review www.kidney-international.

org

Glomerular diseases in pregnancy: pragmatic

recommendations for clinical management
Fadi Fakhouri1, Nora Schwotzer1, Gianfranca Cabiddu2,3, Jonathan Barratt4, Hélène Legardeur5,
Vesna Garovic6,7, Alejandra Orozco-Guillen8, Jack Wetzels9, Eric Daugas10,11, Gabriella Moroni12,13,
Marina Noris14, Vincent Audard15,16, Manuel Praga17, Elisa Llurba18,19, Grégoire Wuerzner1,
Rossella Attini20, David Desseauve5, Elena Zakharova21,22, Claudio Luders23, Kate Wiles24,
Filomena Leone25, Shilpanjali Jesudason26,27, Nathalie Costedoat-Chalumeau28,29, Andrea Kattah6,
Virgilia Soto-Abraham30, Alexandre Karras31, Jai Prakash32, Liz Lightstone33,34, Pierre Ronco35,36,
Claudio Ponticelli37, Gerald Appel38, Giuseppe Remuzzi14, Vassilis Tsatsaris39,40 and
Giorgina Barbara Piccoli36
1
Service de Néphrologie et d’Hypertension, Département de Médecine, Centre Hospitalier Universitaire Vaudois, and Université de
Lausanne, Lausanne, Switzerland; 2Department of Medical Science and Public Health, University of Cagliari, Cagliari, Italy; 3Department
of Nephrology, San Michele Hospital, ARNAS G. Brotzu, Cagliari, Italy; 4Department of Cardiovascular Sciences, University of Leicester,
Leicester, UK; 5Gynaecology, Woman Mother Child Department of the Lausanne University Hospital (CHUV), Lausanne, Switzerland;
6
Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, USA;
7
Department of Obstetrics and Gynecology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA; 8National Institute of
Perinatology Isidro Espinosa de los Reyes (INPER), Department of Nephrology, Ciudad de Mexico, Mexico; 9Department of Nephrology,
Radboud University Medical Center, Nijmegen, the Netherlands; 10Service de Néphrologie, Hôpital Bichat and Université Paris Cité, Paris,
France; 11Institut national de la santé et de la recherche médicale Inserm U1149, Paris, France; 12Department of Biomedical Sciences,
Humanitas University, Milan, Italy; 13Nephrology and Dialysis Division, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS)
Humanitas Research Hospital, Milan, Italy; 14Istituto di Ricerche Farmacologiche Mario Negri, Istituto di Ricovero e Cura a Carattere
Scientifico (IRCCS), Laboratory of Immunology and Genetics of Rare Diseases, Bergamo, Italy; 15Université Paris Est Créteil, Institut
National de la Santé et de la Recherche Médicale (INSERM), Institut Mondor de Recherche Biomédicale (IMRB), Créteil, France; 16Assistance
Publique des Hôpitaux de Paris (AP-HP), Hôpitaux Universitaires Henri Mondor, Service de Néphrologie et Transplantation, Fédération
Hospitalo-Universitaire « Innovative therapy for immune disorders », Créteil, France; 17Department of Nephrology, Hospital Universitario
12 de Octubre, Complutense University Madrid, Madrid, Spain; 18Department of Obstetrics and Gynaecology, Institut d’Investigació
Biomèdica Sant Pau - IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Madrid, Spain; 19Primary Care Interventions to Prevent Maternal
and Child Chronic Diseases of Perinatal and Developmental Origin Network (RICORS), Instituto de Salud Carlos III, Madrid, Spain;
20
Department of Obstetrics and Gynecology, University of Turin, Città della Salute e della Scienza, Sant’Anna Hospital, Turin, Italy;
21
Nephrology, Moscow City Hospital n.a. Sergey Petrovich Botkin, Moscow, Russian Federation; 22Moscow State University of Medicine
and Dentistry, Moscow, Russian Federation; 23Centro de Nefrologia e Dialise, Hospital Sirio-Libanes, São Paulo, Brazil; 24Department of
Women’s Health, Barts Health NHS Trust, London, UK; 25Clinical Nutrition Unit, S. Anna Hospital, Città della Salute e della Scienza, Turin,
Italy; 26Central Northern Adelaide Renal and Transplantation Service (CNARTS), Royal Adelaide Hospital, Adelaide, South Australia,
Australia; 27Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, South Australia, Australia; 28Centre de Référence
Maladies Auto-Immunes et Systémiques Rares de l’île de France, Cochin Hospital, Université Paris Cité, Paris, France; 29Unité de l’Institut
national de la santé et de la recherche médicale (INSERM) Unité 1153, Center for Epidemiology and Statistics (CRESS), Paris, France;
30
Pathology Department, Hospital General de México Dr Eduardo Liceaga, México City, México; 31Paris University, Paris, France; Renal
Division, Georges Pompidou European Hospital, Paris, France; 32Department of Nephrology, Institute of Medical Sciences, Banaras Hindu
University, Varanasi, Uttar Pradesh, India; 33Imperial Lupus Centre, Department of Medicine, Imperial College London, London, UK;
34
Section of Renal Medicine and Vascular Inflammation, Department of Medicine, Imperial College London, London, UK; 35Sorbonne
Université, and Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche S1155, Paris, France; 36Department of
Nephrology, Centre Hospitalier du Mans, Le Mans, France; 37Independent Researcher, Milano, Italy; 38Division of Nephrology, Columbia
University Medical Center and the New York Presbyterian Hospital, New York, New York, USA; 39Maternité Port-Royal, Fédération
Hospitalo-Universitaire Prématurité (FHU PREMA), Assistance Publique des Hôpitaux de Paris AP-HP, Hôpital Cochin, AP-HP, Paris, France;
and 40Centre-Université de Paris, Université de Paris, Paris, France

Our understanding of the various aspects of pregnancy in

Correspondence: Fadi Fakhouri, Service de Néphrologie et d’Hypertension, women with kidney diseases has significantly improved in
Centre Hospitalier Universitaire Vaudois, Rue du Bugnon 17, 1003 Lausanne,
the last decades. Nevertheless, little is known about specific
Switzerland. E-mail: [email protected]; or Giorgina Piccoli, Department of
Nephrology, Centre Hospitalier du Mans, 194 Avenue Rubillard, 72037, Mans, kidney diseases. Glomerular diseases are not only a
France. E-mail: [email protected] frequent cause of chronic kidney disease in young women,
Received 26 July 2022; revised 10 October 2022; accepted 18 October but combine many challenges in pregnancy: immunologic
2022; published online 5 December 2022 diseases, hypertension, proteinuria, and kidney tissue

264 Kidney International (2023) 103, 264–281

F Fakhouri et al.: Glomerular diseases in pregnancy review

damage. An international working group undertook the in pregnancy, thus limiting detection of GD in pregnancy.
review of available current literature and elicited expert With these caveats in mind, GDs identified before or during
opinions on glomerular diseases in pregnancy with the aim pregnancy are likely to be underestimated, particularly in low-
to provide pragmatic information for nephrologists to middle-income countries, where kidney function testing
according to the present state-of-the-art knowledge. This may be limited, although CKD prevalence is high.9–11
work also highlights areas of clinical uncertainty and General population data indicate that 3% to 6% of women
emphasizes the need for further collaborative studies to of child-bearing age have CKD9, up to 3% of women with
improve maternal and fetal health. CKD are of child-bearing age,12 and up to 3.3% of pregnant
women have laboratory evidence of CKD.13 In an Australian
Kidney International (2023) 103, 264–281; https://doi.org/10.1016/
j.kint.2022.10.029 study, 0.3% of pregnant women had a kidney diagnostic code,
KEYWORDS: fetal complications; glomerular diseases; immunosuppressive
but only 0.01% had an identified immunologic disease or
drugs; kidney biopsy; pregnancy GD,14 likely reflecting poor identification of GD in pregnancy.
Copyright ª 2022, International Society of Nephrology. Published by Early GD may influence pregnancy outcomes but can be
Elsevier Inc. All rights reserved. missed in pregnancy and only diagnosed later in life. A study
of Norwegian women who had a kidney biopsy at any time
after their last pregnancy found that those who had a history

W
of preterm birth or preeclampsia had higher rates of focal
omen with various chronic diseases often consider
segmental glomerular sclerosis (FSGS), crescentic glomeru-
successful pregnancy as a demonstration of having
lonephritis, or anti-neutrophil cytoplasm antibody vasculitis,
regained a “normal” life. This applies to women
compared with women who had a normal pregnancy.15 A
with chronic kidney diseases (CKDs)1,2 and particularly to
high prevalence of GD in preeclamptic patients likewise was
those with glomerular diseases (GDs).
recently reported in Denmark16 and Italy.17 Preeclampsia may
Clinical approaches toward pregnancy in the setting of
be the first sign of a GD, usually diagnosed in the first few
kidney diseases have changed in the last few decades. Preg-
years postpartum, or it may represent one hit in a multiple-
nancy in this population was previously discouraged because
hit pathogenesis of a GD diagnosed later in life.
of concern over maternal complications and unfavorable fetal
Among the GDs diagnosed by kidney biopsies in preg-
outcomes. A significant driver of this change has been the
nancy or in the postpartum period, the most common ones
progress in perinatal care and the management of pregnancy
are FSGS, IgA nephropathy (IgAN), and LN.18,19 Other GDs
in patients with advanced CKD, and those on dialysis.3
are rare, but most of them have been reported in pregnancy.16
However, the acknowledgement of the importance of even
Much more is known about the prevalence of GDs in
minor kidney involvement before, or during, pregnancy,
pregnant women on renal replacement therapy: 35% to 56%
including kidney stones, previous episodes of acute kidney
of women on chronic dialysis or those having received a
injury, kidney donation, or GD even in remission, has
kidney transplant have a GD as their primary renal
broadened the definition of “high-risk pregnancies.”4–6
disease.20,21
Although evidence as to the importance of kidney function
and of kidney adaptation to pregnancy is increasing, little is
known about specific kidney diseases. GDs, which frequently TOOLS FOR THE DIAGNOSIS AND MONITORING OF GDs IN
affect young patients, are particularly relevant in this context. PREGNANCY
Autoimmune-mediated GDs may be affected by the hor- In patients with a GD, as for any pregnancy, the urinary tract
monal milieu in many pregnancies, the prototype of this undergoes substantial hemodynamic adaptations during
being lupus nephritis (LN). GDs may also appear, be initially gestation.22 These changes (Supplemental Table S1) include a
diagnosed, or flare during pregnancy, and subsequent therapy decrease in kidney vascular resistance, an increase in kidney
is often limited by the actual risk or concern for fetal toxicity. blood flow, and a concomitant increase in glomerular filtra-
An international working group undertook a review of the tion rate (38%–56% increase in creatinine clearance23), by the
current literature and expert opinion on GDs in pregnancy first trimester of pregnancy.
with the aim to provide pragmatic information for nephrol- There is currently no widely accepted formula for the
ogists, helpful particularly for the preconception counseling estimation of kidney function in pregnancy. Some authors
of patients, while highlighting areas of clinical uncertainty consider urinary creatinine clearance as the gold standard24—
and debate. and adding 24-hour urine collection allows for a better
assessment of proteinuria. Others recommend evaluating
EPIDEMIOLOGY: WHAT ARE WE TALKING ABOUT? kidney function using serum creatinine concentration and
Robust data defining the prevalence and type of GDs in suggest that serum creatinine concentration >85% (76 mmol/
pregnancy are not available. This is mainly due to variations L), 80% (72 mmol/L), and 86% (77 mmol/L) of the
in capturing and reporting of data on GDs in pregnancy7,8 nonpregnant upper limit of normal in the first, second, and
and the heterogeneity in the study populations and types of third trimester, respectively, should be considered abnormal
studies. There is also a lack of routine kidney function testing in pregnancy25,26 (Supplemental Table S2).

Kidney International (2023) 103, 264–281 265

review F Fakhouri et al.: Glomerular diseases in pregnancy

Staging of CKD in pregnant patients with a GD should be due to their heterogeneity. Pregnancy outcomes have been
based on prepregnancy values, whenever possible.25 The more extensively studied in the most common GDs (namely,
absence of an early decrease in serum creatinine during IgAN or LN), but the general aspects of management prob-
pregnancy compared with prepregnancy concentrations has ably apply to all types of GDs.5 The main pregnancy-
been proposed as a poor prognostic marker of renal function associated adverse events associated with CKD, including
outcome.27 Glomerular hyperfiltration, however, has not been GDs, are summarized in Supplemental Table S3.
associated consistently with better pregnancy-related out- Several studies have assessed pregnancy outcomes in
comes, at least during the early stages of CKD.28 Longitudinal women with GDs, including pregnancies that occurred be-
kidney function (e.g., decrease of estimated glomerular tween the 1960s and late 1990s. The findings of these studies
filtration rate in midterm) in pregnancy may be as relevant as may not reflect the current risks, as they do not consider the
the baseline absolute values.29–31 marked improvements in the management of pregnancy and
As with estimated glomerular filtration rate estimations, of GDs.
there is no consensus regarding the best method for assessing As for maternofetal outcomes excluding kidney function,
proteinuria in pregnancy. Use of the spot urinary protein-to- GDs generally seem to be associated with a higher risk of
creatinine ratio (UPCR) is usually preferred to timed urine adverse pregnancy events compared with patients with other
collections because of the possibility of underestimation,32 types of kidney diseases. This increased risk even applies to
variability,33 and inconvenience, and the potential for treat- women with a GD and CKD stage 1, mild proteinuria (<1 g/
ment delay with the latter. The UPCR is practical for 24 h), or normal blood pressure (i.e., a GD in complete
screening for hypertensive disorders of pregnancy, for which clinical remission). Pregnancy outcomes in these patients are
new onset of proteinuria (UPCR >30 mg/mmol) is still one similar to those of women with kidney transplantation.5,38
discriminating parameter between preeclampsia and gesta- Conversely, with respect to kidney function, women with
tional hypertension. The limitations of spot UPCR or urinary a GD and normal kidney function before pregnancy do not
albumin-to-creatinine ratio are well acknowledged. The have a clearly increased risk of kidney function impairment
recently proposed option of calculating the UPCR and/or during or after pregnancy, even in the long-term, compared
urinary albumin-to-creatinine ratio from a 16- to a 24-hour with nonpregnant women with a GD. This finding has
urine collection may be utilized in pregnant patients with been documented particularly in women with IgAN39,40
GDs.34 The approach balances the advantages of a 24-hour and LN.41,42
urine collection with the practical constraints of this test
(Supplemental Table S1).34 How should women with GD and CKD starting a pregnancy be
Considering the limitations of the indirect methods, and monitored?
the advantages of a precise quantification of kidney function The frequency of kidney function testing is not clearly
and of proteinuria in pregnancy, a working compromise established in pregnant women with a GD. A flowchart
would be to rely, when feasible, on the gold standard, based adapted from recent recommendations from the Italian
on 24-hour urine collection, while acknowledging that in Study Group on Kidney and Pregnancy43 is shown in
some cases surrogate estimations of kidney function (esti- Figure 1.
mated glomerular filtration rate, serum creatinine, and trends One critical point is how to distinguish GD worsening
in UPCR, if possible, on extended-hour urine collections) from preeclampsia. This differential diagnosis is particularly
provide reliable information for the clinical management of challenging because of the heterogeneity of preeclampsia and
patients. its frequent association with all kidney diseases, including
Similarly, what represents a significant increase in pro- GD.44–47 Recent evidence linking preeclampsia to an
teinuria during pregnancy in women with a preexisting GD angiogenic-antiangiogenic imbalance48 has led to the clinical
has not been established; doubling of proteinuria compared use of various biomarkers to predict the occurrence of pre-
with prepregnancy values has been previously used in eclampsia.49 The measurement of the soluble fms-like tyro-
research cohorts.5,35,36 sine kinase 1/placental growth factor ratio is increasingly
being recommended, but its cost-effectiveness remains to be
fully assessed.50 A limited number of studies have assessed the
RISK EVALUATION FOR PREGNANCY, THE WOMAN, AND THE soluble fms-like tyrosine kinase 1/placental growth factor
FETUS IN PATIENTS WITH A KNOWN GD ratio in pregnant women with CKD of various causes. This
Three major determinants of pregnancy-related outcomes are ratio is generally within the normal range in cases of pure
identified: kidney function impairment—the most extensively worsening of preexistent CKD but is increased in the case of
studied and probably the most important factor—protein- preeclampsia.51,52 The interpretation of an alteration in the
uria, and hypertension.5,37 Their effects are most likely also soluble fms-like tyrosine kinase 1/placental growth factor
modulated by the type of kidney disease. ratio should be made with caution, as preeclampsia may be
Little is known regarding the effects that different types of superimposed on CKD. The levels are usually intermediate in
GDs have on pregnancy outcomes. This is probably mainly this setting, but this finding is nonspecific.52–54 Low placental

266 Kidney International (2023) 103, 264–281

F Fakhouri et al.: Glomerular diseases in pregnancy review

Glomerular diseases: CKD stages 4–5 or

for tests and CKD stage 1, previous CKD stage 2, or CKD stage 3 or previous stages with
follow-up during GN in remission, no stage 1 with either previous stages with proteinuria > 3 g
pregnancy proteinuria, normal mild hypertension or resistant hypertension or worsening of
blood pressure proteinuria 0.3–1 g or proteinuria <3 g kidney function

Minimum follow-up 4–6 wk 4 wk 2–3 wk 1–2 wk

Every 4–6 weeks: Serum:

sodium, potassium, calcium,
phosphorus, albumin, creatinine,
urea, uric acid. As for stage 1,
Urine: creatinine, albumin, As for stage 1, As for stage 1,
frequency monthly 24-h 24-h urine
Main biochemical protein (12–16 h collection), collection twice
urinary culture increased urine collection
tests prescribed to 4 wk monthly if
Every 10–12 wks: if possible
possible
creatinine clearance and 24 h
proteinuria if possible;
immunologic tests
as per kidney disease

Imaging Renal ultrasound if not

As for stage 1 As for stage 1 As for stage 1
performed in the previous year

Nutritional parameters at start: As for stage 1, As for stage 1, As for stage 1,

Other ferritin, vitamins D and B12, folate, every 10–12 monthly in patients monthly in patients
albumin, total protein wk on specific diets on specific diets

Figure 1 | Proposed follow-up of patients with glomerular disease (GD) during pregnancy. CKD, chronic kidney disease.

growth factor concentrations in isolation also have predictive No clear definition of nephrotic syndrome in pregnancy,
and diagnostic utility in preeclampsia, and cost-effectiveness particularly the degree of hypoalbuminemia, exists. As serum
has been shown in general obstetric cohorts.55,56 The albumin gradually decreases from the beginning of pregnancy
threshold for distinguishing preeclampsia is, however, higher (mainly due to hyperhydration),57 we suggest the use of a
in women with CKD, with the clinical manifestation of pre- modified definition of nephrotic syndrome, whereby serum
eclampsia hypothesised to occur at lower levels of placental albumin below the lower limit of normal for gestational age
dysfunction when the endothelium is primed by CKD.36 (Supplemental Table S2)57 and proteinuria >3 g/d are sug-
Severely impaired uteroplacental Doppler flows also indi- gestive of nephrotic syndrome. Severe nephrotic syndrome
cate placental involvement, commonly associated with intra- would be defined by a serum albumin <50% of the lower
uterine growth restriction, whereas worsening of kidney limit of normal.
disease is usually associated, in the absence of hypertension, The workup of a patient with nephrotic syndrome and/or
with preserved fetal growth.43 subacute/acute kidney injury aims to predict the underlying
The simplest and perhaps most simplistic way to make a kidney disease and, thus, start probabilistic treatment, based
differential diagnosis between preeclampsia and GD after on patient history, clinical status (presence of extrarenal
delivery is based on the persistence of proteinuria and hy- manifestations suggestive of systemic disorders), and biolog-
pertension beyond 3 months postpartum. The absence of ical tests (mainly autoantibodies and complement assays;
proteinuria, however, does not fully rule it out. Supplemental Tables S4 and S5). Kidney biopsy may be
considered if the diagnosis remains questionable (Figure 2).
DIAGNOSTIC ISSUES IN PATIENTS WITH DE NOVO GD, WITH
PARTICULAR EMPHASIS ON KIDNEY BIOPSY When should a kidney biopsy be performed in pregnancy?
Three distinct situations may be encountered during preg- A kidney biopsy is generally considered in pregnancy when
nancy in women with no history of GD who present with progressive kidney function impairment and/or severe pro-
renal function abnormalities suggestive of GD: (i) detection of teinuria could interfere with pregnancy outcomes, and when
proteinuria and/or hematuria with preserved kidney function, establishing a diagnosis is needed to determine treatment
(ii) diagnosis of nephrotic syndrome, and (iii) occurrence of (Table 150,58–63 and Figure 2).
subacute or acute kidney injury with proteinuria or nephrotic Although an increased bleeding risk is reported in older
syndrome. series, recent data suggest that the procedure may be safe in
The diagnostic approach to these 3 situations is summa- experienced hands.59,60 Furthermore, pregnancy is a valu-
rized in Figure 2. able occasion to diagnose GD using kidney biopsy, in

Kidney International (2023) 103, 264–281 267

review F Fakhouri et al.: Glomerular diseases in pregnancy

Renal abnormalities discovered during pregnancy

Present in up to 20% of Monitor kidney function and proteinuria in pregnancy

a Isolated microscopic hematuria healthy pregnant women Control at least 2–3 mo postpartum

b Nonnephrotic proteinuria Nephrotic syndrome Subacute/acute kidney injury

Clinical status (extrarenal manifestations suggestive of systemic disorders?)

Serum Anti-PLA2R Ab ANA Anti-dsDNA Ab C3 C4 CH50 AP 50

ANCA Anti-GBM Ab
Urine UPCR / UACR on 16- to 24- h urine sample; proteinuria selectivity

Severe nephrotic syndrome

Symptomatic treatment

Nutritional management Diuretics Thrombosis prevention

Consider: Avoid overzealous treatment Stockings
(1) Na+ intake reduction Accept some edema Consider:
<4 g/d Prevent blood pressure (1) Aspirin up to 34 GW
(2) Water restriction (especially <110/70 mm Hg (2) Anticoagulation (low-
if severe hyponatremia) molecular weight heparin) or
Loop diuretics
(3) Protein restriction, plant- ± hydrochlorothiazide (3) Aspirin + low-molecular weight heparin
based diets or amiloride especially if serum albumin < 20–25 g/L

Serum albumin < 20 g/L Can the diagnosis of the underlying kidney (glomerular)
Diuretic-resistant edema disease be predicted with high accuracy based on
history and/or clinical status and/or biomarkers results?

Yes No

Consider a short trial of pregnancy-compatible IS Consider kidney biopsy if its results would
modify the patient’s management and/or
if eGFR declines under treatment. After
Impairment in renal parameters; 30 GW, balance the risks of kidney biopsy with
according to the week of pregnancy those of delivery first and biopsy postpartum

Figure 2 | Management of patients with renal abnormalities suggestive of a glomerular disease discovered during pregnancy. Ab,
antibody; ANA, antinuclear antibody; ANCA, anti-neutrophil cytoplasm antibody; AP 50, alternative pathway activity 50%; CH50, complement
hemolytic activity 50%; dsDNA, double-stranded DNA; eGFR, estimated glomerular filtration rate; GBM, glomerular basement membrane; GW,
gestation weeks; IS, immunosuppressive treatment PLA2R, phospholipase A2 receptor; UACR, urinary albumin-to-creatinine ratio; UPCR, urinary
protein-to-creatinine ratio.

several low- but also high-income countries.11,64 However, without charge.65 For instance, the only series published in
in clinical practice, a kidney biopsy is rarely necessary in the last 5 years, from the largest referral center for
pregnancy, due to the rarity of the diagnosis of de novo complicated pregnancy in Mexico, encompasses only 20
disease or presumably GD, the availability of alternative kidney biopsies performed over a period of 5 years.66
diagnostic options, but also to late referral, because
inducing delivery may be considered as a valuable alter- MANAGEMENT OF SPECIFIC GDs IN PREGNANCY, INCLUDING
native in late gestation, at least in highly resourced settings KNOWN AND DE NOVO FORMS
in which specialized perinatal care is widely available This management refers to 2 distinct situations.

Table 1 | Considerations regarding the use of kidney biopsy in pregnant women

Kidney biopsy in pregnant women
(i) Clinicians are usually reluctant to perform a kidney biopsy during pregnancy. This is because of the increased risk of complications, estimated in a
systematic review to be as high as 7%, compared with 1% after delivery (2% risk of major bleeding in the late second trimester58). The bleeding risk
has been attributed to the increase in kidney blood flow and is thought to be reversible within z3 months after delivery.
(ii) More recent reports indicate that the risks of a kidney biopsy during pregnancy are minor when performed by an experienced physician and suggest
that this procedure may be more frequently considered.59,60
(iii) The availability of laboratory tests, including the characterization of proteinuria, antibody workup for LN, ANCA, and anti-PLA2R antibodies, or the
presence of highly selective proteinuria, may lead first to empiric treatment with postponement of biopsy to the postpartum period (Figure 1).
(iv) A normal ratio of soluble fms-like tyrosine kinase 1/placental growth factor may be useful in ruling out severe or superimposed preeclampsia.50,61
(v) Timing is crucial when considering kidney biopsy. In early pregnancy (<12 weeks), the risks of kidney biopsy are relatively low, and the advantages
of precisely knowing the kidney disease are high. This profile of risks changes throughout pregnancy and may decrease after 30 to 34 weeks.
(vi) In some countries in which the health care system covers pregnancy but not later follow-up, the importance of establishing a clear diagnosis to
guide subsequent therapy may outweigh the risks of kidney biopsy.
(vii) In kidney transplantation, the technically easier access to the grafted kidney may positively affect the risk-to-benefit ratio. In this context, the
differential diagnosis includes graft rejection, recurrence, or a de novo glomerular disease and preeclampsia.62,63
ANCA, anti-neutrophil cytoplasm antibody; LN, lupus nephritis; PLA2R, phospholipase A2 receptor.

268 Kidney International (2023) 103, 264–281

F Fakhouri et al.: Glomerular diseases in pregnancy review

Table 2 | Obstetrical considerations regarding pregnancy in women with GDs

An obstetric perspective of GD in pregnancy

(i) The main obstetric risks are not specific to GD, as they include preeclampsia, preterm delivery, and intrauterine growth restriction.67 The risk of
intrauterine death is also increased, particularly in women with lupus nephritis, diabetic nephropathy, and other systemic immunologic diseases.68
(ii) The severity of preeclampsia is variable; although it may be particularly severe, requiring early therapeutic termination of pregnancy for maternal
rescue at a nonviable gestation or fetal weight, preeclampsia superimposed on GD typically occurs late in pregnancy and is associated with
relatively well-preserved fetal growth, thus being considered by some authors as the hallmark of “maternal” preeclampsia.36,69
(iii) Changes in proteinuria and blood pressure in patients with GD are not necessarily linked to preeclampsia, and may reveal flares of the underlying
disease or, as for proteinuria, may be indicative of hyperfiltration stress. The differential diagnosis may be difficult (see dedicated section).
(iv) The risks for offspring are mainly linked to preterm delivery, which does not only occur in the context of preeclampsia. The reason for this increase is
not clear. The risk of intrauterine growth restriction is also increased, particularly in women with hypertension. Further risks (namely, neonatal unit
admissions and perinatal death) are essentially linked to preterm delivery and its consequences, and severe growth restriction.
(v) Ultrasound screening for fetal growth retardation should be performed monthly, as for other pregnancies at risk for fetal growth restriction. The
frequency of using Doppler ultrasounds should be tailored on the basis of the presence and severity of abnormalities.
(vi) Obtaining available biomarkers to determine the angiogenic-antiangiogenic balance may assist in clinical management; however, their use in this
context is not validated and, because of the heterogeneity of GD in pregnancy, strict surveillance by a skilled multidisciplinary team is the best way
to prevent or attenuate severe complications in these high-risk pregnancies.
(vii) The use of low-dose aspirin prophylaxis is currently a standard of care in all pregnancies at risk for PE, including those in women with GD.70 Early
start (<12 gestational weeks) is indicated to warrant efficacy; treatment is stopped between 34 and 36 gestational weeks, or in the presence of risk
conditions for imminent delivery.
(viii) Vitamin D deficiency should be corrected.71,72
GD, glomerular disease; PE, preeclampsia.

The diagnosis of GD is made before pregnancy duration of remission, and is low after 6 years of relapse-free
In this setting, prepregnancy multidisciplinary counseling and follow-up.73,74
pregnancy planning are highly recommended. Multidisci- Although data are limited, relapse of MCD during preg-
plinary counseling should provide individualized information nancy has been reported in some old series75 and in recent
from both the nephrological and the obstetric perspectives case reports.76 The risk of relapse is likely higher in patients
(Tables 236,67–72 and 3 and Figure 3) about pregnancy-related with corticosteroid-dependent MCD who are on maintenance
risks for the mother (relapse/worsening of her GD and CKD, immunosuppressive therapy (as in nonpregnancy patients).
need for dialysis, and risk of hypertensive disorders of preg- According to limited evidence, relapses are usually controlled
nancy) and for the offspring (Supplemental Table S3). Preg- by corticosteroids, and pregnancy outcomes are generally
nancy planning allows for treatment optimization, notably favorable. The best schedule of corticosteroid treatment for
discontinuation of drugs that are contraindicated in pregnancy. MCD/FSGS has not been fully established and should prob-
ably be determined on a case-by-case basis. Both bolus ste-
The diagnosis of GD occurs during pregnancy roids77 (methylprednisolone, 0.5–1 g intravenously, usually 3
Management should consider the uncertainties surrounding administrations) and oral steroids (0.5–1 mg/kg per day) have
the diagnosis if the latter is not supported by a kidney biopsy been used.76 A regimen of boluses followed by intermediate
(Figure 4). General aspects of the management of severe daily (or alternate days) oral doses may be considered, espe-
proteinuria–nephrotic syndrome during pregnancy are shown cially in women with risk factors (overweight, preexisting or
in Figure 2. gestational diabetes, or hypertension).
Minimal change disease and FSGS. Data from case series Calcineurin inhibitors are an alternative, but they require
(published since 2000) and case reports regarding pregnancy frequent monitoring of blood drug levels and screening for
in patients with minimal change disease (MCD) and FSGS are gestational diabetes.
summarized in Supplemental Tables S6 and S7. In more recent reports of selected cases of MCD with high
Pregnancy in a patient with a history of MCD or of FSGS. In recurrence rates,78,79 pregnancy outcome was favorable with
nonpregnant patients, the risk of relapse decreases with maintenance rituximab therapy.

Table 3 | Practical recommendations for the counseling of women with GD who plan or start a pregnancy
(i) Take into account the woman’s wish during the counseling, in a shared decision approach.
(ii) Integrate psychological aspects of pregnancy in women with GD, which are at least as important as medical aspects.
(iii) Individualize the assessment of pregnancy risks to the patient’s clinical and biological features.
(iv) Give as much as possible an objective assessment of the risk of adverse pregnancy outcomes and progression of CKD. Highlight the areas of un-
certainty, the individual response, as well as the lack of available precise data stratified per kidney function, degree of proteinuria and hypertension,
and type of GD.
(v) In women with eGFR <30 ml/min at the start of pregnancy, discuss the issue of potential dialysis need, during pregnancy or shortly after delivery.
(vi) Explain the need to adapt treatment before/at the start of pregnancy and the therapeutic options in case of potential relapse/exacerbation of GD
during pregnancy.
(vii) Discuss the potential need for induced/premature delivery and prematurity-related complications for the newborn.
CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; GD, glomerular disease.

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review F Fakhouri et al.: Glomerular diseases in pregnancy

Patient with history of a glomerular disease

Prepregnancy counseling

Take into consideration positivity/titer

MN
of anti-PLA2R Ab
(1) Assess disease history
and current status Assess lupus activity with clinical and
LN biological parameters, including complement
dosage but not anti-dsDNA Ab titer

Remission >12–18 mo Remission <12–18 mo Active NS

No IS Current IS Deteriorating renal function
Remission <6 mo

Low added risk Medium added risk High added risk

Discuss risk of relapse/treatment options

Advise against pregnancy
Use induction IS

(1) Reassess maintenance IS and remove teratogenic drugs before pregnancy or at the latest
at positive pregnancy test for ACEI/ARB, and replace them by compatible treatments. Reassess if remission achieved
(2) Achieve a blood pressure target 130/80 mm Hg
(3) Discuss CKD-related risks and motivation/risk ratio accordingly.
All CKD stages carry a risk for pregnancy.

3-mo Follow-up

Check that conditions for a safe pregnancy remain after treatment adaptation
(ideally, UPR <500 mg/g for the preceding 6 mo, normal eGFR)

Add low-dose aspirin (ideally <12 GW)

Figure 3 | Prepregnancy counseling and assessment of a woman with a glomerular disease. Ab, antibody; ACEi, angiotensin-converting
enzyme inhibitor; ARB, angiotensin receptor blocker; CKD, chronic kidney disease; dsDNA, double-stranded DNA; eGFR, estimated glomerular
filtration rate; GW, gestation weeks; IS, immunosuppressive treatment; LN, lupus nephritis; MN, membranous nephropathy; NS, nephrotic
syndrome; PLA2R, phospholipase A2 receptor; UPR, urinary protein/creatinine ratio.

The spectrum of FSGS is broad, and the risks of adverse preeclampsia.86–90 Collapsing lesions are probably much less
pregnancy outcomes are presumably moderate in the presence of frequent. Interestingly, in some reports, FSGS diagnosed in
mild proteinuria, whereas pregnancies with corticosteroid- pregnancy may respond well to treatment, even in the
resistant FSGS with persistent heavy proteinuria/nephrotic presence of severe, collapsing lesions, and these observa-
syndrome and/or CKD are at higher risk for maternal and fetal tions plead for a proactive attitude toward treatment of
complications. In the absence of a large series, and with the FSGS in pregnancy.91
heterogeneity of the disease, a case-by-case strategy is suggested. Membranous nephropathy (MN). Data from series (pub-
The placental transmission of an unknown glomerular lished since 2000) and case reports regarding pregnancy in
permeability factor from the mother with MCD or FSGS to patients with MN are summarized in Supplemental Tables S8
the newborn, leading to transitory nephrotic syndrome, has and S9.
been reported,80–82 but breastfeeding is not contraindicated. The identification of several pathogenic autoantibodies has
MCD or FSGS diagnosed in pregnancy. The occurrence of de radically transformed the diagnosis and management of MN,
novo MCD or FSGS during pregnancy is a rare event.83–85 Its including during pregnancy.92,93 Most recently reported pa-
actual incidence has not been established. The diagnosis of tients with MN in pregnancy have anti–phospholipase A2
MCD/FSGS is often presumed in the absence of kidney bi- receptor (PLA2R) antibodies.94–96 Other autoantibody speci-
opsy, mainly based on the selectivity of proteinuria, its abrupt ficities are rare in this setting, with a single reported case with
onset, and, in the most favorable cases, a prompt response to anti-thrombospondin type-1 domain-containing 7A anti-
corticosteroids (Box 1, case 184). Therapeutic options are bodies.97 Lupus-related MN is covered in another chapter.
similar to those used for recurrences during pregnancy. Rit- Pregnancy in women with a history of MN. The existing
uximab may represent a rescue therapy in patients with literature on pregnancy in women with MN is extremely
corticosteroid- and calcineurin inhibitor–resistant MCD/ dated,98,99 with the exception of a recent publication from
FSGS. Beijing, China.95 Two series that included pregnancies occur-
The diagnosis of FSGS in pregnancy may be challenging, ring in the 1970s and 1980s reported poor maternal and fetal
as FSGS lesions are among the most common lesions found outcomes (24%–35% fetal loss; prematurity rate of 30%–43%)
in kidney biopsies of women with a history of mainly due to first-trimester spontaneous abortions, in patients

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F Fakhouri et al.: Glomerular diseases in pregnancy review

Immunosuppressive treatment options for GD in pregnancy

Maintenance treatment of a GD Relapse/worsening of GD De novo GD during

known before pregnancy during pregnancy pregnancy

A kidney biopsy may (rarely) be considered if the

presentation is atypical for a given GD.

MN IgAN C3G LN
MCD/FSGS Ig-MPGN
Maintenance therapy
CS CNI CS CS
CS + CNI Continue maintenance IS
CNI CNI CNI
Do not reinitiate maintenance IS in case
AZA AZA AZA of lasting remission without IS

HCQ CS AZA CNI

Induction therapy
Start urgent therapy as an alternative to therapeutic
termination of pregnancy up to 16–20 GW.
Rescue treatment to be discussed
Priority is not LN remission, but its containment to
on a case-by-case basis allow pregnancy continuation (fetal growth/maturation)
as far as possible.

First: AZA(1.5–2 mg/kg per day)

AZA+ CNI
CS MP Second: CNI*
CSA (trough level 70–100 mg/L)
+ mandatory IS
TAC (trough level 5–7 mg/L)
Third: RTX (if no more appropriate
alternative; first trimester).
HCQ continued

Maintain tight follow-up as LN flare risk

is high in the 6 mo postpartum.
Maintain maintenance IS ≥6 mo postpartum.

Figure 4 | Management during pregnancy of patients with a known relapsing or de novo glomerular disease (GD). AZA, azathioprine;
C3G, C3 glomerulopathy; CNI, calcineurin inhibitor; CS, corticosteroids; CSA, cyclosporin A; FSGS, focal segmental glomerular sclerosis; GW,
gestation weeks; HCQ, hydroxychloroquine; IgAN, IgA nephropathy; Ig-MPGN, Ig-associated membranoproliferative glomerulonephritis; IS,
immunosuppressive treatment; LN, lupus nephritis; MCD, minimal change disease; MN, membranous nephropathy; MP, methylprednisolone;
RTX, rituximab; TAC, tacrolimus.

who were hypertensive or nephrotic (or both) at conception or strict monitoring should be offered. Calcineurin inhibitors are
early in gestation.100,101 Kidney function deteriorated in a recommended as first-line therapy for their immunosuppres-
single patient whose creatinine clearance was <48 ml/min at sive effects and rather rapid anti-proteinuric effect102 in the
conception. context of pregnancy-related glomerular hyperfiltration.
In the most recent Chinese series of 27 pregnancies in 25 Cyclophosphamide and anti-CD20 antibodies,102,103 which are
women,95 10 adverse maternal-fetal events occurred, including characterized by a delayed clinical response observed outside
fetal loss (11%), preterm delivery (26%), and severe pre- pregnancy, represent a rescue treatment in patients who do not
eclampsia (15%). Heavy proteinuria, especially before the 20th respond to calcineurin inhibitors.
week of gestation, severe hypoalbuminemia, presence of anti- Monitoring should include repeated assessment of anti-
PLA2R antibodies, and absence of remission during preg- PLA2R antibodies in the mother.94 In the absence of spe-
nancy were risk factors for adverse maternal-fetal outcomes. cific guidelines, we recommend adjusting treatment according
If the patient is proteinuric with an immunologically active to the clinical situation, while taking into account the level of
disease (presence of high-titer anti-PLA2R antibodies), autoantibodies.
remission should be achieved with immunosuppressive treat- MN diagnosed during pregnancy. Few cases of de novo
ment. If an anti-CD20 antibody is used, the manufacturer’s PLA2R-associated MN diagnosed during pregnancy have
recommendation is that conception should be avoided for 6 to been published,94,96 and diagnosis is usually based on the
12 months after the last infusion, although the data reporting positivity of autoantibodies. However, if a kidney biopsy is
fetal toxicity are weak and sparse (see dedicated section). performed, immunostaining of the paraffin-embedded biopsy
In the event of an unplanned pregnancy in the setting of with different specific antibodies may allow identification of
nephrotic syndrome, if, after being provided with extensive the causal antigen. Regardless of the results of serology, rec-
information, the patient still wishes to continue her pregnancy, ommendations for treatment are driven by the severity of the

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review F Fakhouri et al.: Glomerular diseases in pregnancy

Box 1 | Case 1

A 20-year-old woman was referred at 24 WG of her first pregnancy because of visual blurring and oliguria, and was found to have proteinuria (3.7 g/
d), low serum albumin (23 g/L), and mild hypertension (140/95 mm Hg). She had gained 10 kg since the start of pregnancy, and leg edema was
present. Urinalysis at the beginning of pregnancy was normal. Hematuria (20 RBCs per HPF) was found on urinalysis; proteinuria was mainly
composed of albumin. The fetal biometry was at the 50th centile, and uteroplacental Doppler flows were normal. Proteinuria rapidly remitted, and
BP normalized following betamethasone treatment to favor lung maturation.
Differential diagnosis
In favor of preeclampsia: Diagnostic criteria (proteinuria, edema, and hypertension) with onset after the 20th gestational week.
Suggesting a different diagnosis: Normal Doppler flows and fetal growth. BP and urine output normalization after steroid pulses. Selective proteinuria.
Not relevant for differential diagnosis: Microscopic hematuria (occasionally present in up to 20% of non-CKD pregnancies).
Indication for further tests
Kidney biopsy: Pro: gold standard for diagnosis. Cons: period of gestation; response to steroids.
Soluble fms-like tyrosine kinase 1/placental growth factor ratio: Pro: normal values make preeclampsia unlikely. Con: not formally validated in the
differential diagnosis between CKD and preeclampsia.
Clinical development
Treatment with oral steroids was started (prednisone, 0.5 mg/kg per day) and slowly tapered, attaining complete remission. Spontaneous labor
occurred at term, with delivery of a healthy female baby, adequate for gestational age.
Comments
This case is paradigmatic of the presentation of nephrotic syndrome, probably related to minimal change disease (rapid response to
steroids and selective proteinuria) in pregnancy. Although a kidney biopsy is not formally contraindicated, the bleeding risks may be
increased, and the prompt response to steroids concomitantly prescribed to improve fetal lung maturation was believed to be sufficient
to guide treatment. No specific recommendation for steroid dosing in pregnancy is available (boluses or oral, initial dose). The use of
serum biomarkers of preeclampsia may support the differential diagnosis but may be altered in forms of superimposed preeclampsia,
even if this often occurs later in pregnancy. Normal fetal growth makes early preeclampsia unlikely. The frequency of controls is also not
established (the available suggestions to perform a clinical control at least monthly may be hard to follow in
low-resourced settings).
BP, blood pressure; CKD, chronic kidney disease; HPF, high-power field; RBC, red blood cell; WG, weeks of gestation.
Adapted from Montersino B, Menato G, Colla L, et al. A young woman with proteinuria and hypertension in pregnancy: is what looks and smells like preeclampsia always
preeclampsia? J Nephrol. 2021;34:1677–1679.84

nephrotic syndrome. Treatment options in patients with weight for gestational age in 10% to 30% of new-
MN and severe nephrotic syndrome are shown in Figures 2 borns.19,47,99,108–113 The grim prognosis reported in relatively
and 4. old studies may simply reflect the severity of kidney disease and
Transplacental transfer of PLA2R antibodies from the the high frequency of nephrotic syndrome.19,99,113 No recent
mother to the fetus has been reported. The concentration of series have specifically addressed the outcomes of pregnancy in
autoantibodies, however, was much lower in cord blood, and women with C3G and Ig-MPGN. There are no published data
the newborns were free of proteinuria at birth and at later supporting the role of pregnancy in the exacerbation of com-
visits. The transfer of PLA2R antibodies into breast milk has plement activation and, thus, of the clinical and pathologic
also been reported, with decreased levels of antibodies in the activity of C3G and Ig-MPGN.
child when breastfeeding was discontinued. Pregnancy, nonetheless, should be carefully planned in
In neonatal MN caused by anti–neutral endopeptidase patients with C3G and Ig-MPGN, ideally with mild forms of
antibodies, mothers do not develop a GD as they lack the these GDs or during a phase of clinical remission. For patients
neutral endopeptidase target antigen. MN in neonates is with clinical or laboratory worsening of the kidney disease
transient because maternal antibodies are short lived, but a during pregnancy (increased proteinuria, declining kidney
few neonates develop severe MN with acute kidney injury that function, or nephrotic syndrome), treatment options include
may require plasma exchange to decrease antibody titer.104 oral corticosteroids, methylprednisolone pulses, azathioprine,
Primary Ig-associated membranoproliferative glomerulone- and calcineurin inhibitors (Figure 4). A kidney biopsy should
phritis and C3 glomerulopathy in pregnancy. be considered on a case-by-case basis, particularly to assess
C3 glomerulopathy and Ig-associated membranoproliferative the respective contributions of chronic/fibrotic lesions and
glomerulonephritis known before pregnancy. Most of the studies acute/inflammatory changes in the decline of kidney func-
describing the outcomes of pregnancy in patients with mem- tion.35 In patients with crescentic, rapidly progressing C3G
branoproliferative glomerulonephritis (MPGN) were pub- and Ig-MPGN, eculizumab is an option.114
lished before the distinction was made between C3 C3G and Ig-MPGN diagnosed during pregnancy. These types
glomerulopathy (C3G) and Ig-associated MPGN (Ig- of GDs are rarely diagnosed during pregnancy, as the diagnoses
MPGN).105–107 Pregnancy in women with MPGN in these are usually based on kidney biopsy findings (Figures 2–4).
dated studies carried a particularly high risk of severe outcomes: Treatment follows the indications mentioned above.
transient or irreversible worsening of kidney function in 10% to IgA nephropathy. Data from series reporting the outcome
30% and 2% to 10% of patients, respectively, fetal or perinatal of pregnancy in patients with IgAN published since 2000 are
loss in 10% to 30% of pregnancies, and prematurity or low summarized in Supplemental Table S10.

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Box 2 | Case 2

A 35-year-old woman was referred at 14 WG of her second (unplanned) pregnancy, for nephrotic proteinuria and macroscopic hematuria with
normal kidney function and mild hypertension. She denied alcohol and illicit drug use. Her first pregnancy had been uneventful. Her clinical history
was remarkable for episodes of macroscopic hematuria, edema, and hypertension, starting 1 year earlier.
On admission, she was normotensive, with slight edema of the lower limbs. The initial proteinuria was 6.6 g/d, serum albumin was 22 g/L, and serum
creatinine was 45 mmol/L. Urinary sediment was characterized by microhematuria. The baby’s growth was normal. Lupus serology was negative. A
kidney biopsy was performed at 18 WG and revealed IgA nephropathy (MEST score: M1E0S1T0C0), along with focal segmental sclerotic lesions
(“tip” lesions).
Differential diagnosis
Preeclampsia: Despite the presence of classic features (proteinuria, edema, and hypertension), the onset was too early in pregnancy. The clinical
history was suggestive of another kidney disease.
Glomerulonephritis: Normal Doppler flows and early onset suggested this diagnosis. History of macrohematuria in a young woman suggested IgA
nephropathy. Although rare outside of pregnancy, nephrotic syndrome is probably more common in IgA nephropathy in pregnancy. Lupus
nephropathy is the main differential diagnosis, together with membranoproliferative glomerulonephritis (albeit usually associated with renal
function impairment and hypertension).
Indication for further tests
Kidney biopsy: Pro: gold standard for diagnosis. Con: higher risk of bleeding, especially after the 20th WG.
Soluble fms-like tyrosine kinase1/placental growth factor ratio: Usually indicated after 20 WG; the differential diagnosis ruling out preeclampsia is clear
herein; the test could, however, be suggested monthly after 20 WG, to rule out superimposed preeclampsia.
Clinical development
Treatment with tacrolimus (3 mg/d) was started at 19 WG, and prednisone was continued for 8 weeks and tapered afterwards. At week 30,
proteinuria had decreased to 0.56 g/24 h. At 35 WG, the patient experienced preterm rupture of membranes, and gave birth to a healthy female
baby weighing 2484 g (35th centile) via cesarean delivery due to fetal bradycardia during labor.
At 6 months of follow-up after delivery, her proteinuria was stable at about 0.5 g/d, with normal kidney function and normal blood pressure.
Comments
This case underlines the fact that pregnancy may modify the natural course of kidney diseases, usually with an increase in proteinuria. The relatively
high prevalence of IgA nephropathy in this age group should be considered in the differential diagnosis. A kidney biopsy, within the limits already
mentioned, may be proposed particularly when, as in this case, the presentation is early in pregnancy (<20 weeks), and the differential diagnosis
includes systemic diseases and potentially progressive glomerulonephritis, in which timely diagnosis and targeted treatment are crucial. The use of
serum biomarkers of preeclampsia may help during follow-up, to rule out superimposed preeclampsia after 20 weeks.
MEST, M ¼ mesangial hypercellularity, E ¼ endocapillary proliferation, S ¼ segmental glomerulosclerosis, T ¼ dubular atrophy/interstitial fibrosis, C ¼ crescents; WG, weeks of
gestation.
Courtesy of Alejandra Orozco-Guillen.

IgAN diagnosed before pregnancy. IgAN is the most com- IgAN—both of which included cohorts predominantly from
mon primary GD worldwide, with a peak incidence between Asia. The study by Wang et al. included 9 cohort or case-
the second and third decades of life. This makes pregnancy a control studies, all with a control group of nonpregnant pa-
concern for many women with IgAN but has also allowed for tients with IgAN, matched for age and kidney function.40
the accumulation of a significant body of data regarding Piccoli et al., in contrast, included both case series and case
pregnancy outcomes in affected women115 (Box 2, case 2). reports, reporting on at least one pregnancy outcome, or
In a recent register-based cohort study from Sweden, in- long-term kidney function.69 These cohorts included Asian
vestigators compared outcomes from 327 pregnancies in 208 and non-Asian patients with IgAN who have distinct pre-
women with biopsy-verified IgAN and 1060 pregnancies in a sentation, severity of the disease, and treatment strategies. The
matched reference population of women without IgAN, with different study design precludes any detailed comparisons,
secondary comparisons with sisters of women with IgAN.116 but most probably there is no difference in outcomes, once
IgAN was associated with an increased risk of preterm patients are stratified for baseline kidney function.
birth, preeclampsia, being born small for gestational age, and The results of these meta-analyses suggest that although
cesarean delivery. Absolute risks were low for intrauterine pregnancy does not appear to confer a specific risk for kidney
(0.6%) or neonatal (no cases) death and for a low 5-minute function impairment in IgAN with preserved kidney func-
Apgar score (1.5%) and did not differ from the reference tion, there is an increased risk of adverse pregnancy outcomes
population. Sibling comparisons suggested increased risks of commensurate with the degree of prepregnancy kidney
preterm birth, preeclampsia, and small for gestational age function impairment, blood pressure control, and protein-
newborn in those with IgAN, but not of cesarean delivery. uria. The risks may be lower than those reported in other
This study did not, however, include data on kidney biopsy, glomerular and systemic diseases.117 However, there may be a
kidney function, or proteinuria, and therefore pregnancies more rapid loss of kidney function for those women who
could not be stratified on the basis of IgAN disease activity or experience pregnancy-related complications.118 IgAN may
severity.116 rarely be associated with “flares” during pregnancy, including
There have been 2 recently published systematic reviews episodes of visible hematuria, requiring a careful workup for
and meta-analyses of kidney and pregnancy outcomes in other causes of hematuria. Some women may experience de

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Box 3 | Case 3

A 36-year-old woman was referred at 12 WG of her second pregnancy. She had a history of lupus nephropathy (class III in a kidney biopsy performed
10 years earlier), previous lupus anticoagulant positivity (currently negative), chronic hypertension for 5 years, and normal kidney function. At
referral, her treatment included prednisone, 10 mg; azathioprine, 100 mg; acetylsalicylate, 100 mg; and transdermal clonidine. She had developed
gestational diabetes requiring insulin treatment.
During pregnancy, her kidney function remained normal. Antinuclear antibodies were stable at 1:320. Lupus anticoagulant was persistently negative,
and anti-DNA antibodies, which were initially absent, fluctuated between 20 and 60 IU (last control before delivery: 29 IU; normal: <10 IU), with
normal complement level. Proteinuria, which was initially about 0.5 g/24 h, slowly and progressively increased to 1.2 g/24 h before delivery.
At 36 WG, she was admitted to hospital for joint pain. Complement was normal, and lupus anticoagulant was negative.
At 37 WG, obstetric evaluation showed regular fetal growth (on the 10th centile) and normal Doppler flows. The patient had gained 2 kg after
betamethasone was administered to improve lung maturation. A cesarean section was scheduled for the following day. During the night, sudden
fetal bradycardia was detected on monitoring, and an emergency cesarean delivery was performed, delivering a dead-born female baby, weighing
2250 g (6th centile).
No sign of placental abruption was found. Immunohistochemistry performed on the fetal cardiac conduction system ruled out an inflammatory
reaction. The placenta showed extensive fields of villitis and chronic intervillitis with widespread deposits of intervillous fibrin, and presence of
thrombotic occlusion in a fetal vessel in the subchorionic area. The conclusion of the pathologist was placental malperfusion compatible with
alterations on an autoimmune basis.
Intrauterine death and lupus
This case is a reminder of one of the rare, but terrible, challenges typical of lupus in pregnancy (i.e., death of the baby in a late stage of pregnancy).
Although this devastating complication is usually associated with biological signs of lupus activity, the risk is increased also in their absence, as in
this case, in which the only suggestive sign of a lupus flare was the appearance of moderate articular numbness and pain.
The patient had no classic clinical sign of placental dysfunction even if the baby was relatively small for gestational age (6th centile); most important,
Doppler flows were normal. However, the availability of biomarkers defining the angiogenic-antiangiogenic balance, not available in the clinical
context at the time this case was managed, would have been precious both as risk markers and for supporting a precise diagnosis.
Comments
Although, especially in small babies, the indications to follow pregnancy up to “full term” are sound, the late pregnancy-related risks may suggest
delivering as soon as the “term” is reached. In this case, the choice to postpone delivery by 1 day (at 37 WG) was motivated by strategic issues (the
following day being a Monday, with the full team available in the case of complications), in the presence of reassuring biological data and fetal
ultrasounds.
This case is paradigmatic of one of the main challenges in following up patients with lupus in pregnancy: defining the timing of delivery. The study of
angiogenic-antiangiogenic markers, presently widely available, may be useful also in the prediction of intrauterine death.121,122
WG, weeks of gestation.
Courtesy of Rossella Attini.

novo nephrotic syndrome or rapidly progressive glomerulo- pregnancy outcomes is higher in women with active
nephritis, requiring more intensive treatment (see lupus and decreases in parallel with the duration of
below).19,119 Treatment options for IgAN in pregnancy are remission before pregnancy.123 A large meta-analysis
shown in Figures 2 and 4. performed in 2010, gathering data from 2751 pregnan-
IgAN diagnosed during pregnancy. As IgAN can only be cies, quantified the risks of maternal and fetal compli-
diagnosed through a kidney biopsy, it is unusual to make a cations: lupus flare (26%), hypertension (16%), nephritis
new diagnosis during pregnancy, and the diagnosis is more (16%), preeclampsia (8%), and eclampsia (0.8%) in the
commonly made postpartum. Clinical presentation with se- mother; and spontaneous abortion (16%), stillbirth
vere proteinuria during pregnancy is possible, and this pos- (3.6%), neonatal death (2.5%), and intrauterine growth
sibility should be considered in the differential diagnosis of restriction (13%) in the fetus. The successful pregnancy
nephrotic syndrome.19 Rapidly progressive glomerulone- rate was 77%, and the preterm birth rate was 39%.68
phritis due to IgAN has been described120 but is rare, and it Complications and poor pregnancy outcomes, in this
should be managed in the same way as vasculitis in analysis and others, were associated with active lupus and
pregnancy. particularly LN.124 Presence of lupus anticoagulant and
Lupus nephritis. The available data published after 2000 kidney damage modulate the risk of adverse pregnancy
regarding pregnancy in patients with LN are summarized in outcomes.123,125
Supplemental Table S11. Pregnancy outcomes, conversely, are better in patients with
Pregnancy may be considered as a stress test for patients controlled lupus and LN in remission,123,126 with no signifi-
with LN, not only due to the presence and severity of CKD cant renal damage.125 The risk of kidney flare occurring
or of antiphospholipid syndrome (or autoantibodies), but during pregnancy is higher in women with persistent lupus
also because pregnancy may trigger a lupus flare. Pregnancy activity at the time of conception, and is lower when LN
in patients with LN remains a high-risk pregnancy (Box 3, remission has been present for at least 12 months before
case 3121,122). conception.127 Figures 3 and 4 summarize the general prin-
LN diagnosed before pregnancy. The main risk for the ciples for the management of pregnancies in women with
mother is an LN flare. The risk of flares and of adverse systemic lupus or history of LN.128–131

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Table 4 | General considerations regarding the management of hypertension in pregnant women with GD
How should BP be monitored and hypertension diagnosed in pregnancy?

(i) Monitoring blood pressure in pregnant patients with GD is mandatory because in women with even mild CKD the risk of hypertensive disorders
during pregnancy is increased.8,156 Fetal survival is decreased when BP is >140/90 mm Hg during the preconception period.37,110
(ii) To avoid overdiagnosis (white coat hypertension), which almost reaches 30% in the third trimester, or underdiagnosis (masked hypertension, defined
as normal BP measurements in a physician’s office but elevated during the day-to-day activities), out-of-office BP measurement, when available, is
preferred.156
(iii) The prevalence of resistant hypertension (i.e., hypertension not fully controlled by treatment) is elevated (up to 24%) in the second half of high-risk
pregnancies, including in women with GD.157
(iv) Cutoffs for the diagnosis of hypertension in pregnancy are an office systolic BP $140 mm Hg and/or office diastolic BP $90 mm Hg, on at least 2
occasions measured 4 hours apart.158
What is the BP target in pregnant women with GD?

(i) No guidelines are specifically targeted at BP control in pregnant women with CKD or GD.
(ii) A recent position statement on CKD in pregnancy, from the Italian Society of Nephrology, suggests personalizing BP targets, with the aim to attain at
least the targets recommended outside of pregnancy.43 Recent clinical practice guidelines from the United Kingdom,159 again not specifically
addressing GD, but more broadly CKD, recommend a target BP of #135/85 mm Hg during pregnancy.
(iii) We recommend a target BP of 130/80 mm Hg, unless systolic BP is consistently <110 mm Hg or diastolic BP is consistently <70 mm Hg, and/or
symptomatic hypotension occurs. The recommendation may also be supported by a recent study reporting improved outcomes when maintaining
patients on BP medication or initiating treatment early in pregnancy for chronic hypertensive pregnant women with a systolic BP of $140 mm Hg or
a diastolic blood pressure of $90 mm Hg, or both.160
When should ACEi/ARBs be discontinued in patients with GD planning a pregnancy?
(i) This question is still debated.
(ii) In the presence of CKD and GD characterized by significant residual proteinuria, some experts prefer modifying treatment only when pregnancy is
confirmed. This avoids prolonged cessation of ACEi/ARB agents while waiting to conceive, which may take months or even years, especially if past
immunosuppression has had an impact on fertility.
(iii) Other experts prefer to stop ACEi/ARB agents before pregnancy and consider that the magnitude of proteinuria increase will modify patient
counseling.
(iv) The fetal risks may be higher with early exposure to ARB agents,161 but the effects of hypertension, the underlying diseases, and the effects of
specific treatments may be difficult to distinguish.162–164 The advantages of prolonging renoprotective treatment and of starting pregnancy with
low-grade proteinuria, versus the risk of adverse fetal outcomes, should be weighed on a case-by-case basis, taking into consideration kidney
function, severity of proteinuria, type of GD, BP control, and patient adherence to treatment and preferences.
ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BP, blood pressure; CKD, chronic kidney disease; GD, glomerular disease.
The choice of antihypertensive medications may vary from one country to another.

The benefit over risk ratio of hydroxychloroquine use is C3, and complement total activity 50% [CH50] levels) and,
favorable,42,126,132 and this drug is recommended in preg- more rarely, with a kidney biopsy. Proliferative LN in preg-
nancy. Steroids, azathioprine, and calcineurin inhibitors may nancy with declining renal function requires urgent therapy
be used during pregnancy as well.129,133,134 Rituximab may be and the discussion of therapeutic termination of pregnancy in
considered in the absence of more appropriate alternatives in case of organ-threatening disease. The aim of treatment is, at
severe and resistant cases. Belimumab, voclosporin, and ani- least, to attempt to contain LN so as to allow pregnancy
frolumab are not recommended during pregnancy because of continuation and fetal growth for as long as possible. Treat-
lack of experience. ment options are shown in Figure 4.
Low-dose aspirin is strongly recommended in all patients Vasculitis in pregnancy. Vasculitis typically occurs at an
with LN. In the presence of antiphospholipid syndrome, older age, but women of childbearing age are not spared.138–142
aspirin should be added to heparin129 whenever possible Data on pregnancy outcome are related to the 2 main forms of
during the preconception period to prevent fetal loss, kidney vasculitis, anti-neutrophil cytoplasm antibody vasculitis
placental insufficiency, and thrombotic complications. (AAV) and IgA vasculitis.
Furthermore, in the presence of anti-Ro/SSA antibodies, Vasculitis diagnosed before pregnancy. The risk of relapse
systematic fetal heart rhythm monitoring is usually advised during pregnancy in women with AAV remains difficult to
for early detection of fetal atrioventricular block (detected in predict, and the clinical spectrum ranges from mild flares
1%–2% of anti-Ro/SSA pregnancies).135–137 Routine in most cases (crusting rhinitis, skin lesions, and arthritis)
screening, however, has recently been challenged and may be to severe complications mostly documented in case reports
reserved for patients with a history of congenital heart (alveolar haemorrhage, crescentic glomerulonephritis, or
block.137 thrombotic microangiopathy).143–145 A report of 15 preg-
LN diagnosed during pregnancy. LN may be diagnosed nancies in 13 women (11 granulomatosis with polyangiitis
during pregnancy based on clinical status (extrarenal mani- and 2 microscopic polyangiitis) with prior diagnoses of
festations suggestive of lupus), positivity of autoantibodies AAV, all in remission for >6 months at conception,
(mainly anti–double-stranded DNA and anti-Smith anti- showed favorable outcomes. In all planned pregnancies,
bodies), features of complement activation (low serum C4, women were switched to azathioprine in combination with

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review F Fakhouri et al.: Glomerular diseases in pregnancy

Table 5 | Antihypertensive drugs for emergency and nonemergency hypertensive disorders of pregnancy in women with GD
Setting Drug Route Dose Contraindications Adverse effects

Emergency Labetalol I.v. 10–20 mg initially, then 20–80 mg every 10–30 min to a Second- or third-degree Bronchoconstriction
maximum cumulative dose of 300 mg; infusion: 1–2 mg/min AVB Systolic heart failure Fetal bradycardia
Asthma bradycardia
Urapidil I.v. 12.5–25 mg as bolus injection; 5–40 mg/h as continuous Hypotension
infusion Reflex tachycardia
Hydralazine I.v. 5 mg, then 5–10 mg every 20–40 min Hypotension
Reflex tachycardia
Headaches
No emergency Labetalol Oral 100 mg bid to 800 mg tid Second- or third-degree Bronchoconstriction
AVB Fetal bradycardia
Systolic heart failure
Asthma
Bradycardia
Nifedipine Oral 20–30 mg bid Reflex tachycardia
Headaches
a-Methyldopa Oral 250 mg bid to 1000 mg tid; titrate every 48 h Orthostatic
hypotension
Sedation
AVB, atrioventricular block; bid, 2 times a day; GD, glomerular disease; tid, 3 times a day.

prednisolone or additional cyclosporine. Two patients unsuccessful pregnancies (17.4%) were recorded, with 17
experienced a relapse: one developed crescentic glomeru- preterm deliveries (8.3%).
lonephritis that was successfully treated by plasma ex- Women with IgA vasculitis furthermore had an z2-fold
change and i.v. Ig, and one presented with mild crusting risk of spontaneous abortion and preterm delivery and a
rhinitis and subglottic stenosis.138 Transplacental transfer high risk of gestational hypertension (odds ratio, 4.7).141
of anti-myeloperoxidase–anti-neutrophil cytoplasm anti- Vasculitis diagnosed during pregnancy. One systematic re-
body with neonatal alveolar hemorrhage has been view150 identified 27 cases of de novo AAV in pregnancy,
described in a newborn.146 IgA vasculitis flares during most of which occurred in the second trimester. Most
pregnancy have occasionally been reported, and are mostly women were treated with steroids (89%), but 37% received
mild, with purpura and arthralgias; overall, kidney out- cyclophosphamide (mainly before 2005), and a minority
comes have been reported as good.147,148 In the largest received azathioprine, i.v. Ig, plasma exchange, or no ther-
case series of 247 pregnancies in women with IgA vascu- apy. Serious complications included preeclampsia (29%)
litis in pregnancy,149 no flares were observed, but 43 and maternal death (7%). Most infants were born alive and

Table 6 | In addition to the general indications for dietary management in pregnancy, for pregnancies in patients with GDs, the
following indications may be considered
Avoidance of nutritional deficits
(i) Folic acid: water soluble, indicated in the prepregnancy phase for the prevention of neural tube disorders; may be lost in the urine in nephrotic
patients.
(ii) Vitamin D: frequently reduced in advanced CKD; low levels are associated with higher risk of preeclampsia.
(iii) Vitamin B12: may be reduced, particularly in patients on plant-based and low-protein diets.
(iv) Iron may be reduced, especially in patients on plant-based and low-protein diets or lost in nephrotic syndrome.172,173
Although dosing is not advised in the general population, it is advised in patients with CKD with GD, at least by some experts.43
Avoidance of excessive weight gain
Excessive weight gain is associated with adverse pregnancy outcomes, particularly preeclampsia and hypertensive disorders of pregnancy.174,175 The
simple rule of avoiding a weight gain of >1 kg per month should be adapted to prepregnancy body mass index. Use of corticosteroids, when needed,
should be balanced against this risk.
Avoidance of high-protein diets

Particularly in CKD stages 3–5 and in the presence of significant proteinuria, plant-based diets are safe in pregnancy; results from noncontrolled series
suggest that protein-restricted diets and plant-based diets may contribute to proteinuria stabilization in pregnant women with GD.176–178 The safety of
such dietary measures in pregnancy is validated, provided that nutritional deficits are controlled and supplemented when needed.179,180
Food quality
Compelling, albeit limited, data suggest that controlling quality of food and the avoidance of additive and preservation products may play a role in the
stabilization of kidney function in pregnancy.181
CKD, chronic kidney disease; GD, glomerular disease.

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F Fakhouri et al.: Glomerular diseases in pregnancy review

in the third trimester. Pregnancy termination occurred in opportunity for timely diagnosis and treatment.184 Likewise,
23%, but only one intrauterine death was reported, shortly neonatal intensive care units are scarcely available in several
after initiation of therapy; congenital abnormalities were middle- to low-income countries; hence, clinical management
rare. The authors concluded that de novo AAV in pregnancy favors fetal maturation whenever possible to 34 weeks, with
can result in uncomplicated pregnancies; however, serious the aim to avoid the need for admission to neonatal intensive
maternal risks exist.150 A second review151 included 110 care units. Such strategy obviously carries an increase in
patients with AAV, in whom a vasculitis diagnosis was made maternal risks and may lead to a more aggressive attitude
before pregnancy in 69, during pregnancy in 32, and after toward pregnancy termination in high-risk pregnancies.
pregnancy in 9. There were 28 preterm pregnancies, 15
abortions, and 3 stillbirths. Three maternal deaths due to a CONCLUSIONS
vasculitis flare were reported. The authors do not report Pregnancy in women with GDs remains challenging for ne-
significant differences between those who were diagnosed phrologists and obstetricians worldwide. The advances in
before and during pregnancy.151 obstetric care have not only improved prognosis but have led
Postinfectious glomerulonephritis, unusual and complex to a more open attitude toward pregnancy in women with
situations. Virtually all GDs have been reported, at least GDs, whereas the acknowledgement of the impact of even
occasionally, in pregnancy—with reporting biases (preferen- minor kidney involvement on pregnancy outcomes may guide
tial report of extreme cases, and cases with a good outcome). timely interventions.
The immunologic state and glomerular hyperfiltration char- The involvement of patients in shared choices is the key for
acteristic of pregnancy may modulate the clinical, biological, facing, in the best possible way, the challenges of a high-risk
and pathologic picture. Among the rare forms of GDs diag- pregnancy. Although preconception information and prepara-
nosed in pregnancy, acute, postinfectious glomerulonephritis tion is advisable, discovery of a kidney disease in pregnancy is not
has occasionally been reported,152–155 with some cases char- rare and may raise important ethical and psychological issues.
acterized by intense proteinuria, even in the absence of Collaborative prospective studies are still needed to refine
superimposed preeclampsia. our knowledge of pregnancy outcomes in these patients with
relatively rare kidney diseases.
GENERAL MANAGEMENT OF GD IN PREGNANCY
General considerations regarding hypertension and its treat- DISCLOSURE
ment in pregnant women with GDs are summarized in All the authors declared no competing interests.
Tables 48,37,43,110,156–168 and 5.
A detailed discussion on the use of immunosuppressive AUTHOR CONTRIBUTIONS
drugs in pregnant patients is beyond the scope of this review, The multidisciplinary international working group is composed
of experts in the field of glomerular diseases (GDs) and/or of
and the reader may refer to recently published extensive re-
pregnancy in women with kidney diseases. FF and GBP
views for details.169–171 Supplemental Table S12 summarizes coordinated the group. NS and GC reviewed published series
the main basic information regarding the most commonly and cases reports related to pregnancy in women with GDs. GA
employed drugs in pregnancy. Supplemental Table S13 sum- and GR reviewed and amended the whole manuscript. The
marizes the main considerations regarding breastfeeding in sections on IgAN; MCD and FSGS; MN; LN; MPGN and C3G;
women with GDs. postinfectious glomerulonephritis, unusual and complex
Recommendations for the dietary management of preg- situations; and vasculitis were drafted by JB; JW and VA; PR; ED,
NC-C, and LL; MP and FF; AOG; and EZ and AKar; respectively.
nant patients with GD are summarized in Table 6.43,172–181
The sections on hypertension, dietary management, kidney bi-
opsy, and immunosuppressive drugs were drafted by GW; GBP,
Special considerations from middle- to low-income countries FL, and RA; AOG and GBP; and GM, CP, and AKat; respectively.
on pregnancy in patients with GDs The sections on renal function in pregnancy, epidemiology of
Although GDs in pregnancy raise the same clinical challenges GD in pregnancy, complement assays, and antiangiogenic bio-
worldwide, some logistical aspects may modulate their markers were drafted by KW, SJ, VG and EL, and MN, respec-
management during and after pregnancy in highly resourced tively. The section on obstetric perspective was drafted by HL,
versus middle-/low-resourced182,183 countries. DD, and VT. The section on special considerations from middle-
to low-income countries was drafted by CL, JP, and VS-A. FF
The incidence of GDs, as well as of CKD from all causes, is
drafted the figures, and GBP drafted the cases. FF and GBP
higher in many middle- to low-income countries. The drafted the manuscript, incorporating all the sections. All the
chances that a young woman would be diagnosed with a GD, authors reviewed the draft and subsequently the amended
or another form of CKD, in pregnancy is therefore version of the manuscript with significant input.
higher.11,184,185
In some countries, such as Mexico, maternal care is
available free of charge for all citizens, but the coverage is SUPPLEMENTARY MATERIAL
extended only for a short period after delivery. This has Supplementary File (Word)
supported the policy of performing a kidney biopsy during Table S1. Interpretation of kidney function tests in pregnant patients
pregnancy or immediately thereafter not to lose a unique with glomerular disease (GD). CKD, chronic kidney disease; UACR,

Kidney International (2023) 103, 264–281 277

review F Fakhouri et al.: Glomerular diseases in pregnancy

urine albumin-to-creatinine ratio; UPCR, urine protein-to-creatinine based study from HUNT II, Norway. Nephrol Dial Transplant. 2009;24:
ratio; WG, weeks of gestation. 3744–3750.
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