a study on second trimester placental location and the adverse prenancy outcome Thesis submitted to the Kerala University of Health Sciences inpartial fulfilment of the requirements for the Degree of Master of Surgery in Obstetrics and Gynaecology By Dr

a study on second trimester placental location and the adverse prenancy outcome
Thesis submitted to the Kerala University of Health Sciences
inpartial fulfilment of the requirements for the Degree of
Master of Surgery in Obstetrics and Gynaecology

By
Dr. SHEENA KRISHNAN
Post Graduate Student in Obstetrics and Gynaecology
SREE GOKULAM MEDICAL COLLEGE AND RESEARCH FOUNDATION VENJARAMOODU, THIRUVANANTHAPURAM- 695607
KERALA
2016 – 2019
a study on second trimester placental location and the adverse prenancy outcome

By
Dr. SHEENA KRISHNAN
Post Graduate Student in Obstetrics and Gynaecology
DISSERTATION SUBMITTED IN PARTIAL FULFILMENT OF THE RULES AND REGULATIONS FOR THE MS DEGREE EXAMINATION IN OBSTETRICS AND GYNAECOLOGY
KERALA UNIVERSITY OF HEALTH SCIENCES
THRISSUR
2016 – 2019
a study on second trimester placental location and the adverse prenancy outcome

By
Dr. SHEENA KRISHNAN
Post Graduate Student in Obstetrics and Gynaecology
Dissertation submitted to the
Kerala University of Health Sciences, Thrissur, Kerala
in partial fulfilment of the requirements for the degree ofMaster of Surgery in Obstetrics and Gynaecology
Under the guidance ofDr. LEKSHMI M Associate Professor
DEPARTMENT OF OBSTETRICS AND GYNAECOLOGY
SREE GOKULAM MEDICAL COLLEGE AND RESEARCH FOUNDATION VENJARAMOODU, THIRUVANANTHAPURAM KERALA
2016 – 2019
KERALA UNIVERSITY OF HEALTH SCIENCES
THRISSUR
DECLARATION BY THE CANDIDATE
I hereby declare that this thesis entitled “A study on second trimester placental location and the adverse pregnancy outcome” is a bonafide and genuine research work carried out by me, under the guidance of Dr. Lekshmi M, Associate Professor, Department of Obstetrics and Gynaecology, Sree Gokulam Medical College And Research Foundation, Thiruvananthapuram during the period 2016– 2019.

This is submitted to the Kerala University of Health Sciences in partial fulfilment of the rules and regulations for the Master of Surgery Degree Examination in Obstetrics and Gynaecology.

Dr. SHEENA KRISHNAN
Post Graduate Student Department of Obstetrics and GynaecologySree Gokulam Medical College and Research Foundation Thiruvananthapuram
Date:
Place: Thiruvananthapuram

DEPARTMENT OF OBSTETRICS AND GYNAECOLOGY
SREE GOKULAM MEDICAL COLLEGE AND RESEARCH
FOUNDATION, THIRUVANANTHAPURAM, KERALA

CERTIFICATE BY THE GUIDE
This is to certify that the dissertation “A study on second trimester placental location and the adverse pregnancy outcome” is a bonafide and genuine research work done by Dr. Sheena Krishnan under my guidance and supervision in partial fulfilment of the requirements for the degree of Master of Surgery in Obstetrics and Gynaecology.

Dr. LEKSHMI M
Associate Professor
Department of Obstetrics and GynaecologySree Gokulam Medical College and Research Foundation Thiruvananthapuram
Date:
Place: Thiruvananthapuram

DEPARTMENT OF OBSTETRICS AND GYNAECOLOGY
SREE GOKULAM MEDICAL COLLEGE AND RESEARCH
FOUNDATION, THIRUVANANTHAPURAM, KERALA

CERTIFICATE BY THE HEAD OF THE DEPARTMENT
This is to certify that the dissertation “A study on second trimester placental location and the adverse pregnancy outcome” is a bonafide and genuine research work done by Dr. Sheena Krishnan in partial fulfillment of the requirements for the degree of Master of Surgery in Obstetrics and Gynaecology.

Dr. Nazeema.A
Professor and Head of the Department
Department of Obstetrics and GynaecologySree Gokulam Medical College and Research Foundation Thiruvananthapuram
Date:
Place: Thiruvananthapuram
DEPARTMENT OF OBSTETRICS AND GYNAECOLOGY
SREE GOKULAM MEDICAL COLLEGE AND RESEARCH
FOUNDATION, THIRUVANANTHAPURAM, KERALA

CERTIFICATE BY THE HEAD OF THE INSTITUTE
This is to certify that the dissertation “A study on second trimester placental location and the adverse pregnancy outcome” is a bonafide and genuine research work done by Dr. Sheena Krishnan in partial fulfilment of the requirements for the degree of Master of Surgery in Obstetrics and Gynaecology.

Dr. R . Dayananda Babu
Principal
Sree Gokulam Medical College and Research Foundation
Thiruvananthapuram
Date:
Place: Thiruvananthapuram

Copyright
Declaration by the Candidate
I hereby declare that Kerala University of Health Sciences shall have the rights to preserve, use and disseminate this dissertation / thesis in print or electronic format for academic / research purpose.

Signature of the Candidate
Dr. Sheena Krishnan
Date:
Place: Thiruvananthapuram
©Kerala University of Health Sciences, Kerala

STRUCTURED ABSTRACT
BACKGROUND
Hypertensive disorders of pregnancy, including preeclampsia complicate up to 10 % pregnancies worldwide .Similarly Intrauterine growth failure affects up to 10% of pregnancies.Placental location has been implicated in preterm birth, in fetal mal-position and malpresentation, small for gestational age, low Apgar score and in development of pre-eclampsia. The placenta is located laterally in majority of patients with abnormal flow velocity waveforms. In the light of these observations, designed a prospective study to find out whether the lateral location of placenta as seen by ultrasound at II trimester of gestation can be used to predict the development of hypertensive disorders,fetal growth disorders and preterm birth.

OBJECTIVE
To find out the proportion of the adverse pregnancy outcome of laterally located placenta in comparison to normally located placenta among all cases of singleton pregnancy.

To find out the proportion of lateral placental location from 2nd trimester ultrasonography in all singleton pregnancy.

MATERIAL AND METHODS
This prospective observational study was carried out in Department of Obstetrics and Gynaecology at Sree Gokulam Medical College And Research Foundation from March 2017 to August 2018 on 614 pregnant women over a period of 18months.

RESULTS
Out of 614 antenatal women 221 (36 %) cases had Anterior placenta ,218 (35.5 % ) had posterior placenta , 68 (11.1 % ) had fundal placenta and 107 (17.4 % ) cases had lateral placenta .

Out of 72 hypertensive patients, 28 (38.9%) had laterally located placenta with chi-square value of 172.31 and p value of <0.01 which is statistically significant. so placental laterality can be simple and reliable predictor of preeclampsia.
Out of 68 patient who was having IUGR, 44 (64.7%) had lateral placenta with significantly increased P value ( P <0.01 ) and chi-square value of 172.31 ,so there is positive correlation between IUGR and lateral placenta.
.

CONCLUSION
Placental laterality as determined by ultrasound at 18-24 weeks is a simple yet reliable noninvasive and cost effective predictive screening test for adverse pregnancy outcome.

KEY WORDS
Placenta, Preeclampsia, Preterm, IUGR
INDEX
Sl.No. Contents Page
1 STRUCTURED ABSTRACT 2 INTRODUCTION 3 OBJECTIVES 4 REVIEW OF LITERATURE & BACK GROUND 5 RELEVANCE 6 MATERIALS AND METHODS 7 OBSERVATIONS AND RESULTS 8 DISCUSSION 9 CONCLUSION 10 BIBLIOGRAPHY 13 ANNEXURES 14 15
ANNEXURE
LIST OF ANNEXES Page No
ANNEXURE I– PROFORMA ANNEXURE II- CONSENT FORMS ANNEXURE III- KEY TO MASTER CHART ANNEXURE IV- MASTER CHART
LIST OF TABLES
Table No Name Page No
Table 1 Percentage distribution of the sample according to age Table 2 Percentage distribution of the sample according to obstetric score Table 3 Percentage distribution of the sample according to USG finding of placental location Table 4 Percentage distribution of the sample according to maternal outcome Table 5 Percentage distribution of the sample according to mode of delivery Table 6 Percentage distribution of the sample according to birth weight Table 7 Percentage distribution of the sample according to Apgar score Table 8 Comparison of maternal outcome based on USG findings of placental location Table 9 Comparison of birth weight based on USG findings of placental location Table 8 Comparison of Apgar score at 1 minute based on USG findings of placental location Table 9 Comparison of Apgar score at 5 minute based on USG findings of placental location Table 10 Comparison of maternal outcome based on obstetric score LIST OF FIGURES
Figure No Name Page No
Graph 1 Percentage distribution of the sample according to age Graph 2 Percentage distribution of the sample according to obstetric score Graph 3 Percentage distribution of the sample according to USG finding of placental location Graph 4 Percentage distribution of the sample according to maternal outcome Graph 5 Percentage distribution of the sample according to mode of delivery Graph 6 Percentage distribution of the sample according to birth weight Graph 7 Percentage distribution of the sample according to Apgar score Graph 8 Comparison of maternal outcome based on USG findings of placental location Graph 9 Comparison of birth weight based on USG findings of placental location Graph 10 Comparison of Apgar score at 1 minute based on USG findings of placental location Graph 11 Comparison of Apgar score at 5 minute based on USG findings of placental location Graph 12 Comparison of maternal outcome based on obstetric score INTRODUCTION
Placenta is an important connecting organ between mother and fetus, a lot of fetus problems related with placenta. It is the vital link between the mother and the fetus for metabolic exchange, endocrine and otherbody functions, is critical for maternal, neonatal wellbeing.

The blood supply of placenta is not uniformly distributed. As such, the size of implantation and resultant location of the placenta within the uterus are likely important determinants of placental blood flow and therefore pregnancy success. Placental location has been implicated in preterm birth, in fetal mal-position and malpresentation, small for gestational age, low Apgar score and in development of pre-eclampsia.1-4 The significance of placental location in the uterine cavity has been studied extensively.

Several methods have been used to document placental location, including manual exploration of uterus, soft tissue x-ray films, isotopic placentography. In the past two decades, ultrasound has proved to be the safest, easiest and most accurate method for assessing placental location. USG of placenta is primarily directed toward determining the location of the placenta and identifying its abnormalities in the later weeks of pregnancy.

However, the advent of high-resolution transvaginal ultrasound (TVS) has revolutionized the understanding of placental studies, and it is believed that placental evaluation in early pregnancy could be useful in identifying the risks for subsequent disorders. The site of implantation that decides the location of placenta is likely to be important determinant of placental blood flow and therefore pregnancy outcome.

Ultrasound imaging has become an integral component of routine prenatal medical care for most pregnant women. During an obstetrical ultrasound, evaluation of the fetus is chief priority but often, the other components (placenta, umbilical cord, and amniotic fluid) which represent an integral part of gestation, are arguably not given the attention they deserve.

Preeclampsia occurs only in the presence of placenta?. The poorly perfused placenta may be the origin of factors which gain access to maternal vasculature and cause endothelial cell dysfunction. Reduced placental perfusionin preeclampsia is thought to result from failure of the trophoblasts to invade maternal spiral artery?. Among the various predictors for preeclampsia, the placental location by ultrasound at 18-24 weeks is very cost effective, noninvasive, and has a good positive predictive value. There is a significant association between placental location and uterine artery resistance and adverse outcomes such as preeclampsia and IUGR.

It has been shown that in humans, both uterine arteries have a significant number of branches and that each supply the corresponding side of the uterus. Although
anastomoses between the two uterine arteries exist, there is no proof that these are functional. When the placenta is laterally located, the uterine artery closer to the placenta has lower resistance than one opposite it. In patients with centrally located placentas both uterine arteries demonstrated similar resistance. When the placenta is centrally located, the uteroplacental blood flow needs are met with by equal distribution from both uterine arteries.However, when placenta is laterally located, in the majority of cases the uteroplacental blood flow needs are met with primarily by one of the uterine arteries with some contribution from the other uterine artery via collateral circulation. The degree of collateral circulation may not be the same in all subjects and deficient contribution may facilitate the development of preeclampsia, intrauterine growth retardation or both. The significance of normal placentation for this cytotrophoblasitc invasion is high and the cytotrophoblasts fail to adopt a vascular adhesion phenotype in preeclampsia. Quantitative analysis of trophoblast invasion in preeclampsia had shown restricted invasion of trophoblastic cells in preeclampsia?.This may explain the reduced trophoblastic invasion in laterally situated placenta when the uteroplacental blood flow needs are mainly met with by that side uterine artery.

There is a significant association of posterior placenta and preterm labour and stillbirth?. This is probably because placenta located on the posterior uterine wall may be somehow less efficient due to the anatomy of that wall. As a result of uneven uterine blood supply, the posterior wall of the pregnant uterus is longer and somewhat thicker. Each of these factors may affect uterine blood supply, especially as the uterus expands to accommodate the pregnancy.

In the light of these observations, we designed a prospective study to find out whether the location of placenta as seen by ultrasound at 18-24 weeks of gestation can be used to prediction of adverse pregnancy outcome. Result of this study may provide insight as second trimester placental localization by USG can be used as effective screening modalility for various pregnancy related complication and its outcome.

OBJECTIVES
Primary objective:
To find out the proportion of the adverse pregnancy outcome of laterally located placenta in comparison to normally located placenta among all cases of singleton pregnancy attending antenatal clinic in SreeGokulam medical college and research foundation.

Secondary objective:
To find out the proportion of lateral placental location from 2nd trimester ultrasonography in all singleton pregnancy.

REVIEW OF LITERATURE AND BACK GROUND
The placenta is a fetal organ of pregnancy, responsible for providing nutrition and oxygen to the fetus as well as excretory functions.

Placenta is formed by fetal and maternal components( 10)
maternal component: decidua placentalis is the inner portion of the placenta, which is formed by trophoblastic invasion of endometrium
fetal component: chorion frondosum is formed by an arterial plexus (branches of the umbilical artery), protruding into intervillous spaces as chorionic villi
Placenta is derived from the Greek word, plakuos, meaning “flat cake” (9 )and this reflects its typical appearance. The placenta was noted by Aristotle and Galen, but the term originates with Fallopius who called it the “placenta uterina”.

Typically, the placenta is discoid in shape. The placenta normally lies along the anterior or posterior wall of the uterus and may extend to the lateral wall with increasing gestational age (9).

Ultrasound is the first-line modality in imaging the placenta due its wide availability and its use of non-ionising radiation. The placenta appears as a uniformly echogenic (intermediate echogenicity) structure along uterine wall, with a deep hypoechoic band separating it from normal uterine myometrium. This retroplacental hypoechoic band is vital to rule out implantation disorders and its normal appearance should not be confused with retroplacental hematoma 1. There may also be numerous anechoic areas, representing venous lakes, within the placenta itself 4. 
4. Butler P, Mitchell A, Healy JC. Applied Radiological Anatomy. Cambridge University Press. (2012) ISBN:0521766664. Read it at Google Books – Find it at Amazon The placenta will be classified as central when it is equally distributed between the right and the left side of the uterus irrespective of anterior, posterior or fundal position. When 75% or more of the placental mass is to one side of the midline, it is classified as unilateral right or left placenta

The placenta at term weighs ~470 g and measures ~22 cm in diameter with a thickness of 2.0-2.5 cm 3. Placental thickness is usually directly proportional to gestational age, to the extent that it can often predict the gestation weeks (e.g. 21 mm thickness at 21 weeks gestation).

Due to the changing morphology of placental substance with increasing gestation, maturity grading of the placenta is conveniently done.

The umbilical cord typically inserts at the centre of the placental bulk.

Anatomy of the placenta In order to understand the chronological development of the chorionic villi it is important to have a comprehensive overview of placental anatomy. In this diagram, the placenta is roughly four months old and various fundamental structures can be recognized, namely the umbilical cord, the amnion, the chorionic plate, the already advanced branching of the villi, the basal plate and the cotyledon. Fig. 13 – Placenta at around the fourth month 1234567 Umbilical cordAmnionChorionic plateIntervillous space (maternal blood) Basal plateCotyledonVillus
Development of the placental villi
While the embryo is nourished in the first weeks through simple diffusion, later, due to its rapid growth, it needs a more powerful gas and nutrient exchange system. This is made possible by the development of the utero-placental circulation system in which the circulation systems of the mother and of the embryo get closer together, thus allowing an exchange of gases and metabolites via diffusion.It must be always kept in mind, though, that maternal and fetal blood never come into direct contact with each other.

This system decays after the ninth day in the lacunar stage
Through the lytic activity of the syncytiotrophoblast the maternal capillaries are eroded and anastomose with the trophoblast lacunae, forming the sinusoids. At the end of the pregnancy the lacunae communicate with each other and form a single, connected system that is delimited by the syncytiotrophoblast and is termed the intervillous space. 
Between the 11th and 13th day cytotrophoblast cells penetrate into the cords of the syncytiotrophoblast creating the primary trophoblast villiAfter the 16th day the extra-embryonic mesoblast also grows into this primary trophoblast villus, which is now called a secondary villus   and expands into the lacunae that are filled with maternal blood. As was already mentioned, the ST forms the outermost layer of every villus. At the end of the 3rd week the villus mesoblast differentiates into connective tissue and blood vessels. They connect up with the embryonic blood vessels. Villi that contain differentiated blood vessels are called tertiary villi .

From this time on gases, nutrients, and waste products that diffuse through the maternal and fetal blood must pass through a total of four layers:
Capillary endothelium of the villus
Loose connective tissue that surrounds the endothelium
Cytotrophoblast
Syncytiotrophoblast
These four elements together form the placental barrier.

After the 4th month the cytotrophoblast in the tertiary villi disappear slowly, the villi divide further and become very thin, whereby the distance between the intervillous space with maternal blood and the fetal vessels gets smaller. The villi that arise in this way are called free villi.

The cytotrophoblast layer The cytotrophoblast of the anchoring villus expands until a further layer outside the syncytiotrophoblast arises, forming the cytotrophoblast layer . It slips in between the syncytiotrophoblast and the uterine endometrium.

Over the course of the 4th month the cytotrophoblast cells slowly disappear out of the villus wall and the chorionic plate. They persist, however, in the cytotrophoblast layer. The cytotrophoblast cells penetrate into the decidua and the myometrium and also colonize the wall of the spiral arteries close to their openings.

This invasion of the maternal vessels by the cytotrophoblast leads to the destruction of the smooth muscle layer and to a partial replacement of the endothelial cells. It is responsible for the change in elasticity of the spiral arteries, whereby the blood circulation of this fetoplacental unit is adapted to the rapid growth of the fetus. This phenomenon of cell exchange is absent in preeclampsia or an intra-uterine growth retardation.An excessive proliferation of the cytotrophoblast can lead to tumor formation, especially to a chorion carcinoma.

Fetal and maternal blood circulation systems

The umbilical arteries supply deoxygenated blood from the fetus to the placenta. There are usually two umbilical arteries present together with one umbilical vein in the umbilical cord. The umbilical arteries surround the urinary bladder and then carry all the deoxygenated blood out of the fetus through the umbilical cord. Inside the placenta, the umbilical arteries connect with each other at a distance of approximately 5 mm from the cord insertion in what is called the Hyrtl anastomosis.1 Subsequently, they branch into chorionic arteries or intraplacental fetal arteries.2The umbilical arteries are actually the latter of the internal iliac arteries (anterior division of) that supply the hind limbswith blood and nutrients in the fetus.

The pressure inside the umbilical artery is approximately 50 mmHg.3 Gordon, Z.; Elad, D.; Almog, R.; Hazan, Y.; Jaffa, A. J.; Eytan, O. (2007). “Anthropometry of fetal vasculature in the chorionic plate”. Journal of Anatomy. 211 (6): 698–706. doi:10.1111/j.1469-7580.2007.00819.x. PMC 2375851. PMID 17973911.

Jump up^ Hsieh, FJ; Kuo, PL; Ko, TM; Chang, FM; Chen, HY (1991). “Doppler velocimetry of intraplacental fetal arteries”. Obstetrics and gynecology. 77 (3): 478–82. PMID 1992421.

Jump up^ Fetal and maternal blood circulation systems From Online course in embryology for medicine students. Universities of Fribourg, Lausanne and Bern (Switzerland). Retrieved on 6 April 2009
The placental circulation brings into close relationship two circulation systems: the maternal and the fetal. The supply of blood to the placenta is influenced by various factors, especially by the arterial blood pressure, uterine contractions, tobacco abuse, medications and hormones. Placental blood flow is increased at term and amounts to 500 ml/min (80% of the uterine perfusion).

The fetal circulation system The villus capillaries are branches of the umbilical vessels. Fetal blood comes via the two umbilical arteries in the villi and leaves the placenta through a single umbilical vein .Their supply amounts to approximately 40% of the fetal heart blood volume per minute.The blood pressure in the umbilical artery amounts to 50 mmHg and the blood flows through finer vessels that cross through the chorionic plate to the capillaries in the villi where the arterial blood pressure falls to 30 mmHg. In the umbilical vein the pressure is 20 mm Hg. The pressure in the fetal vessels and their villus branches always lies over that of the intervillous space. This protects the fetal vessels from collapse .

Fig. 33 – Utero-placental circulation system  Legend

Fetal blood flows via the umbilical artery, where the blood pressure amounts to 50 mm Hg, through finer vessels in the chorionic plate, in order to finally reach the capillaries in the villi, where the pressure sinks to 30 mm Hg.

1 umbilical arteries
2 umbilical vein
3 fetal capillaries
The maternal circulation system During the pregnancy the uterine circulation constantly adapts in order to be adequate for the growing metabolic needs of the embryo. Via the spiral arteries (80 -100 mm Hg) that come from the uterine arteries , maternal blood gets into the intervillous spaces in a region delimited by the anchoring villi. Subsequently the blood leaves the intervillous spaces via the uterine veins that are arranged in the periphery of the intervillous space.The flow of the placental blood amounts to 600 cm3/min and the pressure in the spiral arteries to 70 mm Hg. In the intervillous spaces the pressure falls to only 10 mm Hg .The blood in the intervillous space is exchanged 2-3 times per minute.

Fig. 34 – Maternal circulation system  Legend
Maternal blood arrives at the intervillous space via arteries that open directly into the intervillous space. At the placental level, it thus finds itself temporarily outside the vessel network
1 Spiral arteries2 Uterine veins3 Intervillous spacesA Basal plate
THE PLACENTAL BARRIER
The placental barrier is composed of structures that separate the maternal and the fetal blood .The makeup of the placental barrier changes over the course of the pregnancy.

In the first trimester it consists of the syncytiotrophoblast, the cytotrophoblast (Langhans’ cells), the villus mesenchyma (in which numerous ovoid Hofbauer cellsthat exhibit macrophage properties are found) and the fetal capillary walls. Fig. 35 – Villus in the first trimenon  Legend

123456 Intervillous spaceSyncytiotrophoblastCytotrophoblastVillus mesenchymaFetal capillariesHofbauer macrophages

Fig. 35The villus has an intact syncytio- and cytotrophoblast layer. In the villus interior there are mesenchymal cells with macrophages and fetal capillaries.

During the 4th month the cytotrophoblast disappears from the villus wall and the thickness of the barrier decreases while the surface area increases (roughly 12 m2towards the end of the pregnancy). In the 5th month the fetal vessels have multiplied their branches and gotten closer to the villus surface. Fig. 36 – Villus in the second trimester  Legend

123456 Intervillous spaceSyncytiotrophoblastCytotrophoblastVillus mesenchymaFetal capillariesHofbauer macrophages

Fig. 36In the middle third of the pregnancy the capillaries migrate to the villus surface. The cytotrophoblast layer disappears slowly and the syncytiotrophoblast layer becomes thinner.

During the 6th month the nuclei of the syncytiotrophoblast group together in the so-called proliferation knots. The other zones of the syncythiothrophoblast lack nuclei and are adjacent to the capillaries (exchange zones). Fig. 37 – Placental barrier in a mature villus  Legend

123456789 Intervillous space (with maternal blood)Placental barrier of a terminal villusFetal capillariesMerged basal membranes of the fetal capillary and of the syncythiothrophoblast Endothelial cellsRare cytotrophoblast cellsBasal membrane of the capillariesBasal membrane of the trophoblast portion Syncytiotrophoblast with proliferation knots (nuclei rich region)

Fig. 37At its thinnest part, the placental barrier is reduced to the nucleus-free syncytiotrophoblast, the merged basal membrane and the endothelium.

It has been shown that in humans, both uterine arteries have a significant number of branches and each supply the corresponding side of the uterus. Although anastomoses between the two uterine arteries exist, there is no proof that these are functional.6 When the placenta is laterally located, the uterine artery close to the placenta has lower resistance than the one opposite from it. In patients with centrally located placenta, both uterine arteries demonstrate similar resistance. When the placenta is centrally located, the uteroplacental blood flow needs are met by equal contribution from both uterine arteries. However, when the placenta is laterally located, in the majority of the patients, the uteroplacental blood flow needs are to be met primarily by one of the uterine artery, with some contribution by the other uterine artery via collateral circulation.7 This degree of collateral circulation; however, may not be the same in all patients and deficient contribution may facilitate the development of preeclampsia, IUGR or both. The existence of major vascular anastomoses in some patients may explain the normal uterine flow velocity waveform and absence of preeclampsia and IUGR despite the presence of a unilateral placenta.8 In normal pregnancies, the spiral arterioles that supply the placental bed undergo trophoblast induced conversion to uteroplacental arterioles. The significance of normal placentation for this cytotrophoblastic invasion is high and the cytotrophoblasts fail to adopt a vascular adhesion phenotype in preeclampsia.6,9 In preeclampsia conversion of the spiral arterioles is incomplete.10 It involves only the subplacental venules. If there were no functional anastomoses between right and left uterine arteries, in cases with unilaterally located placentas, one would expect the ipsilateral uterine artery systolic/diastolic ratios to change more than the contralateral ratios in hypertensive pregnancies. This may explain the reduced trophoblastic invasion in laterally situated placenta when the uteroplacental blood flow need is mainly met by one side uterine artery.
In case of unilateral placenta, the absence or insufficient trophoblastic invasion of arteries on contralateral side, specifically the spiral arteries that the endovascular cytotrophoblast should invade result in decreased blood flow to the fetus which may cause intrauterine growth restriction.
6. Dekker GA, Sibai BM. Etiology and pathogenesis of preeclampsia. Current Concepts Am J Obstetgynaecol 1998;179(5):1359-75.
7. Kofinas AD, Penry M, Swain M, et al. The effect of placental location on uterine artery flow velocity wave forms. Am J Obstet Gynaecol 1988;159(6):1504-8.
8. Ito Y, Shono M, Uchiyama A, et al. Resistance index of uterine artery and placental location in intrauterine growth retardation. Acta Obst Gynaecol Scand 1998;77(4):385-90.
9. Walker JJ. Current thoughts on pathophysiology of preeclampsia/eclampsia. In: Stud J, ed. Progress in obstetrics and gynaecology. Edinburg: Churchill Livingstone 1998:177-188.
10. Roberts JM, Hubel CA. Is oxidative stress the link in the two-stage model of pre-eclampsia. Lancet 1999;354(9181):788-9.
Non-invasive Doppler velocimetric studies of the uterine arteries in the second trimester reveal that abnormal wave forms indicating defective uterine perfusion is primarily a consequence of placental implantation when one uterine artery is the dominant supply of the intervillous flow.4,5
The placenta is located laterally in majority of patients with abnormal flow velocity waveforms.4
4. Fleischer A, Schulman H, Farmakides G, Bracero L, Grunfeld L, Rochelson B et al. Uterine artery Doppler velocimetry in pregnant women with hypertension. Am J Obstet ; Gynecol. 1986;154:806-13.
5. Schulman H, Winter D, Farmakides G, Ducey J, Guzman E, Coury A et al. Pregnancy surveillance with Doppler velocimetry of uterine and umbilical arteries. Am J Obstet Gynecol. 1989;160:192-6.
Hypertensive disorders of pregnancy, including preeclampsia complicate up to 10 % pregnancies worldwide constituting one of the greatest causes of maternal and perinatal morbidity and mortality worldwide .

Hypertensive disorders during pregnancy are classified into 4 categories, as recommended by the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy: 1) gestational hypertension 2) preeclampsia 3 ) eclampsia, 4) chronic hypertension 5) preeclampsia superimposed on chronic hypertension¹
Gestational Hypertension
Gestational hypertension, formerly known as pregnancy-induced hypertension or PIH, is the new onset of hypertension after 20 weeks of gestation. The diagnosis requires that the patient have:
Elevated blood pressure (systolic ? 140 or diastolic ? 90 mm Hg, the latter measured using the fifth Korotkoff sound)
Previously normal blood pressures
No protein in the urine
No manifestations of preeclampsia, eclampsia.

Also known as transient hypertension, gestational hypertension is actually diagnosed retrospectively when the patient does not develop preeclampsia and if blood pressure returns to normal by the 12-week postpartum visit.

Preeclampsia
Preeclampsia is a multiorgan disease process of unknown etiology (11) characterized by the development of hypertension and proteinuria after 20 weeks of gestation.

There are various theories of pathogenesis of preeclampsia. The most popular theory is immunologic.

During a normal pregnancy, fetal syncytial trophoblasts penetrate and remodel maternal spiral arteries, causing them to dilate into large, flaccid vessels. This remodeling accommodates the vast, increased maternal circulation needed for adequate placental perfusion. This remodeling is somehow prevented in preeclamptic pregnancies: the placenta is unable to properly burrow into the maternal blood vessels, leading to intrauterine growth restriction and other fetal manifestations of the disorder. Investigators speculate that this incomplete placentation is due to maternal immunologic intolerance of foreign fetal genes. Evidence in support of this theory is that the risk of preeclampsia is highest in a first pregnancy and decreases with the length of time a woman has lived with the father before becoming pregnant. Furthermore, risk is also increased in multiparous women who are pregnant by a new partner. Others theories of pathogenesis of preeclampsia are angiogenic factors (increased sFlt-1, decreased placental growth factor levels) (4, 5) cardiovascular maladaptation and vasoconstriction, genetic predisposition (maternal, paternal, thrombophilias) (6, 7) immunologic intolerance between fetoplacental and maternal tissue (8), platelet activation, vascular endothelial damage or dysfunction (8). Several factors are associated with preeclampsia and they are antiphospholipid antibody syndrome, chronic hypertension, chronic renal disease, elevated body mass index, maternal age older than 40 years, multiple gestation, nulliparity, preeclampsia in a previous pregnancy (particularly if severe or before 32 weeks of gestation), pregestational diabetes mellitus.
1. Barton JR, O’brien JM, Bergauer NK, Jacques DL, Sibai BM. Mild gesta tional hypertension remote from term: progression and outcome. Am J Obstet Gynecol. 2001;184(5):979–983. PubMed
4. Levine RJ, Thadhani R, Qian C, et al. Urinary placental growth factor and risk of preeclampsia. JAMA. 2005;293(1):77–85. PubMed
5. Levine RJ, Maynard SE, Qian C, et al. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med. 2004;350(7):672–683. PubMed
6. Esplin MS, Fausett MB, Fraser A, et al. Paternal and maternal com ponents of the predisposition to preeclampsia. N Engl J Med. 2001;344(12):867–872. PubMed
7. Mignini LE, Latthe PM, Villar J, Kilby MD, Carroli G, Khan KS. Mapping the theories of preeclampsia: the role of homocysteine. Obstet Gynecol. 2005;105(2):411–425. PubMed
8. Sibai BM. Diagnosis and management of gestational hypertension and preeclampsia. Obstet Gynecol. 2003;102(1):181–192. PubMed
11. Salvig JD, olsen SF, Secher NJ. Effects of fish oil supplementation in late pregnancy on blood pressure: a randomised controlled trial. Br J Obstet Gynaecol. 1996;103(6):529–533. PubMed
Diagnosis
Preeclampsia is defined as elevated blood pressure after 20 weeks of gestation (? 140 mm Hg systolic or ? 90 mm Hg diastolic) plus proteinuria (> 0.3 g/24 hours). In clinical practice, we usually use the criteria of two elevated bloodpressure measurements 6 hours apart and a proteinuria of 300 mg in a 24-hour urine specimen. A 24-hour determination is most accurate because urine dipsticks can be affected by variable excretion, maternal dehydration, and bacte riuria . A random urine protein/creatinine ratio of less than 0.21 indicates that significant proteinuria is unlikely with a negative predictive value of 83 percent; however, confirmatory 24-hour urine protein determination is recommended (14). nonspecific. Generalized edema (affecting the face and hands) may be impressive and was once considered a diagnostic criterion, but it is no longer regarded as one because it is too variable. Preeclampsia can range from mild to severe. Severe preeclampsia is defined as any of the following:
Markedly elevated blood pressure measurements (systolic ? 160 mm Hg or diastolic ? 110 mm Hg) taken at least 6 hours apart with the patient on bed rest
Proteinuria (? 5 g/24 hours or ? 3+ on two random samples 4 hours apart)
Manifestations of end-organ disease: oliguria (< 500 mL in 24 hours), cerebral or visual disturbances, pulmonary edema, cyanosis, epigastric or right-upperquadrant pain, impaired liver function, thrombocytopenia, or fetal growth restriction.

Hematologic changes include:
Thrombocytopenia—platelets are dramatically reduced, probably consumed by endothelial injury. Counts can be as low as 20 to 50 x 109/L.

Hemoconcentration—doctors used to follow preeclampsia with serial hematocrits.

Microangiopathic hemolysis—eventually, red cells are sheared through the microcirculation.

Hepatic changes are usually limited to hepatocellular necrosis, demonstrated by elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels.

Occasionally there is subcapsular hemorrhage and even hepatic rupture, which has a 60% maternal mortality rate.

Neurologic changes are common and include headache, blurred vision, scotoma (seeing spots or “snow”), hyperreflexia, and rarely, cortical blindness, and the generalized seizures of eclampsia.

Renal changes. Glomerular endotheliosis is the pathognomonic lesion of preeclampsia: the glomeruli are enlarged, distorted, and filled with occlusions, with hypertrophy of the intracapillary cells. Laboratory testing shows a decreased glomerular filtration rate, decreased renal blood flow (the former more than the latter), and nonselective proteinuria (ie, all proteins including albumin; what a urine dip stick detects).

Fetal changes. Intrauterine growth restriction is very common. Oligohydramnios also occurs, because the amniotic fluid is essentially fetal urine; with poor perfusion through the placenta, the fetus has diminished urine output. Intrauterine demise and placental abruption are not uncommon. Doppler waveforms are typically abnormal, and antenatal testing suggests that the fetus is in jeopardy. We use the ratio of forward flow of blood in the umbilical artery during systole to that during diastole (the “umbilical artery S:D ratio”) to assess the degree of resistance to flow in the placenta. The higher the ratio, the less diastolic flow. The greater the resistance to flow, the greater the peril to the fetus.

HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets) used to be classified as a separate syndrome, but current thinking categorizes it as a manifestation of preeclampsia, occurring in about 20% of severe cases. It is associated with significant maternal and perinatal morbidity. A decreasing platelet count and an increasing l-lactate dehydrogenase level (indicative of both hemolysis and liver dysfunction) reflect disease severity (15, 16).

14. Wheeler TL II, Blackhurst DW, Dellinger EH, Ramsey PS. Usage of spot urine protein to creatinine ratios in the evaluation of preeclampsia. Am J Obstet Gynecol. 2007;196(5):465.e1–4. PubMed
15. Sibai BM. Diagnosis, controversies, and management of the syndrome of hemolysis, elevated liver enzymes, and low platelet count. Obstet Gynecol. 2004;103(5 pt 1):981–991. PubMed
16. Magann EF, Martin JN Jr. Twelve steps to optimal management of HELLP syndrome. Clin Obstet Gynecol. 1999;42(3):532–550. PubMed
Eclampsia
Eclampsia is the development of convulsions in a preexisting pre-eclampsia or it may appear unexpectedly in a patient with minimally elevated blood pressure and no proteinuria. The exact cause is unknown but cerebral ischaemia and oedema were suggested. The timing of an eclamp tic seizure can be antepartum (53 percent), intrapar tum (19 percent), or postpartum (28 percent) (26).

26. Mattar F, Sibai BM. Eclampsia. VIII. Risk factors for maternal morbidity. Am J Obstet Gynecol. 2000;182(2):307–312. PubMed
Chronic Hypertension in pregnancy
Chronic hypertension is high blood pressure that either precedes pregnancy, is diagnosed within the first 20 weeks of pregnancy, or does not resolve by the 12-week postpartum checkup.
Two categories of severity are recognized: mild (up to 179 mm Hg systolic and 109 mm Hg) and severe (? 180 systolic or 110 diastolic). Chronic hypertension complicates about 5% of all pregnancies, and prevalence rates are increasing due to delayed childbearing. Medications should be reviewed when pregnancy is first diagnosed. We cannot recommend with certainty to either stop, start, or continue antihypertensive medications: evidence is mixed whether such actions improve outcome. Methyldopa is the most studied of all antihypertensive medications and is generally the first choice in pregnancy because it has a limited effect on uteroplacental blood flow. Sometimes an alternative must be found because of elevated liver enzymes or complaints of headache. Labetalol, a combined alphablocker and beta-blocker, is the first alternative to methyldopa and is becoming a first-line choice as experience with the drug during pregnancy increases. It is generally well tolerated and has an easier (twice-a-day) dosing schedule than methyldopa. Calcium channel blockers, particularly nifedipine, are being used more frequently, probably because doctors have become familiar with their use to stop premature labor. They seem to be safe and effective, but evidence is sparse. Diuretics have been used in pregnancy despite the theoretical risk of preventing normal blood volume expansion.

Most studies have not found adverse pregnancy outcomes. Nonetheless, caution should be used in cases of impaired uteroplacental perfusion, such as preeclampsia or intrauterine growth restriction. Atenolol and other pure beta-blockers should be avoided: they have been associated with babies born small for their gestational age. Angiotensin-converting enzyme (ACE) inhibitors are contraindicated in the second and third trimester because they are associated with a myriad of congenital anomalies, including renal failure, oligohydramnios, renal dysgenesis, reduced ossification, pulmonary hypoplasia, and fetal and neonatal death. Patients presenting in the first trimester on an ACE inhibitor should either be taken off antihypertensive medications or switched to another agent. Exposure during this time is not an indication for pregnancy termination, however. Angiotensin II receptor antagonists are considered guilty by association because of their similarity to ACE inhibitors, but there are no data to confirm this. Chronic hypertension accounts for a disproportionate amount of maternal and perinatal morbidity and mortality, mostly because of an increased risk of superimposed preeclampsia. There is an increased risk of prematurity, birth of infants who are small for their gestational age, intrauterine death, placental abruption, and cesarean delivery.

Complication rates are directly related to the severity and duration of elevated blood pressures. For instance, patients with severe hypertension in the first trimester have a greater than 50% risk of developing superimposed preeclampsia. All hypertensive patients should undergo increased surveillance, serial laboratory tests throughout pregnancy, serial ultrasound scans to follow growth, and antenatal testing. The baby should be delivered vaginally if possible.

Management of preeclampsia
Preeclampsia places both mother and fetus at risk. It is, however, a maternal disorder. The mainstay of treatment is early detection and managed delivery to minimize both maternal and fetal risks. If the pregnancy is at term, the decision is easy: the baby should be delivered. The decision to deliver involves balancing the risks of worsening preeclampsia against those of prematurity. Delivery is generally not indicated for women with mild preeclampsia until 37 to 38 weeks of gestation and should occur by 40 weeks (1, 7). If remote from term, the mother should be admitted for evaluation. She will need:
Baseline and serial laboratory tests (complete blood cell count, BUN, creatinine, uric acid, ALT, AST).

Ultrasonography to measure fetal growth and amniotic fluid volume and Doppler ultrasonography.Umbilical artery systolic/diastolic ratios measured by Doppler ultrasonography may detect early uteroplacental insufficiency (17, 18).

Antenatal testing (nonstress test or biophysical profile). The biophysical profile is an assessment of fetal well-being. Fetuses that are well oxygenated behave normally by twisting, squirming, flexing and extending extremities, and breathing. Fetuses that are hypoxic lie still, trying to conserve oxygen.

A 24-hour urine collection for protein. The goals of treatment are to prevent seizures, lower blood pressure to avoid maternal end-organ damage, and expedite delivery.

Magnesium sulfate is still the drug of choice for preventing and arresting eclamptic seizures. It has the additional benefit of reducing the incidence of placental abruption (19). Serum magnesium levels should be monitored in women with elevated serum creatinine levels, decreased urine output, or absent deep tendon reflexes (20).

Magnesium toxicity can lead to respiratory paralysis, cen tral nervous system depression, and cardiac arrest. The antidote is calcium gluconate, 1 g infused intravenously over two minutes (21).

Antihypertensive medications are used solely to prevent maternal morbidity and have no effect on disease progression or preventing eclampsia. Medications must be given with caution: if blood pressure is lowered too fast, it can have a dramatic effect on uteroplacental perfusion and can cause an already compromised fetus to rapidly decompensate and become bradycardic. Preferred medications are hydralazine (5-10 mg intravenous bolus every 10-15 minutes), labetalol, nicardipine, and sodium nitroprusside. Intravenous labetalol and hydralazine are commonly used for the acute management of preeclamp sia (22, 23).

Diuretics are usually contraindicated because of the already collapsed intravascular volume. However, if the pulmonary capillary wedge pressure is high, diuretics are necessary.

Intravenous hydration for oliguria must be given cautiously to avoid pulmonary edema, ascites and cardiopulmonary overload. If there is no evidence of pulmonary edema, a trial of fluid resuscitation (500 mL over an hour) should be given.

Delivery Decisions in Severe Preeclampsia
Delivery is the only cure for preeclampsia. Corticosteroids are administered to accelerate fetal lung maturity (8). Interventionist management advocates induction or cesarean delivery 12 to 24 hours after corticosteroid administration (24). Contraindications to expectant management include persistent severe symptoms, multiorgan dysfunction, severe IUGR (i.e., estimated fetal weight below the 5th percentile), suspected placental abruption, or nonreassuring fetal testing (24).

Method of delivery can be vaginal delivery or caesarean section. Vaginal delivery may be commenced in vertex presentation by: amniotomy + oxytocin if the cervix is favourable or prostaglandin vaginal tablet (PGE2) if the cervix is not favourable. Caesarean section is indicated in foetal distress, late deceleration occurs with oxytocin challenge test, failure of induction of labour and other indications as contracted pelvis and malpresentations.

Some experts recommend cesarean delivery for fetuses younger than 30 weeks when the cer vix is not ripe, but a trial of induction may be considered (8, 22). In patients with HeLLP syn drome, cesarean delivery carries special risks, such as bleeding from thrombocytopenia and difficulty controlling blood pressure because of depleted intravascular volume (15, 25).

Postpartum Management
Eclampsia may occur postpartum; the greatest risk of postpartum eclampsia is within the first 48 hours (20).

Magnesium sulfate is continued for 12 to 24 hours, or occasionally longer if the clinical situation warrants. Generally, once the placenta is delivered, the disease rapidly improves. Large fluid shifts should occur immediately postpartum, and diuresis indicates that the syndrome is resolving. However, women with severe and early onset of disease may worsen before getting better. The physiologic changes of preeclampsia are completely reversible after delivery. However, maternal morbidity caused by severe hypertension, hemorrhage, or anesthetic complications may be permanent.

Barton JR, O’brien JM, Bergauer NK, Jacques DL, Sibai BM. Mild gesta tional hypertension remote from term: progression and outcome. Am J Obstet Gynecol. 2001;184(5):979–983. PubMed
7. Mignini LE, Latthe PM, Villar J, Kilby MD, Carroli G, Khan KS. Mapping the theories of preeclampsia: the role of homocysteine. Obstet Gynecol. 2005;105(2):411–425. PubMed
8. Sibai BM. Diagnosis and management of gestational hypertension and preeclampsia. Obstet Gynecol. 2003;102(1):181–192. PubMed
15. Sibai BM. Diagnosis, controversies, and management of the syndrome of hemolysis, elevated liver enzymes, and low platelet count. Obstet Gynecol. 2004;103(5 pt 1):981–991. PubMed
17. Neilson JP, Alfirevic Z. Doppler ultrasound for fetal assessment in high risk pregnancies. Cochrane Database Syst Rev. 2000;(2):CD000073. PubMed
18. Williams KP, Farquharson DF, Bebbington M, et al. Screening for fetal well-being in a high-risk pregnant population comparing the nonstress test with umbilical artery Doppler velocimetry: a randomized controlled clinical trial. Am J Obstet Gynecol. 2003;188(5):1366–1371. PubMed
19. Duley L, Gülmezoglu AM, Henderson-Smart DJ. Magnesium sulphate and other anticonvulsants for women with pre-eclampsia . Cochrane Database Syst Rev. 2003;(2):CD000025. PubMed
20. Sibai BM. Diagnosis, prevention, and management of eclampsia. Obstet Gynecol. 2005;105(2):402–410. PubMed
21. Dildy GA. Complications of preeclampsia. In: Critical Care Obstetrics. 4th ed. Malden, Mass. Blackwell Publishing. 2004
22. Report of the National High Blood Pressure Education Program Work ing Group on High. Blood Pressure in Pregnancy. Am J Obstet Gynecol. 2000;183(1):S1–S22. PubMed
23. ACoG Committee on Practice Bulletins. ACoG Practice Bulletin. Chronic hypertension in pregnancy. Obstet Gynecol. 2001;98(1 suppl):177–185. PubMed
24. Sibai BM, Mercer BM, Schiff E, Friedman SA. Aggressive versus expect ant management of severe preeclampsia at 28 to 32 weeks’ gesta tion: a randomized controlled trial. Am J Obstet Gynecol. 1994;171(3):818–822. PubMed
25. Barton JR, Sibai BM, Clin Perinatol. Barton JR, Sibai BM. Diagnosis and management of hemolysis, ele vated liver enzymes, and low platelets syndrome. Clin Perinatol. 2004;31(4):807–833. PubMed
Management of eclampsia
General measures include:
Care for respiratory system by:
head-down tilt to help drainage of bronchial secretion,
frequent change of patient position,
keep upper respiratory tract clear by aspiration of mucous through a plastic airway,
prophylactic antibiotic and
oxygen is administered during and after fits.

a medical pro fessional skilled in performing intubations should be immediately available (27).

The tongue is protected from biting by a plastic mouth gauge.

After sedation, a self-retained Foley’s catheter is applied. The hourly output of urine is charted. Proteinuria, haematuria and specific gravity are noticed.

Efficient nursing in a single quiet semi-dark room to prevent any auditory or visual stimuli.

Observation for maternal
pulse
temperature
blood pressure
respiratory rate
tendon reflexes
urine (see before)
number of fits and duration of coma
uterine contraction
Observation for fetal:
FHS.

Magnesium sulfate is the drug of choice because it is more effective in preventing recurrent seizures than phenytoin (Dilantin) or diazepam (Valium) (28, 29-31). If a patient has already received a prophylactic loading dose of magnesium sulfate and is receiving a continuous infusion, an additional 2 g should be given intravenously. Otherwise, a 6-g loading dose is given intravenously over 15 to 20 minutes, followed by maintenance infusion of 2 g per hour. A total of 8 g of magnesium sulfate should not be exceeded over a short period of time (20, 27).
20. Sibai BM. Diagnosis, prevention, and management of eclampsia. Obstet Gynecol. 2005;105(2):402–410. PubMed
27. Aagaard-Tillery KM, Belfort MA. Eclampsia: morbidity, mortality, and management. Clin Obstet Gynecol. 2005;48(1):12–23. PubMed
28. Lucas MJ, Leveno KJ, Cunningham FG. A comparison of magnesium sulfate with phenytoin for the prevention of eclampsia. N Engl J Med. 1995;333(4):201–205. PubMed
29. Which anticonvulsant for women with eclampsia? Evidence from the Collaborative Eclampsia Trial published correction appears in Lancet. 1995;346(8969):258. Lancet. 1995;345(8963):1455–1463.PubMed
30. Duley L, Henderson-Smart D. Magnesium sulphate versus phenytoin for eclampsia. Cochrane Database Syst Rev. 2003;(4):CD000128. PubMed
31. Duley L, Henderson-Smart D. Magnesium sulphate versus diazepam for eclampsia. Cochrane Database Syst Rev. 2003;(4):CD000127. PubMed

Micrograph showing hypertrophic decidual vasculopathy, the histomorphologic correlate of gestational hypertension. H;E stainFETAL GROWTH DISORDERS
Intrauterine growth failure affects up to 10% of pregnancies and is often referred to as small-for gestational age (SGA), intrauterine growth restriction (IUGR) or fetal growth restriction (FGR) . Traditionally, an estimated fetal weight (EFW) or abdominal circumference (AC) below the 10th centile raises concerns over suboptimal intrauterine growth, however the distinction between normal and pathologic growth often cannot reliably be made at this arbitrary cut-off. In addition, approximately 70% of fetuses below the 10th centile will have a normal perinatal outcome Lees et al, 2013. The risk of adverse outcome is proportional to the degree of growth restriction with those below the 3rd centile and/ or abnormal umbilical artery Doppler measurements at greatest risk of morbidity or mortality Unterscheider et al, 2013.
Small-for-gestational age (SGA)
Will be used to describe a physiologically small fetus (ie EFW ;10th centile ,normal amniotic fluid volume and normal umbilical artery Doppler)
Intrauterine growth restriction (IUGR)
Will be used to describe a pathologically small fetus (ie EFW ;10th centile, oligohydramnios, abnormal UA Doppler AND/ OR poor interval growth velocity AND/ OR EFW ;3rd centile )
Suboptimal fetal growth is linked to adverse short and long term outcomes. Neonatal complications include haematological and metabolic problems and impaired thermoregulation. In addition, intraventricular haemorrhage, necrotising enterocolitis, seizures, sepsis, respiratory distress syndrome, retinopathy of prematurity and neonatal death contribute to the perinatal morbidity.

Together with the profound perinatal impact of FGR, consequences may continue into adult life in the form of metabolic disease as a result of prenatal reprogramming and postnatal compensatory catch-up growth. It is now well established, that an adverse intrauterine environment increases disease risk in adulthood leading to metabolic syndrome, hypertension, insulin resistance and type 2 diabetes mellitus, coronary heart disease and stroke Barker et al, 1990; 1993.

Antenatal Detection and Recognition of Risk Factors
The antenatal detection of FGR is of particular concern, given that currently only one third of such pregnancies are prenatally recognised Chauhan et al, 2013; McCowan et al, 2010.

Abdominal palpation and fundal height (FH) measurement have poor sensitivities and specificities; they are, however, the only physical examination methods available.

Serial sonographic assessment of EFW is not feasible in all pregnancies, therefore FH measurement can be used as a proxy for estimating the gestational age of the pregnancy Rondo et al, 2003 or the weight of the fetus Mongelli et al, 2004. More commonly, it is used for fetal growth screening.
A prospective, non-randomised controlled study of 1272 patients Gardosi et al, 1999 found an increased detection of FGR with customised FH charts (48% vs 29%, odds ratio 2.2, 95% confidence interval 1.1-4.5) which was coupled with reduced false-positive assessments. In another study, FH measurement in cm and plotting on a customised fundal height chart shows an improved, but still low, detection of FGR antenatally when compared with conventional methods (36% vs 16%) Wright et al, 2006.
This alarmingly low detection rate of FGR translates into a significantly increased risk of adverse perinatal outcomes for these pregnancies. In particular, pregnancies with unrecognised FGR carry an over 8-fold increased risk of stillbirth when compared to pregnancies without IUGR (19.8 versus 2.4/ 1000 births) Gardosi et al, 2013. It may therefore be reasonable to consider using customised FH and fetal weight standards, which may aid with the interpretation of clinical assessment findings.
FGR is the manifestation of underlying placental, fetal, parental and environmental causes and therefore represents a heterogenous condition.

Causes and Risk Factors of FGR
Maternal
Parity
Ethnicity (minorities, non-white)
Malnutrition, low gestational weight gain
Low pre-pregnancy fruit intake
Vigorous daily exercise
Previous IUGR pregnancy
Extremes of maternal age (;16 years, ;40 years)
Assisted reproductive techniques
Uterine malformations
Low socio-economic status
Low PAPP-A (;0.4 MoM)
Hypertension/ pre-eclampsia
Medical disorders (Systemic lupus erythematosus, pre-existing diabetes, renal disease, restrictive lung disease, cyanotic heart disease, antiphospholipid syndrome, anaemia/ haemoglobinopathy, Crohn’s disease, ulcerative colitis)
Rhesus positive blood type
Paternal
Low birth weight
Fetal
Female gender
Chromosomal abnormalities (aneuploidies, microdeletions)
Genetic syndromes
Congenital malformations
Intrauterine infections (CMV, Toxoplasmosis, Rubella, Varicella, Tuberculosis, HIV, Syphilis, congenital Malaria)
Multiple pregnancy
Placental
Placental developmental abnormalities (abnormal placental shape/ position; chorangiomatosis; distal villous hypoplasia/ accelerated villous maturation/ increased syncytial knotting). Maternal vascular pathology (infarction; retroplacental haemorrhage; increased perivillous fibrinoid deposition). Fetal vascular pathology (cord hypercoiling; true cord knots; abnormal cord insertion; single umbilical artery; fetal thrombotic vasculopathy) Inflammatory Lesions (acute chorioamnionitis/ vasculitis; chronic villitis of unknown aetiology) Other (confined placental mosaicism, placental hypoplasia.
Environmental
Substance misuse
Smoking
High altitude/ hypoxia
Irradiation
Exposure to teratogens (Warfarin, anti-epileptic drugs, methotrexate)
Sonographic Surveillance and Management
Sonographic surveillance, in particular Doppler ultrasound, of pregnancies with IUGR plays a critical role in improving perinatal outcomes by increasing prenatal surveillance and timely delivery.
There is very little evidence from randomised controlled trials to inform best practice for antenatal surveillance regimens in FGR pregnancies Grivell et al, 2012, in particular, no single individual test is available to predict outcome in IUGR, and therefore a combination of examinations is recommended in the careful assessment of growth restricted fetuses.
Biometry, population and customised fetal weight estimation
Evaluation by ultrasound is indicated when small fetal size is suspected clinically. The Hadlock formula is the most widely accepted method of estimating fetal weight using a composite sonographic measurement of fetal head, abdomen and femur Hadlock et al, 1985.
An EFW below the 10th centile is concerning for suboptimal fetal growth, recognising the limitations of this arbitrary cut-off to inform perinatal outcome and the multitude of formulae to calculate EFW. Fetal weight estimation is also influenced by the ultrasound equipment, operator experience, training and competence. In addition, any interpretation of fetal weight in relation to gestational age relies on accurate dating of pregnancies.

Customisation of fetal growth takes into account maternal constitutional variation (ethnicity, height, weight, parity) and has been proposed for a more appropriate identification of fetal growth failure Gardosi et al, 1992. Therefore, in fetuses with EFW below the 10th centile, a customised reference may be obtained to aid with the interpretation of this value.
A customised growth standard was developed using pregnancy data of over 11,000 women in Ireland Unterscheider et al, 2013. The usefulness of fetal weight customisation in the Irish setting is validated in the analysis of 1,116 PORTO fetuses with population based EFW< 10th centile. If customised norms would have been used in the original study, 28% would not have been labelled as FGR, which also translated into improved targeting of infants at risk of adverse perinatal outcome (RR=1.25).

Once FGR is diagnosed, a follow up growth examination with amniotic fluid and umbilical artery Doppler evaluation in 14 days should be arranged given the association between poor interval growth and adverse perinatal outcome. Subsequently, serial follow up of growth is recommended.
This approach is helpful as it allows the study of growth trajectories which may further aid in the differentiation between physiological and pathological FGR Barker et al, 2013.
Biometry assessment any more frequently than at 2-weekly intervals is not recommended because of the limitations and error ranges associated with ultrasound and the fetal growth rate. In addition, a single biometry assessment in the third trimester does not improve perinatal outcome and is therefore not recommended, unless clinically indicated Bricker et al, 2008.

Doppler surveillance
In addition to biometry assessment, various studies have described patterns of Doppler deterioration in IUGR fetuses aiming at understanding the underlying pathophysiology, optimising surveillance strategies and guiding the optimal timing of delivery. Umbilical artery (UA) Doppler is widely accepted as the primary assessment tool in IUGR Alfirevic et al, 2010
However there is on-going debate and controversy on the benefit of assessing vessels other than the UA in the setting of IUGR. Several studies have contributed to the understanding of longitudinal Doppler changes occurring in IUGR. However, these studies have been either retrospective or comprised small patient numbers. Furthermore, it is important to note that in fact most of these papers describing a temporal sequence refer to Doppler abnormalities within a population of IUGR fetuses rather than a predictable progressive sequence occurring within the individual fetus. It is pausible therefore that such prior population data may not actually be applicable to the longitudinal surveillance of the individual fetus in clinical practice Unterscheider et al, 2013.

In the PORTO study (Prospective Observational Trial to Optimise Paediatric Health in IUGR) conducted between January 2010 and June 2012 , the mean time-to-delivery interval for UA PI >95th centile, AEDF and REDF was 26, 12 and 4 days respectively.

Uterine artery (UtA) Doppler assessment, in particular the persistence of UtA notching or a pulsatility index (PI) >95th centile, has been proposed as a promising predictor of pre-eclampsia (PET) and FGR.

This approach has been found to be of little value in the low risk pregnant population, and performs better for the prediction of PET, but with only moderate sensitivity Cnossen et al, 2008.

Therefore screening for uterine artery abnormalities is not recommended, in particular in the absence of useful therapies
As the SMFM clinical guideline on Doppler assessment in IUGR states, there is a large variability in manifestation of Doppler changes in the umbilical, middle cerebral artery (MCA) and ductus venosus (DV).
The cerebroplacental ratio (CPR) is evaluated using MCA Doppler, and is calculated by dividing the MCA pulsatility index (PI) by the UA PI, with a normal value being >1. A CPR <1 signifies cerebral redistribution with increased blood flow to the fetal brain, and has been reported as an adaptive response to a suboptimal intrauterine environment.

Prospective data from the PORTO study showed that brainsparing was significantly associated with adverse perinatal outcomes and that integration of CPR evaluation may be beneficial (specificity 87%, sensitivity 61%). The role of venous Doppler assessment in IUGR, in particular DV Doppler, has been suggested as a more precise predictor of fetal deterioration.
While some authors have suggested use of DV Doppler to guide delivery decisions, it may however have limited utility as DV abnormalities are exhibited by only a minority of IUGR fetuses, usually in close proximity to an abnormal CTG requiring delivery Ferrazzi et al, 2002; Bilardo et al, 2004.

To date, evidence from randomised trials supporting a role for additional Doppler surveillance of middle cerebral artery and ductus venosus in IUGR management is still lacking.
In the TRUFFLE (Trial of Randomized Umbilical and Fetal Flow in Europe) study on the outcome of early fetal growth restriction, women were allocated to one of three groups of indication for delivery according to the following monitoring strategies: (1) reduced fetal heart rate (FHR) short-term variation (STV) on cardiotocography (CTG); (2) early changes in fetal ductus venosus (DV) waveform (DV-p95); and (3) late changes in fetal DV waveform (DV-no-A). However, many infants per monitoring protocol were delivered because of safety-net criteria, for maternal or other fetal indications, or after 32 weeks of gestation when the protocol was no longer applied. The objective of the present posthoc subanalysis was to investigate the indications for delivery in relation to 2-year outcome in infants delivered before 32 weeks to further refine management proposals.

The authors conclude that ,in this subanalysis of infants delivered before 32 weeks, the majority were delivered for reasons other than the allocated monitoring strategy indication. Since, in the DV group, CTG-STV criteria were used as a safety net but in the CTG-STV group, no DV safety-net criteria were applied, we speculate that the slightly poorer outcome in the CTG-STV group might be explained by the absence of DV data. The optimal timing of delivery of fetuses with early intrauterine growth restriction may therefore be best determined by monitoring them longitudinally, with both DV and CTG monitoring.
Visser GHA, Bilardo CM,  TRUFFLE group investigators 2017
Cardiotocography (CTG)
Given that no individual test can precisely predict perinatal outcome, fetal well-being is often assessed with multiple modalities. CTG is widely accepted as the primary method of antenatal fetal monitoring to assess the current status of the fetus.CTG, although highly sensitive, has a 50% false positive rate for the prediction of adverse outcome Evertson et al, 1979.In addition, a meta-analysis Pattison et al, 2000 of its application in high-risk pregnancies failed to demonstrate any beneficial effect in reducing perinatal mortality.
CTG is useful in the detection of acute hypoxia but is a poor test for chronic hypoxia. Nevertheless, a normal CTG is significantly more likely to be followed by a normal delivery and a normal perinatal outcome than an abnormal test.

The use of a computerised CTG Dawes et al, 1992 is thought to be more reliable, objective and accurate than visual inspection Bracero et al, 1999. Reduced short term variability on a computerised CTG analysis may be more closely correlated with acidosis and hypoxia at the time of delivery.
Biophysical Profile (BPP)
Combining biophysical tests with Doppler ultrasound may help improve the prediction of adverse outcomes and initiate delivery before fetal demise occurs.

The biophysical profile score (BPP) is a non-invasive test to assess fetal well-being Manning et al, 1980. An abnormal score is a predictor of significant fetal acidaemia Manning et al, 1995.The BPP integrates 5 parameters to yield a maximum of 10 points (0= abnormal, 2= normal):
Amniotic fluid measurement
Fetal breathing movements
Fetal body movements
Fetal tone
(CTG)
In general, if all of the sonographic variables are normal, the CTG may be excluded, giving a maximum score of 8/8. The usual time to complete a BPP is less than 5 minutes Manning et al, 1981 .The variables however are subject to fetal sleep cycles; thus, continuous observation for at least 30 minutes must occur before a variable can be defined as absent (abnormal). Adding a BPP to Doppler ultrasound may improve the identification of fetuses at increased risk of poor neonatal outcome, but evidence from prospective, randomised studies is lacking. If assessed, delivery is indicated at scores ?4/10 and close monitoring or delivery should be considered at scores ?6/10. It is also important to recognize the limitations of BPP to inform fetal well-being in preterm FGR fetuses.

Timing and Mode of Delivery
Management of FGR in relation to the optimal timing of delivery, in particular when severe and very preterm, requires a careful clinical balance between the risk of antepartum stillbirth due to delaying delivery and iatrogenic prematurity potentially causing significant morbidity or neonatal death by early intervention. Timing of delivery should be individualised, depending on the suspected underlying cause of FGR; in some cases, the optimal mode of delivery is determined following a multi-disciplinary case discussion involving fetal medicine specialists.

The main goals of prolonging intrauterine life are:
Avoiding mortality (24-26 weeks)
Gaining survival (26-28 weeks)
Avoiding morbidity (28-30 weeks)
Gaining maturity (>30 weeks)
Important prenatal determinants of perinatal outcome are gestational age at delivery and birthweight, with best prospects of intact survival at weights over 800grams and gestational ages over 29 weeks Baschat et al, 2007.

The timing of delivery is therefore guided by the degree of growth restriction and gestational age at diagnosis. Additional information on interval growth, amniotic fluid volume, umbilical artery Doppler, biophysical profiling and CTG monitoring is also important in optimising the timing of delivery.
Isolated FGR
In cases of isolated FGR (biometry <10th centile, normal amniotic fluid volume and normal umbilical artery Doppler) it is reasonable to delay delivery until at least 37 weeks, and even until 38-39 weeks gestation.

The Disproportionate Intrauterine Growth Intervention Trial at Term (DIGITAT) examined induction of labour versus expectant management in 650 women with suspected IUGR between 36+0 and 41+0 weeks gestation. Outcomes were comparable with respect to composite neonatal morbidity (5.3% vs 6.1%) and Caesarean delivery rates (14% vs 13.7%). Interestingly, infants in the expectant group more commonly had birthweights <3rd centile when compared to the induction group (30.6% vs 12.5%).

This would suggest that a substantial number of fetuses in the expectant group had worse degree of IUGR or did not continue to grow therefore making a compelling argument for induction of labour once IUGR is suspected.
The authors conclude that there seems to be ‘equivalent fetal and maternal outcomes for induction and expectant monitoring in women with suspected IUGR at term, indicating that both approaches are acceptable’ Boers et al, 2007; 2012.
Given the increased risk of stillbirth (RR 2.3) in FGR pregnancies after the 37th week of gestation Trudell et al, 2013, induction of labour or elective delivery should be considered between 37 and 38 weeks.

This applies in particular to fetuses <3rd centile, who are at up to 7-fold increased risk of stillbirth than fetuses between the 5th and 10th centile Pilliod et al, 2012.

Complicated FGR
An abnormal umbilical artery Doppler in the setting of FGR confers the highest risk of perinatal morbidity and mortality, and this increased risk exists irrespective of gestational age at delivery Unterscheider et al, 2013.
Therefore, in cases of complicated FGR (biometry <10th centile, with abnormal umbilical arterial Dopplers, such as raised pulsatility index >95th centile, absent or reversed end-diastolic flow), antenatal corticosteroids to prevent respiratory morbidity should be administered in a timed manner between 24+0 and 34+0 weeks.
There is growing evidence and long term safety data to support steroid administration even beyond 36 weeks for prevention of neonatal respiratory morbidity after elective Caesarean delivery Stutchfield et al, 2005; 2013.

In this multicentre randomised trial, neonatal intensive care unit (NICU) admission rates for respiratory morbidity were lower for infants who received steroids 48 hours prior to delivery, and this effect was observed at 37 weeks (11.4% vs 5.2%), 38 weeks (6.2% vs 2.8%) and 39 weeks (1.5% vs 0.6%). The authors conclude that antenatal steroids should be considered for elective CS at 37-38 weeks of gestation.

The Growth Restriction Intervention Trial (GRIT) was an RCT comparing immediate versus delayed delivery of compromised fetuses between 24 and 36 weeks’ gestation with respect to survival to hospital discharge and developmental quotient at two years of age. GRIT found, that when obstetricians were uncertain about the timing of delivery, they were prepared to wait for 4 days. The outcomes in the respective groups were comparable with a respect to death prior to discharge (10% vs 9%). No clear benefit of either immediate versus delayed delivery was identified with a trend towards more disability in the immediate delivery group (5% vs 1%).
In cases of increased resistance in the UA, it is reasonable to increase sonographic surveillance to weekly intervals or more frequently if deemed necessary by the managing clinician. Delivery should be considered at 37 weeks and induction of labour is possible with careful CTG monitoring once contractions have started and labour is established Hornbuckle et al, 2000.
Delivery is indicated earlier in cases of AEDF or REDF in the umbilical artery. In this case, patients should be provided with daily CTG surveillance.

In most cases this will require admission to hospital, although some units may have the ability to perform daily CTG surveillance as an outpatient. Following administration of corticosteroids, delivery should occur no later than 34 weeks in cases of AEDF and no later than 30 weeks in cases of REDF.

If there is uncertainty regarding the optimal surveillance and timing of delivery, consultation with fetal medicine specialists and neonatologists should take place to guide surveillance and timing of delivery. It is likely, that fetuses with AREDF do not tolerate labour well and therefore an elective Caesarean delivery may be more appropriate. Magnesium sulfate, which was originally used for seizure prevention and treatment in women with pre-eclampsia, is an effective fetal neuroprotective agent when administered prior to 32 weeks gestation and should be given .

Investigations – antenatal and postnatal
Given the association of IUGR and genetic syndromes, aneuploidy and intrauterine infection, a careful and detailed evaluation of the fetal anatomy is important in determining the underlying cause of FGR. In the presence of concomitant structural abnormalities, polyhydramnios or soft markers, referral to a fetal medicine specialist is recommended, as amniocentesis and/ or TORCH screening may be warranted
Placental abnormalities such as maternal and fetal vascular injuries, placental developmental abnormalities or inflammatory lesions have been linked to adverse pregnancy outcomes including FGR, preterm delivery and stillbirth Redline, 2008. Evaluation of the placenta, cord and membranes can give an important insight into intrauterine environment and explain the origins of FGR. Knowledge of underlying placental causes of FGR may guide treatment and management in subsequent pregnancies given that some of these lesions tend to recur.
To illustrate the importance of placental histopathology and its translation into clinical practice further we give some examples:
Non-infectious chronic villitis of unknown etiology (VUE) is linked to maternal obesity and tends to recur in a more severe degree in subsequent pregnancies; there is uncertainty over prevention however treatment with LDA might be indicated in such cases.
Fetal thrombotic vasculopathy has been described in association with parental thrombophilias and therefore thrombophilia testing in both parents may be indicated.
Massive fibrin deposition and maternal floor infarction is rare and thought to be due to maternal malperfusion, hypercoagulability and trophoblast injury; it recurs in up to 50% of cases.
Placental infarctions are associated with placental developmental abnormalities; treatment with LMWH has the potential to improve placentation and outcome
Kingdom et al, 2011; Dodd et al, 2013.
Risk of Recurrence and Preventative Strategies
Women, who delivered a growth restricted infant in their first pregnancy, are at significantly increased risk of recurrent FGR. This information is crucial for patient counselling and appropriate care in a subsequent pregnancy.
The risk of recurrence was quantified in a large prospective study of 259,481 pregnant women who delivered 2 subsequent singleton pregnancies within the study period Voskamp et al, 2013. In this study, the incidence of FGR was 5% (defined as birthweight below the 5th centile), the risk of recurrent FGR birth was 23%, and this rate was significantly increased when compared to women who delivered an appropriately grown infant in their first pregnancy (3.4%).
Unfortunately, no specific interventions or therapies have been proven to improve poor fetal growth. Preventative strategies involve a review of lifestyle factors such as smoking cessation and dietary advice. Depending on the underlying cause of FGR, treatment with low dose Aspirin (LDA) can be considered in placenta-mediated FGR, maternal hypertensive disease or obstetrical antiphospholipid syndrome. A protective effect of Aspirin is greatest when commenced prior to 16 weeks gestation Bujold et al, 2010; Roberge et al, 2013.
Preliminary data have suggested that the use of low molecular weight heparin (LMWH) for women at particularly high risk of adverse pregnancy complications due to placental dysfunction may significantly reduce the risk of perinatal mortality, preterm birth and low birthweight; treatment with LMWH may be a promising intervention for prevention of these complications, although complete data on adverse infant outcomes are still lacking Dodd et al, 2013; Kingdom et al.

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1 J Ultrasound Med. 2007 Nov;26(11):1481-9. et al in their study found that IUGR pregnancies were nearly 4-fold more likely to have lateral placentation (odds ratio, 3.8; 95% confidence interval, 1.3-11.2) compared with anterior or posterior placentation. They concluded that in Pregnancies complicated by IUGR are significantly more likely than non-IUGR pregnancies to have lateral placentation in the second trimester.

2 , Kaku R et al. Int J Reprod Contracept Obstet Gynecol. 2017 ;in a prospective observational study found that 66% patients in the lateral placenta group developed preeclampsia. Only 36%in the central group developed preeclampsia. The study shows that placental position determined by ultrasonogram in II and III trimester of gestation is an excellent screening tool for the prediction of pre-eclampsia. The test is ideal because it is simple, non-invasive, cost effective and convenient to the women

3, Salama-Bello R, Duncan JR, Howard SL, Song J, Schenone MH et al In their study, there was no difference in the rate of hypertensive disorders of pregnancy between patients with central and laterally located placentas.

4, Yousuf S, Ahmad A, Qadir S, Gul S, Tali SH, Shaheen F, Akhtar S, Dar R et al concluded that Pregnant women with lateral placentas are at significant risk for development of preeclampsia. Lateral placentas when associated with uterine artery Doppler abnormality, risk for development of preeclampsia increases significantly as compared to lateral placentas alone.

5, Tania Kakkar, et al in a prospective study concluded that laterally located placenta on ultrasound done at 18–24 weeks is associated with increased risk of development of preeclampsia. Females with laterally located placenta have a five times greater risk of developing PIH, so these pregnancies may require careful obstetric management to achieve a more favorable outcome and decrease the maternal and perinatal morbidity and mortality associated with preeclampsia.

6, K. D. Seckin et al 2015 As a conclusion, incidences of preeclampsia and FGR were found to be higher in laterally localised placenta cases when compared with those in central localised placenta. Th is association should prompt the clinician for preeclampsia and FGR in pregnant women with laterally localised placentas.

7, Tania Kakkar, et al 2012 in their study showed out of the total 150 women, 84 (56 %) had laterally located placenta and of them, 56 (66.6 %) developed preeclampsia, while the remaining 66 (44 %) had centrally located placenta and of them, 24 (36.3 %) developed preeclampsia. So, the overall risk of developing preeclampsia with laterally located placenta was 5.09 (odds ratio) and 95 % confidence interval (2.40–10.88). The difference was found to be statistically significant, p value (0.00002) by ?2 test. And concluded that females with laterally located placenta determined by USG at 18–24 weeks of gestation have five times greater risk of developing preeclampsia
8, Devarajan K et al 2012 studied among women with lateral versus central/fundal placentas, the respective mean (SD) birth weights were 3298 (550) g and 3352 (579) g (mean difference 54 g, 95% CI 53 to 161; P = 0.32). Relative to central/fundal location, laterally located placentas had an adjusted OR of 0.81 (95% CI 0.42 to 1.54) for SGA and 0.62 (95% CI 0.18 to 2.10) for preeclampsia/gestational hypertension.And concluded that Placental location was not associated with differences in newborn weight or other perinatal outcomes.

9, Fung TY et al 2011 ,concluded in their study that Non-central placental location in the second trimester is associated with an increase risk of adverse obstetric outcome
10, Magann EF et al 2007 , in an Observational study of 3336 pregnancies analyzed Low implantation sites had a greater risk of preterm labor (odds ratio (OR) 1.70, 95% confidence interval (CI) 1.38 to 2.90, P;0.001), preterm delivery (OR 1.86, 95% CI 1.36 to 2.54, P;0.001), fewer fetuses with macrosomia (OR 0.56, 95% CI 0.38 to 0.83, P=0.010) and reduced risk of postpartum hemorrhage (OR 0.56, 95% CI 0.46 to 0.95, P=0.026). High lateral implantations had a greater risk of low 1-min (OR 1.80, 95% CI 1.11 to 2.93, P=0.017) and 5-min (OR 3.49, 95% CI 1.46 to 8.36, P=0.005) Apgar scores.And concluded Low placental implantation was associated with an increased risk of preterm labor, preterm delivery and a reduced risk of postpartum hemorrhage, and of a macrosomic fetus. High lateral implantation was associated with low Apgar scores.

11, Quant HS et al 2016 concluded Second-trimester 3D placental measurements can identify pregnancies at risk of SGA. However, there appears to be no significant improvement compared to those obtained in the first trimester.

12, Kalanithi LE et al 2007 in a case control study found that, the most common placental locations in the second trimester were anterior and posterior.IUGR pregnancies were nearly 4-fold more likely to have lateral placentation (odds ratio, 3.8; 95% confidence interval, 1.3-11.2) compared with anterior or posterior placentation.And concluded that pregnancies complicated by IUGR are significantly more likely than non-IUGR pregnancies to have lateral placentation in the second trimester.

13, J Turk et al  2013 analysed a total of 474 case of women for placental location, feto-maternal outcome and blood groups and found that anterior placental implantation is associated with an increased risk of pregnancy-induced hypertension, gestational diabetes mellitus, placental abruption, intrauterine growth retardation and intrauterine foetal death. Posterior placenta has a significant association with preterm labour and A-positive blood group. Anterior placenta is common in women with O-positive blood group. Placental location may be an important determinant of pregnancy outcome
14, Rab A et al 2013 In their study, compared human placental gene expression patterns of epidermal growth factor (EGF) in pregnancies with intrauterine growth restriction (IUGR) vs. normal pregnancies as control.And concluded that placental expression of EGF was found to be reduced in IUGR pregnancies vs. normal pregnancies. This may partly explain the smaller placental size and placental dysfunction commonly seen with IUGR. An increased incidence of IUGR was observed with maternal age exceeding 35 years. The probability of IUGR correlated with lower gestational weight gain and lower BMI increase during pregnancy.

15, Liberati M et al 1997 conducted a study of Uterine artery Doppler velocimetry in pregnant women with lateral placentas. The aim of this study was to compare the efficacy of placental, non-placental, mean of both uterine arteries Doppler velocimetry at 22-24 weeks gestation in the prediction of pregnancy induced hypertension (PIH) and intrauterine growth retardation (IUGR). Flow velocity waveforms were obtained by means of color and pulsed Doppler in 481 patients with lateral placentas at 22-24 weeks gestation. Placental location was determined by real time ultrasonograph . In patients with laterally implanted placentas a mean of both uterine arteries RI above the 90th centile and the presence of a diastolic notch in the placental uterine artery at 22-24 weeks have a higher predictive value for the subsequent development of PIH and IUGR than the separate evaluation of the 2 uterine arteries.
16 , Kofinas AD et al 1992 evaluated uterine artery resistance by means of continuous wave Doppler ultrasonography in 123 pregnant women with chronic hypertension, preeclampsia, or both. The placental location was determined by real-time ultrasonography. Clinical outcomes were compared according to uterine artery abnormalities. In patients with unilateral placentas (n = 67) the placental uterine artery was found to be a better predictor of poor pregnancy outcome than the nonplacental artery and the mean of the two arteries. placental location was associated with longer stays in neonatal intensive care units and more perinatal deaths.

17, Vainio M et al 2005 concluded that Bilateral notching of uterine arteries at 12–14 weeks is a useful tool in predicting the development of hypertensive disorders in high-risk pregnancies. It is also a suitable test for surveillance of high-risk pregnancie
18, Driul L et al 2002 In their prospective longitudinal study carried out 1008 utero-placental velocimetries at the 20th week of gestation; At the 24th week, 111 velocimetric examinations were confirmed abnormal owing to the presence of a monolateral notch or of an increased resistance index in one of the two uterine arteries. The control group consisted of 729 patients with regular velocimetry. The materno-fetal outcomes were therefore assessed in both study groups.The incidence of preeclampsia and of retarded intrauterine growth retardation (IUGR) was respectively 3.6% and 7.2% in patients with monolateral abnormal Doppler velocimetry. The use of Doppler velocimetry of the uterine arteries with mono lateral alteration cannot be employed alone as a screening test for preeclampsia or retarded intrauterine growth in all pregnancies.

19Tarzamni MK et al 2016 conducted a study of Placental laterality and uterine blood flow at 20-40 weeks’ gestation in low-risk pregnancies. In cases with lateral placentation the mean PI and RI values at 36-40 weeks’ gestation and the mean S/D value at 38-40 weeks were significantly higher in the contralateral than in the ipsilateral uterine arteries. In conclusion, lateral placentation may affect uterine artery blood flow throughout gestation and some Doppler indices near term.
20 , Devarajan K et al 2012 conducted a retrospective cohort study of 796 consecutive singleton births in women who delivered at ? 37 weeks’ gestation and evaluated placental location at the time of the second trimester prenatal ultrasound at 16 to 24 weeks’ gestation. Placental location was classified as lateral or central/fundal . Placental location was not associated with differences in newborn weight or other perinatal outcomes.

21, Gonser M et al 1996 148 pregnancies evaluated prospectively : 115 had a laterally and 33 a centrally located placenta. The incidence of preeclampsia in these groups was 32/115 (28%) and 3/33 (9%) respectively. These data suggest that a laterally located placenta is associated with a significantly increased incidence of preeclampsia, with a risk ratio of 3.1 when compared to pregnancies with centrally located placentas.

22, Staribratova D et al 2009 concluded that  histologic examinations prove unequivocal associations between placental findings and preterm delivery, stillbirth, neonatal death and hypoxic problems
23 , Grgic O et al 2006  studied in order to assess the potential influence of placental implantation site on transabdominal electromyographic (EMG) assessment of the uterine electrical activity in the middle trimester of pregnancy.And concluded from their study that background uterine EMG activity measured from the abdominal surface in the middle trimester of pregnancy does not depend on the placental implantation site.

24 , Ranjita Ghadei et al In their study, the incidence of lateral placentation was 25.33% and Incidence of preeclampsia in patients with lateral placentation was 36.85% which is statistically significant with chi-square value 23.89 and P value ;0.001 .From their study they concluded that Laterally located placenta is associated with 4 times increased risk of developing preeclampsia. So these pregnancies require frequent checkup and careful obstetric management to decrease maternal and perinatal morbidity and mortality
25 , Anuja V Bhalerao et al studied 463 pregnant women with placental localisation and concluded that 73.23% patients with lateral placenta developed preeclampsia
26 , Pai Muralidhar V et al 2005   In their prospective study, out of 426 antenatal women, 324 had central placenta and 102 had unilateral placenta. A total of 71 women developed preeclampsia, of which 52 (74%) had unilaterally located placenta at 20-24 weeks. This relationship was statistically highly significant (P;0.0001). The sensitivity, specificity, positive predictive value and negative predictive value of using placental laterality as a screening test were 73%, 86%, 51% and 94% respectively. And from their study concluded that Placental laterality as determined by ultrasound at 18-24 weeks; is a simple yet reliable and cost effective predictive screening test for development of preeclampsia.

27 , Parul S. Jani et al 2013 conducted a prospective observational study. A total 400 non high risk primigravida with singleton pregnancy were included, Patients who had lateral placenta were subjected for colour Doppler study for determining uterine artery resistance index. All data was analyzed and statistical significance was determined by x2 test and value of p;0.05 is considered significant. Out of 400 cases, 80 (20%) cases had laterally located placenta on ultra sound examination done at 18-24 weeks of gestation. Out of the 80 women with laterally located placenta, 28 (35%) developed preeclampsia. This relationship was statistically significant. All 80 patients who had lateral placenta, 26 patients had raised uterine artery resistance and out of those 26 patients, 22 developed preeclampsia and 54 had no change in uterine artery resistance. Out of those 54 only 6 had preeclampsia (p;0. 001). The sensitivity of determining uterine artery resistance as a predictive test was 84.6%, the specificity 88.8 %, positive predictive value 78.5 % and negative predictive value 92.3%.From their study they concluded that chance of preeclampsia is more in patients with lateral placenta but its sensitivity and specificity increases significantly when it is combined with uterine artery velocimetric waveform study, and we can predict preeclampsia in patient who is having lateral placenta and raised uterine artery resistance.

28 JyotiJaiswal et al 2015 conducted a study to assess the incidence of placental laterality in second trimester and the incidence of hypertensive disorders in laterally situated placenta in comparison to centrally situated placenta. Prediction of preeclampsia by second trimester USG guided placental localization is simple, cheap ,noninvasive ,safe and effective screening method.Laterally situated placenta is associated with highrisk of development of PIH.

Placental laterality can be used as a predictor of PIH with good specificity and negative predictive value.

29 , Sheetal Singh et al 2017 carried out a study of Role of Placental Localization and Uterine Artery Doppler as Predictors for Preeclampsia. Out of the total 500 women approximately 18% (90) of cases showed lateral placenta and 82% (410) showed central placenta on ultrasound examination done at 18-24 weeks of gestation. Among them, 37.7% (34/90) patients developed preeclampsia in lateral placental location.Out of 90 patients 31(34.4%) had raised uterine artery resistance and out of them 26 (83.8%) developed preeclampsia in later weeks of pregnancy. Only 5 %( 8.9%) patients of preeclampsia with lateral placenta had normal uterine artery resistance. Which is statistically significant (p ; .001). The incidence of pre eclamsia was found more in lateral placenta (38%) than in central placenta (11%) which is statistically significant (p ; 0.001).

30 , Patel A et al., they found out of 200 patients, incidence of preeclampsia was 2.5 fold higher than central placenta (p ;0.001 ). Total 40 patients detected with lateral placenta out of them 32.5 % had raised uterine artery resistance and among these raised RI patients, 78.5% developed preeclampsia. Sensitivity and specificity of raised uterine artery resistance in relation to preeclampsia and lateral placenta was approximately 85% and 89% respectively.

31 , Chinnappa M K et al. in their study included 200 cases at the time of anomaly scan. The study population had 15% lateral placenta and 85% had central placenta. The incidence of preeclampsia in their study was 13%. In their study 15 developed preeclampsia out of 30 lateral placentation with chi square value of 42.71 and p value of 0.000. They found 61.5% patients with preeclampsia had abnormal Doppler with a chi –square value of 32.29. The incidence of abnormal Doppler in lateral placenta was 65% with chi square 98.04 . Muralidhar et al. 17. In his study out of 426 women, 324(76%) had central placenta and 102 (24%) had lateral placenta. The relationship was found to be statistically significant p ; 0.0001.

32 , Preety Aggarwal et al 2014 who observed that out of the total 475 women, 263(55.4%) had laterally located placenta and of them 45(17.1%) developed preeclampsia, while the remaining 212(44.6%) had centrally located placenta and of them 13(6.1%) developed preeclampsia. So, the overall risk of developing preeclampsia with laterally located placenta was 3.16 (odds ratio) and 95% confidence interval (1.65–6.03). The difference was found to be statistically significant, p value (0.0005) by ?2 test. From the above study, they concluded that females with laterally located placenta determined byUSG at 18–24 weeks of gestation have greater risk of developing preeclampsia.

33 , Kanika Chandra et al who observed out of the total 100 women, Fifty cases had laterally located placenta, while 50 cases had centrally located placenta on ultrasound examination done at 20–24 weeks of gestation . Out of the 50 women with laterally located placenta, 33 (66 %) developed Pre-eclampsia, while 18 women (36%) out of the remaining 50 women with centrally located placenta developed Pre-eclamps .So, the risk of developing Pre-eclampsia was five times greater in the females with laterally located placenta as compared to those with centrally located placenta. The overall risk of developing PIH with laterally located placenta was was 3.451 (Odds Ratio) and 95% Confidence Interval (1.52 to 7.85). The difference was found to be statistically significant, p value (0.01) by chi-sqaure test.From this study concluded that females with laterally located placenta have a five times greater risk of developing PIH.

34 , Abiramavalli Kannamani et al in their study observed the incidence of preeclampsia in primigravida was 81% and multigravida was 19%. Among the patients with centrally located placenta, the incidence of preeclampsia was 19.1% whereas in the case group which had laterally located placenta the incidence of preeclampsia was 80.9% with a statistically significant p value of 0.01. This screening test has a very high negative predictive value of 96.4% and a sensitivity of 81%. Hence, routine ultrasound and placental position screening can be used as a predictor for the development of hypertensive disorders of pregnancy.
35 , Alpana Singh et al 2015 conducted a  prospective observational study in 347 pregnant women and , a total of 270 patients were analysed, 39 (14.4%) had lateral placenta and among them 17 (43.5%) developed preeclampsia and 24 (61.5%) had small for gestational age baby (p;0.001). 231 (85.5%) had central placenta and among them 49 (21.2%) developed preeclampsia and 63 (27.2%) had small for gestational age baby (p ;0.001). And concluded that  laterally located placenta had significant association with preeclampsia and small for gestational age babies.

36 , Rajeshree A Nandanwar et al In their study of 900 women,found that 549 (55%)females had laterally located placenta and351 (45%) had centrally located placenta. Out of 549 females with laterally located placenta 365 (66.4%) developed PIH as compared to 351 females with centrally located placenta where 128 (36.4%) developed PIH. So the risk of developing PIH was three times greater for females with laterally located placenta. So the risk for development of PIH with laterally located placenta was 3.45 (odds ratio) and 95% confidence interval (2.62-4.57). The difference was found to be highly significant statistically (p; 0.0001 ).

37 Moneet Walia et al 2015 studied Comparison between roll-over test and placental localization for early prediction of preeclampsia. Analysed Of 200 women, 148 had a central placenta and 52 had a unilateral placenta. 37 women had preeclampsia, out of which 68 % had a unilateral placenta and 51 % had positive roll-over test. However when the roll-over test was performed at 24 weeks, it was negative in all study cases. So it had got no role as an early predictor of preeclampsia. From the above study they concludes that ultrasonographic localization of the placenta seems to be a simple and easy to perform predictive test for incipient preeclampsia as compared to the roll-over test.

38 , S Chhabra et al 2013 studied Maternal Neonatal Outcome in Relation to Placental Location, Dimensions in Early Pregnancy and concluded that placental location and dimensions in early pregnancy is useful in identifying risks. 
 
39 , Alexander D. Kofinas et al studied The effect of placental laterality on uterine artery resistance and development of preeclampsia and intrauterine growth retardation in 153 pregnant women with normal pregnancies and 147 women with complicated pregnancies .  In patients with unilateral placentas, the incidence of preeclampsia and intrauterine growth retardation was 2.8-fold and 2.7-fold greater than in patients with central placentas (p ; 0.03 and p ; 0.01). Among all patients unilateral placental location was more likely to be associated with abnormal uterine artery flow velocity waveforms than central placental location (p ; 0.001).They conclude that unilateral placental location may predispose to the development of preeclampsia and intrauterine growth retardation by its effect on uterine artery resistance.

40 , MÜZEYYEN DURAN ERDOLU et al concluded in their study that Foetal sex might affect placental localisation. Doppler parameters and birth weight might also differ according to placental side. These factors should be taken into consideration during the evaluation of obstetric patients.

41 , Filipov E ,  et al studied on Placental location and its influence on the position of the fetus in the uterus and found that that the localization of the placenta influences the fetal position in the uterus.

42 , A. Antsaklis et al studied the effect of gestational age and placental location on the prediction of pre?eclampsia by uterine artery Doppler velocimetry in low?risk nulliparous women and concluded that Pre?eclampsia can be more accurately predicted if, along with the presence of a notch, both gestational age and placental position are taken into account. At week 24 the test maintains a high sensitivity (76.1%), but also has an improved specificity (95.1%) and positive predictive value (34%), which allow the clinician to intervene with a potential preventive treatment
43 , Neetu Singh et al 2015 conducted a study of second trimester placental location as a predictor of adverse pregnancy outcome on 592 pregnant women between 18-24 week and found that in pregnant female in whom placenta was laterally located, there was increased risk of development of preeclampsia with p value highly significant, 2.578 (odds ratio) with 95% CI (1.694-3.924). In 124 preeclampsia patients, 78 (62.9%) had laterally located placenta so placental laterality can be simple and reliable predictor of preeclampsia. In pregnant female who had laterally located placenta, chances of IUGR were also significantly increased with p value ; .0018 and 3.006 (odds ratio) with 95 % CI (1.678-5.385). In 53 female who was having IUGR, 33 (62.26%) had lateral placenta so there is positive correlation between IUGR and lateral placenta.

44 , Shailesh Janardhan Kore et al studied in 200 antenatal women, and found that 161 had central placenta and 39 had unilateral placenta. A total of 32 women developed preeclampsia, of which 19 (59.38%) had unilaterally located placenta at 20-24 weeks. This relationship was statistically highly significant (P;0.0001). The sensitivity, specificity, positive predictive value and negative predictive value of using placental laterality as a screening test were 59.38%, 88.10%, 48.72% and 91.93% respectively.

45 Sandhya K et al analysed Placental Laterality as a Predictor of Preeclampsia and found that out of the total 300 women, 168 (56 %) had laterally located placenta and of them, 112 (66.6 %) developed preeclampsia, while the remaining 112 (44 %) had centrally located placenta and of them, 48 (36.3 %) developed preeclampsia. So, the overall risk of developing preeclampsia with laterally located placenta was 5.09 (odds ratio) and 95 % confidence interval (2.40 to 10.88). The difference was found to be statistically significant, p value (0.00002) by chi-square test. From this study they concluded that females with laterally located placenta determined by USG at 18 to 24 weeks of gestation have five times greater risk of developing preeclampsia.
47 , Garima vats et al 2016 conducted study to find out the placental laterality as predictor of pregnancy induced hypertension, baby weight and low Apgar score. A total of 460 patients were analyzed, 82 (17.8%) had lateral placenta and among them 40 (48.7%) developed preeclampsia and 63 (76.8%) had small for gestational age baby (p;0.001). 378 (82.17%) had central placenta and among them 79 (20.9%) developed preeclampsia and 102(27%) had small for gestational age baby (p;0.001).From this study they concluded that laterally located placenta could be a predictor of poor pregnancy outcomes.

48 , Dr. Deepti Shrivastava et al 2016 in a case control study found that out of the 5 women with laterally located placenta, 4 developed PIH, while out of the remaining 195 subjects with central or fundal placenta, 96 developed PIH . Out of the total 100 PIH subjects 58% (58) developed mild PIH (DBP 90-99 mmHg). Out of these 58, 55 had centrally/fundal located placenta and 3 had laterally located placenta . This showed that no association could be pointed out between the location of placenta and the presence or absence of PIH in contrast to other previous studies in which a majority of PIH patients had laterally located placenta and a majority of normotensive women had central/fundal placenta.

49 , Shivamurthy et al States that lateral location of placenta was more common (52%) with gestational age of 16-24 weeks. As gestational age increased, higher incidence of fundal location (52%) was observed. Mean gestational age for fundal location was 25.6 years, which was higher compared to lateral location, with mean age of 24.4 years.

RATIONALE
This invasion of the maternal vessels by the cytotrophoblast leads to the destruction of the smooth muscle layer and to a partial replacement of the endothelial cells. It is responsible for the change in elasticity of the spiral arteries, whereby the blood circulation of this fetoplacental unit is adapted to the rapid growth of the fetus. This phenomenon of cell exchange is absent in preeclampsia or an intra-uterine growth retardation
In case of unilateral placenta, the absence or insufficient trophoblastic invasion of arteries on contralateral side, result in decreased blood flow to the fetus which may cause intrauterine growth restriction.so placental laterality as determined by ultrasound can be used as a predictor of development of hypertensive disorders and fetal growth disorders.

MATERIALS AND METHODS
This prospective observational study was carried out in Department of Obstetrics and Gynaecology at Sree Gokulam Medical College And Research Foundation. This study was conducted from March 2017 to August 2018 with complete follow-up of the selected pregnancy till delivery. Prior informed consent was taken from all the pregnant women. Total 614 pregnant women attending antenatal clinic both OPD and IPD at 18–24 weeks of gestation without any high risk factor were subjected to ultrasound examination and placental location was determined. The feto- maternal outcome such as the incidence of hypertensive disorders, fetal growth restriction , preterm labor, normal out come , Mode of delivery ,birth weight and the APGAR score were studied .

Study Design -Prospective Observational study
Study Setting- Department of Obstetrics ;Gynaecology ,SreeGokulam Medical College and Research Foundation,
Study Population
All the cases available as per the inclusion and exclusion criteria, attending the antenatal clinic or admitted under Department of Obstetrics and Gynecology in SreeGokulam Medical College And Research Foundation.

Study Period
A period of 18 months from March 2017 to August 2018.

Inclusion Criteria
Pregnantwomen with singleton pregnancy irrespective of parity.

Exclusion Criteria
Chronic hypertension
Those not willing for study
Low lying placenta
STUDY VARIABLES
Independent variable:
Placental location
Outcome variable :
Hypertensive disorders of pregnancy
Fetal growth disorders
Preterm labour
Normal
Mode of delivery
Birth weight
APGAR Score
METHODOLOGY
After approval from the local ethics committee and obtaining informed written consent from each patient attending the antenatal clinic of SreeGokulam Medical College ; Research Foundation and those having singleton pregnancy with no h/o c/c hypertension are selected. All pregnant women get their ultrasound between 18-24 week of gestation. Placental location along with other parameters is assessed. Placental position is located as anterior, posterior and fundal and laterally attached placenta.The feto- maternal outcome like the incidence of hypertensive disorders, fetal growth restriction , preterm labor, mode of delivery and birth weight and the APGAR score are studied among both groups.. Apart from clinical evaluation or by detailed history, physical and gynaecological examination was also done. They were regularly followed till delivery and
Maternal outcome noted in terms of:
Hypertensive disorders of pregnancy
Fetal growth disorders
Preterm labour
Normal
Mode of delivery
Fetal outcome reported in term of:
Birth weight
APGAR Score
SAMPLE SIZE
Total sample size is 614 calculated from the formula:
n=Z2
1? ? /2P(1-P)/d2
? =5%
Z
1-? /2=1.96
P is the proportion=12.9%
9
12.9% is proportion of preeclampsia in anteriorly located placenta
d=20% of P
Ethical issues:
Permission was obtained from the institutional ethical Committee of Sree Gokulam Medical College and Research Foundation. Informed consent was obtained from the patients before the study.

DATA MANAGEMENT
. Data are entered in Microsoft excel and statistical analysis done with SPSS software.

Statistical Analysis
 
Categorical variables were expressed as frequency percentage. Chi square test was used to find association of USG finding and selected variables. P;0.05 was considered the threshold for statistical significance.
Statistical analyses are performed by using a statistical software package SPSS, version 20.0
TIME ANALYSIS
Preparation of Protocol
Ethical Clearance
Study period
Analysis ; Data Entry
Submitting Report
Months
OBSERVATIONS AND RESULTS
This study is performed in 614 pregnant women attending antenatal clinic both OPD and IPD at 18–24 weeks of gestation and subjected to ultrasound examination and placental location was determined. The distribution of feto- maternal outcome such as the incidence of hypertensive disorders, fetal growth restriction , preterm labor, normal out come , Mode of delivery ,birth weight and the APGAR score in anterior ,posterior,fundal,and lateral placenta are studied .

Table 1: Percentage distribution of the sample according to age
Age Count Percent
;/=20 yrs 91 14.8
21-25yrs 256 41.7
26-30 yrs 202 32.9
31-35 yrs 53 8.6
;35yrs 12 2.0
Fig 1 : Percentage distribution of the sample according to age

In this study majority of the women were from the age group 21-25 years (41.7%) and 26-30 year (32.9%) .
Table 2 : Percentage distribution of the sample according to obstetric score
Obstetric score Count Percent
Primi gravida 307 50.0
Multi gravida 307 50.0
Fig 2 :. Percentage distribution of the sample according to obstetric score

Percentage distribution of Primigravida and multigravida were 307 (50 %) in each group in this study.

Table 3: Comparison of maternal outcome based on obstetric score
Maternal outcome Primigravida Multigravida 2 p
Count Percent Count Percent Hypertensive disorders 49 16.0 23 7.5 17.54 p;0.01
Fetal growth disorders 31 10.1 37 12.1 Preterm birth 6 2.0 20 6.5 Normal 221 72.0 227 73.9 The incidence of hypertensive disorders in primigravida is almost double ( 16%) compared to multigravida (7.5 %.) But preterm birth 6.5 %, and fetal growth disorders 12.1 % in multigravida ,is of higher incidence compaired to primigravida and P value is ;0.01, which is statistically significant .

My study is comparable with Ramya Kaku et al ,who observed Preeclampsia is more common in primigravida. In their study showed high incidence of preeclampsia in primigravida (72%) than in multigravida (28%).
Proportion of lateral placental location from 2nd trimester ultrasonography in all singleton pregnancy
Table 4 : Percentage distribution of the sample according to USG finding of placental location
USG finding of placental location Count Percent
Anterior 221 36.0
Posterior 218 35.5
Fundal 68 11.1
Lateral 107 17.4
Proportion of lateral placental location from 2nd trimester ultrasonography in all singleton pregnancy
Fig 3 : Percentage distribution of the sample according to USG finding of placental Location

Out of 614 antenatal women ,placenta on ultrasound examination done at 18-24 weeks of gestation 221 (36 %) cases had Anterior placenta ,218 (35.5 % ) had posterior placenta , 68 (11.1 % ) had fundal placenta and 107 (17.4 % ) cases had lateral
My study is comparable with Jani P.S et al., who observed in their study that out of 400 cases, 320 (80%) cases had central placenta, while 80 (20%) had lateral placenta. 0ut of the 80 patients with lateral placenta 28 (35%) developed preeclampsia
Outcome variables
Table 5: Percentage distribution of the sample according to maternal outcome
Maternal outcome Count Percent
Hypertensive disorders 72 11.7
Fetal growth disorders 68 11.1
Preterm birth 26 4.2
Normal 448 73.0
Outcome variables
Fig 4 :Percentage distribution of the sample according to maternal outcome
In my study Incidence of hypertensive disorders were 11.7 % (72 ) ,fetal growth disorder was 11.1 % (68 ), preterm birth was 4.2 % (26) and normal pregnancy was 73 % (448 ).

Association of placental location and selected variables

Table 6 : Comparison of maternal outcome based on USG findings of placental location
Maternal outcome Anterior Posterior Fundal Lateral 2 P
Hypertensive disorders 15 (20.8) 24 (33.3) 5 (6.9) 28 (38.9) 172.31 p;0.01
Fetal growth disorders 8 (11.8) 15 (22.1) 1 (1.5) 44 (64.7) Preterm birth 8 (30.8) 12 (46.2) 1 (3.8) 5 (19.2) Normal 190 (42.4) 167 (37.3) 61 (13.6) 30 (6.7) Association of placental location and selected variables
Fig 5: Comparison of maternal outcome based on USG findings of placental location

Out of 72 hypertensive patients, 28 (38.9%) had laterally located placenta with chi-square value of 172.31 and p value of ;0.01 which is statistically significant. so placental laterality can be simple and reliable predictor of preeclampsia.
Out of 68 patient who was having IUGR, 44(64.7%) had lateral placenta with significantly increased P value ( P ;0.01 ) and chi-square value of 172.31 ,so there is positive correlation between IUGR and lateral placenta.
Out of 26 preterm birth,12(46.2%) had posteriorly located placenta. In posterior located placenta, there were increased risk of preterm labour .

The results of my study was comparable to those of Muralidhar et al. 17. In his study out of 426 women, 324(76%) had central placenta and 102 (24%) had lateral placenta. The relationship were found to be statistically significant p ; 0.0001.

Table 7: Percentage distribution of the sample according to mode of delivery
Mode of delivery Count Percent
Normal vaginal delivery 446 72.6
Caesarean delivery 168 27.4
Fig 6 : Percentage distribution of the sample according to mode of delivery

The cesarean rate was 27.4% and normal deliveries being 72.6 %.

Table 8 : Comparison of mode of delivery based on USG findings of placental location
Mode of delivery Anterior Posterior Fundal Lateral 2 p
Normal vaginal delivery 160 (35.9) 157 (35.2) 44 (9.9) 85 (19.1) 4.69 0.196
Caesarean delivery 61 (36.3) 61 (36.3) 24 (14.3) 22 (13.1) Fig 7 : Comparison of mode of delivery based on USG findings of placental location

On comparatively analyzing mode of delivery, there was no relation of placental position and mode of delivery.The cesarean rate was 27.4% and normal deliveries being 72.6 %.

Table 9 :Percentage distribution of the sample according to birth weight
Birth weight Count Percent
;1.5 kg 3 0.5
1.5-2.4 kg 99 16.1
2.5-3.4kg 461 75.1
3.5- 4kg 49 8.0
; 4 kg 2 0.3
Fig 8 : Percentage distribution of the sample according to birth weight

The occurrence of birth weight ;1.5 kg was seen in 3 (0.5%),birth weight between 1.5 -2.4 kg was 99 (16.1% ) ,2.5 -3.4 kg group was 461 (75.1% ) and 3.5 -4 kg was 49 (8 %) and neonates ;4 kg was 2 (0.3 % ).

Table 10 : Comparison of birth weight based on USG findings of placental location
Birth weight Anterior Posterior Fundal Lateral 2 p
;1.5 kg 1 (33.3) 2 (66.7) 0 (0) 0 (0) 88.79 p;0.01
1.5-2.4 kg 19 (19.2) 29 (29.3) 4 (4) 47 (47.5) 2.5-3.4kg 178 (38.6) 171 (37.1) 53 (11.5) 59 (12.8) 3.5- 4kg 22 (44.9) 16 (32.7) 10 (20.4) 1 (2) ; 4 kg 1 (50) 0 (0) 1 (50) 0 (0) Fig 9 : Comparison of birth weight based on USG findings of placental location

Out of 99 (16.1 % )neonates with birth weight between 1.5-2.4 kg ,47 (47.5 % ) cases had lateral placenta in antenatal scan, with P value of ;0.01 ,which is significant.

Table 11 : Percentage distribution of the sample according to Apgar score
Apgar score Count Percent
1 Minute ;9 586 95.4
;9 28 4.6
5 Minute ;9 607 98.9
;9 7 1.1
Fig 10 :Percentage distribution of the sample according to Apgar score

Out of 614 neonates, 586 (95.4 % ) had Apgar score of 9 at 1 minute ,only 28 (4.6 %) had Apgar score ;9 at 1 minute . 607 (98.9 % ) had Apgar score of 9 at 5 minute ,only 7 (1.1 %) had Apgar score ;9 at 5 minute .

Table 12 : Comparison of apgar score at 1 minute based on USG findings of placental location
Apgar score at 1 minute Anterior Posterior Fundal Lateral 2 p
;9 213 (36.3) 206 (35.2) 66 (11.3) 101 (17.2) 1.57 0.665
;9 8 (28.6) 12 (42.9) 2 (7.1) 6 (21.4) Fig 11 : Comparison of apgar score at 1 minute based on USG findings of placental location

Apgar score was not statistically significant in lateral placenta ,and P value showed ;0.665
Table 13 : Comparison of apgar score at 5 minute based on USG findings of placental location
Apgar score at 5 minute Anterior Posterior Fundal Lateral 2 P
;9 218 (35.9) 216 (35.6) 68 (11.2) 105 (17.3) 1.48 0.687
;9 3 (42.9) 2 (28.6) 0 (0) 2 (28.6) Fig 12 : Comparison of apgar score at 5 minute based on USG findings of placental location

Apgar score at 5 minute was not statistically significant in lateral placenta ,and P value showed ;0.687.

DISCUSSION
The significance of placental location in the uterine cavity had been studied extensively. In the past two decades, ultrasound has been proved to be the safest, easiest and most accurate method for assessing placental location. Multiple studies were done to establish association of placental location and adverse pregnancy outcome like preeclampsia, IUGR, and preterm birth.There is a significant association between placental location and uterine artery resistance. High uterine artery resistance leads to decreased uterine artery blood flow and adverse pregnancy outcomes. In case of unilateral placenta, the absence or insufficient trophoblastic invasion of arteries on contralateral side, result in decreased blood flow to the fetus which may cause intrauterine growth restriction and preeclampsia.

In normal pregnancies, the spiral arterioles that supply the placental bed undergo trophoblast induced conversion to uteroplacental arterioles. The significance of normal placentation for this cytotrophoblastic invasion is high
and the cytotrophoblasts fail to adopt a vascular adhesion phenotype in pre-eclampsia15. In preeclampsia
conversion of the spiral arterioles is incomplete16. It involves only the subplacental veneouls. If there were no
functional anastomoses between right and left uterine arteries, in cases with unilaterally located placentas, one
would expect the ipsilateral uterine artery systolic/ diastolic ratios to change more than the contralateral ratios in
hypertensive pregnancies. This may explain the reduced trophoblastic invasion in laterally situated placenta when the uteroplacental blood flow need are mainly met by one side uterine artery.

15. Das Gupta S. Pathophysiology and prevention of pregnancy induced hypertension. New Delhi, JP Publications. Recent Adv. In
Obstet and Gynaecol. 1:14-31.

16. Roberts JM and Hubel CA. Is oxidative stress the link in the two stage model of preeclampsia. Lancet. 1999; 354:788-9.

In my study majority of the women were from the age group 21-25 years (41.7%) and 26-30 year (32.9%) .

And percentage distribution of Primigravida and multigravida were 307 (50 %) in each group in my study.

The incidence of hypertensive disorders in primigravida is almost double ( 16%) compared to multigravida (7.5 %.) . And preterm birth 6.5 %, and fetal growth disorders 12.1 % in multigravida ,is of higher incidence compaired to primigravida and P value is ;0.01, which is statistically significant .

My study is comparable with Ramya Kaku et al ,who observed Preeclampsia is more common in primigravida. In their study showed high incidence of preeclampsia in primigravida (72%) than in multigravida (28%).
Out of 614 antenatal women,in our study placental location on ultrasound examination done at 18-24 weeks of gestation showed 221 (36 %) cases of Anterior placenta ,218 (35.5 % ) cases of posterior placenta , 68 (11.1 % ) cases of fundal placenta and 107 (17.4 % ) cases of lateral placenta.
My study is comparable with Jani P.S et al., who observed in their study that out of 400 cases, 320 (80%) cases had central placenta, while 80 (20%) had lateral placenta. 0ut of the 80 patients with lateral placenta 28 (35%) developed preeclampsia
In my study Incidence of hypertensive disorders were 11.7 % (72 ) ,fetal growth disorder was 11.1 % (68 ), preterm birth was 4.2 % (26) and normal pregnancy was 73 % (448 ).

In my study, out of 72 hypertensive patients, 28 (38.9%) had laterally located placenta with chi-square value of 172.31 and p value of ;0.01 which is statistically significant. Out of 68 patient who was having IUGR, 44(64.7%) had lateral placenta with significantly increased P value ( P ;0.01 ) and chi-square value of 172.31. The results were comparable to the study done by Lucy et al.9 The results of which showed that development of PIH and IUGR pregnancies were nearly fourfold more in lateral placentation. The results of my study is comparable to those of Muralidhar et al.8 In his study, a total of 426 unselected singleton pregnant women were included. Out of 426 women, 324 had centrally located placenta and 102 had unilateral placenta. A total of 71 women had developed preeclampsia of which 52 (74%) had unilaterally located placenta. The relationship was found to be statistically significant p;0.0001.
8. Muralidhar PV, Jyothi P. Placental lateriality by ultrasound-a simple yet reliable predictive test for preeclampsia. J Obstet Gynecol India. 2005;55:431-3.
9. Bramham K, Briley AL, Seed P, Poston L, Shennan AH, Chappell LC. Adverse maternal and perinatal outcomes in women with previous preeclampsia: a prospective study. Am J Obstet Gynecol. 2011; 204(6):512e1-9.
In my study it was seen that laterally located placenta on ultrasound done at 18-24 weeks was associated with increased risk of development of hypertensive disorders and fetal growth disorders. This result is in accordance with Kofinas et al who concluded that in women with unilateral placenta, the incidence of preeclampsia was 2.8-fold greater than those with centrally located placenta. Similar to my study Anuja V Bhalero et al reported that out of 300 women, 168 (56%) females had laterally located placenta and 132 (44%) had centrally located placenta.9,10 Out of the 168 women with laterally located placenta, 112 (66.6%) developed PIH as compared to 132 females with centrally located placenta where 48 (36.6%) developed PIH. So, the risk of developing PIH was five times greater for the females with laterally located placenta as compared to those with centrally located placenta.
The result of my study Is also comparable to study done by Gonser et al that lateral implantation increases the risk of preeclampsia.11
Out of 26 preterm birth,12(46.2%) had posteriorly located placenta in my study. From this conclude that posterior located placenta, there is increased risk of preterm labour. My study findings are consistent with another study done by Shulman et al that shows significant association of posterior placenta and preterm labour.8
The cesarean rate was 27.4% and normal deliveries being 72.6 %. On comparatively analyzing mode of delivery, there was no relation of placental position and mode of delivery.The cesarean rate was 27.4% and normal deliveries being 72.6 %.

The occurrence of birth weight ;1.5 kg was seen in 3 (0.5%),birth weight between 1.5 -2.4 kg was 99 (16.1% ) ,2.5 -3.4 kg group was 461 (75.1% ) and 3.5 -4 kg was 49 (8 %) and neonates ;4 kg was 2 (0.3 % ).Out of 99 (16.1 % )neonates with birth weight between 1.5-2.4 kg ,47 (47.5 % ) cases had lateral placenta in antenatal scan, with P value of ;0.01 ,which is significant.

Out of 614 neonates, 586 (95.4 % ) had Apgar score of 9 at 1 minute ,only 28 (4.6 %) had Apgar score ;9 at 1 minute . 607 (98.9 % ) had Apgar score of 9 at 5 minute ,only 7 (1.1 %) had Apgar score ;9 at 5 minute . Apgar score was not statistically significant in lateral placenta ,and P value showed ;0.665
Similar results are found in study by Hadley et al. The results in my study are in accordance with Kalaniti et al who studied that in IUGR babies chances to find lateral placenta are more than 3.8 times than normal babies.2 my study is an effort to establish the association of placental location with different maternal and neonatal outcome so that it can help us to determine various maternal and fetal complications in form of hypertensive disorders of pregnancy preterm labour, and fetal growth disorders etc. So placental locations in second trimester can be used as a predictor to screen out high risk pregnant females which will help in prevention of adverse pregnancy outcome.

1Hadley CB, Main DM, Gabbe SG. Risk factors for premature rupture of the fetal membranes. Am J Perinatol. 1990;7:374-9.

2. Kalanithi LE, Illuzzi JL, Nossov VB, Frisbaek Y,Abdel-Razeq S, Copel JA, et al. Intrauterine growth restriction and placental location. J Ultrasound Med. 2007;26:1481-9.

9. Kofinas AD, Penry M, Swain M, Hatjis CG. Effect of placental laterality on uterine artery resistance anddevelopment of preeclampsia and intrauterine growth retardation. AM.J Obstet Gynecol. 1989;161:153-69.

10. Bhalerao AV, Kulkarni S, Somalwa S. Lateral placentation by USG: A simple predictor of PET: J South Asian Obs Gynae. 2013;5(2):68-71.

11. Gonser M, Tillack N, Pfeiffer KH, Mielke G. Placental location and incidence of preeclampsia. Ultraschall Med. 1996;17:236-8.

CONCLUSION
The significance of centrally located placenta for normal cytotrophoblastic invasion is high and the cytotrophoblasts fail to invade spiral arteriols in preeclampsia and in intra uterine growth restriction. In case of unilateral placenta, the absence or insufficient trophoblastic invasion of arteries on contralateral side, specifically the spiral arteries that the endovascular cytotrophoblast should invade result in decreased blood flow to the fetus which may cause intrauterine growth restriction. Placental location can be easily done by antenatal USG. In our study and other similar studies showed incidence of hypertensive disorder and intrauterine growth restriction is high in lateral located placenta. So in this study, we concluded that USG in pregnant women
during 18-24 week of gestation is a simple yet reliable and cost effective predictive screening test for hypertensive disorders ,fetal growth disorders.

 
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ANNEXURES
Annexure IPROFORMA
PATIENT DETAILS
Patient Name:
Age:
Obstetric Score:
MRD No. :
Abortions:
DOA:
Booked / Unbooked:
PRESENTING COMPLAINTS:
OBSTETRIC HISTORY:
PREVIOUS PREGNANCIES:
No. History of Pregnancy Delivery Puerperium Outcome
MENSTRUAL HISTORY:
Menarche at:
Previous cycles:
Regularity Duration Flow Any other
LMP:
EDD:
PAST HISTORY:
FAMILY HISTORY:
PERSONAL HISTORY:
SOCIOECONOMIC HISTORY:
GENERAL EXAMINATION:
Built:
Nourishment:
Height:
Weight:
Pallor:
Icterus:
Lymphadenopathy:
Oedema:
Breast Examination:
VITAL SIGNS:
Temperature:
Pulse:
BP:
RR:
SYSTEMIC EXAMINATION:
CVS:
RS:
CNS:
ABDOMINAL EXAMINATION:
Inspection
Palpation
Abdominal Girth in cms :
Symphysiofundal Height:
Fundal grip:
Ht. Of fundus:
Presentation:
Position:
Lie:
Pelvic grip:
Pelvic grip:
Clinical evidence of oligohydramnios:
1. Foetal Heart Sounds
PELVIC EXAMINATION:
ANTENATAL COMPLICATIONS:
Abruption-placenta:
Foetal Distress:
Any other:
DIAGNOSIS:
INVESTIGATIONS:
Hb%:
Urine:
Blood Group and Rh typing:
Others:
ULTRASOUND:
Period of gestation at USG done
Placental location
Delivery Notes
Operative Notes
Indication for LSCS
FOETAL OUTCOME:
Apgar score
1 min:
5 min
Birth weight:
Annexure 2
KEY TO MASTER CHART
A .SERIAL NUMBER
B .MRD NUMBER
C .AGE
1 .A – ?/=20 yrs
2 .B -21-25yrs
3 .C -26-30 yrs
4 .D -31-35 yrs
5 .E – >35yrs
D .OBSTETRIC SCORE
`1 .A PRIMIGRAVIDA
.B MULTIGRAVIDA
E .POG at which anomaly scan taken
.A -18wks
.B -19wks
.C -20wks
.D -21wks
.E -22wks
.F -23wks
.G-24wks
F .USG finding of placental location
.A –anterior
.B –posterior
.C -fundal
.D -lateral
G .MATERNAL OUTCOME
.A –hypertensive disorders
.B –fetal growth disorders
3 .C – preterm birth
4 .D -normal
H .MODE OF DELIVERY
.A –normal vaginal delivery
.B –caesarean delivery
I .BIRTH WEIGHT
.A <1.5 kg
.B 1.5-2.4 kg
.C 2.5-3.4kg
.D 3.5- 4kg
.E > 4 kg
J .APGAR SCORE AT 1 MINUTE
.A >9
.B <9
K . APGAR SCORE AT 5 MINUTE
.A >9
.B <9
ANNEXURE 3
MASTER CHART
ANNEXURE 4
SUBJECT INFORMATION AND INFORMED CONSENT
I, Dr.SHEENA KRISHNAN, PG student in the Department of Obstetrics and Gynaecology, Sree Gokulam Medical College and Research Foundation, Venjaramoodu, Trivandrum invite you to participate in my study titled “STUDY ON SECOND TRIMESTER PLACENTAL LOCATION AND THE
ADVERSE PREGNANCY OUTCOME”. This study is being done to assess the fetomaternal outcomes of pregnancies with placental location .This study is being conducted after getting Ethical clearance from the Institutional Ethical Committee. If you need any clarification, you may please contact my guide Dr.LEKSHMI M,Associate Professor of Obstetrics & Gynaecology, SGMC&RF in her mobile number (9846876868) or myself in the phone number (8547903361).

Date:Dr.SHEENA KRISHNAN
Patient identification in this trial:………………………………
………………………………………………………………… Name of the PrincipalInvestigator…………………………… Tel. No …………………
I, Mr/ Mrs…………………………., have been fully informed by the doctor in detail about the nature and purpose of the study, titled STUDY ON SECOND TRIMESTER PLACENTAL LOCATION AND THE ADVERSE PREGNANCY OUTCOME .I understand that my participation is voluntary & that I am free to withdraw at any time from this study & such withdrawal will not affect my legal rights including the quality of medical care I receive.

I understood that I will not be referred to by name in any of the reports concerning the study & In turn I cannot restrict in any way the use of the information collected about me from my participation in the research and sections of any of my medical notes may be looked by responsible individuals.

I give permission for the individuals to have access to my records with this understanding, I agree voluntarily to take part in this study.

I agree to take part in the above study.

Date:
Place: (Signature/ Left ThumpImpression)
Name of the Participant:……………………………………………………. Relative:……………………………………………………….
Complete postal Address:……………………………………………………….

This is to certify that above consent has been obtained in my presence
Date: Signature of thePrincipal
Investigator
Place:
(1)Witness–1(2)Witness–2
……………………………………
SignaturesSignatures
NameandaddressName andaddress
ACKNOWLEDGEMENT
I express my sincere and deep sense of gratitude to Dr.Nazeema.A, Professor and HOD, Department of Obstetrics and Gynaecology, Sree Gokulam Medical College and Research Foundation, Venjaramoodu, Trivandrum for the valuable guidance, expert advice and constant encouragement given to me in the preparation of thisdissertation.

I express my sincere and deep heartfelt sense of gratitude to my guide Dr.LEKSHMI M, Associate Professor, Department of Obstetrics and Gynaecology, Sree Gokulam Medical college and Research Foundation who with her knowledge and experience has provided able guidance, direct supervision and constant encouragement throughout in the preparation of this dissertation. Working under her guidance was an enrichingexperience.

I am thankful to the Director Dr.K.KManojan, DeanDr.Chandramohan, Principal Dr.R.Dayananda Babu &Medical Superintendent Dr.PBSulekha Devi, of Sree Gokulam Medical College and Research Foundation, Venjaramoodu, Trivandrum, for allowing me to conduct this study.

I thank once again Ms Manju. L, Statistician, SGMC&RF for their help in the statistical analysis of this dissertation.

I am extremely grateful to all my teachers and colleagues in the Department of Obstetrics and Gynaecology, for their support and valuable inputs during the clinical work of mystudy.

I am very grateful to all those patients who were the subjects in this study and without their cooperation; this study would not have been possible.

I am extremely grateful to my parents who were the pillar of strength during this study and my PGcourse.

My sincere gratitude and heartfelt thanks to my husband Harish. Kumar .R who is my source of inspiration and whose love helped me to survive the tough times.

Above all I thank GOD Almighty, whose blessing has always guided me in my endeavors.

Dr. SHEENA KRISHNAN

LIST OF ABBREVIATIONS
-Amniotic fluid index
NST-Non stress test
IUGR-Intra Uterine growth restriction
FGR-Fetal growth restriction
a/c-Acute
FHR-Fetal heart rate
TVS-Trans Vaginal Ultrasonography
WHO-World Health Organization
Mm-Millimeter
POG-Period of gestation
USG-Ultrasound scan
CTG – Cardiotography
LSCS – Lower segment cesarean section
NICU – Neonatal intensive care unit