One per cent of couples will experience three or more losses; 5% will experience two or more losses. Based on the incidence of sporadic pregnancy loss, the incidence of recurrent pregnancy loss should be approximately 1 in 300 pregnancies. However, epidemiologic studies have revealed that 1%
to 2% of women experience recurrent pregnancy loss.
ASSESSMENT AND EVALUATION OF A COUPLE WITH RPL The first visit after referral for RPL should allow time for the clinician to review the patient’s history, which includes medical, obstetric, family history, and genetic history but also information on lifestyle of both the male and female partner.
Life style assessment
Assessment of below mentioned lifestyle factors in both the male and female partner is recommended.
Medical History
In addition to lifestyle factors, information should be collected on a previous diagnosis of medical conditions that may be associated with RPL.
THE RPL CLINIC PRE REQUISITES
Recognition of the patient as an individual Good listening
Clear and sensitive language Honesty
Supportive care Kindness
The following elements are required in a RPL clinic:
1. Staffing
Experienced staff members (gynaecologists/ fertility doctors) appropriately trained in ultrasound. Ideally there should also be trained and qualified psychologists/ social workers/counsellors either onsite or accessible, who offer support tailored to the psychological needs of the couples.
2. First Visit
The first visit should allow time for the clinician to review the patient’s history, to answer questions and to propose a plan for investigations and, perhaps, treatment.
3. Equipment/ Location
The clinic should have excellent ultrasound provision and offer 3D ultrasound or additional saline or gel infusion sonography with the appropriate laboratories for further testing. The outpatient clinic is preferably not located next to an antenatal clinic, maternity unit or obstetrics department ward.
4. Provision of information
Staff should be aware that many women with RPL will already have information from a variety of sources, and some explanation and re-education may be needed.
5. Appropriate evaluation
This should include discussion of wishes or views that the patient already has regarding the investigations she wants or does not want. It is crucial to explain before testing that investigations may not identify a likely cause or causes for previous losses, and what this means for the future. It is equally important to explain that there are some causes for which there is little or no or known treatment or where treatment outcomes are uncertain.
6. Treatment plan and active participation in research
If results show no obvious cause, couples may be very distressed, even if statistics suggest that the prognosis is good. They may need a plan for additional support. When diagnosed with a problem for which treatment is uncertain, couples will need more information about possible benefits and disadvantages.
RISK FACTORS FOR RPL AGE
Advanced female age is a risk factor for female subfertility, fetal anomalies, stillbirth, and obstetric complications. To achieve a one-child family, couples should start trying before age 32,. Most studies evaluating male age have reported a significant association between increasing male age and the incidence of miscarriage.
TABLE 1:
AGE IN YEARS PREGNANCY LOSS %
20 – 24 11
25 – 29 12
30 – 34 15
35 – 39 25
40 – 44 51
>45 93
STRESS
Studies have suggested that maternal stress during pregnancy is possibly associated with an increased risk of several adverse pregnancy and birth outcomes but the impact of stress on the risk of miscarriage or recurrent pregnancy loss is yet to be explained.
OCCUPATIONAL
Based on only a few small studies exposure to occupational and environmental factors such as heavy metals, pesticide, and lack of micronutrients seems to be associated with an increased risk of pregnancy loss in women.
CHRONIC ENDOMETRITIS
Chronic endometritis is characterized by a plasma cell infiltrate in the endometrium associated with a range of pathological organisms.
There have been a series of papers suggesting about 7-58% prevalence of chronic endometritis in women with RPL. Antibiotics were found to remove the endometritis with an apparent improvement in live birth rate.
However, this concept has not been tested in randomized controlled trials.
ENDOMETRIAL DECIDUALIZATION
The mechanism of endometrial changes in early pregnanc - endometrial decidualizationand during the menstrual cycle is not yet completely elucidated. Endometrial cells seem to form a checkpoint for embryo quality resulting in implantation processes for normal embryos and rapid demise of endometrium in case of “abnormal” embryos. Recent observations have suggested that in women with RPL abnormal decidualization may render the endometrium excessively permissive to implantation (i.e. a defect in the checkpoint) but unable to sustain the pregnancy but further studies are needed before any firm conclusions or recommendations can be formulated for clinical practice.
SMOKING
Smoking is strongly associated with adverse obstetric and neonatal outcomes, including ectopic pregnancy, stillbirth, placenta praevia,
preterm birth, low birth weight, and congenital anomalies. Studies have also reported associations between maternal smoking during pregnancy and problems during childhood, including sudden infant death syndrome, obesity, psychosocial problems and malignancies. Smoking cessation is therefore recommended to all pregnant women. The impact of smoking or smoking cessation on pregnancy loss in women with RPL is less clear.
OBESITY
Obesity has a significant impact on female reproductive health.
Increased body mass index (BMI) is associated with subfertility, poorer outcomes following fertility treatment, and pregnancy loss. More recent studies on obesity and RPL also found an association. Boots and colleagues assessed the frequency of a euploid miscarriage in 372 women with RPL. There were 117 subsequent miscarriages and the frequency of a euploid miscarriage among obese women was 58% compared with 37%
of non-obese women. Gradual weight loss has been shown to improve fertility and the outcomes of fertility treatments. Maternal obesity is a strong risk factor in RPL, but there are no studies evaluating the impact of weight loss on subsequent PL. However, weight loss has a positive impact on fertility outcomes and reduced weight is associated with reduced complications during pregnancy and birth, and reduced cardiovascular and diabetic morbidity and mortality.
CAFFEINE INTAKE
Some studies have also suggested caffeine intake as a risk factor for RPL, but not all studies reported an association. An association has been described between caffeine intake and late pregnancy loss. Based on the evidence, it is unclear whether caffeine intake is a risk factor for RPL.
AETIOLOGICAL FACTORS AND THEIR DIAGNOSES
RPL as a clinical entity defined by requiring diagnostic testing and therapeutic intervention is a balance between knowledge of the increased risk for subsequent fetal loss and the ability of finding a more possibly a treatable aetiology for the presumably identified disorder. At present, there exist a small number of accepted etiologies for RPL.
CHART 1 - CAUSES
GENETIC ANATOMIC AUTOIMMUNE INFECTIONS ENDOCRINE UNEXPLAINED
These include
Parental chromosomal abnormalities (2-5%), Uterine anatomic abnormalities (10 -15%)
Antiphospholipid antibody syndrome (APS) (20%).
Other possible etiologies include:
Endocrine disorders (17 – 20%) Coagulation Disorders,
Immunologic anomalies, Maternal infections (0.5-5%) Environmental factors AND Unexplained (40-5-%)
After evaluation for this extremely diverse plethora of causes, approximately half of cases remain unexplained.
1. Genetic Factors
Approximately 2% to 4% of RPL is associated with most commonly balanced reciprocal or Robertsonian translocations, a balanced structural chromosome rearrangement. In addition to these, it may also be associated with chromosomal inversions, insertions, and mosaicism.
Single gene defects, such as those associated with cystic fibrosis or sickle cell anaemia, are seldom associated with RPL. Appropriate evaluation of RPL predominantly includes parental karyotyping. Genetic counselling is
of paramount significance and is indicated in all cases of RPL associated with parental chromosomal abnormalities.
Depending on the particular diagnosis, directed therapy may include in vitro fertilization with preimplantation genetic diagnosis. The use of donor gametes may be suggested in cases involving genetic anomalies that always result in embryonic aneuploidy.
GENETIC ANALYSIS OF THE PLACENTAL TISSUE:
The use of embryoscopy, direct visualization of the embryo or early foetus in utero has shown that these abnormalities occur in 86-91%
of miscarriages where an embryo is present. Some of these phenotypically abnormal embryos will also be genetically abnormal, as will some phenotypically normal embryos. The preferred method of genetic analysis is array-CGH, as this is not limited by tissue culture failure or false negative results due to maternal cell contamination. New techniques such as next generation sequencing (NGS) may be useful in the near future.
PARENTAL GENE ANALYSIS
Abnormal parental karyotypes were found in around 1.9% of couples (n=20432) referred for genetic testing after recurrent pregnancy loss in a large retrospective cohort study (Franssen et al., 2006, Barber et al., 2010).
It was decided to recommend parental karyotyping in RPL couples only after an individual risk assessment.
Parental karyotyping can be recommended based on genetic history (for instance in case of the previous birth of a child with congenital abnormalities, offspring with unbalanced chromosome abnormalities in the family, or detection of a translocation in the pregnancy tissue). For other couples, the benefit of the test is limited as the chances of finding an abnormality are very low: in couples with female age above 39, less than three pregnancy losses and a negative family history, the chance of being a carrier of a translocation is very low (Franssen et al., 2005).
Parental karyotyping may provide couples with a possible contributing factor and prognostic information for the subsequent pregnancy.
Regarding prognosis, couples should be informed that, even if a parental abnormality is found after karyotyping, the cumulative live birth rates are good, as are the chances of a healthy child, despite a higher risk of a subsequent pregnancy loss.
2. Anatomical Factors
Anatomic abnormalities are thought to cause miscarriage by Interrupting the vasculature of the endometrium,
Prompting an abnormal placentation and Promoting inadequate placentation.
Those that interrupt the vasculature of endometrium:
These include
congenital uterine anomalies, intrauterine adhesions, and Uterine fibroids or polyps.
The uterine septum is the congenital uterine anomaly most closely linked to RPL, with a 76% risk of spontaneous pregnancy loss among affected patients. Other Müllerian anomalies, including unicornuate, didelphic and bicornuate uteri have been associated with smaller increases in the risk for RPL. The role of the arcuate uterus in causing RPL is unclear. The presence of intrauterine adhesions, sometimes associated with Asherman syndrome, may significantly impact placentation and result in early pregnancy loss. Intramural fibroids larger than 5 cm, as well as submucosal fibroids of any size, can cause RPL.
Although congenital anomalies caused by prenatal exposure to diethylstilboestrol are clearly linked to RPL, this is becoming less clinically relevant as most affected patients move beyond their reproductive years.
Sonohysterography (or hysterosonography) (SHG) appears a safe procedure which provides more information about uterine abnormalities than hysterosalpingography (HSG) or ultrasound (US) alone. SHG is accurate in diagnosing and classifying congenital uterine malformations.
In addition, SHG has a higher sensitivity and specificity than HSG or diagnostic hysteroscopy to diagnose uterine malformations in general.
Three-dimensional US allows visualization of the internal and external contour of the uterus, has high sensitivity and specificity, and it is non- invasive. It appears to be very accurate for the diagnosis and classification of congenital uterine malformations. Two-dimensional US and hysterosalpingography (HSG) are non-invasive and widely available.
HSG has a good sensitivity for diagnosing more pronounced uterine malformations, but it is limited in differentiating between the types of malformations. Overall, 2D transvaginal ultrasound (TV-US) and HSG are suboptimal to diagnose uterine malformations, based on a poor accuracy and limited potential in classifying malformations, especially when used in isolation. Sono-Embryoscopy and Uterine Doppler US have been suggested for the investigation of uterine malformations in women with RPL, but there is not enough evidence to support these techniques in the routine investigation of RPL. Cervical weakness is a recognized cause of second-trimester pregnancy loss, but the true incidence is unknown, since the diagnosis is essentially a clinical one. The diagnosis is usually based on a history of second-trimester miscarriage preceded by spontaneous rupture of membranes or painless cervical dilatation. There is currently no objective test able to identify women with cervical weakness in the non-pregnant state.
ACQUIRED UTERINE MALFORMATIONS:
Although the relevance of acquired uterine malformations in RPL is unclear, these malformations can be diagnosed with imaging techniques used in the detection of congenital malformations. 2D US is not a sensitive method to detect uterine adhesions. When suspected, a hysteroscopy has to be performed. Submucosal fibroids and endometrial polyps can be detected with 3D US, SHG, 2D US, or HSG. Hysteroscopy is considered the gold standard.
From the evidence, it can be concluded that congenital uterine malformations are more prevalent in women with RPL, as compared to controls. For acquired uterine malformations, there is no convincing evidence that these malformations are associated with or contribute to RPL. The recommendation of uterine assessment in all women with RPL is consistent and constant over time.
3. Hormonal Factors
Luteal phase defect (LPD), polycystic ovarian syndrome (PCOS), diabetes mellitus, thyroid disease, and hyperprolactinemia are among the endocrinologic disorders implicated in approximately 17% to 20% of RPL.
*LPD
Traditionally, LPD has been proposed to result from inadequate production of progesterone by the corpus luteum and endometrial maturation insufficient for proper placentation. It is diagnosed when there is a persistent lag of longer than 2 days in the histologic development of the endometrium compared with the day of the menstrual cycle. Today, the true role of LPD in RPL is controversial and endometrial biopsies for LPD diagnosis are rarely indicated. Studies have found evidence of PCOS in at least 40% of women with RPL.
* PCOS
Insulin resistance and the resultant hyperinsulinemia that is often present in cases of PCOS (as well as T2DM) may also play a role in RPL, as evidenced by the decreased rate of spontaneous pregnancy loss when patients undergo therapy with the insulin sensitizing drug, metformin.
Poorly controlled type 1 diabetes mellitus is also associated with an increased risk of spontaneous abortion.
*DYSTHYROID STATE
Although untreated hypothyroidism is clearly associated with spontaneous miscarriage and RPL, the connection between antithyroid antibodies and RPL in euthyroid patients is currently under great debate.
Evaluation of endocrine disorders should include measurement of the thyroid-stimulating hormone (TSH) level.
*OVARIAN RESERVE TESTING
From the association between advanced maternal age and RPL, it is suggested that diminished ovarian reserve could be a causative or prognostic factor in RPL. Ovarian reserve can be assessed with measurements of FSH, oestrogen (E2), inhibin B, and anti-Müllerian hormone (AMH), or ultrasound investigation to determine antral follicle count (AFC) and ovarian volume.
4. Infectious Etiologies
Certain infections, including Listeria monocytogenes, Toxoplasma gondii, rubella,
herpes simplex virus (HSV), measles,
cytomegalovirus, and
Coxsackieviruses, are known or suspected to play a role in sporadic spontaneous pregnancy loss. However, the role of infectious agents in recurrent loss is less clear, with a proposed incidence of 0.5%2 to 5%.
The proposed mechanisms for infectious causes of pregnancy loss include:
(1) Direct infection of the uterus, foetus, or placenta, (2) Placental insufficiency,
(3) Chronic endometritis or endocervicitis, (4) Amnionitis, or
(5) Infected intrauterine device.
5. Immunologic Factors
Because a foetus is not genetically identical to its mother, it is reasonable to infer that there are immunologic events that must occur to allow the mother to carry the foetus throughout gestation without rejection. APS, requires particular attention as it has been clearly linked with many poor obstetric outcomes, including RPL.
Diagnosis of APS:
APS is characterized by the presence of at least 1 clinical and 1 laboratory criterion:
1. Clinical – 1 or more confirmed episodes of vascular thrombosis (venous, arterial, or small vessel)
2. Pregnancy complications including
a. Either 3 or more consecutive pregnancy losses at less than 10 weeks of gestation,
b. 1 or more fetal deaths at greater than 10 weeks of gestation, or
c. at least 1 preterm birth ( 34 weeks) due to severe preeclampsia or placental insufficiency
3. Laboratory (repeated at least 2 times, more than 12 weeks apart) – Positive plasma levels of the anticardiolipin antibodies (IgG or IgM) at medium to high levels
The mechanisms by which APS results in RPL are incompletely understood.
Thrombotic Etiologies
Both inherited and combined inherited/acquired thrombophilia are common, with more than 15% of the white population carrying an inherited thrombophilia mutation.23 the most common of these are the factor V Leiden mutation, mutation in the promoter region of the prothrombin gene, and mutations in the gene encoding methylene tetrahydrofolate reductase (MTHFR). The potential association between RPL and heritable thrombophilia is based on the theory that impaired placental development and function secondary to venous and/or arterial thrombosis could lead to miscarriage.
Based on studies that have shown maternal blood to begin flowing within the intervillous spaces of the placenta at approximately 10 weeks of gestation, the link between thrombophilia and pregnancy losses at greater than 10 weeks of gestation is more widely accepted than a link to those that occur prior to 10 weeks of gestation. However, evidence that the transfer of nutrition from the maternal blood to the fetal tissues depends on uterine blood flow, and thus may be affected by thrombotic events occurring there, suggests a role for thrombophilia in pregnancy losses regardless of gestational age.
Male factors
There is a moderate body of evidence indicating associations between RPL and poor quality sperm; particularly sperm with elevated DNA fragmentation. These associations are independent of female factors. Since there is also clear evidence that sperm DNA damage is caused by unhealthy lifestyles (such as smoking, obesity and excessive exercise), clinicians could make couples aware of these risks. Prospective studies with appropriate controls (matched for age, fertility status and lifestyle) are needed to elucidate these trends further.
Unexplained factors
More than half of the cases fall under this category.
Progesterone has been shown to be beneficial in decreasing the miscarriage rate among women who have experienced at least 3 losses.
LDA has also been investigated as a potential therapy for unexplained RPL. Its use prior to and during pregnancy has only been proven to increase live birth rates among those women with previous miscarriages beyond 13 weeks of gestation.
TABLE 2:
ETIOLOGY& DIAGNOSIS
ETIOLOGY DIAGNOSTIC EVALUATION
GENETIC Parental karyotype
ANATOMIC HSG, 2D/3D usg, SIS
ENDOCRINE Tsh, prolactin, ovarian reserve testing, antithyroid antibodies, tests for insulin resistance
INFECTIOUS High vaginal swab culture
sensitivity
AUTOIMMUNE ACL antibodies ,lupus
anticoagulant
NON APS THROMBOPHILIAS Homocysteine,factor v leiden, protein c resistance, prothrombin promoter mutation
TREATMENT MODALITIES
*FOR GENETIC FACTORS
A number of interventions and treatments have been explored for couples with RPL due to genetic/chromosomal causes. Genetic counselling, including a family history the outcomes following further attempts to conceive, and any relevant prenatal diagnostic tests should be offered to all couples with RPL with a known parental karyotype abnormality.
PREIMPLANTATION GENETIC TESTING (PGT) FOR UNEXPLAINED RPL
Preimplantation genetic testing for aneuploidy (PGT-A) (previously preimplantation genetic screening [PGS] or preimplantation diagnosis of aneuploidy [PGD-A]), where an IVF cycle creates embryos which are biopsied and screened for chromosomal anomalies prior to implantation, has been proposed as a potential treatment for RPL. The data from published studies is limited by the PGS (PGT-A) technique used, as the vast majority have employed FISH with an embryo biopsy at Day 3, which only looks at a specific number of chromosomes at an early stage of embryo development where mosaicism is higher. Whole genome techniques such as array-CGH or Next Generation Sequencing (NGS) with a biopsy taken at blastocyst stage, looking at all chromosomes, are recognized to be more accurate screening techniques.
PREIMPLANTATION GENETIC TESTING FOR RPL WITH GENETIC BACKGROUND
Preimplantation genetic testing for monogenic/single gene defects (PGT-M) or chromosomal structural rearrangements (PGT-SR), previously PGD, is an established alternative to invasive prenatal diagnosis and as such may avoid termination of pregnancy in couples with a high risk of transmitting genetic disorders such as various monogenic diseases and for structural chromosome abnormalities, the latter being found in the RPL population.
*INHERITED THROMBOPHILIA 1. Role of Anticoagulants
A recent systematic review reported no benefit of low molecular weight heparin (LMWH) for prevention of pregnancy loss in women with hereditary thrombophilia and prior late ( 10 weeks) pregnancy loss (LBR LMWH versus no LMWH: RR 0.81; 95% CI 0.38-1.72; 5 RCTs; n=308) or recurrent early (< 10 weeks) pregnancy loss (LBR LMWH versus no LMWH: RR 0.97; 95% CI 0.80-1.19; 2 RCTs; n=66) (Skeith et al., 2016).
2. Steroids
No studies regarding steroids for hereditary thrombophilia and RPL have been found.
3. Intravenous immunoglobulins
No studies regarding treatment with Intravenous immunoglobulins (IvIg) for hereditary thrombophilia and RPL were retrieved.
4. Folic acid and vitamins
Most studies on treatment with folic acid and vitamins have focused on RPL women with a mutation in the MTHFR gene and/or hyperhomocysteinemia.
*FOR ANTI PHOSPHOLIPID ANTIBODY SYNDROME 1. Anticoagulants
A benefit of heparin (UFH or LMWH) and aspirin, as compared to aspirin alone, with regard to first trimester losses was reported in the review of summarizing five RCTs of 398 women with RPL and APS (OR 0.39; 95% CI 0.24-0.65; NNT 4).
The observed benefit of LMWH and aspirin as compared to aspirin alone did not reach statistical significance for RPL (OR 0.70; 95% CI 0.34-1.45; n=186; 2 RCTs), and was absent when the analysis was limited to studies that included late pregnancy losses (OR 2.28; 95% CI 0.43-12.13; n=150; 2 RCTs) (Ziakas et al., 2010).
2. Steroids
Steroids (prednisone) have been evaluated as treatment for women with RPL and presence of antiphospholipid antibodies and no benefit was found for prednisone combined with aspirin compared to heparin/aspirin (RR 1.17; 95% CI 0.47-2.93; one RCT; n=45). Furthermore, several adverse outcomes were reported associated with prednisone; there was a significant increase in premature delivery and severe pre-eclampsia.
3. Intravenous immunoglobulin
Based on three RCTs, a review concluded that treatment with intravenous immunoglobulin (IvIg) did not reduce the chance of pregnancy loss in women with RPL and antiphospholipid antibodies
*FOR ENDOCRINE FACTORS DYSTHYROID STATE
Prompt referral to an endocrinologist is recommended.
If hypothyroidism is identified in women with RPL, treatment with levothyroxine is recommended based on existing guidelines and possible maternal and fetal complications associated with untreated hypothyroidism during pregnancy.
For women with subclinical hypothyroidism and RPL, treatment with levothyroxine is insufficiently evidence-based and it should be further investigated.
LPD
Results on hCG as a treatment for RPL show a positive effect of treatment on miscarriage rate. However, studies are considered too limited to recommend the use of hCG in women with RPL and luteal phase
INSULIN
Indirect evidence could support the use of metformin treatment to increase the live birth rate in women with PCOS, but in the absence of any substantial studies in women with RPL and PCOS, the GDG decided metformin is not recommended.
OVULATION INDUCTION
Controlled ovarian stimulation by human menopausal gonadotropins could be beneficial for decreasing the chance of a next pregnancy loss in women with RPL diagnosed with luteal phase insufficiency (Li et al., 2001)
HYPERPROLACTINEMIA
In women with RPL and hyperprolactinemia, bromocriptine treatment normalizes serum prolactin levels and it could be effective for increasing the chance of a live birth. However, this conclusion is based on a single small study, and hence should be confirmed
VITAMIN D
Based on the significant prevalence of vitamin D deficiency in women with RPL and the possibly associated obstetrical and fetal complications, prescribing vitamin D supplementation can be considered, even though evidence for the effectiveness is absent. With regard to harm, most experts agree that supplemental vitamin D is safe in dosages up to 4,000 IU per day during pregnancy or lactation, even though data on the safety of higher doses are lacking.
*FOR INHERITED ANATOMICAL FACTORS
1. For women with RPL and septate uterus, observational studies suggest a benefit of treatment in reducing the miscarriage rate. This was also the conclusion of a recent meta-analysis of uterine malformations (not specific for RPL): women who underwent hysteroscopic septum resection had a significantly decreased probability of spontaneous miscarriage compared with women who did not undergo treatment, however, the effect on fertility (i.e. the chance of becoming pregnant after surgery) is unclear.
2. For Müllerian malformations other than septate uterus, there are currently no high quality studies to support surgery for improving the live birth rate or decreasing the miscarriage rate. Furthermore, the risk of subfertility after surgery should be clarified.
3. In the event of irreparable anatomic uterine abnormalities and RPL, IVF with transfer of embryos to an appropriately selected gestational carrier (surrogacy) can be an option.
* FOR MALE FACTORS 1. Smoking Cessation 2. Targeting Obesity
3. Medications like selective serotonin reuptake inhibitors, corticosteroids, antibiotics, anti-inflammatories and even codeine can harm sperm function.
4. Varicocele repair
5. Nutrition and antioxidants
*FOR UNEXPLAINED FACTORS 1. Lymphocyte Infiltration Therapy
In the 1980s deliberate immunization of women with RPL with allogeneic lymphocytes (lymphocyte immunization therapy or LIT) became increasingly used. The theory for using LIT was that women with RPL lack anti-paternal antibodies or blocking antibodies that protect the foetus against rejection, and the subsequent production of these antibodies
2. Intra Venous Immuno Globulin Therapy
Intravenous immunoglobulin (IvIg) is known to reduce symptoms in many autoimmune and inflammatory diseases through a multitude of
mechanisms including elimination of immune complexes, interactions with Fc-receptors, elimination of activated complement factors, interference with antigen presentation and neutralization of inflammatory cytokines.
3. Glucocorticoid Therapy
Glucocorticoids exhibit a beneficial clinical effect in most autoimmune inflammatory diseases and are therefore a potential useful therapy in women with RPL with a suspected immune aetiology. The evidence points toward some beneficial effect of prednisolone in women with RPL selected due to positivity for selected biomarkers. However, there are adverse events associated with the use of prednisone, heralding it from being the most preferred.
4. Anticoagulant Therapy
Based on a meta-analysis and results of two subsequent large randomized controlled trials there is no evidence that heparin alone, aspirin alone, or heparin in combination with low-dose aspirin improves the live birth rate in unexplained RPL.
5. Progesterone Therapy
A recent meta-analysis, including the recent trials showed a benefit of progesterone on miscarriage rate and live birth rate (Saccone et al., 2017). Vaginal progesterone during early pregnancy has no beneficial
effect in women with unexplained RPL. There is some evidence that oral dydrogesterone initiated when fetal heart action can be confirmed may be effective. Furthermore, as progesterone is important during implantation of the embryo, benefit from supplementation may be realized if progesterone is administered from the luteal phase, rather than after a positive pregnancy test. More trials are needed to evaluate oral progesterone and administration of progesterone from the luteal phase.
6. G – CSF
Granulocyte – macrophage colony-stimulating factor (GM-CSF) and granulocyte colony – stimulating factor (G-CSF) are growth factors that may promote trophoblast growth and have been proposed to have anti-abortive effects based on animal studies. Although the mechanism is unknown, studies have been conducted in women with RPL and recurrent implantation failure.
7. ENDOMETRIAL SCRATCHING
Scratching of the endometrium in the luteal phase prior to an IVF/ICSI cycle has gained widespread use in women with recurrent implantation failure; the theory is that the procedure will liberate cytokines and chemo-attractants of importance for subsequent embryo implantation.
RESULTS AND ANALYSIS
AGE
TABLE 3: AGE DISTRIBUTION OF THE STUDY GROUP
Age Group In Years Frequency Percent
18 - 20 yrs 8 8.0
21 - 25 yrs 48 48.0
26 - 30 yrs 38 38.0
31 - 35 yrs 5 5.0
Above 35 yrs 1 1.0
Total 100 100.0
This table shows the age wise distribution of the study group.
Majority (48%) of the patients were in the age group of 21 to 25 years.
The mean age of the study group was 25.34.
CHART 2: AGE DISTRIBUTION OF THE GROUP
0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0 45.0 50.0
18 - 20 yrs 21 - 25 yrs 26 - 30 yrs 31 - 35 yrs Above 35 yrs 8.0
48.0
38.0
5.0
1.0
Age Distribution
EDUCATION
TABLE 4: EDUCATION DISTRIBUTION OF THE STUDY GROUP
Education Distribution
Of The Study Group Frequency Percent
GRADUATE 3 3.0
ILLITERATE 26 26.0
PRIMARY SCHOOL 35 35.0
SECONDARY SCHOOL 36 36.0
Total 100 100.0
From this table it suggests that 36% of the population attended secondary schooling followed by 35% who completed primary schooling.
CHART 3: EDUCATION DISTRIBUTION OF THE GROUP Education
GRAD ILL PRIM SEC
SOCIOECONOMIC CLASS
TABLE 5: SOCIOECONOMIC CLASS OF THE STUDY GROUP
Socioeconomic Class Frequency Percent
2 2 2.0
3 24 24.0
4 35 35.0
5 39 39.0
Total 100 100.0
From this table it is understood that majority of the patients belonged to lower socioeconomic class – class 5 (39%) followed by class 4 (35%).
CHART 4: SOCIOECONOMIC CLASS OF THE STUDY GROUP
2%
24%
35%
39%
Socio Economic class
2 3 4 5
OBSTETRIC CODE
TABLE 6: OBSTETRIC CODE OF THE STUDY POPULATION
PRIMARY RPL SECONDARY RPL
81 19
Obstetric Code Frequency Percent
G10P9LO 1 1.0
G3A2 51 51.0
G3P1L0A1 5 5.0
G3P2L0 6 6.0
G4A3 13 13.0
G4P1L0A2 1 1.0
G4P1L1A2 10 10.0
G5A4 3 3.0
G5P1L1A3 8 8.0
G6P1L1A4 1 1.0
G7A6 1 1.0
Total 100 100.0
This table shows the distribution of obstetric code of the patients who are included in the study. In primary RPL,about 2 consecutive pregnancy losses were found in 51% of the patients , 3 consecutive pregnancy losses in 13% of the patients, 4 consecutive losses in 3% of patients and 6 consecutive losses in 1%. And secondary RPL was found in 19% of patients.
CHART 5: OBSTETRIC CODE OF THE STUDY POPULATION
0 10 20 30 40 50 60
G10P9LO G3A2 G3P1L0A1 G3P2L0 G4A3 G4P1L0A2 G4P1L1A2 G5A4 G5P1L1A3 G6P1L1A4 G7A6
1
51 5
6
13 1
10 3
8 1
1
Obstetric Code
TABLE 7. GENETIC ETIOLOGY
GENETIC Frequency Percent
AR 1 1.0
NO 99 99.0
Total 100 100.0
From the paternal karyotyping, it was found that only one patient had recurrent pregnancy losses due to Autosomal Recessive disorder (ACHONDROPLASIA)
CHART 6: GENETIC ETIOLOGY IN THE STUDY GROUP
1%
99%
Genetic
AR NO
TABLE 8: ANATOMICAL ETIOLOGY IN THE STUDY GROUP
Anatomical Frequency Percent
CI 5 5.0
NO 94 94.0
SEPTATE UTERUS 1 1.0
Total 100 100.0
Recurrent second trimester abortions due to cervical incompetency was found in 5% of patients and septate uterus was diagnosed by hysterolaparoscopy in 1% of patients.
CHART 7: ANATOMICAL ETIOLOGY IN THE STUDY GROUP
5%
94%
1%
Anatomical
CI NO SEPTATE UTERUS
TABLE 9: HORMONAL FACTORS IN THE STUDY GROUP
Hormonal Frequency Percent
HASHIMOTOS 1 1.0
HYPERTHYROID 2 2.0
HYPOTHYROID 20 20.0
NO 77 77.0
Total 100 100.0
Dysthyroid state was found in 23% of the patients and among these autoimmune hashimotos was found in 1% of them. Two patients had a TSH value of more than 5mIu/L.
CHART 8: HORMONAL FACTORSIN THE STUDY GROUP
0 20 40 60 80
HASHIMOTOS HYPERTHYROID HYPOTHYROID NO
1 2
20
77
Hormonal
TABLE 10: IMMUNOLOGIC FACTORS IN THE STUDY GROUP
Immunological Frequency Percent
APS + 2 2.0
POSSIBLE APS+ 1 1.0
NO 97 97.0
Total 100 100.0
This table suggests that Antiphospholipid antibody syndrome was responsible for pregnancy losses in 3% of the patients and 97% had no immunological basis for recurrent abortions.
CHART 9: IMMUNOLOGICAL FACTORS IN STUDY GROUP
0 20 40 60 80 100
APLA + POSSIBLE APLA+
NO
2 1
97
Immunological
TABLE 11: INFECTIVE ETIOLOGY IN STUDY GROUP
INFECTIVE Frequency Percent
HVS+ 1 1.0
TORCH + 1 1.0
NO 98 98.0
Total 100 100.0
This table suggests that torch – IgM positive rubella was found in 1% of the patients and infection was the cause of preterm labour in 1% of the patients. Other 98% had no infective etiology.
CHART 10: INFECTIVE ETIOLOGY IN STUDY GROUP
0 20 40 60 80 100
HVS+
TORCH + NO
1 1
Infective
TABLE 12: OTHER ETIOLOGICAL FACTORS
OTHERS Frequency Percent
GDM 2 2.0
GDM (I) 1 1.0
GDM,GHTN 2 2.0
GHTN 7 7.0
RHD 1 1.0
From this table it is clear that cause of recurrent pregnancy losses was unknown in 53% of the cases and gestational diabetes mellitus and gestational hypertension were also found to be responsible for 5% and 7% of pregnancy losses.
CHART 11: OTHER ETIOLOGICAL FACTORS IN THE STUDY GROUP
0 10 20 30 40 50 60
2 1 2
7
1
55
32
Others
TABLE 13: MODE OF DELIVERY IN THE STUDY POPULATION
Mode Of Delivery Frequency Percent
INCOMPLETE ABORTION 2 2.0
LN 24 24.0
LSCS 66 66.0
MISSED ABORTION 5 5.0
OUTLET FORCEPS 1 1.0
SE 2 2.0
Total 100 100.0
This table shows that 66% of the patients were delivered by LSCS followed by normal vaginal delivery in 25% of the patients and 9% of the patients ended up in abortions again.
2%
24%
66%
5%
1% 2%
Mode of delivery
INCOMPLETE ABORTION LN LSCS MISSED ABORTION OUTLET SE
Though 66% of the patients were delivered by LSCS and only 25%
of the patients had vaginal delivery, there was no significant difference in the neonatal morbidity. as mentioned earlier, 2 patients had incomplete abortions at 7 and 8 weeks respectively, 5 patients had missed abortions at 6 to 8 weeks and 2 patients had spontaneous expulsion of dead born in second trimester.
TABLE 14: INDICATIONS FOR LSCS
INDICATION NUMBER OF PATIENTS
FETAL ALARM SIGNAL 22
FETAL DISTRESS 18
FAILED INDUCTION 15
SEVERE
OLIGOHYDRAMINOS/IUGR
2
CPD MAJOR 9
The most common indication for LSCS was fetal alarm signal in 22% of patients followed by fetal distress in 18% and failed induction in 15%.
CHART 13: INDICATIONS FOR LSCS
22
18 15
2
9
INDICATION
FETAL ALARM SIGNAL FETAL DISTRESS FAILED INDUCTION SEVERE OLIGO CPD MAJOR
TABLE 15: BABY DETAILS
Baby details Frequency Percent 9
P 16 17.0
T 75 83.0
TOTAL 100 100
Out of the total patients delivered, 75% had full term deliveries and 16% had preterm deliveries, due to severe oligohydraminos, IUGR, and infective causes.9% of cases aborted.
TABLE 16: BABY SEX
BABY SEX Frequency Percent
9 9
BOY 44 44.0
GIRL 47 47.0
Total 100 100.0
Out of the total 91 babies that were delivered, 47% were girls and 44% were boys in the study.
TABLE 17: APGAR AT BIRTH
Apgar At Birth Frequency Percent
9 9.0
5/10,7/10 1 1.0
6/10,6/10 1 1.0
6/10,7/10 4 4.0
6/10,8/10 3 3.0
7/10,8/10 80 80.0
7/10,8/10 IUGR 2 2.0
Total 100 100.0
Among the babies that were delivered, 80% had good 1 minute and 5 minute apgar at birth of 7/10 and 8/10, however 1% of the babies which had lower 1 minute apgar of 5/10 was found to be well when followed up.
TABLE 18: NICU ADMISSION
ADMISSION IN NICU Frequency Percent
9 9.0
NO 57 57.0
YES 34 34.0
Total 100 100.0
Out of the 91 babies that were delivered, NICU admission was required in 34% of the babies. And the other 57% babies required no admission at birth. The mean birth weight of the babies were 2.682 kg.
CHART 14: NICU ADMISSION DETAILS
63%
37%
NICU Admission
NO YES
TABLE 19: NEONATAL MORBIITY
Neonatal Morbidity Frequency Percent
NIL 63 63.0
HYPOTHYROID 17 17.0
HYPOTHYROID,RD 2 2.0
IDM 5 5.0
IUGR 2 2.0
LBW 1 1.0
LBW,HYPOTHYROID 1 1.0
P 6 6.0
P, RD 1 1.0
RD 2 2.0
Total 100 100.0
This table shows that the major reason for admission into NICU was due to hypothyroid mothers requiring baby monitoring in 19%
followed by preterm in 7% , infant of diabetic mothers in 5% and respiratory distress in 5%.
CHART 15: NEONATAL MORBIDITY
0 10 20 30 40 50 60 70
NIL HYPOTHYROID HYPOTHYROID,RD IDM IUGR LBW LBW,HYPOTHYROID P P, RD RD
67 17
2 1
2 1 1
6 1
2
Neonatal morbidity
DISCUSSION
Out of the 13,828 patients who attended the antenatal outpatient department in our hospital, 151 women were found to have recurrent pregnancy losses, which accounted for 1.09% incidence. And among those 151 patients, 100 patients were followed up during this study.
From this study of 100 pregnant women with recurrent pregnancy losses, the age distribution was maximum in 21 to 25 years( 48%),5 patients were above 30 years and 1 patient above 35 years and hence the mean age was found to be 25.34 years. Primary RPL was found in 81% of the patients whereas Secondary RPL was found in 19% of the patients.
Almost 51% of the patients had 2 consecutive abortions, followed by three ,four, five and six consecutive abortions in 13%,3%,1%
respectively.1 patient who had previous 9 no live pregnancies was also followed up during the study with great care and observation under admission.
Among the various causes of RPL found in the study, endocrinal cause was found in maximum patients accounting for 23%, followed by anatomical factors in 6% of patients, APS positive in 3%, infective etiology in 2%, and genetic factors in 1% of these patients. Also it was found that obstetric complications like gestational diabetes mellitus and hypertensive disorders of pregnancy accounted for 12% of the pregnancy losses and in about 53% of the studied population, no definitive etiology was found , hence attributed to Idiopathic RPL. Saito et al and Jivraj
reported a rate of 7% and 13% endocrinal etiology for RPL in their study respectively whereas in my study it was found in 23% of the population, and they also reported an incidence of 2% and 3.3% of diabetes and hypertensive disorders accounting for RPL ,which in my study was found in 5% and 7% respectively indicating that sedentary lifestyle and stress and obesity accounted for the increased incidence of these hormonal changes and obstetric complications found in them. Anatomical factors were responsible for 9% of cases in study by Saito et al, which has reduced to 6% now in the study which could be explained due to increased use of radiological techniques to diagnose and treat earlier thereby preventing complications. According to Jivraj et al and Saito et al 66% and 30% of RPL was attributed due to unknown etiology and in my study unexplained RPL accounted for 53% of patients.
Among these 100 patients who were followed up during the study, 5 patients who had cervical incompetency underwent cervical encerclage( D”adato et al reported successful outcome of 73.3% after cervical encerclage procedure), 1 patient with bacterial vaginosis was treated with a course of capsule doxycycline 100mg for 5 days and tablet metronidazole 400mg for 7 days, and APS positive patients (3%) were on injection heparin and tablet low dose aspirin until term. Apart from these, dysthyroid state found in 23% of patients were treated with tablet thyroxine and carbimazole for hypothyroid and hyperthyroid respectively, and among them two patients who had TSH levels of 8 and 11mIU/L
were on high dose of thyroxine is to be mentioned. Gestational diabetes patients were put on meal plan and insulin in 3% and 1% respectively and hypertensive patients were started on anti hypertensives. The remaining patients were on tablet folic acid, low dose aspirin, nutritional supplements ,assurance and regular follow up.
Regarding the outcome of the pregnancy, 91% of the patients had sustained successful pregnancy whereas 9% of them suffered from another abortion. Out of the 91% patients delivered, 75% had full term deliveries beyond 37 completed weeks of gestation and 16% had preterm deliveries. Thus majority of patients had successful outcome. Almost 80% of the babies who were delivered had good apgar at birth. 66% of the patients were delivered by lower segment caesarean section followed by vaginal birth in 24% patients and outlet forceps delivery in 1% patient.
The main indication for LSCS was fetal alarm signal in 22% followed by fetal distress in 18% and failed induction in 15% after inducing labour.
This increased rate of caesarean sections could also be attributed to the fact that there are increasing maternal complications and the outcome of subsequent successful pregnancy decrease with advancing maternal age and also depending upon the number of previous abortions. This was reported in the study by Van Oppenraaij et al who concluded the effects of maternal complications as significant predictors of current pregnancy outcomes.
Among the babies delivered, about 34% of them required NICU admission due to preterm (16%), respiratory distress, dysthyroid mothers, diabetic mothers and 2 babies had IUGR.
It could be observed from the study that as the number of abortions increase the successful outcome of pregnancy decreases and the one patient with previous 9 abortions had a preterm IUGR baby which well explains the importance of the condition. Age also has a profound effect on the pregnancy outcome as the rate of complications increase with increasing maternal age. And patients with secondary RPL had good outcome with a higher success rates compared to the ones with primary RPL. This was also reported in the study by Regan et al.
COMPARISON WITH OTHER STUDIES MY
STUDY
SAITO ET AL
TANYA PRADHAN
INCIDENCE 1.09% 1 - 2% 1%
IDIOPATHIC ETIOLOGY 53% 66% 65%
ANATOMICALFACTORS 6%` 9% 20%
ENDOCRINE FACTORS 23% 7% 6%
OBSTETRIC
COMPLICATIONS
12% 2% 9%
SUCCESSFUL
PERINATAL OUTCOME
91% 62.5% 77.1%
