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A 21-Year-Old Pregnant Woman with Hypertension and Proteinuria

• Andrea Luk,

* To whom correspondence should be addressed. E-mail: [email protected]

• Ching Wan Lam,
• Wing Hung Tam,
• Anthony W. I Lo,
• Enders K. W Ng,
• Alice P. S Kong,
• Wing Yee So,
• Chun Chung Chow
• Andrea Luk, 
• Ronald C. W Ma, 
• Ching Wan Lam, 
• Wing Hung Tam, 
• Anthony W. I Lo, 
• Enders K. W Ng, 
• Alice P. S Kong, 
• Wing Yee So, 

Published: February 24, 2009

• https://doi.org/10.1371/journal.pmed.1000037
• Reader Comments

Citation: Luk A, Ma RCW, Lam CW, Tam WH, Lo AWI, Ng EKW, et al. (2009) A 21-Year-Old Pregnant Woman with Hypertension and Proteinuria. PLoS Med 6(2): e1000037. https://doi.org/10.1371/journal.pmed.1000037

Copyright: © 2009 Luk et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: The authors received no specific funding for this article.

Competing interests: RCWM is Section Editor of the Learning Forum. The remaining authors have declared that no competing interests exist.

Abbreviations: CT, computer tomography; I, iodine; MIBG, metaiodobenzylguanidine; MRI, magnetic resonance imaging; SDH, succinate dehydrogenase; SDHD, succinate dehydrogenase subunit D

Provenance: Commissioned; externally peer reviewed

Description of Case

A 21-year-old pregnant woman, gravida 2 para 1, presented with hypertension and proteinuria at 20 weeks of gestation. She had a history of pre-eclampsia in her first pregnancy one year ago. During that pregnancy, at 39 weeks of gestation, she developed high blood pressure, proteinuria, and deranged liver function. She eventually delivered by emergency caesarean section following failed induction of labour. Blood pressure returned to normal post-partum and she received no further medical follow-up. Family history was remarkable for her mother's diagnosis of hypertension in her fourth decade. Her father and five siblings, including a twin sister, were healthy. She did not smoke nor drink any alcohol. She was not taking any regular medications, health products, or herbs.

At 20 weeks of gestation, blood pressure was found to be elevated at 145/100 mmHg during a routine antenatal clinic visit. Aside from a mild headache, she reported no other symptoms. On physical examination, she was tachycardic with heart rate 100 beats per minute. Body mass index was 16.9 kg/m 2 and she had no cushingoid features. Heart sounds were normal, and there were no signs suggestive of congestive heart failure. Radial-femoral pulses were congruent, and there were no audible renal bruits.

Baseline laboratory investigations showed normal renal and liver function with normal serum urate concentration. Random glucose was 3.8 mmol/l. Complete blood count revealed microcytic anaemia with haemoglobin level 8.3 g/dl (normal range 11.5–14.3 g/dl) and a slightly raised platelet count of 446 × 10 9 /l (normal range 140–380 × 10 9 /l). Iron-deficient state was subsequently confirmed. Quantitation of urine protein indicated mild proteinuria with protein:creatinine ratio of 40.6 mg/mmol (normal range <30 mg/mmol in pregnancy).

What Were Our Differential Diagnoses?

An important cause of hypertension that occurs during pregnancy is pre-eclampsia. It is a condition unique to the gravid state and is characterised by the onset of raised blood pressure and proteinuria in late pregnancy, at or after 20 weeks of gestation [ 1 ]. Pre-eclampsia may be associated with hyperuricaemia, deranged liver function, and signs of neurologic irritability such as headaches, hyper-reflexia, and seizures. In our patient, hypertension developed at a relatively early stage of pregnancy than is customarily observed in pre-eclampsia. Although she had proteinuria, it should be remembered that this could also reflect underlying renal damage due to chronic untreated hypertension. Additionally, her electrocardiogram showed left ventricular hypertrophy, which was another indicator of chronicity.

While pre-eclampsia might still be a potential cause of hypertension in our case, the possibility of pre-existing hypertension needed to be considered. Box 1 shows the differential diagnoses of chronic hypertension, including essential hypertension, primary hyperaldosteronism related to Conn's adenoma or bilateral adrenal hyperplasia, Cushing's syndrome, phaeochromocytoma, renal artery stenosis, glomerulopathy, and coarctation of the aorta.

Box 1: Causes of Hypertension in Pregnancy

• Pre-eclampsia
• Essential hypertension
• Renal artery stenosis
• Glomerulopathy
• Renal parenchyma disease
• Primary hyperaldosteronism (Conn's adenoma or bilateral adrenal hyperplasia)
• Cushing's syndrome
• Phaeochromocytoma
• Coarctation of aorta
• Obstructive sleep apnoea

Renal causes of hypertension were excluded based on normal serum creatinine and a bland urinalysis. Serology for anti-nuclear antibodies was negative. Doppler ultrasonography of renal arteries showed normal flow and no evidence of stenosis. Cushing's syndrome was unlikely as she had no clinical features indicative of hypercortisolism, such as moon face, buffalo hump, violaceous striae, thin skin, proximal muscle weakness, or hyperglycaemia. Plasma potassium concentration was normal, although normokalaemia does not rule out primary hyperaldosteronism. Progesterone has anti-mineralocorticoid effects, and increased placental production of progesterone may mask hypokalaemia. Besides, measurements of renin activity and aldosterone concentration are difficult to interpret as the renin-angiotensin-aldosterone axis is typically stimulated in pregnancy. Phaeochromocytoma is a rare cause of hypertension in pregnancy that, if unrecognised, is associated with significant maternal and foetal morbidity and mortality. The diagnosis can be established by measuring levels of catecholamines (noradrenaline and adrenaline) and/or their metabolites (normetanephrine and metanephrine) in plasma or urine.

What Was the Diagnosis?

Catecholamine levels in 24-hour urine collections were found to be markedly raised. Urinary noradrenaline excretion was markedly elevated at 5,659 nmol, 8,225 nmol, and 9,601 nmol/day in repeated collections at 21 weeks of gestation (normal range 63–416 nmol/day). Urinary adrenaline excretion was normal. Pregnancy may induce mild elevation of catecholamine levels, but the marked elevation of urinary catecholamine observed was diagnostic of phaeochromocytoma. Conditions that are associated with false positive results, such as acute myocardial infarction, congestive heart failure, acute cerebrovascular event, withdrawal from alcohol, withdrawal from clonidine, and cocaine abuse, were not present in our patient.

The working diagnosis was therefore phaeochromocytoma complicating pregnancy. Magnetic resonance imaging (MRI) of neck to pelvis, without gadolinium enhancement, was performed at 24 weeks of gestation. It showed a 4.2 cm solid lesion in the mid-abdominal aorto-caval region, while both adrenals were unremarkable. There were no ectopic lesions seen in the rest of the examined areas. Based on existing investigation findings, it was concluded that she had extra-adrenal paraganglioma resulting in hypertension.

What Was the Next Step in Management?

At 22 weeks of gestation, the patient was started on phenoxybenzamine titrated to a dose of 30 mg in the morning and 10 mg in the evening. Propranolol was added several days after the commencement of phenoxybenzamine. Apart from mild postural dizziness, the medical therapy was well tolerated during the remainder of the pregnancy. In the third trimester, systolic and diastolic blood pressures were maintained to below 90 mmHg and 60 mmHg, respectively. During this period, she developed mild elevation of alkaline phosphatase ranging from 91 to 188 IU/l (reference 35–85 IU/l). However, liver transaminases were normal and the patient had no seizures. Repeated urinalysis showed resolution of proteinuria. At 38 weeks of gestation, the patient proceeded to elective caesarean section because of previous caesarean section, and a live female baby weighing 3.14 kg was delivered. The delivery was uncomplicated and blood pressure remained stable.

Following the delivery, computer tomography (CT) scan of neck, abdomen, and pelvis was performed as part of pre-operative planning to better delineate the relationship of the tumour to neighbouring structures. In addition to the previously identified extra-adrenal paraganglioma in the abdomen ( Figure 1 ), the CT revealed a 9 mm hypervascular nodule at the left carotid bifurcation, suggestive of a carotid body tumour ( Figure 2 ). The patient subsequently underwent an iodine (I) 131 metaiodobenzylguanidine (MIBG) scan, which demonstrated marked MIBG-avidity of the paraganglioma in the mid-abdomen. The reported left carotid body tumour, however, did not demonstrate any significant uptake. This could indicate either that the MIBG scan had poor sensitivity in detecting a small tumour, or that the carotid body tumour was not functional.

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In June 2008, four months after the delivery, the patient had a laparotomy with removal of the abdominal paraganglioma. The operation was uncomplicated. There was no wide fluctuation of blood pressures intra- and postoperatively. Phenoxybenzamine and propranolol were stopped after the operation. Histology of the excised tumour was consistent with paraganglioma with cells staining positive for chromogranin ( Figures 3 and 4 ) and synaptophysin. Adrenal tissues were notably absent.

The tumour is a well-circumscribed fleshy yellowish mass with maximal dimension of 5.5 cm.

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The tumour cells are polygonal with bland nuclei. The cells are arranged in nests and are immunoreactive to chromogranin (shown here) and synaptophysin.

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The patient was counselled for genetic testing for hereditary phaeochromocytoma/paraganglioma. She was found to be heterozygous for c.449_453dup mutation of the succinate dehydrogenase subunit D (SDHD) gene ( Figure 5 ). This mutation is a novel frameshift mutation, and leads to SDHD deficiency (GenBank accession number: 1162563). At the latest clinic visit in August 2008, she was asymptomatic and normotensive. Measurements of catecholamine in 24-hour urine collections had normalised. Resection of the left carotid body tumour was planned for a later date. She was to be followed up indefinitely to monitor for recurrences. She was also advised to contact family members for genetic testing. Our patient gave written consent for this case to be published.

https://doi.org/10.1371/journal.pmed.1000037.g005

Phaeochromocytoma in Pregnancy

Hypertension during pregnancy is a frequently encountered obstetric complication that occurs in 6%–8% of pregnancies [ 2 ]. Phaeochromocytoma presenting for the first time in pregnancy is rare, and only several hundred cases have been reported in the English literature. In a recent review of 41 cases that presented during 1988 to 1997, maternal mortality was 4% while the rate of foetal loss was 11% [ 3 ]. Antenatal diagnosis was associated with substantial reduction in maternal mortality but had little impact on foetal mortality. Further, chronic hypertension, regardless of aetiology, increases the risk of pre-eclampsia by 10-fold [ 1 ].

Classically, patients with phaeochromocytoma present with spells of palpitation, headaches, and diaphoresis [ 4 ]. Hypertension may be sustained or sporadic, and is associated with orthostatic blood pressure drop because of hypovolaemia and impaired vasoconstricting response to posture change. During pregnancy, catecholamine surge may be triggered by pressure from the enlarging uterus and foetal movements. In the majority of cases, catecholamine-secreting tumours develop in the adrenal medulla and are termed phaeochromocytoma. Ten percent of tumours arise from extra-adrenal chromaffin tissues located in the abdomen, pelvis, or thorax to form paraganglioma that may or may not be biochemically active. The malignant potential of phaeochromocytoma or paraganglioma cannot be determined from histology and is inferred by finding tumours in areas of the body not known to contain chromaffin tissues. The risk of malignancy is higher in extra-adrenal tumours and in tumours that secrete dopamine.

Making the Correct Diagnosis

The diagnosis of phaeochromocytoma requires a combination of biochemical and anatomical confirmation. Catecholamines and their metabolites, metanephrines, can be easily measured in urine or plasma samples. Day collection of urinary fractionated metanephrine is considered the most sensitive in detecting phaeochromocytoma [ 5 ]. In contrast to sporadic release of catecholamine, secretion of metanephrine is continuous and is less subjective to momentary stress. Localisation of tumour can be accomplished by either CT or MRI of the abdomen [ 6 ]. Sensitivities are comparable, although MRI is preferable in pregnancy because of minimal radiation exposure. Once a tumour is identified, nuclear medicine imaging should be performed to determine its activity, as well as to search for extra-adrenal diseases. I 131 or I 123 MIBG scan is the imaging modality of choice. Metaiodobenzylguanidine structurally resembles noradrenaline and is concentrated in chromaffin cells of phaeochromocytoma or paraganglioma that express noradrenaline transporters. Radionucleotide imaging is contraindicated in pregnancy and should be deferred until after the delivery.

Treatment Approach

Upon confirming the diagnosis, medical therapy should be initiated promptly to block the cardiovascular effects of catecholamine release. Phenoxybenzamine is a long-acting non-selective alpha-blocker commonly used in phaeochromocytoma to control blood pressure and prevent cardiovascular complications [ 7 ]. The main side-effects of phenoxybenzamine are postural hypotension and reflex tachycardia. The latter can be circumvented by the addition of a beta-blocker. It is important to note that beta-blockers should not be used in isolation, since blockade of ß2-adrenoceptors, which have a vasodilatory effect, can cause unopposed vasoconstriction by a1-adrenoceptor stimulation and precipitate severe hypertension. There is little data on the safety of use of phenoxybenzamine in pregnancy, although its use is deemed necessary and probably life-saving in this precarious situation.

The definitive treatment of phaeochromocytoma or paraganglioma is surgical excision. The timing of surgery is critical, and the decision must take into consideration risks to the foetus, technical difficulty regarding access to the tumour in the presence of a gravid uterus, and whether the patient's symptoms can be satisfactorily controlled with medical therapy [ 8 , 9 ]. It has been suggested that surgical resection is reasonable if the diagnosis is confirmed and the tumour identified before 24 weeks of gestation. Otherwise, it may be preferable to allow the pregnancy to progress under adequate alpha- and beta-blockade until foetal maturity is reached. Unprepared delivery is associated with a high risk of phaeochromocytoma crisis, characterised by labile blood pressure, tachycardia, fever, myocardial ischaemia, congestive heart failure, and intracerebral bleeding.

Patients with phaeochromocytoma or paraganglioma should be followed up for life. The rate of recurrence is estimated to be 2%–4% at five years [ 10 ]. Assessment for recurrent disease can be accomplished by periodic blood pressure monitoring and 24-hour urine catecholamine and/or metanephrine measurements.

Genetics of Phaeochromocytoma

Approximately one quarter of patients presenting with phaeochromocytoma may carry germline mutations, even in the absence of apparent family history [ 11 ]. The common syndromes of hereditary phaeochromocytoma/paraganglioma are listed in Box 2 . These include Von Hippel-Lindau syndrome, multiple endocrine neoplasia type 2, neurofibromatosis type 1, and succinate dehydrogenase (SDH) gene mutations. Our patient has a novel frameshift mutation in the SDHD gene located at Chromosome 11q. SDH is a mitochondrial enzyme that is involved in oxidative phosphorylation. Characteristically, SDHD mutation is associated with head or neck non-functional paraganglioma, and infrequently, sympathetic paraganglioma or phaeochromocytoma [ 12 ]. Tumours associated with SDHD mutation are rarely malignant, in contrast to those arisen from mutation of the SDHB gene. Like all other syndromes of hereditary phaeochromocytoma, SDHD mutation is transmitted in an autosomal dominant fashion. However, not all carriers of the SDHD mutation develop tumours, and inheritance is further complicated by maternal imprinting in gene expression. While it may not be practical to screen for genetic alterations in all cases of phaeochromocytoma, most authorities advocate genetic screening for patients with positive family history, young age of tumour onset, co-existence with other neoplasms, bilateral phaeochromocytoma, and extra-adrenal paraganglioma. The confirmation of genetic mutation should prompt evaluation of other family members.

Box 2: Hereditary Phaeochromocytoma/Paraganglioma Syndromes

• Von Hippel-Lindau syndrome
• Multiple endocrine neoplasia type 2A and type 2B
• Neurofibromatosis type 1
• Mutation of SDHB , SDHC , SDHD
• Ataxia-telangiectasia
• Tuberous sclerosis
• Sturge-Weber syndrome

Key Learning Points

• Hypertension complicating pregnancy is a commonly encountered medical condition.
• Pre-existing chronic hypertension must be considered in patients with hypertension presenting in pregnancy, particularly if elevation of blood pressure is detected early during pregnancy or if persists post-partum.
• Secondary causes of chronic hypertension include renal artery stenosis, renal parenchyma disease, primary hyperaldosteronism, phaeochromocytoma, Cushing's syndrome, coarctation of the aorta, and obstructive sleep apnoea.
• Phaeochromocytoma presenting during pregnancy is rare but carries high rates of maternal and foetal morbidity and mortality if unrecognised.
• Successful outcomes depend on early disease identification, prompt initiation of alpha- and beta-blockers, carefully planned delivery, and timely resection of the tumour.

Phaeochromocytoma complicating pregnancy is uncommon. Nonetheless, in view of the potential for catastrophic consequences if unrecognised, a high index of suspicion and careful evaluation for secondary causes of hypertension is of utmost importance. Blood pressure should be monitored in the post-partum period and persistence of hypertension must be thoroughly investigated.

Author Contributions

All authors participated in the management of the patient or writing of the article. AL and RCWM wrote the article, with contributions from all the authors.

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Hypertensive disorders of pregnancy: definition, management, and out-of-office blood pressure measurement

• Hirohito Metoki 1 , 2 ,
• Noriyuki Iwama 2 , 3 ,
• Hirotaka Hamada 3 ,
• Michihiro Satoh 1 , 2 ,
• Takahisa Murakami 1 , 2 ,
• Mami Ishikuro 2 &
• Taku Obara 2 , 4  

Hypertension Research volume  45 ,  pages 1298–1309 ( 2022 ) Cite this article

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Hypertensive disorders of pregnancy increase the risk of adverse maternal and fetal outcomes. In 2018, the Japanese classification of hypertensive disorders of pregnancy was standardized with those of other countries, and a hypertensive disorder of pregnancy was considered to be present if hypertension existed during pregnancy and up to 12 weeks after delivery. Strategies for the prevention of hypertensive disorders of pregnancy have become much clearer, but further research is needed on appropriate subjects and methods of administration, and these have not been clarified in Japan. Although guidelines for the use of antihypertensive drugs are also being studied and standardized with those of other countries, the use of calcium antagonists before 20 weeks of gestation is still contraindicated in Japan because of the safety concerns that were raised regarding possible fetal anomalies associated with their use at the time of their market launch. Chronic hypertension is now included in the definition of hypertensive disorders of pregnancy, and blood pressure measurement is a fundamental component of the diagnosis of hypertensive disorders of pregnancy. Out-of-office blood pressure measurements, including ambulatory and home blood pressure measurements, are important for pregnant and nonpregnant women. Although conditions such as white-coat hypertension and masked hypertension have been reported, determining their occurrence in pregnancy is complicated by the gestational week. This narrative review focused on recent reports on hypertensive disorders of pregnancy, including those related to blood pressure measurement and classification.

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Introduction.

In Japan, “pregnancy toxemia”, with three main features, “hypertension,” “proteinuria,” and “edema”, was defined and classified in 1982 [ 1 ] and then again in 1984 [ 2 ]. This term was widely used until 2005, when it was changed to “pregnancy-induced hypertension.” In 2018, the classification was standardized with those of other countries, and “hypertensive disorders of pregnancy (HDP)” were considered to be present if hypertension existed during pregnancy and up to 12 weeks after delivery [ 3 ]. High blood pressure before pregnancy (chronic hypertension) is now included in the definition of HDP. Among the various hypotheses explaining the etiology of HDP, the two-stage theory and angiogenesis imbalance are the most plausible. The two-stage theory of the etiology of HDP may have led to the novel possibility of treatment/prevention for HDP. Furthermore, assessing the circulating levels of angiogenic factors may have diverse clinical roles in preventing adverse outcomes in HDP [ 4 ]. This narrative review focused on recent reports on HDP, including those related to blood pressure measurement and classification.

Classification and definition of hypertensive disorders of pregnancy

HDP are classified into four types: preeclampsia, gestational hypertension, superimposed preeclampsia, and chronic hypertension [ 5 ]. Preeclampsia is defined as hypertension after 20 gestational weeks with proteinuria, organ damage, or uteroplacental dysfunction. Gestational hypertension is similar to preeclampsia; however, the condition is defined as hypertension alone after 20 gestational weeks. Based on the Japan Society for the Study of Hypertension in Pregnancy (JSSHP), superimposed preeclampsia is defined as hypertension accompanied by organ damage or proteinuria [ 3 , 5 ].

In normal pregnancy, spiral artery remodeling occurs, where trophoblastic cells invade the decidua and replace the endothelial cells and vascular smooth muscle of the decidua spiral artery. As a result, the maternal blood vessels begin to perfuse into the interchorionic space, which increases the partial pressure of oxygen in the placenta and reduces systemic vascular resistance (Fig.  1A ). Angiogenic factors, vascular endothelial growth factors (VEGFs), and placental growth factors (PlGFs) affect angiogenesis intracellularly through the receptor VEGFR-1 (Fig.  1B ). Uterine natural killer (uNK) cells and regulatory T cells are essential for maintaining pregnancy and inhibiting allogeneic responses toward the fetus [ 6 , 7 ]. Decidual uNK cells control trophoblast invasion by producing interleukin-8 and interferon-inducible protein-10 chemokines and secrete a series of angiogenic factors [ 8 ]. Early vascular changes resulting from desquamation, such as intimal vacuolation and disintegration, and thinning of the tunica media occur before trophoblastic cells are present near the spiral arteries of the uterus [ 9 ].

Schematic diagram of the two-stage theory of preeclampsia. In normal pregnancy, appropriate EVT invasion into the maternal endometrium (red arrow) leads to sufficient maternal blood flow from the spiral artery ( A ). PlGF, which is secreted from the placenta, activates VEGF and maintains a healthy endothelium ( B ). On the other hand, in preeclamptic pregnancy, incomplete invasion of the EVT (blue arrow) leads to insufficient maternal blood flow from the spiral artery and subsequent placental hypoxia ( C ). sFlt1 is then secreted from the placenta, which suppresses VEGF, resulting in systemic endothelial dysfunction and the appearance of various clinical symptoms ( D ). HELLP syn. hemolysis, elevated liver enzymes, low platelet count syndrome, FGR fetal growth restriction, NK cells natural killer cells, EVT extravillous trophoblast, PlGF placental growth factor, sFlt1 soluble fms-like tyrosine kinase-1, VEGF vascular endothelial growth factor

Preeclampsia

Preeclampsia is a complex medical disorder [ 10 ]. According to recent guidelines in Japan [ 5 ] and other countries [ 10 , 11 , 12 , 13 , 14 ], preeclampsia is characterized by hypertension with maternal acute kidney injury, liver dysfunction, neurological features, hemolysis or thrombocytopenia, or fetal growth restriction. Preeclampsia is thought to originate from the placenta because of the rapid improvement of clinical symptoms of preeclampsia after placenta delivery [ 15 ], while retained placenta leads to the development of preeclampsia; the removal of the placenta by intrauterine curettage results in disappearance of the symptoms [ 16 ].

Insufficient angiogenesis and remodeling cause an incomplete increase in the partial pressure of oxygen in the fetal placental circulation (Fig.  1C ), resulting in placental ischemia and damage [ 17 ]. Stimulated soluble VEGFR-1 (sFlt-1) production in trophoblast cells inhibits PlGF production and soluble endoglin (sEng) production [ 18 ]. Inhibition of VEGF and PlGF by sFlt-1 suppresses the invasion of trophoblastic cells into the shed membrane and damages vascular endothelial cells (Fig.  1D ). By binding and antagonizing TGF-β, sEng inhibits the invasion of cytotrophoblast cells [ 19 ]. The transition of these factors into maternal circulation causes the maternal symptoms of preeclampsia [ 20 , 21 ]. Placental abnormalities in early pregnancy may cause chronic uteroplacental insufficiency, local ischemia, and the release of inflammatory cytokines, resulting in earlier maternal hypertension in early-onset preeclampsia [ 22 , 23 , 24 ]. In contrast, late-onset preeclampsia is more frequently based on placental dysfunction associated with chronic oxidative stress due to maternal metabolic abnormalities such as obesity and insulin resistance [ 22 , 23 , 25 ]. At the same time, there is much overlap in placental pathology and continuous features in desmoplastic vascular lesion pathology among the four HDP subtypes [ 26 ].

Superimposed preeclampsia

Superimposed preeclampsia is defined as chronic hypertension or kidney disease that progresses to preeclampsia [ 3 ]. It should be noted that in countries other than Japan, it basically refers only to superimposed chronic hypertension [ 10 , 11 , 12 , 13 , 14 ]. Vascular endothelial dysfunction is reported to predict the development of superimposed preeclampsia in chronic hypertension [ 27 ]. In preeclampsia following de novo gestational hypertension, early placental calcification and weight gain precede preeclampsia [ 28 ]. Pregnant women with IgA nephropathy [ 29 ] and chronic kidney disease [ 30 ] had 7.3- and 10.4-fold greater risks of preeclampsia than others, respectively.

Chronic hypertension in pregnancy

Blood pressure during early pregnancy seems important in pregnancies complicated by hypertension [ 31 , 32 ]. A systolic blood pressure <130 mmHg within 14–15 weeks of gestation was reported to reduce the risk of early-onset superimposed preeclampsia in women with chronic hypertension [ 33 ]. As described in a later section on white-coat hypertension, it is essential to diagnose whether a patient has sustained or white-coat hypertension. Because chronic hypertension is a risk factor for perinatal mortality in both early and late gestation, a planned delivery at 37 to 38 weeks of gestation is reported to be a superior balance of risk [ 34 ].

Maternal outcomes

Regarding the risk of developing cardiovascular diseases later in life, although there are differences among HDP subtypes, Veerbeek et al. [ 35 ] reported that all types of HDP seem to be associated with high risks. Gestational hypertension is reported to be associated with a 4.2-fold higher risk for future chronic hypertension [ 36 ] and a greater risk of cardiovascular disease, coronary heart disease, and heart failure [ 37 ]. Preeclampsia is associated with a fourfold increased risk of future heart failure and a twofold increased risk of coronary heart disease, stroke, and death due to coronary heart or cardiovascular disease [ 38 ]. Women with HDP were reported to have a 6.3-fold higher risk for future hypertension within 2 years postpartum compared to controls [ 39 ] and a 4.9-fold higher risk of chronic kidney disease in later life [ 40 ].

Birth outcomes

Maternal cardiac output in early pregnancy has been associated with being small for gestational age (SGA) [ 41 ]. Maternal hypertension-related factors were associated with infant growth via placental factors based on the genome wide association study summary statistics of BioBank Japan data and compared with cohort data [ 42 ]. The Hokkaido study showed that women with HDP had 2.1-, 3.5-, and 3.6-fold higher risks of having SGA infants, preterm birth, and infants with low birth weight than those with normotensive pregnancy [ 43 ]. Home [ 44 ] and ambulatory [ 45 ] blood pressure measurements have been shown to be more associated with birth weight than clinic blood pressure; these are reviewed in subsequent sections. The trajectory of maternal blood pressure during pregnancy is also an indicator of infant birth weight [ 46 , 47 , 48 ].

Long-term outcomes of offspring

According to a meta-analysis of eight studies, HDP were associated with a 1.2-fold higher risk of asthma in offspring [ 49 ]. In a study, offspring exposed to HDP had a 1.4- and 1.3-fold higher risk for autism spectrum disorders and attention-deficit hyperactivity disorder, respectively [ 50 ]. The Helsinki Birth Cohort Study reported that offspring exposed to maternal gestational hypertension in utero had an increased risk of type 2 diabetes in late adulthood after adjustment for low birth weight or small for gestational age infants [ 51 ].

The results of studies in Japan on the long-term prognosis of pregnant women with HDP and their children exposed to HDP are now being reported. The TMM BirThree Cohort Study reported that women with superimposed preeclampsia had a 1.8-fold increased risk of having children with autistic behavior at 2 years old compared to normotensive women [ 52 ]. The Hokkaido Birth Cohort Study reported that male children exposed to HDP caught up with their growth and gained more weight by 7 years of age than male children who were not exposed to HDP [ 53 ]. According to observations in the Japan Environment and Children’s Study (JECS), HDP were not a risk factor for offspring regardless of the sensitivity analyses using possible mediating factors such as cesarean delivery, birth weight, and gestational age [ 54 ].

When examining the association between HDP and prognosis, there is no need to adjust for preterm birth and low birth weight because they are included in HDP outcomes and are mediators rather than confounders when considering their impact on the long-term prognosis of offspring [ 49 , 50 , 52 , 53 ]. On the other hand, as mentioned earlier, several studies have performed sensitivity analyses considering the role of HDP as mediators [ 51 , 54 ]. Based on the results of the ongoing mediator analysis and other studies, future studies need to examine possible intervention points for the association between HDP and child outcomes and develop better intervention methods.

Prediction, prevention, and treatment

Associated factors and prediction.

The Fetal Medicine Foundation (FMF) first-trimester prediction model (the FMF triple test) has high detection rates of 90% and 75% for the prediction of early and preterm preeclampsia, respectively, with a 10% false-positive rate [ 55 ]. This FMF triple test consists of a combination of maternal factors and measurements of mean arterial pressure, the uterine artery pulsatility index, and serum placental growth factor. An Asia-wide study using an algorithm developed by the FMF in Asian people confirmed the validity of the FMF triple test with a detection rate of 64% for the prediction of preterm preeclampsia with a 10% false-positive rate [ 56 ].

In addition to the FMF triple test, several predictors have been reported in individual studies, and those presented in this study are listed in Table  1 .

The JECS is a cohort study that started in 2011 to investigate the relationship between environmental exposure and child health. Several studies on HDP have been conducted with the JECS cohort. Higher levels of HbA1c at a nondiabetic level [ 57 ], both lower and higher Na intake before pregnancy [ 58 ], elevated serum IgE levels during the first trimester [ 59 ], higher caffeine intake [ 60 ], working a schedule of ≥36 h per week with night shifts [ 61 ], smoking [ 62 ], alcohol consumption [ 63 ], and becoming pregnant with in vitro fertilization and embryo transfer [ 64 ] were associated with the risk of hypertensive disorders of pregnancy. Moreover, coffee intake was associated with a decreased risk of HDP [ 60 ]. Although this is a large cohort study, some studies reported that no association between the exposures and outcomes can be found, such as calcium intake and HDP among primiparas [ 65 ]. The JECS involves a novel approach to adjunct studies. The peak areas of N-dimethylglycine and S-methylcysteine were significantly higher in the first-trimester serum of patients with early-onset HDP than in controls [ 66 ].

Sleep quality in early pregnancy may help predict elevated systolic blood pressure in the first trimester [ 67 ], and overnight oxygen saturation screening ~1 month before the due date may be useful in predicting late-onset gestational hypertension [ 68 ]. Unmodifiable factors include twin pregnancy [ 69 , 70 ] and residing in a high-altitude area (>2500 m) [ 71 , 72 ]. Blood pressure is known to be elevated in twin pregnancy [ 69 ], regardless of whether the pregnancy is a dichorionic or monochorionic diamniotic twin pregnancy [ 70 ]; therefore, pregnant women with unmodifiable factors should be followed up as high-risk pregnancies.

Several efforts to perform comprehensive metabolomic analysis in samples of pregnant women have been reported, such as the C-MATCH [ 73 ] and HELIX studies [ 74 ]. The metabolite profiles of women who developed HDP were comparable to those of women with normal pregnancies with longer gestation in the Maternity Log study, which is an adjunct to the BirThree cohort study [ 75 ].

Aspirin administration has been described in various guidelines as effective in preventing the onset of preeclampsia. The ASPRE study showed that aspirin treatment for pregnant women at high risk for preeclampsia reduced the incidence of preeclampsia to 0.38 [ 76 ]. The NICE [ 11 ], ACOG [ 12 ], USPSTF [ 77 ], SOGC [ 13 ], SOMANZ [ 14 ], and ISSHP [ 10 ] guidelines state that aspirin should be administered to high-risk pregnant women. However, the Japanese guidelines from the JSSHP that were issued in 2015 state that aspirin should be given to a limited number of women [ 78 ], while those that were issued in 2021 state that aspirin should be considered for women with preeclampsia to prevent recurrence in subsequent pregnancy [ 5 ]. In Asian women, the dose-dependent efficacy of low-dose aspirin [ 79 ] and its efficacy in women with blood pressure of 130–139/80–89 mmHg, which is included in the American College of Cardiology/American Heart Association definition of Stage 1 hypertension or mild hypertension [ 80 ], have also been reported. However, a study reported that aspirin has poor efficacy when started at 12–20 weeks gestation [ 81 ]. The ADA guidelines also strongly recommended aspirin for women with diabetic pregnancies until 2020 [ 82 ]; moreover, the recommendations became weaker in the 2021 edition and later editions [ 83 ]. A recent study reported limited efficacy of aspirin in preventing preeclampsia among women with diabetic pregnancies [ 84 ]. Future studies are warranted on eligible subjects and administration methods.

In principle, in Japan, inpatient management is recommended for HDP patients with blood pressure of 160/110 mmHg or higher, antihypertensive treatment should be given if a patient’s blood pressure is repeatedly found to be 160/110 mmHg or higher, and antihypertensive treatment is considered if a patient’s blood pressure is 140/90 mmHg or higher. Furthermore, if a patient has recurrent blood pressure of 160/110 mmHg or higher or has preeclamptic symptoms, magnesium sulfate should be administered to prevent eclampsia, and if management at the patient’s own facility is difficult, referral to a higher-level medical facility should be considered [ 5 ].

There are concerns that antihypertensive treatment during pregnancy may increase the risk of placental abruption and preterm delivery [ 85 ]. Data from Scotland showed a 2.3-fold increase in congenital defects with the use of antihypertensive drugs [ 86 ]. However, untreated hypertension, not antihypertensive medication, is a risk to the child [ 87 ]. The CHIPS study reported no significant group differences in the risk of pregnancy loss, high-level neonatal care, or overall maternal complications between less-tight (target office diastolic blood pressure of 100 mmHg) and tight (target office diastolic blood pressure of 85 mmHg) control of hypertension in pregnancy [ 88 ]. A recent meta-analysis showed that blood pressure-lowering treatment significantly prevented not only severe hypertension, preeclampsia, and severe preeclampsia but also placental abruption and preterm birth, while the risk of SGA was increased [ 89 ].

Currently, Japanese guidelines refer to methyldopa, hydralazine, and labetalol as oral antihypertensive drugs that can be used during pregnancy, while nifedipine can only be used after 20 weeks of pregnancy [ 5 ]. Guidelines for the use of different antihypertensive drugs have not been developed. There is a possibility of improved maternal prognosis with physiological nomogram-guided care and tailored pharmacological intervention [ 90 ]. In Japan, the use of calcium antagonists in early pregnancy is still not approved on the package label, and deviation from the guidelines is a concern [ 91 ]. However, in Japan, the most frequently prescribed oral antihypertensive drug during pregnancy is nifedipine, followed by methyldopa, hydralazine, and furosemide [ 92 ]. It has been reported that the risk of birth defects due to amlodipine use in the first trimester was not significantly different compared to the risk of the use of other antihypertensives in a case–control study in Japan [ 93 ]; more extensive observation is urgently needed.

Similar concerns have been raised regarding long-term prognosis. A comparison of the long-term prognosis of infants between treatment groups in a historical cohort study also reported the possibility of attention-deficit hyperactivity disorder and sleep disorders in infants whose mothers received drug interventions for gestational hypertension [ 94 ]. On the other hand, studies examining the effects of antihypertensive medications may not have examined baseline blood pressure levels [ 86 ], or baseline blood pressure levels may be obviously different [ 94 ]; hence, the risk of antihypertensive medication use must be carefully assessed. Such concerns are expected to be clarified by national-scale cohort studies.

Blood pressure measurement during pregnancy

There are several debates regarding how blood pressure should be measured during pregnancy [ 95 ]. Reports suggest that blood pressure values in pregnant women with preeclampsia vary depending on the measurement environment [ 96 ]. Hurrell et al. conducted a detailed review of blood pressure measurements in pregnant women [ 97 ]. A recent meta-analysis also confirmed that both systolic and diastolic blood pressure decrease by ~4 mmHg in the second trimester [ 98 ]; the results were very similar to those of a single cohort study investigating the use of home blood pressure [ 99 ].

Ambulatory blood pressure measurement

Ambulatory blood pressure measurement is valuable for diagnosing masked or white-coat hypertension (16) and assessing diurnal variations in blood pressure in pregnant women [ 100 , 101 ]. Normal daytime values for ambulatory blood pressure monitoring in pregnant women have been reported to be less than 130/77 mmHg at ≤22 weeks, 133/81 mmHg at 26–30 weeks, and 135/86 mmHg after 30 weeks [ 102 ]. Diurnal variations in blood pressure during pregnancy have been reported to be nocturnal declines of 12–14%/18–19% in systolic/diastolic blood pressure [ 100 ]. It has also been reported that nocturnal declines in blood pressure are attenuated before gestational hypertension nephropathy becomes apparent [ 101 ]. Among 146 Japanese pregnant women with suspected HDP, ambulatory blood pressure monitoring was more strongly associated with SGA infants, with an odds ratio of 1.74 times for every 10 mmHg increase (95% CI: 1.28–2.38; P  = 0.001) compared with office blood pressure measurement (OR: 1.40; 95% CI: 0.92–2.13; P  = 0.11) [ 45 ].

Home blood pressure measurement

Home blood pressure measurement is suitable for detecting long-term and seasonal variations in blood pressure. In a 2008 statement on home blood pressure measurement, the American Heart Association noted that “Home blood pressure measurement is theoretically ideal for monitoring changes in blood pressure during pregnancy because it is the best technique for providing multiple readings recorded at the same time of day over prolonged periods of time.” [ 103 ]. Furthermore, a report from the consensus meeting of the European Council on Hypertension issued around the same time stated that “Home blood pressure monitoring, although at present not commonly practiced in this setting, has considerable potential in improving the management of pregnant women.” [ 104 ]. According to the Japanese Society of Hypertension guidelines, for general (nonpregnant) patients, if the results of office blood pressure and home blood pressure measurements are different, the home blood pressure result has priority for treatment [ 91 ]. In pregnancy, home blood pressure measurements may be taken by pregnant women before recommendations are made by health care providers. Using home blood pressure monitoring, seasonal blood pressure [ 99 ] and hemodynamic changes are well observed. In a study that simultaneously included both home and clinic blood pressure levels in early pregnancy, the adjusted odds ratios for having a baby that was 500 g smaller per standard deviation increase in mean and diastolic blood pressure were 1.29 (95% CI: 1.04–1.59) and 1.28 (95% CI: 1.04–1.58) for home blood pressure and 1.02 (95% CI: 0.83–1.24) and 1.06 (95% CI: 0.87–1.30) for clinic blood pressure, respectively, with only home blood pressure measurements having a significant association [ 44 ]. Furthermore, the maternal blood pressure trajectory during pregnancy was an indicator of infant birth weight [ 46 ]. However, no study has determined whether interventions based on home blood pressure measurements improve outcomes.

Several values have been proposed as the diagnostic threshold of home blood pressure based on population distribution and regression with office blood pressure values. Using the standard major axis method, the home blood pressure values reported to be equivalent to a clinical blood pressure of 140/90 mmHg were 120.8/83.5 mmHg, 126.0/85.2 mmHg, and 136.3/89.3 mmHg in the first, second, and third trimesters, respectively [ 105 ]. However, no consensus value has been established [ 106 ].

A meta-analysis reported in 2020 summarized nine studies and noted that the use of home blood pressure measurements in the antenatal period was associated with a reduced risk of induction of labor, hospitalization before delivery, and diagnosis of preeclampsia and that the number of prenatal visits was significantly lower in the home blood pressure group, but there was no significant difference in the combined maternal, fetal, or neonatal outcomes compared to conventional care [ 107 ].

Clinical significance of white-coat hypertension

White-coat hypertension is a condition in which a patient has high blood pressure in the office but normal blood pressure outside the office. Generally, 24-h ambulatory blood pressure monitoring or home blood pressure monitoring may be used to identify white-coat hypertension. Ishikuro et al. reported that among pregnant women who were normotensive, the white-coat effect during pregnancy was 4.1/3.8, 3.4/1.6, and 1.8/2.4 mmHg in early, mid-, and late pregnancy, respectively [ 108 ]. When the factors affecting the white-coat effect were examined in the same population, no significant differences were found for body mass in sex, age, or family history of hypertension. However, the effect was significantly greater in primiparas than in multiparas in early pregnancy for systolic blood pressure and in late pregnancy for diastolic blood pressure [ 109 ]. A meta-analysis of 16 studies on the white-coat effect showed that office blood pressure measurements were 4/3 (3–6/2–4) mmHg higher than home blood pressure measurements [ 106 ]. White-coat hypertension is prevalent in women with preexisting diabetes and may indicate an increased risk of developing pregnancy-induced hypertensive disorders later in life [ 110 ].

Based on ambulatory blood pressure monitoring in early pregnancy, it has been reported that 22% of pregnant women have sustained hypertension, and 8% of those with white-coat hypertension develop preeclampsia; thus, white-coat hypertension in pregnancy may have a relatively good prognosis [ 102 ]. It is essential to recognize that hypertension in the office may not necessarily require antihypertensive treatment if the blood pressure outside the office is normal. However, 42% of pregnant women with white-coat hypertension in early pregnancy showed hypertension both in the office and out of the office until delivery [ 102 ]; therefore, careful follow-up is necessary in such cases.

Clinical significance of masked hypertension

There are few studies on masked hypertension in pregnant women. Salazar et al. reported that masked hypertension is a prevalent and high-risk condition. An office blood pressure of ≥125/75 mmHg in the second half of gestation seems appropriate for indicating out-of-office measurements in women with high-risk pregnancies [ 111 ]. Pregnant women with masked hypertension had a 7.8 times higher risk of preeclampsia than those who were normotensive [ 112 ]. Unlike white-coat hypertension, masked hypertension cannot be detected unless all pregnant women who are at risk receive out-of-office blood pressure measurements. Therefore, further study is needed to determine which women should undergo blood pressure measurement outside the office.

Present blood pressure monitoring situations in clinical practice

According to a survey reported in 2021, 89.3% of obstetricians took blood pressure measurements in an outpatient setting only once per occasion if a woman’s blood pressure was normal. However, if the pregnant women had hypertension, 54.8% took a second measurement, and 40.3% repeated blood pressure measurements until a stable reading was obtained [ 113 ]. Furthermore, 62.8% of the obstetricians recorded the lowest value when they measured blood pressure twice, and 69.0% of the physicians recorded the last measurement when the blood pressure was measured until it stabilized [ 113 ]. Therefore, when conducting research based on databases, researchers need to recognize some variation in the measurements recorded on each measurement occasion. On the other hand, blood pressure measurements for research purposes at a venue different from that of the antenatal checkup was reported to be equivalent to home blood pressure measurements and significantly lower than those at antenatal checkups, and the possibility of a stressful environment during the antenatal checkup causing an increase in blood pressure should be considered [ 114 ].

A survey of family medicine and obstetrics/gynecology physicians providing prenatal care at a tertiary obstetrics hospital in Canada found that obstetricians were more likely to use home blood pressure monitoring. In contrast, family physicians were more likely to use 24 h ambulatory blood pressure monitoring as a diagnostic aid. While obstetricians were more likely than family physicians to use effective home blood pressure monitoring during pregnancy and monitor hypertension with home blood pressure monitoring, family physicians were significantly more likely than obstetricians to target “tight” blood pressure control [ 115 ].

In a survey of 128 patients conducted in the United States, postpartum women perceived a telehealth technology remote intervention as a safe and easy-to-use method, with an acceptable burden of care and an overall satisfactory method of monitoring blood pressure in the postpartum period [ 116 ]. A survey conducted in Belgium reported that 80% of midwives and 67% of obstetricians who used remote blood pressure monitoring in pregnancy perceived digital technologies as an important component of prenatal monitoring [ 117 ]. The results of an online survey of obstetricians in the United Kingdom showed that the percentage of obstetricians who thought that home blood pressure measurements and urinalysis were helpful indicators of clinical diagnosis rose from 88% before the COVID-19 pandemic to 96% after the pandemic. In addition, 47% of the obstetricians agreed that pregnant women would change their predetermined medications based on their measured blood pressure levels [ 118 ].

Novel attempt at blood pressure telemonitoring

In 2008, the transmission of home blood pressure measurements was discussed [ 119 ], but the explorations of remote monitoring are rapidly progressing during the COVID-19 pandemic. A study examined current practices and attitudes concerning home-based blood pressure and cardiotocography monitoring and telemonitoring in high-risk pregnancies requiring maternal and fetal monitoring and reported that home-based monitoring and telemonitoring were offered in 26% and 23% of hospitals, respectively, in the Netherlands [ 120 ]. In a retrospective comparison, the digital platform among high-risk pregnancies significantly reduced prenatal visits, ultrasounds, and hypertension-related hospitalizations compared to usual care without self-monitoring.

As mentioned earlier, the Maternity Log study [ 75 ] attempted to collect life logs, including home blood pressure measurements. There have been text-based attempts at blood pressure management in the postpartum period [ 121 ]. A study attempted to use a smartphone application to monitor home blood pressure in Belgium [ 122 ]. A prospective, randomized, controlled trial, called BP-PRESELF, using home blood pressure measurements is ongoing to assess whether home blood pressure monitoring in women with a history of preeclampsia/HELLP syndrome during pregnancy is a valuable tool for the early detection of chronic hypertension [ 123 ].

Blood pressure measurement during pregnancy is crucial in diagnosing HDP. The precise measurement and evaluation of blood pressure, including its variability, will continue to play an essential role in determining the prognosis and elucidating the pathogenesis of HDP.

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Acknowledgements

All authors have significantly contributed to and agree with the content of the manuscript. We would like to thank Editage ( www.editage.com ) for English language editing.

This study was supported by Grants for Scientific Research [16H05243, 19H03905, 10632242, 19K18659] from the Ministry of Education, Culture, Sports, Science, and Technology of Japan; the Japan Agency for Medical Research and Development (AMED) Birthday [grant number: JP21gk0110039]; and a Grant-in-Aid (19DA1001) from the Ministry of Health, Labor and Welfare, Health Research on Children, Youth and Families, Japan.

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Hirohito Metoki, Michihiro Satoh & Takahisa Murakami

Department of Preventive Medicine and Epidemiology, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan

Hirohito Metoki, Noriyuki Iwama, Michihiro Satoh, Takahisa Murakami, Mami Ishikuro & Taku Obara

Department of Obstetrics and Gynecology, Tohoku University Hospital, Sendai, Japan

Noriyuki Iwama & Hirotaka Hamada

Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Japan

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HM concurrently holds the noncompensated subdirectorship at the Tohoku Institute for Management of Blood Pressure, which is supported by Omron Health Care Co. Ltd., and is involved in collaborative research with Omron Health Care in another study. HM has also received grants or scholarships from Academic Contributions from Pfizer Japan Inc., Astellas Research Support, Daiichi Sankyo Co. Ltd., Bayer Academic Support, Otsuka Pharmaceutical Co., Ltd, Takeda Research Support, Eli Lilly Japan K.K., Baxter Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Chugai Pharmaceutical Co., Ltd., and Teijin Pharma Limited. These companies were not involved in this review article.

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Metoki, H., Iwama, N., Hamada, H. et al. Hypertensive disorders of pregnancy: definition, management, and out-of-office blood pressure measurement. Hypertens Res 45 , 1298–1309 (2022). https://doi.org/10.1038/s41440-022-00965-6

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DOI : https://doi.org/10.1038/s41440-022-00965-6

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• Antihypertensive Agents
• Blood Pressure
• Hypertension
• Pregnancy-Induced
• Masked Hypertension
• White-Coat Hypertension

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Metrics details

Hypertension is the most common medical problem encountered in pregnancy and is a leading cause of perinatal and maternal morbidity and mortality. However, its magnitude and risk factors yet not adequately assessed at the study area.

Facility-based retrospective unmatched case-control study was conducted to identify risk factors associated with Hypertensive disorders of pregnancy in Nekemte Referral Hospital just two years back from study period July 1, 2015, to June 30, 2017. Bivariate logistic regression was considered for inclusion in to the multivariate logistic regression. Finally, multi varaite analysis were done to identify risk factors of hypertensive disorders of pregnancy.

Among 6826 total delivery records from July 2015 –June 2017, 199 women developed hypertension during pregnancy. Among 199 women 153(76.9%) were pre-eclampsia/eclampsia,28(14.1%) were gestational hypertension, 14(0.7%) were superimposed hypertension and 4 (2.9%) were chronic hypertension.

Age ≥ 35 (AOR: 2.51, 95% CI: 1.08, 5.83), rural residential area (AOR: 1.79, 95% CI: 1.150, 2.799), prim gravida (AOR: 3.39, 95% CI: 2.16, 5.33), null parity (AOR: 4.35, 95% CI: 2.36, 8.03), positive history of abortion (AOR: 4.39, 95% CI: 1.64, 11.76), twin pregnancy (AOR: 3.78, 95% CI: 1.52, 9.39), lack of ANC follow up (AOR: 3.05, 95% CI: 1.56, 5.96) as well as positive pre-existing hypertension (AOR: 3.81, 95% CI: 1.69, 8.58), positive family history of hypertension (AOR: 5.04, 95% CI: 2.66, 9.56) and positive history of diabetes mellitus (AOR: 5.03, 95% CI: 1.59, 15.89) were risk factors for hypertensive disorders during pregnancy.

This study found that Women with hypertension during pregnancy have a greater risk of developing adverse pregnancy outcome as compared to normotensive pregnant women. so, identification of these risk factors would be useful for early diagnosis of hypertension disorders during pregnancy to give appropriate clinical monitoring and treatments and timely managing maternal and perinatal complications.

Peer Review reports

Hypertension is a clinical term used to describe high blood pressure [ 1 , 2 ]. Hypertension in pregnancy is defined as: “Systolic blood pressure greater than or equal to 140 mmHg and/or diastolic blood pressure greater than or equal to 90 mmHg which usually confirmed within four hours apart measurement” [ 2 ].

Hypertension disorder of pregnancy encompasses a spectrum of conditions including pre-existing hypertension, gestational hypertension, preeclampsia/eclampsia, and superimposed hypertension.

These conditions range from a mild increase in blood pressure at term with no additional signs or symptoms to severe complications with potential for significant maternal, fetal and neonatal harm [ 3 ]. Globally, a significant number of women die every year from pregnancy-related causes and more than half of these deaths occur in sub-Saharan Africa [ 4 ]. Approximately 12% of the maternal deaths are associated with hypertensive disorders in pregnancy such as pregnancy-induced hypertension [ 1 , 2 , 3 , 4 ,]. For that reason, hypertension complications are among the main public health issues worldwide.

A Hospital-based cross-sectional study conducted in Jimma University Specialized Hospital in Ethiopia showed that the overall prevalence of hypertensive disorders of pregnancy was 8.5% of which severe preeclampsia and eclampsia accounted for 51.9 and 23.4%, respectively [ 5 ]. Moreover, the study done in Debre Brehan Referral Hospital indicated that among 8626 pregnant women who obtained delivery services, 340(3.9%) of them had hypertensive disorders with an increasing trend from 1.8% in 2011 to 5.7% in 2014 [ 6 ].

On the other hand, though in Ethiopia, the efforts have been done to identify the risk factors of hypertension and to overcome its effect, its prevalence and risk factors were increasing in the country. The study area population was found in the western part of the country. The study area was the place where the population was highly affected by hypertension disorders during pregnancy. Besides, there is a scarcity of study conducted on risk factors associated with HDP in Nekemte Referral Hospital.

Therefore, it is essential to undertake this study to determine the risk factors and its complications both on mothers and on new-borne in the Hospital.

The facility-based retrospective case-control study was conducted to identify risk factors associated with hypertensive disorders of pregnancy in Nekemte Referral Hospital from July 1, 2015, to June 30, 2017.

Source population

All mothers who delivered in Nekemte Referral hospital.

Study population

Cards of mothers who gave birth in Nekemte referral hospital from of July 2015 to June 2017 and found to have hypertensive disorders during pregnancy.

Control group

Cards of mothers who gave birth in the hospital and not identified to have hypertensive disorders during pregnancy.

Sample size determination

The sample size was determined on the assumptions of the ratios of 1:2, (cases to controls) power 80%, alpha value 95%, and odd ratio 2 by considering relevant factors from other studies that have significant association with hypertension [ 7 , 8 , 9 , and].

From Table 1 , The final sample size was taken from diabetes by adding 10% for incomplete record reviews for the control group since it is the maximum for case (243) and for control (534) the total sample size was 777.

Sampling technique and procedure

Among 6826 records of pregnant mothers who gave birth in the study areas, from July 2015 to June 2017 were first sorted for hypertension and without hypertension. Then, based on 1:2 ratios of samples of cases and controls, respectively, 534 (including 10% for incomplete records) normotensive deliveries were randomly selected.

Out of 777 selected records, 44 cases and 136 controls were excluded from analysis for incomplete of the necessary information. The final data of the study were collected from 199 (81.9%) cases and 398 (74.5%) controls which adds to up 597 women by inclusion criteria.

Variables of the study

A. Dependent variable : Hypertensive disorder of pregnancy.

B. Independent variables.

Demographic variables : Age, Residential area, Marital status, Plan of pregnancy.

Obstetric factors : Gravida. Parity. Abortion history, ANC follow up, Multiplicity of pregnancy.

Medical Disease factors : Pre-existing hypertension, Family history of hypertension. History of diabetes mellitus.

Data collection

Data was collected from record review using a structured and pre-tested checklist. The training was given for both data collectors and supervisors. Three midwives were assigned to collect the data, one supervisor was assigned to supervise the quality data collection.

Data analysis procedures

Records that shows hypertension during pregnancy were taken as case group and the remaining registries were taken as a control group. Then, to identify the sample and control group, the medical record was retrieved and checked for hypertension during pregnancy.

Accordingly, records that show one of the four of HDP types (gestational hypertension, chronic hypertension, pre-eclampsia/ eclampsia or superimposed hypertension) were taken as case group first and then from the remaining registries control group was randomly obtained.

The criteria were an elevation of blood pressure for gestational hypertension whereas blood pressure, protein urea and other laboratory investigations were used as a criterion for other types of hypertensive disorders. Then finally descriptive statics and logistic regression were used. Descriptive statistics such as frequency, a measure of central tendency and measure of dispersion where were calculated to describe the study sample and presented with tables and figures. To determine factors that were significantly associated with hypertension, the first bivariate logistic regression was done. Then, multiple logistic analysis was performed for those variables identified as significant on bivariate analysis.

Among 6826 of the total delivery records during the study period, 243 (3.56%) women had HDP. Of 777 selected records, 44 cases and 136 controls were excluded from analysis for incomplete of necessary information. The final data of the study were collected from 199 (81.9%) of cases and 398 (74.5%) of controls which adds to up 597 women.

Demographic characteristics of women with and without HDP

The mean age of cases was 26.1(SD: ±6.1) which was higher than that of the controls 24.4(SD: ±4.9). Eighty-six (43.2%) of the cases and 218(54.8%) of the controls were below the age of 25 years whereas 28(14.1%) of the cases and 19(4.8%) of the controls were above the age of 35 years ( Table 2 ).

Medical disease history of women with and without HDP

Concerning to medical disease factors, 35(17.6%) of cases and 15(3.8%) of controls had positive pre-existing hypertension whereas 164(82.4%) of cases and 383(96.2%) of controls had not pre-existing hypertension.

Obstetric history characteristics of women with and without HDP

Among study participants, 109 (54.8%) of the case group and 102(25.6%) of the control group were identified for prim gravida while 90(45.2%) cases and 296(74.4%) of controls were of multigravida pregnancies ( Table 3 ). Regarding parity, 64(32.2%) of cases and 24(6.0%) of controls were found to be nulliparous whereas 135(67.8%) of cases and 374(94.0%) controls were of parity greater or equal to 1. The parity difference between two groups was significant (χ2 (1, n  = 597) =70.02, p  = .00, phi = −.35).

As it showed in Fig. 1 : there were 153 (76.9%) pre-eclampsia/ eclampsia, 28 (14.1%) gestational hypertension, 14(7.0%) superimposed hypertension, and 4(2.0%) chronic hypertension (Fig. 1 ).

Percentage of Prevalence of Hypertension disorders among cases of the study

Multivariate analysis of risk factors for women with and without HDP

The multivariate analysis revealed that, the age category of 35 years and above (AOR: 2.51, 95% CI: 1.08, 5.83), rural dwellers (AOR: 1.79, 95% CI: 1.15, 2.80), prim gravida pregnancies (AOR: 3.39, 95% CI: 2.16, 5.33),null parity (AOR: 4.35, 95% CI: 2.36, 8.03),women who had positive history of abortion (AOR: 4.39, 95% CI: 1.64, 11.76),Twin pregnancies (AOR: 3.78, 95% CI: 1.52, 9.39), ANC follow up (AOR: 3.05, 95% CI: 1.56, 5.96), positive pre-existing history of hypertension (AOR: 3.81, 95% CI: 1.69, 8.58),family history of hypertension (AOR: 5.04, 95% CI: 2.66, 9.56) History of diabetes mellitus (AOR: 5.03, 95% CI: 1.59, 15.89) were risk factors for hypertension disorders during pregnancy ( Table 4 ).

Differences in maternal outcomes between women with and without HDP

Regarding the onset of labor, induced labor or C/S 108(54.3%) for cases and 48(12.1%) controls. The difference of onset of labor between those with and without HDP groups was significant (χ2 (1, n  = 597) = 123.50, p  = .000, phi = .46) ( Table 5 ).

Normal and instrumental deliveries were higher among controls (60.8%) and (44.2%) than cases (29.9%) and (16.1%) respectively.

Differences in perinatal outcomes between women with and without HDP

There was low birth weight for 72(36.2%) cases and 15(3.8%) controls (Fig. 2 ).

Delivery modes for women with and without Hypertension disorders of pregnancy

The difference of number of low birth weight between both groups was significant (χ2 (1, n  = 597) = 123.76, p  = .000, phi = .46) ( Table 6 .)

Risk factors of hypertension disorders during pregnancy

This study was conducted to identify the possible risk factors, maternal and perinatal outcomes of hypertensive disorders in pregnancy in Nekemte Referral Hospital, Ethiopia. The study revealed that the proportion of hypertensive disorders of pregnancy was 3.56%, which was lower than the study conducted in Tikur Anbessa Hospital, Jimma University Specialized Hospital and Debre Berhan Referral Hospital [ 3 , 5 , 6 , 10 ]. The reason might be due to the development of awareness creation made on controlling danger signs of maternal health by extension health workers in the current study than earlier study in a rural area.

This study showed that the extreme ages of reproductive years were found to be risk factors for hypertension during pregnancy with high incidence rates in old ages of greater than 35 years in comparison with the age range of 25–29 years. Concerning the current study, a hospital-based cross-sectional study conducted in Dassie Referral Hospital [ 11 ] and in Derashe, woreda [ 7 ] in Ethiopia reported that late age 30 years in some cases and age greater than 35 years in most cases were significantly associated with Hypertensive disorders of pregnancy.

About two folds of cases of HDP (64.8%) were living in a rural area comparing to urban residence for this study. Then the rural residential area was found to be one of the risk factors of HDP.

This finding was similar to a study done in Jimma hospital of a similar country [ 5 ].

In the current study, those women with prim gravida pregnancies had 3.40 times higher odds of developing hypertension disorders as compared with their counterparts. Also, the occurrence of HDP was reported more serious in prim gravida mothers of case groups than the control group [ 12 ]. This is maybe because getting pregnancy for the first time likely induces psychological stress and physical boredom that make women at risk of the development of HDP.

In this study, women with previous abortions had 4.40 times higher odds of more likely to develop hypertensive disorders than with no previous abortion. Which is inconsistent with the current findings. For instance, a study conducted in Iran reported a noticeable effect of the history of abortion on increasing the risk of mild preeclampsia [ 13 ]. further noted that there was no significant difference in the incidence of preeclampsia between women with no history of previous abortion and term pregnancy and women who had previous preterm birth [ 14 , 15 ].

This study indicated that twin pregnancies had more than three folds of developing hypertension during pregnancy as compared with having singleton pregnancies. This result is in line with the research conducted in Northeastern Ethiopia [ 11 ]. This study has shown that lack of antenatal care had more likely associated with hypertension disorder during pregnancy. A similar finding was found in Egypt [ 16 ] in which preeclampsia was higher in women who had not ANC follow up. This could be due to women who had ANC follow up might get preventive measures for preeclampsia from health care providers during their ANC follow up.

The present study revealed that the positive previous history of preeclampsia was significantly associated with the development of hypertension. Women who had pre-existing hypertension were more likely to develop hypertensive disorders compared to women who had a negative family history of hypertension.

This study coincides with the findings reported as women presenting preeclampsia/eclampsia constituted a high-risk group for developing long term chronic hypertension [ 17 ]. Besides, there is consensus in the literature regarding the role of the previous history of preeclampsia as a contributing factor for preeclampsia [ 8 , 10 , 18 ].

In this study, a family history of hypertension had also a significant relationship with hypertensive disorders of pregnancy. Women who had a positive family history of hypertension were more likely to develop hypertensive disorders compared to women who had a negative family history of hypertension. More similar studies including in the Tigray region, Ethiopia revealed that a positive family history of chronic hypertension was a risk factor for HDP [ 8 , 10 , 15 , 18 , 19 , 20 , 21 , 22 ].

From these findings, it seems that both maternal and fetal genes play a role in this syndrome. Therefore, for pregnant women with a family history of HDP, it should be monitored carefully both perinatally and in the postpartum period.

Another finding showed that gestational diabetes mellitus was significantly associated with hypertension disorders during pregnancy. It is supported by numerous studies that diabetes mellitus was considerable risk factors for the development of preeclampsia [ 10 , 23 , 24 , 25 ].

In this study, diabetes Mellitus was found to be an important risk factor for developing HDP. It was 5.03 times higher for the positive history of diabetes mellitus. Thus, actions in public health focused to prevent these diseases are important to also prevent preeclampsia.

Differences in pregnancy outcomes between women with and without HDP

Cases and control of this study found to have significant differences in maternal and perinatal comes. Accordingly, induced labor or cesarean sections (CS) was significantly higher in cases 81(40.7%) than in controls 8(2.0%). Besides, data obtained on the mode of delivery show that Cesarean Section was higher in cases than in controls were as normal spontaneous vaginal delivery and instrumental deliveries were more common in controls than in cases.

The difference between the prevalence of abruption placenta complication between women with and without HDP was found to be significant.

The magnitude of the abruption placenta was more than three-fold in cases compared to in controls. Corresponding to this finding, it was reported that placental abruption was a common complication of mothers experiencing any type of hypertension during pregnancy [ 26 , 27 ].

A considerable number of studies have reported that preterm birth was significantly higher in women with HDP than without. For instance, a study conducted in China indicated that 29.36% of women who had HDP gave birth before 37 weeks of gestation than 6.78% of women without HDP [ 26 ]. Besides, a study in Portugal showed a statistically significant association between preterm delivery and severity of HDP [ 28 ].

Of course, it is very important to conducted further studies with adequate samples in different parts of our country to determine the magnitude of difference that case and control groups have on giving preterm births.

A study conducted in Mettu Karl Referral Hospital reported that 120.37 perinatal mortality per 1000 deliveries, 10.2% stillbirth rate,30.5% low birth weight, low 18.5% APGAR score and 31.4% preterm delivery outcomes in women with HDP [ 29 ].

Besides Tesfaye A and Tilahun M. indicated 21.2% of infants of women with HDP were admitted in a neonatal intensive care unit [ 30 ].

Regarding pregnancy complications, among women with HDP in this study, 24.6, 9.5, 8.0, 3.5, and 3.5% of them had developed complications of eclampsia, abruption placenta, DIC, acute renal failure, and pulmonary edema, respectively.

To this end, many studies reported similar findings [ 1 , 6 , 31 , 32 , 33 ]. The findings show that both maternal and fetal morbidity and mortality were higher in HDP. That is, maternal and perinatal complications women with HDP are common elsewhere in our world with a more severe rate in developing countries. Thus, improving antenatal care for pregnant mothers in our country is indispensable.

Strength and limitation of the study

This study was done on the hypertensive disorders during pregnancy, which is one of the major maternal and perinatal cause of death. The use of a case-control study design helped to compare the effect of hypertension disorder between women with and without HDP.

We utilized secondary data; which might be encountered to lack some of variables.

There were missed variables such as socio-demographic characteristic such as maternal education level, maternal weight, and height, smoking status of mothers.

Conclusions and recommendations

Women with hypertension during pregnancy have a greater risk of having adverse pregnancy outcomes as compared to normotensive pregnant women. Old age, rural residential area, being single, nulliparity, positive history of abortion, twin pregnancy, lack of ANC follows up, positive pre-existing hypertension, positive family history of hypertension and positive diabetes mellitus were identified as risk factors for developing hypertensive disorders of pregnancy.

Recommendation

Based on the findings the following recommendations were given.

Strengthening ANC service to strengthen counseling and managing the complication early.

Strengthening neonatal intensive care unit (including expansion) in health facilities could be an important input in reducing neonatal complications.

Availability of data and materials

The data sets used and analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

Antenatal care

Adjusted odd ratio

Cesarean section

Confident Interval

Disseminated intravascular coagulopathy

Hypertension disorders during pregnancy

Standard Deviation

Institute of Health A. National Maternity Data Development Project 1 National Maternity Data Development Project: Hypertensive disorders during pregnancy Hypertensive disorders during pregnancy. 2014;1–9.

Queensland Clinical Guidelines. Hypertensive disorders of pregnancy. Queensland: Author; 2015.

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Acknowledgments

The researcher acknowledges to Wollega University, College of Health Science, Department of Midwifery, and Nekemte specialized Hospital card room, Obstetric, and Gynecologic Department for their support during data collection.

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Leta Hinkosa

Nekemte Referral Hospital, Oromia Regional National State, Nekemte, Ethiopia

Almaz Tamene

Department of Midwifery, College of Medicine and Health Sciences, Wechamo University, Hossana, Ethiopia

Negeso Gebeyehu

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LH wrote the proposal, participated in data collection, analyzed the data and drafted the paper. AT and NG approved the proposal with some revisions, participated in data analysis and revised subsequent drafts of the paper. All authors read and approved the final manuscript.

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Hinkosa, L., Tamene, A. & Gebeyehu, N. Risk factors associated with hypertensive disorders in pregnancy in Nekemte referral hospital, from July 2015 to June 2017, Ethiopia: case-control study. BMC Pregnancy Childbirth 20 , 16 (2020). https://doi.org/10.1186/s12884-019-2693-9

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Hypertensive disorders of pregnancy: Case definitions & guidelines for data collection, analysis, and presentation of immunization safety data

Caroline e. rouse.

a Brigham and Women's Hospital, Boston, MA, USA

Linda O. Eckert

b University of Washington, Seattle, WA, USA

Blair J. Wylie

c Massachusetts General Hospital, Boston, MA, USA

Deirdre J. Lyell

d Stanford University, Stanford, CA, USA

Arundhathi Jeyabalan

e University of Pittsburgh, Pittsburgh, PA, USA

Sonali Kochhar

f Global Healthcare Consulting

Thomas F. McElrath

1. preamble, 1.1. need for developing case definitions and guidelines for data collection, analysis, and presentation for the hypertensive disorders of pregnancy as adverse events following immunization.

There is no universally accepted case definition of gestational hypertension, preeclampsia or eclampsia that occurs following immunisations. This is a missed opportunity, as data comparability across trials or surveillance systems would facilitate data interpretation and promote the scientific understanding of the event. As immunization is considered an essential element of care in pregnancy, the potential complications of this procedure should be understood. Additionally, vaccine studies may be conducted in a variety of settings, including those with fewer resources to perform the same diagnostic testing as in higher resource settings. It is important to provide definitions that can be utilized widely.

Around 10% of all pregnant women will be affected by a hypertensive disorder during pregnancy [1] . Hypertensive disorders of pregnancy are a significant contributor to maternal and neonatal morbidity and mortality, and are implicated in 10–15% of maternal deaths worldwide [1] , [2] . The exact mechanism responsible for hypertensive diseases of pregnancy, in particular preeclampsia, is not known. One leading hypothesis is that abnormalities in the development of the uteroplacental unit lead to increased hypoxemia and oxidative stress, which in turn lead to endothelial dysfunction and abnormalities in vascular tone and coagulation [3] , [4] .

Hypertensive disease in pregnancy encompasses a spectrum of conditions, including gestational hypertension, preeclampsia (which can be further qualified as having severe features), eclampsia, chronic hypertension with superimposed preeclampsia and HELLP (Hemolysis, Elevated Liver Enzymes, Low Platelets) syndrome. Because of differences among the guidelines issued by international societies, diagnosis can occasionally become confusing as terminology may vary. Nevertheless, it is important to differentiate hypertensive disorders that predate pregnancy from those that occur during pregnancy, as well as to categorize patients into more or less serious cases. Furthermore, the specific diagnosis has important treatment implications, such as timing of delivery. The definitive treatment for hypertensive diseases of pregnancy is delivery.

The association of vaccination with the hypertensive diseases of pregnancy has not been well studied and the exact incidence is not known. There are observational studies as well as case reports of hypertensive disease developing in women after vaccine administration but no causal link has been described. Furthermore, the case definitions for the observational studies are not well defined, with several studies relying solely on ICD-9 codes.

1.2. Methods for the development of the case definition and guidelines for data collection, analysis, and presentation for the hypertensive disorders of pregnancy as adverse events following immunization

Following the process described in the overview paper [5] as well as on the Brighton Collaboration Website, http://www.brightoncollaboration.org/internet/en/index/process.html , the Brighton Collaboration Preeclampsia Working Group was formed in 2015 and included members with clinical, academic and public health background. The composition of the working and reference group as well as results of the web-based survey completed by the reference group with subsequent discussions in the working group can be viewed at: http://www.brightoncollaboration.org/internet/en/index/working_groups.html .

To guide the decision-making for the case definition and guidelines, a literature search of publications in English was performed using Medline, Embase and the Cochrane Libraries, including the terms vaccines, vaccination, or immunization (or terms beginning with vaccin-, immuni-, inoculat-), and [hypertension AND pregnancy] or [preeclampsia or eclampsia] (or preeclam-, eclamp-). The search resulted in the identification of 516 references. All abstracts were screened for possible reports of preeclampsia, eclampsia or hypertension in pregnancy following immunization. Twenty-seven articles with potentially relevant material were reviewed in more detail, in order to identify studies using case definitions or, in their absence, providing clinical descriptions of the case material. Data collected from these 27 articles included information on the study type, the vaccine, the diagnostic criteria or case definition put forth, the time interval since time of immunization, and any other symptoms. References that lacked hypertensive diseases of pregnancy as an outcome were excluded.

Most publications were of observational studies, though there were also several publications from vaccine adverse event reporting groups. Only one publication [6] specified the criteria used to diagnose preeclampsia in study participants. Four of the publications reported using ICD-9 diagnostic codes to collect cases of preeclampsia/eclampsia or pregnancy related hypertension [2] , [7] , [8] , [9] .

1.3. Rationale for selected decisions about the case definition of preeclampsia as an adverse event following immunization

1.3.1. the terms for hypertension in pregnancy.

The terms “eclampsia,” “preeclampsia,” “gestational hypertension” and “pregnancy-induced hypertension” are commonly used in clinical practice. “Pregnancy-induced hypertension” is a term referring to hypertensive disorders of pregnancy in general, but lacks the specificity of the other terms, and so the Brighton definitions will refer only to “eclampsia,” “preeclampsia,” and “gestational hypertension.” All of these disorders are characterized by elevations in blood pressure. Preeclampsia and eclampsia have additional diagnostic criteria based on laboratory findings by clinical physical exam or patient reported symptoms reflecting the systemic nature of the disease. The diagnosis of gestational hypertension is provisional, in that every woman with new blood pressure elevation in pregnancy should be further evaluated for the development of preeclampsia. It is possible to move from a diagnosis of gestational hypertension to preeclampsia or eclampsia, but not from preeclampsia to gestational hypertension.

1.3.2. Formulating a case definition that reflects diagnostic certainty: weighing specificity versus sensitivity

The number of symptoms and/or signs that will be documented for each case may vary considerably. The case definitions have been formulated such that the Level 1 definition is highly specific for the condition. As maximum specificity normally implies a loss of sensitivity, one additional diagnostic levels have been included in the definition, offering a stepwise increase of sensitivity from Level 1 down to Level 2, while retaining an acceptable level of specificity at all levels. In this way it is hoped that all possible cases of the hypertensive diseases of pregnancy can be captured.

It needs to be emphasized that the grading of definition levels is entirely about diagnostic certainty, not clinical severity of an event. Thus, a clinically very severe event may appropriately be classified as Level 2 rather than Level 1 if it could reasonably be ascribed to an etiology other than the hypertensive diseases of pregnancy. Detailed information about the severity of the event should additionally be recorded, as specified by the data collection guidelines.

1.3.3. The timing of development of preeclampsia in the context of vaccine administration

Preeclampsia and gestational hypertension are conventionally defined as developing after 20 weeks gestation [10] , but there can be great variability in exact timing of presentation of the disease. In one study, approximately 10% of the preeclampsia diagnoses were made before 34 weeks gestation [11] . Preeclampsia can develop up to 6 weeks postpartum and, in fact, 20–50% of eclampsia occurs in the postpartum period [12] , [13] . The progression from normal blood pressure to hypertension to preeclampsia can proceed rapidly, gradually, or not at all. Because of the unpredictability in development and progression of the disease, it is important for the purpose of vaccine trials to record the temporal relationship between immunization and development of any preeclampsia-related complication of pregnancy.

1.3.4. Rationale for individual criteria related to the case definition

1.3.4.1. gestational hypertension.

Gestational hypertension refers to new onset hypertension after 20 weeks of gestation [10] , [14] , [15] . The use of “20 weeks gestation” as a diagnostic criterion is somewhat arbitrary, as there is no specific physiologic change known that occurs at this gestational age that permits the development of preeclampsia. However, given that this convention is widely used, the Brighton Collaboration will continue to utilize it for the sake of continuity.

Accurate blood pressure measurement is fundamental for the diagnosis of a hypertensive disorder of pregnancy. The WHO released a document in 2003 detailing the proper protocols and techniques that should be utilized when measuring blood pressure. While it is outside the scope of this document to present a comprehensive guide to accurate blood pressure measurement, several important points should be highlighted. Regardless of the type of device used to measure blood pressure, accuracy should be checked regularly by comparing the measurement device to a calibrated device, and health care providers should be properly trained in taking blood pressure measurements. Blood pressure should be measured with the patient in a seated position, with the arm at the level of the heart. An appropriate cuff size should be chosen based on the patient's size (generally a length that is 1.5 times the circumference of the patient's arm). The systolic blood pressure is the pressure at which the first sounds can be heard. The disappearance of sounds, or the fifth phase, is the best measurement of diastolic blood pressure.

Blood pressure is considered elevated if the systolic blood pressure is ≥140 mmHg or the diastolic blood pressure is ≥90 mmHg, sustained over time. The length of time that the blood pressure should remain elevated varies as well, from 15 min [16] to 4 h depending on which organization guidelines are followed [10] . The Brighton Collaboration favors a longer time interval of sustained blood pressure elevations. However, with respect to the potential logistical concerns in some settings of keeping a woman for observation for several hours, we propose that a diagnosis of hypertension be made if the systolic blood pressure is ≥140 mmHg or the diastolic blood pressure is ≥90 mmHg on two measurements at a minimum of one hour apart.

1.3.4.2. Preeclampsia

Preeclampsia has conventionally been defined as the development of gestational hypertension and proteinuria after 20 weeks gestation [2] , [10] , [14] , [15] , [16] . We consider preeclampsia as a systemic condition of endothelial dysfunction in which hypertension is a primary presenting sign. Other organ systems will manifest this dysfunction in fashions specific to their physiology. Historically, microvascular dysfunction in the kidney has been recognized as proteinuria.

Proteinuria can be quantified by 24 h urine collection, a spot protein:creatinine ratio, or with urinary dipstick. Proteinuria of ≥300 mg in a 24 h urine specimen (the gold standard for measurement of proteinuria), or ≥0.30 on a spot protein:creatinine ratio, or ≥1+ on a dipstick meets the criteria for preeclampsia [2] , [10] , [14] , [15] , [16] . Routine visual dipstick urinalysis has been shown to have false positive rates at “1+” of 67–83%, and false negative rates at “nil” or “trace” of 8–18% [17] . Automated urinalysis improves the sensitivity of this test to 74% [18] . The sensitivity and specificity of the protein:creatinine ratio are higher at 93% and 92%, respectively [18] . Given the potential variation in resources available to test for proteinuria, the Brighton Collaboration will permit any of these measures of proteinuria, though 24 h urine collection and protein:creatinine ratio are preferred.

Preeclampsia can be further classified as having “severe features” with development of laboratory abnormalities or symptoms. The progression to preeclampsia with severe features represents the clinical recognition of the additional involvement of maternal organ systems. Because certain clinical findings associated with severe disease increase the morbidity and mortality of preeclampsia [19] , they are included in the Brighton Collaboration definition. The diagnosis of severe preeclampsia requires new onset hypertension (as described above) and one of the following criteria enumerated below. Given the multi-system nature of preeclampsia, these will be presented by system:

NOTE that preeclampsia with severe features can be diagnosed in the presence or absence of proteinuria.

• • Vascular:
• ∘ Severely elevated blood pressures, with systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥110 mmHg, which is confirmed after only minutes (to facilitate timely antihypertensive treatment)
• • Neurologic:
• ∘ Development of a severe headache (which can be diffuse, frontal, temporal or occipital) that generally does not improve with over the counter pain medications (such as acetaminophen/paracetamol)
• ∘ Development of visual changes (including photopsia, scotomata, cortical blindness) [20]
• ∘ Eclampsia, or new-onset grand mal seizures in a patient with preeclampsia, without other provoking factors (such as evidence of cerebral malaria or preexisting seizure disorder). Seizures are often preceded by headaches, visual changes or altered mental status [21]
• • Hematologic:
• ∘ New onset thrombocytopenia, with platelet count <100,000/μL
• • Gastrointestinal:
• ∘ New onset of nausea, vomiting, epigastric pain
• ∘ Transaminitis (AST and ALT elevated to twice the upper limit of normal)
• ∘ Liver capsular hemorrhage or liver rupture
• • Renal:
• ∘ Worsening renal function, as evidenced by serum creatinine level greater than 1.1 mg/dL or a doubling of the serum creatinine (absent other renal disease)
• ∘ Oliguria (urine output <500 mL/24 h)
• • Respiratory:
• ∘ Pulmonary edema (confirmed on clinical exam or imaging)

While complications of pregnancy such as intrauterine growth restriction, placental abruption and stillbirth are utilized as diagnostic criteria for preeclampsia with severe features by some societies [15] , [16] , the Brighton Collaboration has chosen not to include these in our definition since these conditions frequently exist independently of the hypertensive disorders of pregnancy and may represent a separate set of pathologies. We recommend that these complications should certainly be reported as pregnancy outcomes in the context of vaccine and other drug trials. The Brighton Collaboration working groups on stillbirth, intrauterine growth restriction and vaginal bleeding in pregnancy will have publications forthcoming to help guide diagnosis of these related conditions. http://www.brightoncollaboration.org .

1.3.5. Related conditions

1.3.5.1. hellp (hemolysis, elevated liver enzymes, low platelets) syndrome.

HELLP syndrome is considered to be a subtype of severe preeclampsia. The diagnosis is based on laboratory evaluation in which all criteria (hemolysis, liver dysfunction, thrombocytopenia) are met [22] , [23] . It is important to note that hypertension may be absent in up to 15% of cases of HELLP syndrome. While we recognize HELLP as part of the preeclampsia spectrum of disease, this diagnosis is not the focus of this document, and so will not be further addressed.

1.3.5.2. Chronic hypertension

Chronic hypertension refers to elevation in the systolic blood pressure to ≥140 mmHg or the diastolic blood pressure to ≥90 mmHg, sustained over a length of time (as described above) that is diagnosed either prior to pregnancy or prior to 20 weeks gestation. Hypertension that occurs in early gestation is likely to predate pregnancy, hence the establishment of 20 weeks as a boundary for the diagnosis of chronic hypertension. Chronic hypertension progresses to preeclampsia in 10–50% of cases, depending on the severity of the preexisting hypertension [24] . The diagnosis of superimposed preeclampsia (preeclampsia superimposed on chronic hypertension) is made based on the following criteria:

• • preexisting hypertension (described above) PLUS any one of the following:
• ∘ new onset proteinuria (as described above)
• ∘ worsening of preexisting proteinuria
• ∘ development of any of the laboratory abnormalities or clinical findings consistent with severe preeclampsia

1.3.5.3. Postpartum preeclampsia

While some of the physiologic changes of pregnancy take longer to return to a pre-pregnancy state, the postpartum period, or puerperium, encompasses the six weeks following delivery [25] . The exact incidence of new-onset postpartum preeclampsia or hypertension is difficult to measure since most women do not return to their care provider until 6 weeks after the delivery, but estimates range from 0.3% to 27% [26] . The criteria for a postpartum diagnosis of the hypertensive disorders of pregnancy are the same as the antepartum criteria.

1.3.6. Timing post immunization

We postulate that a definition designed to be a suitable tool for testing associations requires ascertainment of the outcome (e.g. a hypertensive disorder of pregnancy) independent from the exposure (e.g. immunisations). Therefore, to avoid selection bias, a restrictive time interval from immunization to onset of a hypertensive disorder of pregnancy should not be an integral part of such a definition. Instead, where feasible, details of this interval should be assessed and reported as described in the data collection guidelines. Care should be taken to avoid creating spurious associations between vaccine administration and hypertensive disorders, given that vaccines are generally administered during specific times during pregnancy. Case–control studies are needed to further evaluate the potential link.

Further, hypertensive disorders of pregnancy are common, affecting up to 10% of pregnant women [1] , and can occur outside the controlled setting of a clinical trial or hospital. In some settings it may be impossible to obtain a clear timeline of the event, particularly in less developed or rural settings. In order to avoid selecting against such cases, the Brighton Collaboration case definition avoids setting arbitrary time frames, though the immunization should precede the hypertensive disorder.

1.3.7. Differential diagnoses

Other diagnoses should be considered during the workup of hypertension in pregnancy. The differential is broad, including but not limited to conditions such as preexisting renal disease, thrombotic thrombocytopenic purpura/hemolytic uremic syndrome, acute fatty liver of pregnancy, primary liver disease, cardiomyopathy, pheochromocytoma, and thyrotoxicosis. Seizures in pregnancy can be caused by a preexisting seizure disorder, cerebral malaria, metabolic abnormalities, or cerebral anatomic abnormalities such as a space-occupying lesion. Ensuring accurate diagnosis is of great importance, as treatment can vary widely based on the etiology of the patient's symptoms.

2. Case definitions

2.1. Guidelines for data collection, analysis and presentation

As mentioned in the overview paper, the case definition is accompanied by guidelines which are structured according to the steps of conducting a clinical trial, i.e. data collection, analysis and presentation. Neither case definition nor guidelines are intended to guide or establish criteria for management of ill infants, children, or adults. Both were developed to improve data comparability.

2.2. Periodic review

Similar to all Brighton Collaboration case definitions and guidelines, review of the definition with its guidelines is planned on a regular basis (i.e. every three to five years) or more often if needed.

3. Guidelines for data collection, analysis and presentation of the hypertensive disorders of pregnancy, as presented in document

It was the consensus of the Brighton Collaboration Hypertensive Disorders of Pregnancy Working Group to recommend the following guidelines to enable meaningful and standardized collection, analysis, and presentation of information about these conditions. However, implementation of all guidelines might not be possible in all settings. The availability of information may vary depending upon resources, geographical region, and whether the source of information is a prospective clinical trial, a post-marketing surveillance or epidemiological study, or an individual report of hypertension in pregnancy. Also, as explained in more detail in the overview paper in this volume, these guidelines have been developed by this working group for guidance only, and are not to be considered a mandatory requirement for data collection, analysis, or presentation.

3.1. Data collection

These guidelines represent a desirable standard for the collection of data on availability following immunization to allow for comparability of data, and are recommended as an addition to data collected for the specific study question and setting. The guidelines are not intended to guide the primary reporting of the hypertensive disorders of pregnancy to a surveillance system or study monitor. Investigators developing a data collection tool based on these data collection guidelines also need to refer to the criteria in the case definition, which are not repeated in these guidelines. The Brighton Collaboration has developed guidelines for data collection https://brightoncollaboration.org/public/resources/standards/guidelines.html ; and data collection forms https://brightoncollaboration.org/public/resources/data-collection-forms.html .

Guidelines below have been developed to address data elements for the collection of adverse event information as specified in general drug safety guidelines by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use [27] , and the form for reporting of drug adverse events by the Council for International Organizations of Medical Sciences [28] . These data elements include an identifiable reporter and patient, one or more prior immunisations, and a detailed description of the adverse event, in this case, of a hypertensive disorder of pregnancy following immunization. The additional guidelines have been developed as guidance for the collection of additional information to allow for a more comprehensive understanding of development of the hypertensive disorders of pregnancy following immunization.

3.1.1. Source of information/reporter

For all cases and/or all study participants, as appropriate, the following information should be recorded:

• 1) Date of report.
• 2) Name and contact information of person reporting 2 and/or diagnosing the hypertensive disorder of pregnancy as specified by country-specific data protection law.
• 3) Name and contact information of the investigator responsible for the subject, as applicable.
• 4) Relation to the patient (e.g., immunizer [clinician, nurse], family member [indicate relationship], other).

3.1.2. Vaccinee/control

3.1.2.1. demographics.

• 5) Case/study participant identifiers (e.g. first name initial followed by last name initial) or code (or in accordance with country-specific data protection laws).
• 6) Date of birth, age, and sex.
• 7) For infants: Gestational age and birth weight.

3.1.2.2. Clinical and immunization history

• 8) Past medical history, including hospitalisations, underlying diseases/disorders, pre-immunization signs and symptoms including identification of indicators for, or the absence of, a history of allergy to vaccines, vaccine components or medications; food allergy; allergic rhinitis; eczema; asthma.
• 9) Any medication history (other than treatment for the event described) prior to, during, and after immunization including prescription and non-prescription medication as well as medication or treatment with long half-life or long term effect. (e.g. immunoglobulins, blood transfusion and immunosuppressants).
• 10) Immunization history (i.e. previous immunisations and any adverse event following immunization (AEFI)), in particular occurrence of a hypertensive disorder in pregnancy after a previous immunization.

3.1.3. Details of the immunization

• 11) Date and time of immunization(s).
• 12) Description of vaccine(s) (name of vaccine, manufacturer, lot number, dose (e.g. 0.25 mL, 0.5 mL, etc.) and number of dose if part of a series of immunisations against the same disease).
• 13) The anatomical sites (including left or right side) of all immunisations (e.g. vaccine A in proximal left lateral thigh, vaccine B in left deltoid).
• 14) Route and method of administration (e.g. intramuscular, intradermal, subcutaneous, and needle-free (including type and size), other injection devices).
• 15) Needle length and gauge.

3.1.4. The adverse event

Specifically document:

• 17) Clinical description of signs and symptoms of the hypertensive disorder of pregnancy, and if there was medical confirmation of the event (i.e. patient seen by physician).
• 18) Date/time of onset, 3 first observation 4 and diagnosis, 5 end of episode 6 and final outcome. 7
• 19) Concurrent signs, symptoms, and diseases.
• 20) Measurement/testing
• • Values and units of routinely measured parameters (e.g. temperature, blood pressure)–in particular those indicating the severity of the event;
• • Method of measurement (e.g. type of thermometer, oral or other route, duration of measurement, etc.);
• • Results of laboratory examinations, surgical and/or pathological findings and diagnoses if present.
• 21) Treatment given for the hypertensive disorder of pregnancy, especially any antihypertensive medication, magnesium sulfate and steroid medications.
• 22) Outcome 7 at last observation.
• 23) Objective clinical evidence supporting classification of the event as “serious”. 8
• 24) Exposures other than the immunization 24 h before and after immunization (e.g. food, environmental) considered potentially relevant to the reported event.

3.1.5. Miscellaneous/general

• 25) The duration of surveillance for the hypertensive disorders of pregnancy should be predefined based on
• • Biologic characteristics of the vaccine e.g. live attenuated versus inactivated component vaccines;
• • Biologic characteristics of the vaccine-targeted disease;
• • Biologic characteristics of the hypertensive disorders of pregnancy including patterns identified in previous trials (e.g. early-phase trials); and
• • Biologic characteristics of the vaccinee (e.g. nutrition, underlying disease like immunodepressing illness).
• 26) The duration of follow-up reported during the surveillance period should be predefined likewise. It should aim to continue to resolution of the event.
• 27) Methods of data collection should be consistent within and between study groups, if applicable.
• 28) Follow-up of cases should attempt to verify and complete the information collected as outlined in data collection guidelines 1–24.
• 29) Investigators of patients with a hypertensive disorder of pregnancy should provide guidance to reporters to optimize the quality and completeness of information provided.
• 30) Reports of hypertensive disorders of pregnancy should be collected throughout the study period regardless of the time elapsed between immunization and the adverse event. If this is not feasible due to the study design, the study periods during which safety data are being collected should be clearly defined.

3.2. Data analysis

The following guidelines represent a desirable standard for analysis of data on the hypertensive disorders of pregnancy to allow for comparability of data, and are recommended as an addition to data analyzed for the specific study question and setting.

• 31) Reported events should be classified in one of the following five categories including the three levels of diagnostic certainty. Events that meet the case definition should be classified according to the levels of diagnostic certainty as specified in the case definition. Events that do not meet the case definition should be classified in the additional categories for analysis.

Event classification in 5 categories 9

Event meets case definition

• 1) Level 1: Criteria as specified in the Hypertensive Disorders of Pregnancy case definition
• 2) Level 2: Criteria as specified in the Hypertensive Disorders of Pregnancy case definition

Event does not meet case definitionAdditional categories for analysis

• 3) Reported hypertensive disorder of pregnancy with insufficient evidence to meet the case definition 10 , 11
• 4) Not a case of a hypertensive disorder of pregnancy
• 32) The interval between immunization and reported hypertensive disorder of pregnancy could be defined as the date/time of immunization to the date/time of onset 3 of the first symptoms and/or signs consistent with the definition. If few cases are reported, the concrete time course could be analyzed for each; for a large number of cases, data can be analyzed in the following increments:

Subjects with a hypertensive disorder of pregnancy by interval to presentation

• 33) The duration of a possible hypertensive disorder of pregnancy could be analyzed as the interval between the date/time of onset 2 of the first symptoms and/or signs consistent with the definition and the end of episode 6 and/or final outcome. 7 Whatever start and ending are used, they should be used consistently within and across study groups.
• 34) If more than one measurement of a particular criterion is taken and recorded, the value corresponding to the greatest magnitude of the adverse experience could be used as the basis for analysis. Analysis may also include other characteristics like qualitative patterns of criteria defining the event.
• 35) The distribution of data (as numerator and denominator data) could be analyzed in predefined increments (e.g. measured values, times), where applicable. Increments specified above should be used. When only a small number of cases is presented, the respective values or time course can be presented individually.
• 36) Data on hypertensive disorders of pregnancy obtained from subjects receiving a vaccine should be compared with those obtained from an appropriately selected and documented control group(s) to assess background rates of hypersensitivity in non-exposed populations, and should be analyzed by study arm and dose where possible, e.g. in prospective clinical trials.

3.3. Data presentation

These guidelines represent a desirable standard for the presentation and publication of data on hypertensive disorders of pregnancy following immunization to allow for comparability of data, and are recommended as an addition to data presented for the specific study question and setting. Additionally, it is recommended to refer to existing general guidelines for the presentation and publication of randomized controlled trials, systematic reviews, and meta-analyses of observational studies in epidemiology (e.g. statements of Consolidated Standards of Reporting Trials (CONSORT), of Improving the quality of reports of meta-analyses of randomized controlled trials (QUORUM), and of Meta-analysis Of Observational Studies in Epidemiology (MOOSE), respectively) [29] , [30] , [31] .

• 37) All reported events of hypertensive disorders of pregnancy should be presented according to the categories listed in guideline 31.
• 38) Data on possible hypertensive disorders of pregnancy should be presented in accordance with data collection guidelines 1–24 and data analysis guidelines 31–36.
• 39) Terms to describe hypertensive disorders of pregnancy such as “low-grade”, “moderate”, “high”, or “significant” are highly subjective, prone to wide interpretation, and should be avoided, unless clearly defined.
• 40) Data should be presented with numerator and denominator (n/N) (and not only in percentages), if available.

Although immunization safety surveillance systems denominator data are usually not readily available, attempts should be made to identify approximate denominators. The source of the denominator data should be reported and calculations of estimates be described (e.g. manufacturer data like total doses distributed, reporting through Ministry of Health, coverage/population based data, etc.).

• 41) The incidence of cases in the study population should be presented and clearly identified as such in the text.
• 42) If the distribution of data is skewed, median and range are usually the more appropriate statistical descriptors than a mean. However, the mean and standard deviation should also be provided.
• 43) Any publication of data on the hypertensive disorders of pregnancy should include a detailed description of the methods used for data collection and analysis as possible. It is essential to specify:
• • The study design;
• • The method, frequency and duration of monitoring for the hypertensive disorders of pregnancy;
• • The trial profile, indicating participant flow during a study including drop-outs and withdrawals to indicate the size and nature of the respective groups under investigation;
• • The type of surveillance (e.g. passive or active surveillance);
• • The characteristics of the surveillance system (e.g. population served, mode of report solicitation);
• • The search strategy in surveillance databases;
• • Comparison group(s), if used for analysis;
• • The instrument of data collection (e.g. standardized questionnaire, diary card, report form);
• • Whether the day of immunization was considered “day one” or “day zero” in the analysis;
• • Whether the date of onset 3 and/or the date of first observation 4 and/or the date of diagnosis 5 was used for analysis; and
• • Use of this case definition for the hypertensive disorders of pregnancy, in the abstract or methods section of a publication. 12

The findings, opinions and assertions contained in this consensus document are those of the individual scientific professional members of the working group. They do not necessarily represent the official positions of each participant's organization (e.g., government, university, or corporation). Specifically, the findings and conclusions in this paper are those of the authors and do not necessarily represent the views of their respective institutions.

Acknowledgements

The authors are grateful for the support and helpful comments provided by the Brighton Collaboration (Jan Bonhoeffer, Jorgen Bauwens) and the reference group (see https://brightoncollaboration.org/public/what-we-do/setting-standards/case-definitions/groups.html for reviewers), as well as other experts consulted as part of the process. Finally, we would like to thank the members of the ISPE Special Interest Group in Vaccines (VAX SIG) for the review of, constructive comments on. Brighton Collaboration would like to acknowledge The Global Alignment of Immunization Safety Assessment in Pregnancy (GAIA) Project, funded by the Bill and Melinda Gates Foundation.

2 If the reporting center is different from the vaccinating center, appropriate and timely communication of the adverse event should occur.

3 The date and/or time of onset is defined as the time post immunization, when the first sign or symptom indicative of a hypertensive disorder of pregnancy occurred. This may only be possible to determine in retrospect.

4 The date and/or time of first observation of the first sign or symptom indicative for a hypertensive disorder of pregnancy can be used if date/time of onset is not known.

5 The date of diagnosis of an episode is the day post immunization when the event met the case definition at any level.

6 The end of an episode is defined as the time the event no longer meets the case definition at the lowest level of the definition.

7 E.g. recovery to pre-immunization health status, spontaneous resolution, therapeutic intervention, persistence of the event, sequelae, death.

8 An AEFI is defined as serious by international standards if it meets one or more of the following criteria: (1) it results in death, (2) is life-threatening, (3) it requires inpatient hospitalization or results in prolongation of existing hospitalization, (4) results in persistent or significant disability/incapacity, (5) is a congenital anomaly/birth defect, (6) is a medically important event or reaction.

9 To determine the appropriate category, the user should first establish, whether a reported event meets the criteria for the lowest applicable level of diagnostic certainty, e.g. Level two. If the lowest applicable level of diagnostic certainty of the definition is met, and there is evidence that the criteria of the next higher level of diagnostic certainty are met, the event should be classified in the next category. This approach should be continued until the highest level of diagnostic certainty for a given event could be determined. Major criteria can be used to satisfy the requirement of minor criteria. If the lowest level of the case definition is not met, it should be ruled out that any of the higher levels of diagnostic certainty are met and the event should be classified in additional categories four or five.

10 If the evidence available for an event is insufficient because information is missing, such an event should be categorized as “Reported hypertensive disorder of pregnancy with insufficient evidence to meet the case definition”.

11 An event does not meet the case definition if investigation reveals a negative finding of a necessary criterion (necessary condition) for diagnosis. Such an event should be rejected and classified as “Not a case of a hypertensive disorder of pregnancy”.

12 Use of this document should preferably be referenced by referring to the respective link on the Brighton Collaboration website ( http://www.brightoncollaboration.org ).

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Surrogate Moms Have Higher Rates of Pregnancy Complications

Key Takeaways

Surrogate mothers have a higher risk of pregnancy complications

They are four times more likely to have complications compared to women who conceive naturally

They also are twice as likely to have complications as women with IVF-aided pregnancies

TUESDAY, Sept. 24, 2024 (HealthDay News) -- Surrogate moms have a higher risk of pregnancy complications than other pregnant women, a new study finds.

About 8% of surrogate mothers developed a severe complication like high blood pressure or serious bleeding during delivery , Canadian researchers report.

By comparison, only 2% of women who conceive naturally and 4% of women who conceive via IVF develop similar complications, researchers found.

This is one of the first large-scale studies to compare outcomes between the three different types of pregnancy, they noted.

“Clinicians involved in the care of individuals and couples who need a gestational carrier to build their family should counsel their patients and the gestational carriers about the potential risk during pregnancy and early postpartum,” said lead researcher Dr. Maria Velez , an adjunct scientist with the Institute for Clinical Evaluative Services in Kingston, Ontario.

For the study, researchers analyzed data on more than 863,000 births in Ontario, Canada, between 2012 and 2021. Nearly 98% of pregnancies involved natural conception, compared with 1.8% conception with IVF and 0.1% a surrogate.

Overall risk of complications is higher for surrogates, researchers found, and surrogates have a specifically higher risk of high blood pressure and bleeding after delivery.

Surrogates were also more likely to have a preterm birth, results show.

The new study was published Sept. 23 in the Annals of Internal Medicine .

Further study is needed to figure out why surrogate moms are at greater risk for complications, researchers said.

“There are guidelines about the eligibility criteria to minimize the risk of pregnancy complications among gestational carriers,” Velez said in an institute news release. “However, these guidelines are not always strictly followed.”

More information

Yale Medicine has more on surrogacy .

SOURCE: Institute for Clinical Evaluative Services, news release, Sept. 23, 2024

What This Means For You

Women with a surrogate pregnancy should be sure to follow proper health care guidelines to reduce their risk of complications.

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