CHAPTERS CONTRIBUTED

Case STUDY:
Obstetric Vasculopathy: HYPERTENSIVE DISORDERS OF PREGNANCY

AUTHOR:
Pankaj Desai*
DESIGNATION
Consultant Obgyn Specialist
Dean (Students) & Assoc. Professor (VRS)
Department of Obgyn
Medical College
Baroda
ADDRESS:
Janani Maternity Hospital
Opp. Alankar Apartments
Dandia Bazaar
Baroda 390001
EMAIL:
drpankajdesai@gmail.com

INTRODUCTION:

In simplest terms obstetric vasculopathy means disease of vessels resulting from an obstetric event. This first step in the understanding of obstetric vasculopathies is the simplest and most preliminary step. Immediately from here the complexity of this science begins. It is indeed this complexity that makes it very beautiful but challenging, intriguing and therefore enticing for keen students to decode its mysteries. Obstetric vasculopathy is not the vasculopathy that occurs in the maternal vascular system. It is the vasculopathy that occurs at the fetomaternal interface. Immunology has the most important role in its etiopathology. Inherited probably by an amorphous genetic propensity at the fetomaternal system, there occurs a series of changes at this interface which invites seemingly totally diverse and apparently unrelated conditions.

In early days it was perceived that one condition leads to the other. But as advances in understanding increased it became clear that this is not a cause-effect relationship but are fruits of the same pathology. Currently obstetric vasculopathies include:
• Recurrent spontaneous missed abortions of late first trimesters and second trimesters.
• Preeclampsia
• Intrauterine Growth retardation (IUGR)
• Accidental hemorrhage
• Fetal demise of non-anomalous pregnancies with association of any one of the above conditions.

Newer additions continued to get added which included hyperhemocystenemia. SLE associated pregnancies are a special class. They have a magnified manifestation of vasculopathy thereby enabling a closer look at this miraculous but mysterious phenomenon1.

The clinical spectrum of obstetric vasculopathies can be diverse and vast. Multisystem involvement of the pregnant female further enlarges the clinical profile of these conditions. Many times clinical teachers of the subject have tried to divide the spectrum of clinical features into major features, minor features and features of associates & complications. However this type of grouping may be clinically helpful but it may not remain watertight. This is because there can be a considerable overlap from one group to the other. This case study profiles one such complex case in light of modern thinking.

CASE STUDY:
Mrs A was a 29 years old, Hindu married woman. She hailed from an urban area and lived in a nuclear family with her husband. She was a computer professional with a regular office-time job. She presented to us in the interval period (when not pregnant) with complaints of repeated adverse obstetric outcomes. Her menstrual history revealed regular menstrual cycles. Her obstetric history revealed following important details:

• First two fetal demise at 28-30 weeks and in both instances she had PIH and the babies were IUGR.
• Third was a spontaneous miscarriage at 11 weeks after FHS were seen. It was a fetal demise
• Fourth was a full term still birth and she had severe PIH with IUGR.

She had no contributory past, personal or family history.
On clinical examination she was of average built and well nourished. She was not obese. Her height was 156 cms. Her weight was 68 Kgms. She appeared non-anemic, her vital signs were normal and there was no other contributory feature on systemic examination.

Her blood investigations revealed Hemoglobin: 11.3 gms./dl, Total Count of 6900, Differential Count showed 73 Polymorphs, 25 Lymphocytes, 1 Eosinophil and 1 Monocyte. Serum Creatinine was 0.9. She tested negative for Antiphospholipid antibodies, SLE and hyperhemocystenemia. Urine examination was non-contributory.

Diagnosis: On basis of her history, clinical features and investigations she was diagnosed as having obstetric vasculopathy 1.
Management in interval period: She was explained the pathophysiology of alloimmune process active in her leading to these clinical features in simplest words possible. She was also reassured of a strong possibility of getting a successful outcome. Without unduly alarming her, she was sensitized to the challenges involved in the likelihood of recurrence and reappearance of any of these conditions in subsequent pregnancy. She was guided to the fact that the treatment of cause was still not known to science as it was shrouded in scientific mystery. But the treatment of effect gives very positive results. She was promised a good tender loving support and care all throughout. As regards the drug treatment she was put on tablet aspirin in a dose of 1.2 mgs. / Kg / day and tablet folic acid 5 mgs. /day. She was advised not to wait for subsequent pregnancy and can plan it as and when she was emotionally ready for it.

After about six months she presented with an early 6 weeks pregnancy on home pregnancy test done by her on missing her periods, ten days before. At the clinic, her history was thoroughly reviewed once again. On examination, she appeared non-anemic and her vital signs were normal. Clinical examination revealed signs of early pregnancy. Ultrasonography confirmed a live intrauterine singleton pregnancy, corresponding with the weeks of gestation.

She was already on low-dose aspirin and folic acid which were indeed continued. Inj. Heparin (unfractionated) was started in the dose of 5000 IU subcutaneously daily. She was also put on Inj. HCG 5000 IU intramuscularly weekly and Tab. Natural Micronized Progesterone 200 mgs intavaginally twice daily. HCG and Progesterone were discontinued at 12 weeks.
She was advised a weekly follow-up at the hospital when her USG was done for fetal viability and fetal growth. On these weekly visits she was also administered Injection HCG and was given time to interact with the attending doctor who would patiently solve her queries if any. This was part of TLC policy of the hospital for subjects or recurrent adverse obstetric outcomes.

At 11-14 weeks her I-Trimester scan was done. It revealed normal NT, presence of nasal bone, absent tricuspid Incompetence and normal flow through Ductus Venosus. All of these made her a low-risk subject on basis of these soft markers for Trisomy. However she being a high-risk subject for Obstetric Vasculopathies was subjects to Uterine Artery Doppler. It showed a PI of 2.21 and presence of diastolic notch (Figure 1). Iron and calcium supplementation was started now and aspirin and heparin were also continued. Her weekly visits were now discontinued in favour of monthly visits.

At 20 weeks she was subjected to a Level III scan which revealed no congenital anomalies in the baby. But the uterine artery showed a persistence of diastolic notch and PI of 1.8. This indicated that the process of obstetric vasculopathy was still on and so same treatment including aspirin + heparin combination was continued.

At 24 weeks of her pregnancy, on her regular follow-up visits every month her BP remained normal and fetal growth was also normal, as judged on clinical examination. However at 26 weeks of pregnancy, she recorded a rise in BP for the first time. Her BP was found to be 130/90 indicating a mild preeclampsia. There were a few interesting decisions that were to be taken now:

• Role of adding anti-oxidants like Vit. C and E:
o Combined Vit. C and E supplementation does not decrease the risk of preeclampsia and should not be offered to gravidas for the prevention of preeclampsia or other pregnancy induced hypertensive disorders 2.
• Role of adding compounds like:L-Arginine
o Some articles and reviews do discuss the role of these amino acids in pregnancy. In one large meta-analysis data from seven RCTs involving 916 patients were enrolled. This study demonstrates L-arginine supplementation is superior to placebo in lowering diastolic pressure and prolonging pregnancy in patients with gestational hypertension with or without proteinuria, but the effect on lowering systolic pressure and increasing neonatal weight was not statistically significant 3.
• DHA
o It is postulated that DHA supplementation, early in pregnancy, may reduce the incidence of deep placentation disorders including preeclampsia. One recent study based on their own hypothesis states that if our hypothesis is correct, DHA supplementation, early in pregnancy, will become a safe and effective strategy for primary prevention of highly relevant pregnancy diseases, such as preterm birth, preeclampsia, and fetal growth restriction 4. However, results being inconsistent more research is needed to take a final stand on the matter
• Vitamin D3
o Very few studies are currently available on the role of this compound in prevention of obstetric vasculopathies. The evidence base is currently insufficient to support definite clinical recommendations regarding vitamin D supplementation in pregnancy 5.
• Sildenafil:
o This compound seems to have a rationale. Also limited studies have shown a reduction in PI of subjects being given sildenafil being given in a dose of 25mgms three times a day. But these studies are still silent about this effect getting effectively translated into clinical effects. Thus this limited data makes the use of this compound at best empirical if not irrational
None of these agents except L-Arginine were started in this pregnant subject. L-Arginine was administered in a dose of 3 grams per day orally daily
Another set of agents that were to be decided for at this stage were:
• Antihypertensives:
o Most studies do not favour the use of antihypertensives in mild preeclampsia but some studies leave it to the clinician to decide, individualising decision-making as per the situation and the pregnant subject
o In this subject Tab. Nifedipine was started in a dose of 10mgms three times a day
• Corticosteroids:
o For improving fetal lung maturity and other fetal benefits corticosteroids Betamethasone was administered in a dose of 12 mgs intramuscularly once. This was repeated after 24 hours. It brought the total Betamethasone administered to the prescribed 24 mgs. Fetal survival at and after 26 weeks of maturity has greatly improved in our setup. We are able to salvage foetuses of 26 weeks pregnancy and about 750 grams and more in weight.

She was not admitted in the hospital as she was regular in follow-up. She was called every fortnightly for follow-up.
At 33 weeks pregnancy, another challenge of IUGR arose. Her BP had risen to 160/100 mm of Hg. Being a pregnant women having obstetric vasculopathy, IUGR also appeared. On clinical examination this was suspected and confirmed on USG. In other circumstances had the colour Doppler technology not been well understood and available, a decision to induce labour would have been taken. But with modern understanding the situation was different. It was decided to monitor her BP and place her under USG and colour Doppler watch. USG showed an early IUGR with Amniotic Fluid Index (AFI) of 7.57 (low – normal). On colour Doppler PI of MCA was 1.38 and that of Umbilical artery was 1.0. This brought the Cerebro-placental ratio (CPR) at 1.38. The cut-out for this is universally accepted as 1.0 6. In view of her fetal condition not being compromised, labour was not induced. It was decided to continue a weekly follow-up.

After a week: 34 W 4 Days, BP was still the same, not increasing or decreasing and the IUGR foetus had an expected birth weight of 1876 grams. AFI was still low-normal (Figure 2). Head circumference to Abdominal circumference (HC: AC) ratio showed an IUGR but it was not deteriorating (Figure 3). On colour Doppler PI of MCA was 1.30 (Figure 4) and that of umbilical artery was 1.01 (Figure 5). This brought the Cerebro-placental ratio (CPR) at 1.3 (still above the critical 1.0). It was therefore decided to continue the pregnancy. At 35 weeks Aspirin and heparin were discontinued. None of the parameters had worsened so pregnancy was continued with weekly follow-up.

At 36 weeks her BP rose to 170/108. In view of this caesarean section was done for severe preeclampsia with IUGR and she delivered a new-born child of 1900 grams. It had normal APGAR and did not require any support. It was not admitted to NICU and was discharged with the mother on sixth post-operative day on exclusive breast-feeding.

DISCUSSION:
Obstetric vasculopathies are a set of apparently heterogeneous and poorly understood conditions. They constitute the single largest group of derangements that can endanger the life of both – the mother and/or the unborn child. Seemingly unrelated obstetric diagnoses like recurrent miscarriages due to fetal demise, preeclampsia, IUGR, recurrent still births and accidental hemorrhage all seem to have the same underlying etiopathology. They are for that reason grouped into one large set coined as “Obstetric Vasculopathies”.

Both, autoimmune as well as alloimmune mechanisms are apparently responsible in causation of obstetric vasculopathies. Alloimmune mechanism is by exclusion. This means that once suspected on basis of history of one or more of the conditions included in the basket of Obstetric Vasculopathies, investigations for autoimmune mechanisms are requested. These include testing for Antiphospholipid antibodies, SLE and hyperhemocystenemia. If these are negative as was found in this subject, alloimmune mechanism is diagnosed to be operational. However management of both, remain the same.

Colour Doppler serves as a whistle-blower in obstetric vasculopathies. Literally, a whistle-blower is a person who tells the public or someone in authority about alleged dishonest or illegal activities (misconduct) occurring in a government department or private company or organization. Here this word is used to indicate the role of uterine artery in telling obstetricians about the impending preeclampsia and its problems. In fact the role of uterine artery Doppler is not confined to predicting preeclampsia now, but goes much beyond. Colour Doppler as applied to obstetric conditions has been proved to be a game-changer in prediction, management decisions and prognostication as it comes out so vividly in this case. Resistance to blood flow in the uterine arteries can be important and effective method to predict and monitor preeclampsia. Resistance to this blood flow can be measured by the presence (and subsequent disappearance) of diastolic notch as well as the standard colour Doppler indices namely Pulsatility Index (PI), Resistance Index (RI) and Systolic: Diastolic (S: D) ratio.

Aspirin: In subjects with obstetric vasculopathies 1.2 mg /kg of aspirin is recommended. This is to be given as soon as pregnancy diagnosis is made. Data from large randomized shows that low-dose aspirin initiated in early pregnancy is an efficient method of reducing the incidence of preeclampsia and IUGR 7. There is a school of thought which also recommends the use of low dose aspirin preconceptionally (as was done in this subject). It is recommended by these groups that aspirin should be started in the same low dose at least three months prior to conception. It should then be continued though the trimesters once pregnancy occurs. It is discontinued at 36 weeks and intervention be planned at 37 weeks. However the advantage of such an administration before conception is not well established. Therefore the order of the day is to individualize and leave it to the obstetrician.

Heparin: Another very vital weapon in the armamentarium of the obstetrician who deals with obstetric vasculopathies is heparin. This is started as soon as pregnancy is diagnosed or when the subject reports to the clinician whichever is earlier. Heparin - unfractionated heparin (UH) is administered in a dose of 5000 I.U. subcutaneously. A consistently asked question is which heparin should be given? Two types of heparin are available in the market. One is the regular or unfractionated heparin (UH) as it is called and the other is the low molecular weight (LMWH) or fractionated heparin. The answer to this question is critical as price factor is involved. LMW heparin is much more costly than regular heparin. Therefore the answer to the question is: It doesn’t matter. Both these formulations are equally effective. There is no significant difference in the adverse drug reactions of both these formulations of heparin. Over a period of time it has been found that none of the two UH or LMWH need any monitoring for coagulation profile alterations in the dosage in which they are given 8. Therefore if cost is an important factor, regular heparin can be safely given for prevention of obstetric vasculopathies. The duration for which heparin needs to be given is now based on colour Doppler of uterine artery results. We stop Heparin if Diastolic notch disappears and PI is less than 1.0 9. Alternatively if colour Doppler features do not appear it is interpreted that the process of vasculopathy is still unattenuated. In such subjects, we stop heparin at 36 weeks and induce labour at 37.

This case report highlights some changing trends in approach to subjects with Preeclampsia I particular and Obstetric Vasculopathies in general:

• Clinical history of specific adverse obstetric outcomes is most critical in diagnosing Obstetric Vasculopathies.
• Management of these subjects should start from the interval period to get better results.
• Aspirin + Heparin gives best results in these subjects.
• Colour Doppler is the mainstay now in management of these subjects. In I-Trimester uterine artery colour Doppler helps in identifying high-risk subjects. At mid-trimester the same artery Doppler helps in identifying low-risk subjects. In III-trimester Middle Cerebral artery, Umbilical Artery – their ratios and flow through Ductus Venosus helps in critical decision-making about obstetric interventions.
• Many new drug treatments are flooding the market of which very few are found to be effective.
CONCLUSION:
Obstetric Vasculopathies especially preeclampsia is a common occurrence in obstetric practice. Nevertheless its management is a challenge. An obstetrician, who is well informed and with deep understanding of this condition, can manage it rationally and get very favourable results.

REFERENCES:
1. Desai P: General Aspects of Obstetric Vasculopathies: Obstetric Vasculopathies: Jaypee Publishers: Delhi. Ed. 1, Pg. 3, 2013
2. Basaran A1, Basaran M, Topatan B: Combined vitamin C and E supplementation for the prevention of preeclampsia: a systematic review and meta-analysis: Obstetrical & Gynaecological Survey: October 2010 - Volume 65 - Issue 10 - pp 653-667
3. Gui S1, Jia J, Niu X, Bai Y, Zou H, Deng J, Zhou R: Arginine supplementation for improving maternal and neonatal outcomes in hypertensive disorder of pregnancy: a systematic review: J Renin Angiotensin Aldosterone Syst. 2014 Mar;15(1):88-96.
4. Carvajal JA1: Docosahexaenoic acid supplementation early in pregnancy may prevent deep placentation disorders. Biomed Res Int. 2014; 2014:526895.
5. Harvey NC, Holroyd C, Ntani G, Javaid K, Cooper P, Moon R, Cole Z, Tinati T, Godfrey K, Dennison E, Bishop NJ, Baird J, Cooper C: Vitamin D supplementation in pregnancy: a systematic review. Health Technol Assess. 2014 Jul; 18(45):1-190.
6. Greggory R. DeVore: The importance of the cerebroplacental ratio in the evaluation of fetal well-being in SGA and AGA fetuses: AJOG, July 2015, 213(1), 5–15
7. Bujold E, Roberge S, Lacasse Y, Bureau M, Audibert F, Marcoux S, Forest JC, Giguère Y. Prevention of preeclampsia and intrauterine growth restriction with aspirin started in early pregnancy: a meta-analysis. Obstet Gynecol. 2010 Aug; 116(2 Pt 1):402-14.
8. Gómez-Outes A1, Rocha E, Martínez-González J, Kakkar VV. Cost effectiveness of bemiparin sodium versus unfractionated heparin and oral anticoagulants in the acute and long-term treatment of deep vein thrombosis. Pharmacoeconomics. 2006; 24(1):81-92.
9. Desai P, Desai M: Uterine Artery Pulsatility Index less than 1.0 as an Isolated Marker in Predicting Low-risk Subjects for Preeclampsia: International Journal of Reproduction, Contraception, Obstetrics and Gynecology: 5 (5) May 2016

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